ManagedCare. Oncology. Oncology. MMA and Medicare. New Drug Updates. Improving Outcomes. Reimbursement. Coding, Reimbursement and Therapies

Transcription

1 ManagedCare Oncology For Decision Makers in Managed Care Spring MMA and Medicare Shifting Fee Schedules Improving Outcomes in Advanced Renal Cell Carcinoma Oncology Reimbursement Managed Care Challenges and Considerations Coding, Reimbursement and Therapies in the Treatment of Renal Cell Carcinoma New Drug Updates Angiogenesis Inhibitors

2 Think outside the bag. *INDICATION: XELODA is indicated as first-line treatment of patients with metastatic colorectal carcinoma when treatment with fluoropyrimidine therapy alone is preferred. Combination chemotherapy has shown a survival benefit compared to 5-FU/LV alone. A survival benefit over 5-FU/LV has not been demonstrated with XELODA monotherapy. Use of XELODA instead of 5-FU/LV in combinations has not been adequately studied to assure safety or preservation of the survival advantage. IMPORTANT SAFETY INFORMATION WARNING: For patients receiving XELODA and warfarin concomitantly, frequent monitoring of INR or prothrombin time (PT) is recommended. A clinically important drug interaction between XELODA and warfarin has been demonstrated. Altered coagulation parameters and/or bleeding and death have been reported. Clinically significant increases in PT and INR have been observed within days to months after starting XELODA, and infrequently within one month of stopping XELODA. Age greater than 60 and a diagnosis of cancer independently predispose patients to an increased risk of coagulopathy. XELODA is contraindicated in patients who have a known hypersensitivity to capecitabine or to any of its components or to 5-fluorouracil. XELODA is contraindicated in patients with known dihydropyrimidine dehydrogenase (DPD) deficiency. Copyright 2004 by Roche Laboratories Inc. All rights reserved

3 Covered by Medicare Think XELODA. For metastatic colorectal cancer * XELODA is also contraindicated in patients with severe renal impairment. Patients with moderate renal impairment require dose reduction. XELODA can induce diarrhea, sometimes severe. Patients with severe diarrhea should be carefully monitored. Patients 80 years old receiving XELODA monotherapy, and patients 60 years old receiving XELODA in combination with docetaxel, may experience a greater incidence of grade 3 or 4 adverse events. XELODA may cause fetal harm when given to a pregnant woman. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with XELODA. In XELODA monotherapy for metastatic colorectal cancer, the most common adverse events ( 10%) in patients receiving either XELODA or 5-FU/LV (%;%) were anemia (80;79), diarrhea (55;61), hand-foot syndrome (54;6), hyperbilirubinemia (48;17), nausea (43;51), fatigue/weakness (42;46), abdominal pain (35;31), dermatitis (27;26), vomiting (27;30), appetite decreased (26;31), stomatitis (25;62), pyrexia (18;21), edema (15;9), constipation (14;17), dyspnea (14;10), neutropenia (13;46), pain (12;10), back pain (10;9), and headache (10;7). Grade 3/4 adverse events ( 5%) in patients receiving either XELODA or 5-FU/LV (XELODA G3/4;5-FU/LV G3/4) were hyperbilirubinemia (23;6), hand-foot syndrome (17;1), diarrhea (15;12), abdominal pain (10;5), vomiting (5;5), ileus (5;3), stomatitis (3;15), and neutropenia (3;21). Please see summary of XELODA Prescribing Information on adjacent pages for indications and usage, contraindications, warnings including boxed WARNING, precautions, and adverse reactions.

4 Brief summary of prescribing information. For complete prescribing information, please consult official package insert. WARNING XELODA Warfarin Interaction: Patients receiving concomitant capecitabine and oral coumarin-derivative anticoagulant therapy should have their anticoagulant response (INR or prothrombin time) monitored frequently in order to adjust the anticoagulant dose accordingly. A clinically important XELODA- Warfarin drug interaction was demonstrated in a clinical pharmacology trial (see CLINICAL PHARMACOLOGY and PRECAUTIONS). Altered coagulation parameters and/or bleeding, including death, have been reported in patients taking XELODA concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon. Postmarketing reports have shown clinically significant increases in prothrombin time (PT) and INR in patients who were stabilized on anticoagulants at the time XELODA was introduced. These events occurred within several days and up to several months after initiating XELODA therapy and, in a few cases, within 1 month after stopping XELODA. These events occurred in patients with and without liver metastases. Age greater than 60 and a diagnosis of cancer independently predispose patients to an increased risk of coagulopathy. INDICATIONS AND USAGE:Colorectal Cancer: XELODA is indicated as firstline treatment of patients with metastatic colorectal carcinoma when treatment with fluoropyrimidine therapy alone is preferred. Combination chemotherapy has shown a survival benefit compared to 5-FU/LV alone. A survival benefit over 5-FU/LV has not been demonstrated with XELODA monotherapy. Use of XELODA instead of 5-FU/LV in combinations has not been adequately studied to assure safety or preservation of the survival advantage. Breast Cancer Combination Therapy: XELODA in combination with docetaxel is indicated for the treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing chemotherapy. Breast Cancer Monotherapy: XELODA monotherapy is also indicated for the treatment of patients with metastatic breast cancer resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen or resistant to paclitaxel and for whom further anthracycline therapy is not indicated, eg, patients who have received cumulative doses of 400 mg/m 2 of doxorubicin or doxorubicin equivalents. Resistance is defined as progressive disease while on treatment, with or without an initial response, or relapse within 6 months of completing treatment with an anthracycline-containing adjuvant regimen. CONTRAINDICATIONS: XELODA is contraindicated in patients with known hypersensitivity to capecitabine or to any of its components. XELODA is contraindicated in patients who have a known hypersensitivity to 5-fluorouracil. XELODA is contraindicated in patients with known dihydropyrimidine dehydrogenase (DPD) deficiency. XELODA is also contraindicated in patients with severe renal impairment (creatinine clearance below 30 ml/min [Cockroft and Gault]) (see CLINICAL PHARMACOLOGY:Special Populations). WARNINGS: Renal Insufficiency: Patients with moderate renal impairment at baseline require dose reduction (see DOSAGE AND ADMINISTRATION). Patients with mild and moderate renal impairment at baseline should be carefully monitored for adverse events. Prompt interruption of therapy with subsequent dose adjustments is recommended if a patient develops a grade 2 to 4 adverse event as outlined in Table 14 in DOSAGE AND ADMINISTRATION. Coagulopathy: See Boxed WARNING. Diarrhea: XELODA can induce diarrhea, sometimes severe. Patients with severe diarrhea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated. In the overall clinical trial safety database of XELODA monotherapy (N=875), the median time to first occurrence of grade 2 to 4 diarrhea was 34 days (range from 1 to 369 days). The median duration of grade 3 to 4 diarrhea was 5 days. National Cancer Institute of Canada (NCIC) grade 2 diarrhea is defined as an increase of 4 to 6 stools/day or nocturnal stools, grade 3 diarrhea as an increase of 7 to 9 stools/day or incontinence and malabsorption, and grade 4 diarrhea as an increase of 10 stools/day or grossly bloody diarrhea or the need for parenteral support. If grade 2, 3 or 4 diarrhea occurs, administration of XELODA should be immediately interrupted until the diarrhea resolves or decreases in intensity to grade 1. Following a reoccurrence of grade 2 diarrhea or occurrence of any grade 3 or 4 diarrhea, subsequent doses of XELODA should be decreased (see DOSAGE AND ADMINISTRATION). Standard antidiarrheal treatments (eg, loperamide) are recommended. Necrotizing enterocolitis (typhlitis) has been reported. Geriatric Patients: Patients 80 years old may experience a greater incidence of grade 3 or 4 adverse events (see PRECAUTIONS: Geriatric Use). In the overall clinical trial safety database of XELODA monotherapy (N=875), 62% of the 21 patients 80 years of age treated with XELODA experienced a treatmentrelated grade 3 or 4 adverse event: diarrhea in 6 (28.6%), nausea in 3 (14.3%), hand-and-foot syndrome in 3 (14.3%), and vomiting in 2 (9.5%) patients. Among the 10 patients 70 years of age and greater (no patients were >80 years of age) treated with XELODA in combination with docetaxel, 30% (3 out of 10) of patients experienced grade 3 or 4 diarrhea and stomatitis, and 40% (4 out of 10) experienced grade 3 hand-and-foot syndrome. Among the 67 patients 60 years of age receiving XELODA in combination with docetaxel, the incidence of grade 3 or 4 treatment-related adverse events, treatment-related serious adverse events, withdrawals due to adverse events, treatment discontinuations due to adverse events and treatment discontinuations within the first two treatment cycles was higher than in the <60 years of age patient group. Pregnancy: XELODA may cause fetal harm when given to a pregnant woman. Capecitabine at doses of 198 mg/kg/day during organogenesis caused malformations and embryo death in mice. In separate pharmacokinetic studies, this dose in mice produced 5 -DFUR AUC values about 0.2 times the corresponding values in patients administered the recommended daily dose. Malformations in mice included cleft palate, anophthalmia, microphthalmia, oligodactyly, polydactyly, syndactyly, kinky tail and dilation of cerebral ventricles. At doses of 90 mg/kg/day, capecitabine given to pregnant monkeys during organogenesis caused fetal death. This dose produced 5 -DFUR AUC values about 0.6 times the corresponding values in patients administered the recommended daily dose. There are no adequate and well-controlled studies in pregnant women using XELODA. If the drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with XELODA. PRECAUTIONS: General: Patients receiving therapy with XELODA should be monitored by a physician experienced in the use of cancer chemotherapeutic agents. Most adverse events are reversible and do not need to result in discontinuation, although doses may need to be withheld or reduced (see DOSAGE AND ADMINISTRATION). Combination With Other Drugs: Use of XELODA in combination with irinotecan has not been adequately studied. Hand-and-Foot Syndrome: Hand-and-foot syndrome (palmar-plantar erythrodysesthesia or chemotherapy-induced acral erythema) is a cutaneous toxicity (median time to onset of 79 days, range from 11 to 360 days) with a severity range of grades 1 to 3. Grade 1 is characterized by any of the following: numbness, dysesthesia/ paresthesia, tingling, painless swelling or erythema of the hands and/or feet and/or discomfort which does not disrupt normal activities. Grade 2 hand-andfoot syndrome is defined as painful erythema and swelling of the hands and/or feet and/or discomfort affecting the patient s activities of daily living. Grade 3 hand-and-foot syndrome is defined as moist desquamation, ulceration, blistering or severe pain of the hands and/or feet and/or severe discomfort that causes the patient to be unable to work or perform activities of daily living. If grade 2 or 3 hand-and-foot syndrome occurs, administration of XELODA should be interrupted until the event resolves or decreases in intensity to grade 1. Following grade 3 hand-and-foot syndrome, subsequent doses of XELODA should be decreased (see DOSAGE AND ADMINISTRATION). Cardiotoxicity: The cardiotoxicity observed with XELODA includes myocardial infarction/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, electrocardiographic changes, and cardiomyopathy. These adverse events may be more common in patients with a prior history of coronary artery disease. Dihydropyrimidine Dehydrogenase Deficiency: Rarely, unexpected, severe toxicity (eg, stomatitis, diarrhea, neutropenia and neurotoxicity) associated with 5-fluorouracil has been attributed to a deficiency of dihydropyrimidine dehydrogenase (DPD) activity. A link between decreased levels of DPD and increased, potentially fatal toxic effects of 5-fluorouracil therefore cannot be excluded. Hepatic Insufficiency: Patients with mild to moderate hepatic dysfunction due to liver metastases should be carefully monitored when XELODA is administered. The effect of severe hepatic dysfunction on the disposition of XELODA is not known (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). Hyperbilirubinemia: In the overall clinical trial safety database of XELODA monotherapy (N=875), grade 3 (1.5-3 x ULN) hyperbilirubinemia occurred in 15.2% (n=133) and grade 4 (>3 x ULN) hyperbilirubinemia occurred in 3.9% (n=34) of 875 patients with either metastatic breast or colorectal cancer who received at least one dose of XELODA 1250 mg/m 2 twice daily as monotherapy for 2 weeks followed by a 1-week rest period. Of 566 patients who had hepatic metastases at baseline and 309 patients without hepatic metastases at baseline, grade 3 or 4 hyperbilirubinemia occurred in 22.8% and 12.3%, respectively. Of the 167 patients with grade 3 or 4 hyperbilirubinemia, 18.6% (n=31) also had postbaseline elevations (grades 1 to 4, without elevations at baseline) in alkaline phosphatase and 27.5% (n=46) had postbaseline elevations in transaminases at any time (not necessarily concurrent). The majority of these patients, 64.5% (n=20) and 71.7% (n=33), had liver metastases at baseline. In addition, 57.5% (n=96) and 35.3% (n=59) of the 167 patients had elevations (grades 1 to 4) at both prebaseline and postbaseline in alkaline phosphatase or transaminases, respectively. Only 7.8% (n=13) and 3.0% (n=5) had grade 3 or 4 elevations in alkaline phosphatase or transaminases. In the 596 patients treated with XELODA as first-line therapy for metastatic colorectal cancer, the incidence of grade 3 or 4 hyperbilirubinemia was similar to the overall clinical trial safety database of XELODA monotherapy. The median time to onset for grade 3 or 4 hyperbilirubinemia in the colorectal cancer population was 64 days and median total bilirubin increased from 8 µm/l at baseline to 13 µm/l during treatment with XELODA. Of the 136 colorectal cancer patients with grade 3 or 4 hyperbilirubinemia, 49 patients had grade 3 or 4 hyperbilirubinemia as their last measured value, of which 46 had liver metastases at baseline. In 251 patients with metastatic breast cancer who received a combination of XELODA and docetaxel, grade 3 (1.5 to 3 x ULN) hyperbilirubinemia occurred in7%(n=17) and grade 4(>3 x ULN)hyperbilirubinemia occurred in 2%(n=5). If drug-related grade 2 to 4 elevations in bilirubin occur, administration of XELODA should be immediately interrupted until the hyperbilirubinemia resolves or decreases in intensity to grade 1. NCIC grade 2 hyperbilirubinemia is defined as 1.5 x normal, grade 3 hyperbilirubinemia as 1.5 to 3 x normal and grade 4 hyperbilirubinemia as >3 x normal. (See recommended dose modifications under DOSAGE AND ADMINISTRATION.) Hematologic: In 875 patients with either metastatic breast or colorectal cancer who received a dose of 1250 mg/m 2 administered twice daily as monotherapy for 2 weeks followed by a 1-week rest period, 3.2%, 1.7%, and 2.4% of patients had grade 3 or 4 neutropenia, thrombocytopenia or decreases in hemoglobin, respectively. In 251 patients with metastatic breast cancer who received a dose of XELODA in combination with docetaxel, 68% had grade 3 or 4 neutropenia, 2.8% had grade 3 or 4 thrombocytopenia, and 9.6% had grade 3 or 4 anemia. Carcinogenesis, Mutagenesis and Impairment of Fertility: Adequate studies investigating the carcinogenic potential of XELODA have not been conducted. Capecitabine was not mutagenic in vitro to bacteria (Ames test) or mammalian cells (Chinese hamster V79/HPRT gene mutation assay). Capecitabine was clastogenic in vitro to human peripheral blood lymphocytes but not clastogenic in vivo to mouse bone marrow (micronucleus test). Fluorouracil causes mutations in bacteria and yeast. Fluorouracil also causes chromosomal abnormalities in the mouse micronucleus test in vivo. Impairment of Fertility: In studies of fertility and general reproductive performance in mice, oral capecitabine doses of 760 mg/kg/day disturbed estrus and consequently caused a decrease in fertility. In mice that became pregnant, no fetuses survived this dose. The disturbance in estrus was reversible. In males, this dose caused degenerative changes in the testes, including decreases in the number of spermatocytes and spermatids. In separate pharmacokinetic studies, this dose in mice produced 5 -DFUR AUC values about 0.7 times the corresponding values in patients administered the recommended daily dose. Information for Patients (see Patient Package Insert): Patients and patients caregivers should be informed of the expected adverse effects of XELODA, particularly nausea, vomiting, diarrhea, and hand-and-foot syndrome, and should be made aware that patient-specific dose adaptations during therapy are expected and necessary (see DOSAGE AND ADMINISTRATION). Patients should be encouraged to recognize the common grade 2 toxicities associated with XELODA treatment. Diarrhea: Patients experiencing grade 2 diarrhea (an increase of 4 to 6 stools/day or nocturnal stools) or greater should be instructed to stop taking XELODA immediately. Standard antidiarrheal treatments (eg, loperamide) are recommended. Nausea: Patients experiencing grade 2 nausea (food intake significantly decreased but able to eat intermittently) or greater should be instructed to stop taking XELODA immediately. Initiation of symptomatic treatment is recommended. Vomiting: Patients experiencing grade 2 vomiting (2 to 5 episodes in a 24-hour period) or greater should be instructed to stop taking XELODA immediately. Initiation of symptomatic treatment is recommended. Hand-and-Foot Syndrome: Patients experiencing grade 2 hand-and-foot syndrome (painful erythema and swelling of the hands and/or feet and/or discomfort affecting the patients activities of daily living) or greater should be instructed to stop taking XELODA immediately. Stomatitis: Patients experiencing grade 2 stomatitis (painful erythema, edema or ulcers of the mouth or tongue, but able to eat) or greater should be instructed to stop taking XELODA immediately. Initiation of symptomatic treatment is recommended (see DOSAGE AND ADMINISTRATION). Fever and Neutropenia: Patients who develop a fever of F or greater or other evidence of potential infection should be instructed to call their physician. Drug-Food Interaction: In all clinical trials, patients were instructed to administer XELODA within 30 minutes after a meal. Since current safety and efficacy data are based upon administration with food, it is recommended that XELODA be administered with food (see DOSAGE AND ADMINISTRATION). Drug-Drug Interactions: Antacid: The effect of an aluminum hydroxide- and magnesium hydroxide-containing antacid (Maalox) on the pharmacokinetics of XELODA was investigated in 12 cancer patients. There was a small increase in plasma concentrations of XELODA and one metabolite (5 -DFCR); there was no effect on the 3 major metabolites (5 -DFUR, 5-FU and FBAL). Anticoagulants: Patients receiving concomitant capecitabine and oral coumarin-derivative anticoagulant therapy should have their anticoagulant response (INR or prothrombin time) monitored closely with great frequency and the anticoagulant dose should be adjusted accordingly (see Boxed WARNING and CLINICAL PHARMACOLOGY). Altered coagulation parameters and/or bleeding have been reported in patients taking XELODA concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon. These events occurred within several days and up to several months after initiating XELODA therapy and, in a few cases, within 1 month after stopping XELODA. These events occurred in patients with and without liver metastases. In a drug interaction study with single-dose warfarin administration, there was a significant increase in the mean AUC of S-warfarin. The maximum observed INR value increased by 91%. This interaction is probably due to an inhibition of cytochrome P450 2C9 by capecitabine and/or its metabolites (see CLINICAL PHARMACOLOGY). CYP2C9 substrates: Other than warfarin, no formal drug-drug interaction studies between XELODA and other CYP2C9 substrates have been conducted. Care should be exercised when XELODA is coadministered with CYP2C9 substrates. Phenytoin: The level of phenytoin should be carefully monitored in patients taking XELODA and phenytoin dose may need to be reduced (see DOSAGE AND ADMINISTRATION: Dose Modification Guidelines). Postmarketing reports indicate that some patients receiving XELODA and phenytoin had toxicity associated with elevated phenytoin levels. Formal drug-drug interaction studies with phenytoin have not been conducted, but the mechanism of interaction is presumed to be inhibition of the CYP2C9 isoenzyme by capecitabine and/or its metabolites (see PRECAUTIONS: Drug-Drug Interactions: Anticoagulants). Leucovorin: The concentration of 5-fluorouracil is increased and its toxicity may be enhanced by leucovorin. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly leucovorin and fluorouracil. Pregnancy: Teratogenic Effects: Category D (see WARNINGS). Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with XELODA. Nursing Women: Lactating mice given a single oral dose of capecitabine excreted significant amounts of capecitabine metabolites into the milk. Because of the potential for serious adverse reactions in nursing infants from capecitabine, it is recommended that nursing be discontinued when receiving XELODA therapy. Pediatric Use: The safety and effectiveness of XELODA in persons <18 years of age have not been established. Geriatric Use: Physicians should pay particular attention to monitoring the adverse effects of XELODA in the elderly (see WARNINGS: Geriatric Patients). ADVERSE REACTIONS: Colorectal Cancer: Table 1 shows the adverse events occurring in 5% of patients from pooling the two phase 3 trials in colorectal cancer. Rates are rounded to the nearest whole number. A total of 596 patients with metastatic colorectal cancer were treated with 1250 mg/m 2 twice a day of XELODA administered for 2 weeks followed by a 1-week rest period, and 593 patients were administered 5-FU and leucovorin in the Mayo regimen (20 mg/m 2 leucovorin IV followed by 425 mg/m 2 IV bolus 5-FU, on days 1-5, every 28 days). In the pooled colorectal database the median duration of treatment was 139 days for capecitabine-treated patients and 140 days for 5-FU/LV-treated patients. A total of 78 (13%) and 63 (11%) capecitabine and 5-FU/LV-treated patients, respectively, discontinued treatment because of adverse events/intercurrent illness. A total of 82 deaths due to all causes occurred either on study or within 28 days of receiving study drug: 50 (8.4%) patients randomized to XELODA and 32 (5.4%) randomized to 5-FU/LV. Table 1. Pooled Phase 3 Colorectal Trials: Percent Incidence of Adverse Events Related or Unrelated to Treatment in 5% of Patients XELODA 5-FU/LV (n=596) (n=593) Total Grade3Grade4 Total Grade3 Grade4 (%) (%) (%) (%) (%) (%) Number of Patients With > One Adverse Event Body System/ Adverse Event GI Diarrhea Nausea <1 Vomiting 27 4 < <1 Stomatitis 25 2 < Abdominal Pain 35 9 < Gastrointestinal Motility 10 <1 7 <1 Disorder Constipation 14 1 < Oral Discomfort Upper GI Inflammatory 8 < Disorders Gastrointestinal 6 1 <1 3 1 Hemorrhage Ileus Skin and Subcutaneous Hand-and-Foot NA 6 1 NA Syndrome Dermatitis Skin Discoloration 7 <1 5 Alopecia 6 2 <1 General Fatigue/Weakness Pyrexia Edema Pain Chest Pain <1 Neurological Peripheral Sensory 10 4 Neuropathy Headache Dizziness* 8 <1 8 <1 Insomnia 7 7 Taste Disturbance <1 1 Metabolism Appetite Decreased 26 3 < <1 Dehydration 7 2 < Eye Eye Irritation <1 Vision Abnormal 5 2 Respiratory Dyspnea <1 1 Cough 7 <1 1 8

5 XELODA 5-FU/LV (n=596) (n=593) Total Grade3 Grade4 Total Grade3 Grade4 (%) (%) (%) (%) (%) (%) Respiratory (cont.) Pharyngeal Disorder 5 5 Epistaxis 3 <1 6 Sore Throat 2 6 Musculoskeletal Back Pain <1 Arthralgia Vascular Venous Thrombosis 8 3 <1 6 2 Psychiatric Mood Alteration 5 6 <1 Depression 5 4 <1 Infections Viral 5 <1 5 <1 Blood and Lymphatic Anemia 80 2 < <1 Neutropenia Hepatobiliary Hyperbilirubinemia Not observed *Excluding vertigo NA = Not Applicable Breast Cancer Combination: The following data are shown for the combination study with XELODA and docetaxel in patients with metastatic breast cancer in Table 2. In the XELODA and docetaxel combination arm the treatment was XELODA administered orally 1250 mg/m 2 twice daily as intermittent therapy (2 weeks of treatment followed by 1 week without treatment) for at least 6 weeks and docetaxel administered as a 1-hour intravenous infusion at a dose of 75 mg/m 2 on the first day of each 3-week cycle for at least 6 weeks. In the monotherapy arm docetaxel was administered as a 1-hour intravenous infusion at a dose of 100 mg/m 2 on the first day of each 3-week cycle for at least 6 weeks. The mean duration of treatment was 129 days in the combination arm and 98 days in the monotherapy arm. A total of 66 patients (26%) in the combination arm and 49 (19%) in the monotherapy arm withdrew from the study because of adverse events. The percentage of patients requiring dose reductions due to adverse events was 65% in the combination arm and 36% in the monotherapy arm. The percentage of patients requiring treatment interruptions due to adverse events in the combination arm was 79%. Treatment interruptions were part of the dose modification scheme for the combination therapy arm but not for the docetaxel monotherapy-treated patients. Table 2. Percent Incidence of Adverse Events Considered Related or Unrelated to Treatment in 5% of Patients Participating in the XELODA and Docetaxel Combination vs Docetaxel Monotherapy Study XELODA1250mg/m 2 /bid Docetaxel With Docetaxel 100 mg/m 2 /3 weeks 75 mg/m 2 /3 weeks (n=251) (n=255) Total Grade3 Grade4 Total Grade3 Grade4 (%) (%) (%) (%) (%) (%) Number of Patients With One Adverse Event Body System/ Adverse Event GI Diarrhea < <1 Stomatitis < Nausea Vomiting Constipation Abdominal Pain 30 <3 < Dyspepsia Dry Mouth 6 <1 5 Skin and Subcutaneous Hand-and-Foot NA 8 1 NA Syndrome Alopecia Nail Disorder Dermatitis Rash Erythematous 9 <1 5 Nail Discoloration 6 4 <1 Onycholysis Pruritus 4 5 General Pyrexia Asthenia 26 4 < Fatigue Weakness Pain in Limb 13 < Lethargy Pain 7 <1 5 1 Chest Pain (non-cardiac) 4 <1 6 2 Influenza-like Illness 5 5 Neurological Taste Disturbance 16 <1 14 <1 Headache Paresthesia 12 < Dizziness 12 8 <1 Insomnia 8 10 <1 Peripheral Neuropathy Hypoaesthesia 4 <1 8 <1 Metabolism Anorexia <1 Appetite Decreased 10 5 Weight Decreased 7 5 Dehydration <1 <1 Eye Lacrimation Increased 12 7 <1 Conjunctivitis 5 4 Eye Irritation 5 1 Musculoskeletal Arthralgia Myalgia Back Pain 12 < Bone Pain 8 < XELODA1250mg/m 2 /bid Docetaxel With Docetaxel 100 mg/m 2 /3 weeks 75 mg/m 2 /3 weeks (n=251) (n=255) Total Grade 3 Grade 4 Total Grade 3 Grade 4 (%) (%) (%) (%) (%) (%) Cardiac Edema 33 <2 34 <3 1 Blood Neutropenic Fever Respiratory Dyspnea 14 2 < Cough <1 Sore Throat <1 Epistaxis 7 <1 6 Rhinorrhea 5 3 Pleural Effusion Infection Oral Candidiasis 7 <1 8 <1 Urinary Tract Infection 6 <1 4 Upper Respiratory Tract Vascular Flushing 5 5 Lymphoedema 3 <1 5 1 Psychiatric Depression Not observed NA = Not Applicable Table 3. Percent of Patients With Laboratory Abnormalities Participating in the XELODA and Docetaxel Combination vs Docetaxel Monotherapy Study XELODA1250mg/m 2 /bid Docetaxel With Docetaxel 100 mg/m 2 /3 weeks 75 mg/m 2 /3 weeks (n=251) (n=255) Body System/ Total Grade3 Grade4 Total Grade3 Grade4 Adverse Event (%) (%) (%) (%) (%) (%) Hematologic Leukopenia Neutropenia/ Granulocytopenia Thrombocytopenia Anemia <1 Lymphocytopenia Hepatobiliary Hyperbilirubinemia Breast Cancer XELODA Monotherapy: The following data are shown for the study in stage IV breast cancer patients who received a dose of 1250 mg/m 2 administered twice daily for 2 weeks followed by a 1-week rest period. The mean duration of treatment was 114 days. A total of 13 out of 162 patients (8%) discontinued treatment because of adverse events/intercurrent illness. Table 4. Percent Incidence of Adverse Events Considered Remotely, Possibly or Probably Related to Treatment in 5% of Patients Participating in the Single Arm Trial in Stage IV Breast Cancer Adverse Event Phase 2 Trial in Stage IV Breast Cancer (n=162) Body System/ Total Grade 3 Grade 4 Adverse Event (%) (%) (%) GI Diarrhea Nausea 53 4 Vomiting 37 4 Stomatitis 24 7 Abdominal Pain 20 4 Constipation 15 1 Dyspepsia 8 Skin and Subcutaneous Hand-and-Foot NA Syndrome Dermatitis 37 1 Nail Disorder 7 General Fatigue 41 8 Pyrexia 12 1 Pain in Limb 6 1 Neurological Paresthesia 21 1 Headache 9 1 Dizziness 8 Insomnia 8 Metabolism Anorexia 23 3 Dehydration Eye Eye Irritation 15 Musculoskeletal Myalgia 9 Cardiac Edema 9 1 Blood Neutropenia Thrombocytopenia Anemia Lymphopenia Hepatobiliary Hyperbilirubinemia Not observed NA = Not Applicable OTHER ADVERSE EVENTS: XELODA and Docetaxel in Combination: Shown below by body system are the clinically relevant adverse events in <5% of patients in the overall clinical trial safety database of 251 patients (Study Details) reported as related to the administration of XELODA in combination with docetaxel and that were clinically at least remotely relevant. In parentheses is the incidence of grade 3 and 4 occurrences of each adverse event. It is anticipated that the same types of adverse events observed in the XELODA monotherapy studies may be observed in patients treated with the combination of XELODA plus docetaxel. Gastrointestinal: ileus (0.39), necrotizing enterocolitis (0.39), esophageal ulcer (0.39), hemorrhagic diarrhea (0.80) Neurological: ataxia (0.39), syncope (1.20), taste loss (0.80), polyneuropathy (0.39), migraine (0.39) Cardiac: supraventricular tachycardia (0.39) Infection: neutropenic sepsis (2.39), sepsis (0.39), bronchopneumonia (0.39) Blood and Lymphatic: agranulocytosis (0.39), prothrombin decreased (0.39) Vascular: hypotension (1.20), venous phlebitis and thrombophlebitis (0.39), postural hypotension (0.80) Renal: renal failure (0.39) Hepatobiliary: jaundice (0.39), abnormal liver function tests (0.39), hepatic failure (0.39), hepatic coma (0.39), hepatotoxicity (0.39) Immune System: hypersensitivity (1.20) XELODA Monotherapy: Shown below by body system are the clinically relevant adverse events in <5% of patients in the overall clinical trial safety database of 875 patients (phase 3 colorectal studies 596 patients, phase 2 colorectal study 34 patients, phase 2 breast cancer studies 245 patients) reported as related to the administration of XELODA and that were clinically at least remotely relevant. In parentheses is the incidence of grade 3 or 4 occurrences of each adverse event. Gastrointestinal: abdominal distension, dysphagia, proctalgia, ascites (0.1), gastric ulcer (0.1), ileus (0.3), toxic dilation of intestine, gastroenteritis (0.1) Skin and Subcutaneous: nail disorder (0.1), sweating increased (0.1), photosensitivity reaction (0.1), skin ulceration, pruritus, radiation recall syndrome (0.2) General: chest pain (0.2), influenza-like illness, hot flushes, pain (0.1), hoarseness, irritability, difficulty in walking, thirst, chest mass, collapse, fibrosis (0.1), hemorrhage, edema, sedation Neurological: insomnia, ataxia (0.5), tremor, dysphasia, encephalopathy (0.1), abnormal coordination, dysarthria, loss of consciousness (0.2), impaired balance Metabolism: increased weight, cachexia (0.4), hypertriglyceridemia (0.1), hypokalemia, hypomagnesemia Eye: conjunctivitis Respiratory: cough (0.1), epistaxis (0.1), asthma (0.2), hemoptysis, respiratory distress (0.1), dyspnea Cardiac: tachycardia (0.1), bradycardia, atrial fibrillation, ventricular extrasystoles, extrasystoles, myocarditis (0.1), pericardial effusion Infections: laryngitis (1.0), bronchitis (0.2), pneumonia (0.2), bronchopneumonia (0.2), keratoconjunctivitis, sepsis (0.3), fungal infections (including candidiasis) (0.2) Musculoskeletal: myalgia, bone pain (0.1), arthritis (0.1), muscle weakness Blood and Lymphatic: leukopenia (0.2), coagulation disorder (0.1), bone marrow depression (0.1), idiopathic thrombocytopenia purpura (1.0), pancytopenia (0.1) Vascular: hypotension (0.2), hypertension (0.1), lymphoedema (0.1), pulmonary embolism (0.2), cerebrovascular accident (0.1) Psychiatric: depression, confusion (0.1) Renal: renal impairment (0.6) Ear: vertigo Hepatobiliary: hepatic fibrosis (0.1), hepatitis (0.1), cholestatic hepatitis (0.1), abnormal liver function tests Immune System: drug hypersensitivity (0.1) Postmarketing: hepatic failure OVERDOSAGE: The manifestations of acute overdose would include nausea, vomiting, diarrhea, gastrointestinal irritation and bleeding, and bone marrow depression. Medical management of overdose should include customary supportive medical interventions aimed at correcting the presenting clinical manifestations. Although no clinical experience using dialysis as a treatment for XELODA overdose has been reported, dialysis may be of benefit in reducing circulating concentrations of 5 -DFUR, a low molecular-weight metabolite of the parent compound. Single doses of XELODA were not lethal to mice, rats, and monkeys at doses up to 2000 mg/kg (2.4, 4.8, and 9.6 times the recommended human daily dose on a mg/m 2 basis). Maalox is a registered trademark of Novartis. Taxotere is a registered trademark of Aventis Pharmaceuticals Products Inc. For full Taxotere prescribing information, please refer to Taxotere Package Insert. R X only Revised: April 2003 Printed in USA Copyright by Roche Laboratories Inc. All rights reserved.

6 12 mco contents Spring 2006 Issue 1 features 12 Improving Value Oncology Reimbursement: Managed Care Challenges and Considerations By Michael Waterbury, VP, Healthcare Services, Oxford Health Plans, LLC. Oncology therapies present a unique situation for both providers and payors alike in that these physician-administered agents carry two separate reimbursable components: one for the drug itself and one for the service rendered by the physician in administering the drug. 33 Drug & Administration Compendia Coding, reimbursement, and available therapies in the treatment of renal cell carcinoma Regulatory & Reimbursement Is the Medicare fee schedule the standard for office-based drug infusion payment? By Roberta L. Buell, VP, Patient & Provider Services, P4 Healthcare, LLC. While most private payors are familiar with the Medicare Prescription Drug Improvement and Modernization Act (MMA) as it pertains to prescription drug coverage, there are many aspects of MMA that effect the way Medicare pays for office-based infusion services with which payors are unfamiliar. A better understanding of this system by payors is necessary to ensure that reimbursement is fair. 10 departments 10 Correspondence By Kjel Johnson, PharmD, Publisher, Managed Care Oncology Welcome to our first edition of Managed Care Oncology. Find out what value MCO will bring to you. 16 Facts & Figures Data and accompanying graphics on reimbursement practices, information management, and oncology spending. 18 Drug Therapy Reviews Improving Outcomes in Advanced Renal Cell Carcinoma By Dr. Jeffery A. Scott, President, P4 Healthcare, LLC. Epidemiology, treatment, and cost considerations in the treatment of advanced renal cell carcinoma. 28 Pipeline Report New Drug Update: Angiogenesis Inhibitors By Howard A. Skip Burris III, MD, Director of Drug Development, The Sarah Cannon Research Institute The recently developed angiogenesis inhibitors target the development of the 28 vasculature feeding tumors as a means of inhibiting the tumors growth. 49 Calendar of Events Dates and locations of upcoming meetings, workshops, and conferences of interest to managed care oncology professionals. 50 Clinical Trial Update By John W. Mucenski, BS, PharmD, Director, Pharmacy Operations, UMPC Cancer Centers A review of recent clinical trials in the field of oncology. Included are the methods, results, conclusions, and managed care implications of each trial reviewed Resources & References A comprehensive list of information sources relevant to managed care oncology professionals. 9 Advertising Index 6 managedcareoncology Spring 2006

7 FOR THE PREVENTION OF CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING (CINV) BETTER IN ACUTE, BETTER IN DELAYED Better Overall Prevention (Complete Response) *1-3 Acute ALOXI 72.0% vs ondansetron/dolasetron 60.6% Delayed ALOXI 64.0% vs ondansetron/dolasetron 46.8% NCCN -preferred treatment prior to moderately emetogenic chemotherapy (MEC) and a recommended treatment prior to highly emetogenic chemotherapy. 4 *p<0.025 for pair-wise difference (two-sided Fisher s exact test) between ALOXI and ondansetron/dolasetron. Complete response defined as no emetic episode and no use of rescue medication. Pooled data from two identically designed Phase 3 clinical trials involving MEC. 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. ALOXI is contraindicated in patients known to have hypersensitivity to the drug or any of its components. It should be administered with caution in patients who have or may develop prolongation of cardiac conduction intervals, particularly QTc. Most commonly reported adverse reactions include headache (9%) and constipation (5%). Please see the following brief summary of prescribing information. NCCN is a registered trademark of the National Comprehensive Cancer Network. ALOXI ALLIANCE PROGRAM Reimbursement hotline: ALOXI MGI PHARMA, INC., Bloomington, MN U.S.A. AL0006 2/06

8 References: 1. 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: 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-HT 3 receptor antagonist: results of a phase III, single-dose trial versus dolasetron. Cancer. 2003;98: Rubenstein EB, Gralla RJ, Eisenberg P, et al. Palonosetron (PALO) compared with ondansetron (OND) or dolasetron (DOL) for prevention of acute and delayed chemotherapyinduced nausea and vomiting (CINV): combined results of two phase III trials [abstract]. Proc Am Soc Clin Oncol. 2003;22:729.Abstract NCCN Practice Guidelines in Oncology v :antiemesis. National Comprehensive Cancer Network.Available at: October 19, BRIEF SUMMARY OF PRESCRIBING INFORMATION INDICATIONS AND USAGE ALOXI is indicated for: 1) the prevention of acute nausea and vomiting associated with initial and repeat courses of moderately and highly emetogenic cancer chemotherapy, and 2) the prevention of delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy. CONTRAINDICATIONS ALOXI is contraindicated in patients known to have hypersensitivity to the drug or any of its components. PRECAUTIONS General Hypersensitivity reactions may occur in patients who have exhibited hypersensitivity to other selective 5-HT 3 receptor antagonists. Although palonosetron has been safely administered to 192 patients with preexisting cardiac impairment in the Phase 3 studies, ALOXI should be administered with caution in patients who have or may develop prolongation of cardiac conduction intervals, particularly QTc. These include patients with hypokalemia or hypomagnesemia, patients taking diuretics with potential for inducing electrolyte abnormalities, patients with congenital QT syndrome, patients taking anti-arrhythmic drugs or other drugs which lead to QT prolongation, and cumulative high dose anthracycline therapy. In 3 pivotal trials, ECGs were obtained at baseline and 24 hours after subjects received palonosetron or a comparator drug. In a subset of patients ECGs were also obtained 15 minutes following dosing. The percentage of patients (<1%) with changes in QT and QTc intervals (either absolute values of > 500 msec or changes of > 60 msec from baseline) was similar to that seen with the comparator drugs. Drug Interactions Palonosetron is eliminated from the body through both renal excretion and metabolic pathways. Therefore, the potential for clinically significant drug interactions with palonosetron appears to be low (See CLINICAL PHARMACOLOGY, Drug-Drug Interactions section of the Full Prescribing Information). Carcinogenesis, Mutagenesis, Impairment of Fertility In a 104-week carcinogenicity study in CD-1 mice, animals were treated with oral doses of palonosetron at 10, 30 and 60 mg/kg/day. Treatment with palonosetron was not tumorigenic. The highest tested dose produced a systemic exposure to palonosetron (Plasma AUC) of about 150 to 289 times the human exposure (AUC= 29.8 ng h/ml) at the recommended intravenous dose of 0.25 mg. In a 104-week carcinogenicity study in Sprague-Dawley rats, male and female rats were treated with oral doses of 15, 30 and 60 mg/kg/day and 15, 45 and 90 mg/kg/day, respectively.the highest doses produced a systemic exposure to palonosetron (Plasma AUC) of 137 and 308 times the human exposure at the recommended dose. Treatment with palonosetron produced increased incidences of adrenal benign pheochromocytoma and combined benign and malignant pheochromocytoma, increased incidences of pancreatic Islet cell adenoma and combined adenoma and carcinoma and pituitary adenoma in male rats. In female rats, it produced hepatocellular adenoma and carcinoma and increased the incidences of thyroid C-cell adenoma and combined adenoma and carcinoma. Palonosetron was not genotoxic in the Ames test, the Chinese hamster ovarian cell (CHO/HGPRT) forward mutation test, the ex vivo hepatocyte unscheduled DNA synthesis (UDS) test or the mouse micronucleus test. It was, however, positive for clastogenic effects in the Chinese hamster ovarian (CHO) cell chromosomal aberration test. Palonosetron at oral doses up to 60 mg/kg/day (about 1894 times the recommended human intravenous dose based on body surface area) was found to have no effect on fertility and reproductive performance of male and female rats. 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. Pediatric Use Safety and effectiveness in patients below the age of 18 years have not been established. Geriatric Use 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 adjustments or special monitoring are required for geriatric patients. ADVERSE REACTIONS 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 Chemotherapy-Induced Nausea and Vomiting Studies 2% in any Treatment Group ALOXI Ondansetron Dolasetron Event 0.25 mg 32 mg IV 100 mg IV (N=633) (N=410) (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 µg/kg oral dose in a post-operative nausea and vomiting study and one healthy subject received a 0.75 mg IV 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. 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. Very rare cases (<1/10,000) of hypersensitivity reactions and injection site reactions (burning, induration, discomfort and pain) were reported from post-marketing experience. 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 µg/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. DOSAGE AND ADMINISTRATION Dosage for Adults The recommended dosage of ALOXI is 0.25 mg administered as a single dose approximately 30 minutes before the start of chemotherapy. Repeated dosing of ALOXI within a seven day interval is not recommended because the safety and efficacy of frequent (consecutive or alternate day) dosing in patients has not been evaluated. Use in Geriatric Patients and in Patients with Impaired Renal or Hepatic Function No dosage adjustment is recommended. Dosage for Pediatric Patients A recommended intravenous dosage has not been established for pediatric patients. Administration ALOXI is to be infused intravenously over 30 seconds.aloxi should not be mixed with other drugs. Flush the infusion line with normal saline before and after administration of ALOXI. NDC Number Prescribing information as of January 2006 Jointly manufactured by Cardinal Health, Albuquerque, NM, USA, or Pierre Fabre, Médicament Production, Idron, Aquitaine, France, and Helsinn Birex Pharmaceuticals Ltd, Dublin, Ireland Mfd for Helsinn Healthcare, SA, Switzerland Distributed and marketed by MGI PHARMA, INC., Bloomington, MN under license of Helsinn Healthcare, SA, Switzerland. ALOXI is a registered trademark of Helsinn Healthcare, SA, Lugano, Switzerland MGI PHARMA, INC., Bloomington, MN U.S.A. AL0179 2/06

9 ManagedCare For Decision Makers in Managed Care Published by: ICORE Healthcare, LLC 5850 T.G. Lee Blvd., Suite 510 Orlando, FL i-CORE tel i-CORE fax Publishing Staff Publisher Kjel A. Johnson, PharmD Clinical Editor-in-Chief Stan Winokur, MD Managing Editor David J. Goldstein, MHP, PMP Oncology Managed Care Oncology is published by ICORE Healthcare, LLC in conjunction with Penton Custom Media. All rights reserved. Publishing Offices 1300 E. 9th Street Cleveland, OH tel fax Account Director Angela Vannucci Media Services Manager Susan Durishin Creative Directors Dave Bosak Greg Kiskadden Advertising and Sales For information on advertising in Managed Care Oncology contact: Bob Heiman (856) tel (856) fax Subscription Services To subscribe to Managed Care Oncology, visit Managed Care Oncology Editorial Advisory Board Chandra P. Belani, MD Professor of Medicine, University of Pittsburgh School of Medicine Co-Director, Lung and Thoracic Malignancies Program, University of Pittsburgh Cancer Institute Howard A. Skip Burris III, MD Director of Drug Development, The Sarah Cannon Research Institute Richard Cook, PharmD Pharmacy Manager, Clinical and Quality Programs, Blue Care Network of Michigan Jeffrey Crawford, MD Chief of Medical Oncology, Duke University Medical Center William J. Gradishar, MD Professor of Medicine, Director of Breast Medical Oncology, Northwestern University, Feinberg School of Medicine Cliff Hudis, MD Chief, Breast Cancer Medicine Service, Memorial Sloan Kettering Cancer Center Deborah Partsch, PharmD Director, Pharmacy Operations, Highmark Blue Cross Blue Shield Jeffrey Patton, MD Medical Director, Tennessee Oncology Dan Petrylak, MD Associate Professor of Medicine, Columbia University Medical Center 2006 ICORE Healthcare, LLC. All rights reserved. All trademarks are the property of their respective owners. Printed in the U.S.A. The content of Manage Care Oncology, including advertisements, text, graphics, images, information obtained from third parties, and other material is for informational purposes only, and is not intended to be a substitute for professional medical advice, diagnosis or treatment. You should consult your physician regarding your particular medical condition. Managed Care Oncology is not responsible for any loss or damage incurred by readers in reliance upon any advertisements or content contained in the publication.

10 correspondence In 2004, 16% of the total U.S. drug spend was for oncology medications; next year, this portion is expected to be 22%. 2 Moreover, the 2006 U.S. oncology drug spend is expected to eclipse $30 billion. 3 The cause of this rapid increase in treatment costs is primarily due to advances in chemotherapeutic agents: last year, there were 399 cancer medications in various stages of development; this was more than 50% of all drugs in development. 4 This year, about 1.4 million Americans will develop cancer and approximately 600,000 will die from their disease. In fact, about 40% of us will develop cancer at some point in our lives. 1 The cost of caring for people diagnosed with cancer is enormous due to its high incidence and the broad treatment options that are available. In 2004, 16% of the total U.S. drug spend was for oncology medications; next year, this portion is expected to be 22%. 2 Moreover, the 2006 U.S. oncology drug spend is expected to eclipse $30 billion. 3 The cause of this rapid increase in treatment costs is primarily due to advances in chemotherapeutic agents: last year, there were 399 cancer medications in various stages of development; this was more than 50% of all drugs in development. 4 As a result of these cost and utilization statistics, payor executives began to identify the growing impact of cancer medications and treatment at their plans specifically, that the trend rate for the cost of these medications was more than 25% annually. Soon after the measurement of this impact, these same payors began to evaluate various strategies to optimize the quality of care and manage the costs of cancer-related medications. Executives from commercial payor organizations have told me that improving the quality and frequency of oncologyrelated data at health plans and facilitating the provision of these data to their providers are the keys to developing and implementing successful programs to improve the overall value of oncology medications. Paramount to this is access to unbiased information regarding clinical efficacy and cost-efficiency. Specifically, plans began to ask: Where should I focus my efforts to improve the value of chemotherapeutics? How do I determine clinical appropriateness? How can I fairly reimburse providers in a manner that encourages the use of generics and least-costly alternatives when clinically appropriate? Should I continue to allow my oncologists to buy and bill? How do my current specialty pharmacy initiatives fit into the appropriate use of oncology products? How should I communicate my oncology management program to providers, and how can I prevent provider dissatisfaction with any strategic changes? How can I communicate with providers regarding the use of preferred products? 10 managedcareoncology Spring 2006

11 In an effort to provide high-quality, unbiased information to payors and those organizations that are involved in assisting payors in improving the value of cancer drugs, we have developed Managed Care Oncology. Our Clinical Editor-in-Chief, Stan Winokur, MD, and I are committed to address the unmet need you have described to us over the years. As you may know, Stan has dedicated his very noteworthy career to caring for cancer patients and educating providers on how best to do this. In designing this publication, we knew that its success was dependent upon providing timely, detailed, and unbiased information. While each issue of Managed Care Oncology will aim to provide key information regarding a particular therapeutic area or type of cancer, we also are very interested in answering your specific oncology-related questions. Please submit questions at and they will be answered in the following issue by industry and clinical experts. Also, since this journal aims to address your needs, please also feel free to recommend topics to address in successive issues. Thanks in advance for taking time to read this publication. We look forward to working with you throughout 2006 and beyond. Most cordially, Kjel A. Johnson, PharmD Publisher Managed Care Oncology References 1. American Cancer Society, January Drug Trend Report: Navigating the New Health Economy. Franklin Lakes, NJ: Merck-Medco Managed Care, LLC ICORE Healthcare Payor Research, National Cancer Institute, managedcareoncology.com 11

12 improving value Oncology therapies present a unique situation for both providers and payors alike in that these physician-administered agents carry two separate reimbursable components: one for the drug itself and one for the service rendered by the physician in administering the drug. This two-prong reimbursement system has been characterized over the years by a trend towards shifting the proportion of payment from reimbursement that was originally drug-centered to reimbursement that is more weighted in favor of payment for physician-administered services. 12 managedcareoncology Spring 2006

13 Oncology Reimbursement: by Michael Waterbury, VP, Healthcare Services, Oxford Health Plans, LLC. The Challenge of Reimbursement in Managed Care Oncology Oncology healthcare costs continue to trend at more than 20% a year. The cost to deliver care for cancer is becoming increasingly a major focus for health plans. There are many factors driving these costs, with a key driver being the pipeline of new drug treatments and the increasing cost of injectable chemotherapy drugs. This trend necessitates focus and urgency for health plans to find strategies to control these costs ranging from medical management, unit cost reimbursement, and benefit strategies. Many payors are currently evaluating strategies to reimburse for oncology drugs under the medical benefit to their network physicians. The recent move to a new methodology by the government has provided opportunity for payors to evaluate their current methodologies and develop a plan for the future. Oncology therapies present a unique situation for both providers and payors alike in that these physicianadministered agents carry two separate reimbursable components: one for the drug itself and one for the service rendered by the physician in administering the drug. This two-prong reimbursement system has been characterized over the years by a trend towards shifting the proportion of payment from reimbursement that was originally drug-centered to reimbursement that is more weighted in favor of payment for physicianadministered services. The Challenge of Reimbursement in Managed Care Oncology Because providers are profiting from the oncology drugs that they are administering in their practices, revenue becomes an enormous component of the challenge of reimbursing for oncology therapy in managed care. A physician s practice is a business like any other, with one of its goals being profitability. Likewise, payors continue to struggle with healthcare affordability challenges with increasing premiums and increasing levels of uninsured Americans. History also represents a significant component of the challenge in reimbursing for oncology therapies in managed care. As previously mentioned, providers are reimbursed for the drugs they administer in the practice setting. But is this a fair and reasonable manner in which to reimburse? The question arises as to whether the provider should be reimbursed primarily for the drug or for the service. For the most part, current commercial payor models have providers being under-compensated for the drug administration service but overcompensated for dispensing the drug. In attempting to change a long-standing system such as this, a finely tuned balance of proportions for these two components must be figured into the reimbursement equation. The result of this reimbursement approach is that the drug component has increased drastically for many years, proportions and minimizing the contribution of revenue from cognitive services. A closer look at the most common reimbursement methodologies may serve to further elucidate this situation. Reimbursement Methodologies Average Wholesale Price (AWP). The traditional method of reimbursement for oncology products and services is characterized by payors reimbursing providers based on the average wholesale price (AWP) of the therapeutic agents administered in the practice setting. Reimbursement based on AWP can create significant margins on administered drugs and leads to providers making the majority of their profit on the drug component of oncology therapy administration. The primary disadvantage of this AWPbased reimbursement is that, for the managedcareoncology.com 13

14 most part, it is based on no apparent relevance to cost. AWP is not validated or audited by independent sources. Rather, it is self-reported by several third parties, and the result is an unpredictable and uncontrolled form of reimbursement that demonstrates increases in drug reimbursement even when drug cost isn t increasing. Average Sales Price (ASP). A relatively new approach in the area of oncology drug reimbursement is the use of average sales price (ASP) in lieu of AWP. ASP uses drug costs submitted by manufacturers to set drug payment rates. The result is reimbursement that is more closely aligned with true acquisition costs. This realignment in reimbursement distribution ultimately reduces the margin on drug costs and, in turn, addresses the profits made by providers on drug costs. To compensate for this shift in reimbursement, providers are compensated more for the practice-setting services rendered. This method of reimbursement was introduced and is managed by the Centers for Medicare & Medicaid Services (CMS). Specifically, CMS introduced ASP+6% drug reimbursement levels on January 1, 2005, as part of the Medicare Prescription Drug Improvement and Modernization Act (MMA). CMS has also significantly increased the reimbursement for the infusion administration codes over the last few years. Some industry theorists propose that ASP-based reimbursement will eventually suffer from the same afflictions as AWPbased reimbursement, but the laws and regulations involved in ASP-based reimbursement will likely prevent that from happening. The main challenge with ASP-based reimbursement is trying to insure that the cost being reported by manufacturers is fair and accurate, and that the providers can actually access the drugs at those prices. In addition, since oncology drug prices can fluctuate at any time and the ASP is only reported quarterly, reimbursement doesn t immediately catch up with actual costs, potentially leading to a situation where providers are reimbursed less than their cost of acquiring a particular drug. Another concern regarding ASP is that the methodology accounts for all aspects of the cost structure for physicians including free products, rebates, and administrative fees and other contract pricing terms. It has been argued due to market share levels, specific provider contract terms, and the ultimate timing of rebate payments that ASP does not reflect true drug costs for physicians. It has also been theorized that the ASP system drives providers to use more expensive therapies, since the percentage-based reimbursement is more profitable to providers when higher cost agents are employed. If valid, this trend will inevitably drive costs up. However, it has also been argued that using ASPbased methodologies discourages the use of high-margin, generic chemotherapeutics when a clinically superior branded product may be available. Although Medicare s ASP+6% reimbursement was considered by some to be the answer to all of the industry s reimbursement healthcare increasing cost concerns, it has been our experience that far less than 10% of payors have adopted such an approach in the past 18 months. This can be attributed largely to the fact that many health plans are risk-adverse organizations and do recognize the value that oncologists have specifically community oncologists when treating their sickest patient population. For this reason, significant reimbursement structure changes can be difficult. That being said, internal health plan bureaucracy and this aversion to change and risk are factors that make changes to an ASP-based reimbursement methodology slow to market. There is also concern in the possibility that ASP-based reimbursement will reduce revenue for oncologists and drive them to send their patients to be treated in a hospital setting where the costs to health plans will be significantly higher. 14 managedcareoncology Spring 2006

15 Maximum Allowable Cost (MAC). This methodology has long been used on the pharmacy benefit for reimbursement for clinically equivalent drugs. The concept of MAC is relatively simple. This method provides a certain level of payment for drugs within a class. This creates incentive for providers to choose the lower cost clinically equivalent option for treatment. There are a few key chemotherapy treatments where there is opportunity to employ a MAC model. This approach can significantly reduce costs by potentially increasing use of lower cost alternatives which will impact the overall cost of treatment and not just the drug margin component of cost. In addition, a MAC model can provide incentives for physicians to maintain relatively high drug profit margins in certain treatment protocols by utilizing lower cost treatments. In turn, they keep the margin between the cost of the drug treatment and the MAC reimbursement level. This strategy, coupled with an ASP reimbursement level for the treatments without clinically equivalent alternatives, can provide a balanced approach to oncology reimbursement that can be equitable for both the provider and the payor. Unfortunately, few health plans have considered this concept at this time, since few have the knowledge needed to develop such a program and the effort to communicate and implement the program successfully is daunting for some. Looking Forward As we look toward the future of reimbursement for managed care oncology therapies, providers and payors cannot ignore an oncology drug pipeline that is rich with oral chemotherapeutic agents. The main challenge with the reimbursement of oral agents in the oncology specialty is that these formulations necessitate the involvement of more of the managed care infrastructure in the reimbursement process. Oral oncology drugs may bring a third party to the table, the pharmacy benefit manager (PBM), and this can further complicate an already complex process. Additional questions arise from the unique position of oral agents in a specialty that s primarily populated with injectables. Primarily, the challenge of how to reimburse providers for oral medications becomes apparent since oral agents are generally covered under the pharmacy benefit. Furthermore, some providers have presented the concept of being reimbursed for dispensing oral medications in a quality-controlled manner. Many other physician specialties write scripts, not just oncologists, so all providers could make the argument that they should be reimbursed for dispensing any oral prescription from their office. Generally, if a health plan is challenged operationally to implement an ASP-hybrid methodology, one can expect reimbursement for oral chemotherapy agents to be significantly more complex and impact many additional decision points within a given health plan. Considering these challenges, however, many health plans are not ready to embrace or consider implementing such an oral reimbursement strategy. Conclusions Although implementing a fair and balanced reimbursement system in the field of oncology can be a challenging endeavor, it can also be a successful one if there is a certain level of compromise and a mutual understanding between payors and providers. Oncologists want to maintain current profits or grow their profits. However, any health plan move from current industry AWP levels to an ASP approach will reduce the overall reimbursement to the oncologists. The reality is that there has to be some correction for what have been excessive increases to the drug margins for a long period of time. Taking this into consideration, it is acceptable to providers in most cases to receive less reimbursement for the drugs as long as they are receiving more reimbursement for their services. Most physicians recognize this reality and are focused on what level health plans will decide to reimburse for drugs. Will it end up at ASP+6% like CMS, or something higher like ASP+12%, or ASP+20%, mitigating the overall reduction to the oncologists? Incentives, alignment, and partnerships are crucial in the functioning of a sound reimbursement strategy where both quality and affordability objectives are met. In an ideal world, providers would only be reimbursed for services, albeit fairly, and not reimbursed at all for medications. This type of reimbursement strategy can address Continued on p. 44 managedcareoncology.com 15

16 In each issue, Facts & Figures provides snapshots of information key to managed care oncology professionals. This installment of Facts & Figures features data and facts & figures accompanying graphics on reimbursement practices, information management, and oncology spending. Reimbursement Practices Most respondents, of an ICORE Healthcare survey in 2006, feel that a 10%- 20% difference in reimbursement will influence provider prescribing habits. % Difference in Reimbursemant to Change Provider Prescribing Habits Most payors increased other administration fees if they renegotiated reimbursement fees for office-administered drugs. If you renegotiated reimbursement fees for office-administered drugs, did you increase other administration fees? Source: ICORE Healthcare survey of 42 plans representing approximately 51million lives, Source: ICORE Healthcare survey of 24 plans representing approximately 82 million lives, Information Management Matching cancer drug with appropriate use: half of payors do this, but information sources are uncontrolled. Do you monitor and/or manage drug administration and setting based on FDA-approved labeling? Source: ICORE Healthcare survey of 35 plans representing approximately 80 million lives, Where payors receive oncology information: disparate and often unreliable sources. External sources receive 86% of all mentions of sources for information about coverage and reimbursment. The Internet and publications account for the bulk of external resources. Lobbyists, consultants and professional or industry meetings are also common sources of information. Manufacturer representatives were mentioned twice. Primary Source of Oncology Reimbursement Information Source: ICORE Healthcare survey, External Sources Source: ICORE Healthcare survey, managedcareoncology Spring 2006

17 Oncology Spending Spend on Oncology Products Oral chemotherapy is an increasing portion of this spend. Medical Benefit Source: IMS Health Estimates, In 2004 Cholesterol Lowering agents were #1 at $29B. Oncology was #2 at $27B. Oncology Drugs in Development Oral Targeted Therapy Source: Gleason PP, Heaton A. Specialty pharmacy utilization and cost in a large managed care population: analysis of medical and pharmacy benefit claims. Presented at the national American College of Clinical Pharmacy: Annual Meeting, Dallas, TX, Oct Published: Pharmacotherapy 2004;24:1445. Source: Innovations Center Future db Total Specialty 2005 Annual Oncology Spend by Therapy Class Oncology Therapy Class Oncology Per Million Lives $19,526, Anti-Emetic Colony Stimulating Factors Erythropoietins $1,836, $5,105, $4,693, IVIG LHRH Source: ICORE Healthcare survey, $1,586, $1,633, Source: Gleason PP, Heaton A. Specialty pharmacy utilization and cost in a large managed care population: analysis of medical and pharmacy benefit claims. Presented at the national American College of Clinical Pharmacy: Annual Meeting, Dallas, TX, Oct Published: Pharmacotherapy 2004;24:1445. managedcareoncology.com 17

18 reviews therapy Improving Outcomes in Renal Cell Carcinoma by Dr. Jeffery A. Scott, President, P4 Healthcare LLC. Advanced renal cell carcinoma (RCC) is associated with substantial effects on clinical, economic, and quality of life parameters. As recently as 2003, the NCI urged for more research in this area. This has resulted in the recent approvals of Sutent (sunitinib) capsules and Nexavar (sorafenib) tablets by the U.S. Food and Drug Administration (FDA) within the last several months. Epidemiology of Renal Cell Carcinoma Although RCC is uncommon, accounting for approximately 2 3% of adult malignancies, 1,2 it is the main tumor type of all kidney cancers (90 95%). 1 The most common histological type is clear-cell RCC, which accounts for 70 80% of cases. 3 The American Cancer Society estimates that the incidence of kidney cancer in the U.S. in 2006 will be 38,890 cases, and is more common in males (24,650 cases; 63%). 4 It is estimated that 12,840 people will die from kidney cancer in Table 1. Risk factors for renal cell cancer 5 Lifestyle/Diet Cigarette smoking Obesity Occupational/environmental exposures Cadmium Trichloroethylene Petrochemicals Asbestos Genetic/hereditary factors Von Hippel-Lindau syndrome (VHL) Other risk factors Long-term dialysis Diuretics Long-term analgesic use Globally, the U.S. has one of the highest incidences of kidney cancer, 2 with most cases occurring in adults aged years, although various types of kidney cancer may occur in other age groups. The incidence of RCC has increased in the U.S. over the past several years. 2,4 Risk factors for the development of RCC can be divided into several categories: lifestyle/diet, occupational/environmental, genetic/hereditary, and other risk factors (Table 1). 5 Smoking is a key risk factor associated with the development of RCC, and may explain the higher incidence in males. 5 Staging and Prognosis Using the Tumor Node Metastases (TNM) staging system, patients with RCC are staged on the basis of primary tumor extent, involvement of lymph nodes, and presence of distant metastasis. The approach to the patients therapy and prognosis is related to the stage of their tumor. For the purpose of treatment and prognosis, these stages are often simplified as localized (Stages I and II), regional (Stage III), and distant (Stage IV) (Table 2 and Figure 1). 6,7 Table 2. Incidence of kidney cancer by stage* Males Females Localized 62% 67% Regional 18% 16% Distant 20% 17% References *Based on SEER data for managedcareoncology Spring 2006

19 Historically, no effective therapy has been available for the majority of patients diagnosed with advanced RCC. 2 In some patients with limited metastasis, resection of localized lesions has been attempted with modest outcomes. 8 Resection of solitary metastases from renal cell carcinoma (RCC) is associated with a 5-year survival rate of 35% to 50%. 8 In general, metastatic disease is often diffuse and not amenable to resection. 9 Therefore, patients with metastatic RCC have a poor prognosis, with a median survival time of only 6 to 12 months and a 2-year survival rate of 10 20%. 10 Figure 1. Staging overview and five-year survival rates for renal cell carcinoma (adapted from Cohen et al. N Engl J Med. 2005;353: ). 7 The treatment of patients with RCC is dependent on many factors, including cell type (most common is clear cell), age, concurrent medical problems, Eastern Cooperative Oncology Group (ECOG) performance status, and most importantly, the stage of the tumor. In RCC, surgery plays a key role in all stages of the disease. Surgery has curative potential in localized and regional presentations of RCC. For patients with more-advanced disease, resection of primary tumor and metastatic lesions may be considered for cytoreduction and palliation. Systemic Therapy Immunotherapy The standard of care for the treatment of advanced RCC is evolving. Through the 1990s and into the first half of this decade, immunotherapy with interferon and/or interleukin-2 has been one of the main standard treatment options (Table 3). 11 Until recently, proleukin 1 (interleukin-2 [IL-2]) was the only FDAapproved therapy for patients with Table 3. Immunotherapy: standard of care in metastatic renal cell carcinoma* Regimen Indication Dosing Complete response Partial response Median PFS Median overall survival Comments Total price ($)* IFN- Phase II 1 st line metastatic RCC n=39) 18 million IU/d given 3 weekly x 23 weeks 12.9% overall response rate 3.5 months 15.2 months In intermediate prognosis patients 15, High dose IL-2 Metastatic RCC. Nx not required (n=95) 600,000 IU/kg (0.037 mg/kg administered every 8 hours by 15 minute infusion) 8% 15% (post- Nx OR was 24%) 3.1 months 15.5 months 3 (2 PR, 1SD) of 9 with PFS at 3 years; 24 months median duration of response; 1 durable response 125, Low dose IL-2 Metastatic RCC. Nx not required (n=91) 18 million IU/dose x 5 days = 90 million iu/first week followed by 72 million IU/week for additional 5 cycles 3% 7% (post- Nx OR was 14%) 3.1 months 20.4 months 10 (7 CR, 2 PR, 1 SD) of 22 with PFS at 3 years; 12 months median duration of response; 9 durable responses 44, References Adapted from presentations at Fourth Annual Kidney Cancer Symposium, *Drug acquisition cost average wholesale price (AWP). According to Redbook, September 2005, Top 200 Brand names Rx Drugs. Medical Economics, Thompson. managedcareoncology.com 19

20 advanced RCC. 12 High-dose IL-2 was approved in 1992, based on data demonstrating a response rate of 15% in patients with advanced disease. 12,13 Although this overall response rate was considered low, there is a reproducible group of responding patients who achieve durable long-term responses. 2 The initial treatment course with IL-2 needs to be performed in a hospital setting, and many patients who experience IL-2-related toxicities are frequently monitored in intensive care units. 14 IL-2 is a relatively toxic therapy, with complications ranging from fever and chills, neurologic and psychologic side-effects, to fluid overload. 15,16 Additional treatment schedules have been developed that involve lower doses of IL-2, and combinations with various biologics (interferon-a) and standard chemotherapies in an attempt to improve outcomes and reduce toxicities. 12 Although there has been no significant improvement in survival with these regimens, recent data suggest that these may alleviate some of the toxicities and inpatient requirements associated with high dose IL Targeted Therapy Clinical oncology has recently seen the translation of the laboratory evidence of targeted therapy into clinical standards of care. The treatment of HER2+ breast cancer with trastuzumab (Herceptin ), the treatment of EGFR+ tumors with cetuximab (Erbitux ) and erlotinib (Tarceva ), and the use of bevacizumab (Avastin ) in colon cancer has heralded a new era in cancer therapy. Although the use of traditional combination and single-agent cytotoxic chemotherapy has not produced any significant improvement in outcomes for patients with advanced RCC, new, oral, targeted therapies offer hope and improved outcomes. 17 Von Hippel Lindau (VHL) syndrome is a hereditary condition that renders individuals vulnerable to developing hemangioblastomas, visceral cysts, RCCs, pheochromacytomas, and other cancers. 18 The Von Hippel Lindau (VHL) gene encodes a tumor suppressor protein that interacts with hypoxia-inducible factor (HIF) to regulate several target genes. 19,20 Abnormalities of the VHL gene lead to the upregulation of these target genes: vascular endothelial growth factor (VEGF), which stimulates angiogenesis; platelet-derived growth factor (PDGF), which enhances endothelial stabilization; transforming growth factor alpha (TGF-a), which stimulates cell replication. 21 Therefore, it is believed that mutations in the VHL gene may set into motion a series of events leading to increased vascularization and cell growth, implicated in the development of several cancers. In addition to those patients with genetically inherited VHL syndrome, as many as 50 80% of patients with sporadic RCC have been found to have acquired mutations in the VHL gene. 19,22,23 Many of the receptors for HIF-inducible factors have tyrosine kinase activity, and upon ligand binding, activate downstream signal transduction pathways, the best known of which is the Raf/MEK/ERK signaling pathway. These pathways stimulate cellular processes important in the development of cancer and are rational therapeutic targets. Table 5 identifies several targets and potential agents being studied for treatment of RCC. Nexavar (sorafenib) In December 2005, the U.S. FDA approved Nexavar for the treatment of advanced RCC. This is the first new drug approved for the treatment of advanced RCC since the early 1990s. Sorafenib received a broad indication for the treatment of advanced disease. Nexavar is an oral, Table 5. Targets in the pathogenesis of renal cell carcinoma Increased activity of HIF temsirolimus (Wyeth) VEGF pathway Sutent (Pfizer) Nexavar (Bayer) Avastin (Genentech/Roche) PDGF pathway Sutent Nexavar TGF- pathway Tarceva (Roche/OSI/Genentech) multi-kinase inhibitor with effects on tumor cell proliferation and angiogenesis. 24 The approval of Nexavar was driven by recently released Phase III data from TARGETs (Treatment Approaches in Renal Cancer Global Evaluation Trial). The primary goal of this study was to assess overall survival in advanced RCC patients randomized to Nexavar versus placebo. Secondary outcomes were progression-free survival, response rate, and safety. The data have recently been updated at ECCO 2005 by Escudier et al, at which time overall survival was longer for Nexavar than placebo, with a hazard ratio of 0.72 (P=0.018). 25 The median survival was 14.7 months for patients on placebo, and had not been reached for those patients on Nexavar. This reflects a 29% reduction in risk of mortality for patients receiving Nexavar versus placebo. The secondary endpoint of progression-free survival was also positive, favoring the patients treated with Nexavar versus placebo (24 weeks versus 12 weeks; P< ; Figure 2) at the time of a planned analysis. The benefit of Nexavar in prolonging progressionfree survival was consistent among patient subgroups and among those patients who had received prior cytokine therapy and those who had not. Tumor shrinkage was experienced by 76% of Nexavar treated patients compared with 25% in the placebo group. Nexavar 20 managedcareoncology Spring 2006

21 Figure 2. TARGETs data: Progression-free survival benefit of Nexavar vs. placebo was well tolerated; the most common side-effects were diarrhea, rash, hand foot skin reaction, and fatigue. Nexavar is administered as 400 mg (2 x 200 mg) twice daily until progression. Sutent (sunitinib) In January 2006, the FDA announced the approval of Sutent, a new targeted anticancer treatment for patients with gastrointestinal stromal tumors (GIST), a rare stomach cancer, and also for patients with advanced kidney cancer. Sutent is an oral, multi-targeted kinase inhibitor of PDGFR and VEGFR with antiangiogenic and anti-tumor activity. Sutent was approved on the basis of two Phase II trials that demonstrated anti-tumor activity based upon shrinkage of tumors in patients with metastatic RCC. In the first study 83/106 patients who had received at least two cycles, 42 (40%) patients achieved a response, including one complete remission and 41 partial responses. 26 In the second study of 63 patients, 25 (40%) achieved a response, of these 25 partial responses were achieved. 26 In this subset of responders, the median duration of response was 12.5 months, median time to progression was 8.7 months, and median overall survival was 16.4 months. The most commonly reported toxicities from both studies were fatigue, diarrhea, stomatitis and neutropenia. In the second of the two studies, two patients were taken off study after developing decreases in left ventricular ejection fraction >20%. Sutent is administered as a single 50-mg tablet daily for 28 days, followed by a 2-week break. 27 Other Agents in Development Avastin (Bevacizumab) Avastin is a monoclonal antibody directed against VEGF. It is currently approved for first-line therapy of metastatic disease in colorectal carcinoma in combination with chemotherapy. 28 Recent Phase II/III trials have also demonstrated survival benefits when combined with chemotherapy in specific populations of patients with advanced breast and lung cancer. 29 Avastin has been studied in the setting of advanced RCC. Compared with placebo, Avastin significantly delayed time to progression, an effect that was greater with high Avastin doses, but overall survival was not affected. 18 Avastin has also been investigated in Phase II studies in combinationwith EGFR targeted agents, such as Tarceva. Temsirolimus (CCI-779) Temsirolimus is an mtor inhibitor in development for treatment of advanced RCC. Phase II studies have demonstrated activity in patients not felt to be candidates for IL-2 therapy. Ongoing Phase III trials are comparing temsirolimus versus interferon- alone and in combination in the first-line setting. Choosing Therapy A diagnosis of advanced RCC continues to be associated with poor prognosis. However, recent therapeutic advances have improved the outcomes for these patients. Ongoing clinical trials will evaluate the role of combination therapies, as well as provide some interpretation of head-to-head benefits. Today, therapeutic choices will be based on available data, and oncologists must consider several parameters. The first must be evidencebased medicine. Secondly, if clinical Continued on p. 25 managedcareoncology.com 21

22

23

24

25 outcomes are similar, the issues of toxicity must be reviewed. This toxicity has impact on quality of life, as well as expense related to use of adjunctive medications, hospitalization, and absence from the workplace. Therefore, the overall economics are also important and take on a larger role when efficacy and toxicity are equivalent. Which Drug? Patients diagnosed today with advanced RCC have multiple options. For some patients IL-2 alone or in combination remains a standard of care for some patients in the first-line setting. However, with the broad indications and recent launch of targeted therapies (Nexavar, Sutent ), many clinicians may decide to proceed immediately to single-agent, oral, targeted treatment. This choice will be made after consideration of patient risk factors and overall performance status. Although IL-2 therapy is associated with toxicities, a subset of long-term survivors has been observed. Pending head-to-head studies versus the newer targeted therapies, biologic therapy should remain a standard for patients with good performance status, who would be likely to tolerate such treatment. For patients in whom the potential toxicity of immunotherapy may overshadow the anticipated benefit, a targeted therapy with Nexavar or Sutent may be warranted. Since we have no head-to-head data comparing Nexavar with Sutent, we can only compare available data in the approved labels of the two drugs (Tables 6 and 7). 25,26 Table 6. Efficacy of Nexavar vs Sutent Nexavar Sutent Sutent Phase III Phase II (Trial 1) Phase II (Trial 2) Data presentation ECCO 2005 ECCO 2005 ECCO 2005 Data as of May 2005 April 2005 April 2004 Number of patients Overall response rate 10% 40 (42%) 36.5% Stable disease 74% 24 (23%) 25% Median time to disease N/A N/A* 8.7 months progression Median progression-free 5.5 months N/A N/A survival Median overall survival Not reached Not reached 16.4 months Key findings include: 1. Overall survival statistically significant for Nexavar 2. No published or presented Phase III data for Sutent 3. Patient populations not same in all three studies 4. Higher number of patients treated in Nexavar studies versus Sutent studies 5. Higher response rate with Sutent, although in Phase II non-randomized fashion *Study still ongoing Table 7. Key toxicities > grade 3 associated with Nexavar vs Sutent Toxicity Nexavar (n=451) Sutent (n=169) Any toxicity 95% 100% all grades Any toxicity 38% 73% grade 3 or 4 Fatigue 5% 11% Diarrhea 2% 5% Nausea <1% (any = 23%) 2% (any = 54%) Vomiting <1% (any = 16%) 4% (any = 37%) Hypertension 3% 6% Peripheral edema 0% 1% Rash <1% 1% Dry skin 0% 0% Hand foot skin reaction 6% 3% Hemorrhage/bleeding 2% 1% Joint pain 2% 1% Shortness of breath 3% 5% Key findings include: 1. Both drugs well tolerated compared with biologics 2. Frequency of total events > grade 3 was higher in Sutent 3. Label for Sutent includes warning regarding effect on LVEF and need for baseline and periodic evaluation of LV function, as 15% of patients had reduction in LVEF below lower limit of normal Sutent inhibits UG1A1 and UGT1A9 pathways. This may affect metabolism of other drugs, such as irinotecan 30 managedcareoncology.com 25

26 Cost Nexavar is priced at $5, Average Wholesale Price (AWP) per bottle of mg tablets, and Sutent is price at $8, AWP per bottle of 30 capsules. However, dosing schedules for these two drugs are very different. Nexavar is given twice daily (2 x 200-mg tablets for a total daily dose of 800 mg) for a mean duration of 180 days. Sutent is given 50 mg once daily, intermittently (4 weeks on therapy, followed by a 2-week rest period) for a mean duration of 28.6 weeks, or 4.77 cycles. A more meaningful comparison is the total cost of treatment. For Nexavar this is $32,497.50, and for Sutent this is $38, Other factors that should be considered are the likelihood of dose reduction, monitoring costs, and costs to treat adverse events. In the clinical trials, 12% of Nexavar treated patients had a dose reduction (data on file, Bayer). For Sutent, one or more dose reductions occurred in 22 to 35% of patients. 27 Dose reductions could occur during or at the end of a cycle. For Nexavar, if a dose reduction is needed during a cycle, the dose can be halved to 400 mg once daily, and the patient will take two, 200-mg tablets daily. For Sutent, a dose reduction to 37.5 mg introduces the need for two additional prescriptions, one for 12.5-mg capsules, and one for 25-mg capsules. This creates issues with unused product, unless the dose is subsequently re-escalated. Nexavar and Sutent offer the convenience and cost savings of oral administration. Compared with systemic agents like IL-2, one would expect lower overall costs based upon a reduction in hospitalizations, office visits, therapeutic infusions, and overall supportive care. These factors must be taken into account in any financial analysis. The cost of both drugs compare favorably with other marketed targeted therapies (Table 8). The total cost of care using these new agents reflects the different requirements for patient monitoring, such as the increased expense of Left Ventricular Function analysis with Sutent. The prescribing information recommends performing baseline and periodic evaluation of LVEF while the patient is receiving Sutent, with guidelines for discontinuation of Sutent for LVEF reduction of CHF. 27 Conclusion We are currently witnessing great advancements in the treatment of cancer. Targeted therapy has moved from the laboratory to the clinic. In the setting of advanced RCC, these therapies offer alternatives to existing biologic therapies. Additional studies must be?questions do remain regarding: Role of interleukin and other biologics Appropriate choice in first-line therapy Combinations with biologics or other targeted therapy Choice of sorafenib or sunitinib completed to assist the development of guidelines and pathways to direct the clinician along the appropriate path. For our patients, these drugs offer significant advantages and prolongation of survival (Nexavar ). Pending release of more data, the choice of sorafenib vs sunitinib must be made based on the currently available data. The choice may also be influenced by toxicity and economic factors. References 1. Mancuso A, Sternberg CN. New treatments for metastatic kidney cancer. Canadian Journal of Urology. 2005; Suppl 1:66 70;discussion Pantuck AJ, Zisman A, Belldegrun AS. The changing natural history of renal cell carcinoma. Cancer. 2001;166(5): Table 8. Cost comparison of targeted agents Agent Manufacturer Cancer type Total cost (AWP) Erbitux Bristol Myers / Colon $20, Imclone Avastin Genentech Lung, breast, colon $48, Gleevec Novartis GIST $31, Tarveva Genentech, OSI Lung $4,854.00* Nexavar Bayer, Onyx Renal $32, Sutent Pfizer Renal $38, *Based on only 69 days of treatment compared with an average of months for the other targeted agents. (Data derived from reports researched and developed by SKP Analysis) 3. Storkel S, Eble JN, Adlakha K, et al. Classification of renal cell carcinoma: Workgroup No. 1. Union Internationale Contre le Cancer (UICC) and the American Joint Committee on Cancer (AJCC). 1997;80(5): American Cancer Society internet site: /CAFF2006PWSecured.pdf. 26 managedcareoncology Spring 2006

27 5. McLaughlin JK, Lipworth L. Epidemiologic aspects of renal cell cancer. Seminars in Oncology. 2000;27(2): immunotherapy. Critical Care Nursing Clinics of North America. 1989;1(4): Proceedings of the National Academy of Sciences of the United States of America. 1971;68(4): Surveillance Epidemiology and End Results (SEER) Cancer data Sourced from internet: 7. Cohen HT, McGovern FJ. Renal-cell carcinoma. New England Journal of Medicine. 2005;353(23): Kavolius JP, Mastorakos DP, Pavlovich C, et al. Resection of metastatic renal cell carcinoma Journal of Clinical Oncology. 1998;16(6): Flanigan RC. Role of surgery in patients with metastatic renal cell carcinoma. Seminars in Urologic Oncology. 1996;14(4): Flanigan RC, Campbell SC, Clark JI, et al. Metastatic renal cell carcinoma. Current Treatment Options in Oncology. 2003;4(5): Bleumer I, Oosterwijk E, De Mulder P, Mulders PF. Immunotherapy for renal cell carcinoma. European Urology. 2003;44(1) Gitlitz BJ, Belldegrun A, Figlin RA. Immunotherapy and gene therapy. Seminars in Urologic Oncology. 1996;14(4): Rosenberg SA, Yang JC, Topalian SL. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. The Journal of the American Medical Association (JAMA). 1994;271(12): Budd G, Osgood B, Barna B, et al. Phase I clinical trial of interleukin 2 and alpha-interferon: toxicity and immunologic effects. Cancer Research. 1989;49(22): Dutcher JP, Fisher RI, Weiss G, et al. Outpatient subcutaneous interleukin-2 and interferon-alpha for metastatic renal cell cancer: five-year follow-up of the Cytokine Working Group Study. The Cancer Journal from Scientific American. 1997;3(3): Patel PH, Chaganti RS, Motzer RJ. Targeted therapy for metastatic renal cell carcinoma. British Journal of Cancer. 2006;94(5): Stadler WM. Targeted agents for the treatment of advanced renal call carcinoma. Cancer. 2005;104(11): Yao M, Yoshida M, Kishida T, et al. VHL tumor suppressor gene alterations associated with good prognosis in sporadic clear-cell renal carcinoma. Journal of the National Cancer Institute. 2002;94(20): Knebelmann B, Ananth S, Cohen HT, et al. Transforming growth factor alpha is a target for the von Hippel-Lindau tumor suppressor. Cancer Research. 1998;58(2): Staehler M, Rohrmann K, Haseke N, et al. Targeted agents for the treatment of advanced renal cell carcinoma. Current Drug Targets. 2005;6(7): Leung SK, Ohh M. Playing tag with HIF: the VHL story. Journal of Biomedicine and Biotechnology. 2002;2(3): Nexavar Prescribing Information. FDA internet site. 5/021923lbl.pdf. 25. Escudier B, Szczylik C, Eisen T, et al. European Journal of Cancer (Supplement). 2005;3/2:226. Abstract Motzer R, Rini B, Michaelson M, et al. European Journal of Cancer (Supplement). 2005; 3/2:227. Abstract Sutent Prescribing Information. FDA Web site: 6/021968lbl.pdf. 28. Avastin Prescribing Information. FDA Web site: 4/125085lbl.pdf. 29. Sparano JA, Gray R, Giantonio B, et al. Evaluating antiangiogenesis agents in the clinic: the Eastern Cooperative Oncology Group Portfolio of Clinical Trials. Clin Cancer Research 2004;10(4): Innocenti F, Liu W, Chen P, et al. Haplotypes of variants in the UDPglucuronosyltransferase1A9 and 1A1 genes. Pharmacogenetics and Genomics. 2005;15(5): Byram DA. Future expectations for critical care nurses. Competence in 22. Knudson AG Jr. Mutation and cancer: statistical study of retinoblastoma. managedcareoncology.com 27

28 report pipeline by Howard A. Skip Burris III, MD, Director of Drug Development, The Sarah Cannon Research Institute The concept of inhibiting angiogenesis as a means of blocking tumor growth and development has been around for decades, and over the last several years drugs that can effectively utilize this target have been developed and approved. The vascular endothelial growth factor (VEGF) is thought to play a critical role in tumor growth and metastases. Several drugs designed to inhibit VEGF signaling pathways are currently in development. The small molecule tyrosine kinase inhibitors (TKIs) are one class of drugs designed to target the intracellular VEGF receptors known as VEGFR-1, VEGFR-2, and VEGFR-3. Specifically, the small molecule TKIs compete with ATP to inhibit intracellular kinase activity, affect multiple targets, and are still thought to be active for mutated receptors. These therapeutics are oral, in contrast to the monoclonal antibodies targeting this pathway which are delivered intravenously. Also different from the small molecule TKIs, monoclonal antibodies bind to the extracellular domain and focus on a single target, and questions surround their effect on mutated receptors. The lead monoclonal antibody is bevacizumab (Avastin, Genentech). Angiogenesis is a multifaceted process, and thus there are multiple opportunities for therapeutics to affect this pathway. In addition to inhibiting tumor growth and metastases by blocking angiogenesis, there is growing evidence that increased tumor permeability may lead to greater response rates. Bevacizumab was initially approved for the treatment of metastatic colon cancer based on improvements in tumor responses, time to progression, and overall survival when given in combination with irinotecan and 5-fluorouracil. These positive results with bevacizumab have been expanded into combinations for colon cancer utilizing oxaliplatin. At the recent American Society of Clinical Oncology (ASCO) meeting, the activity of bevacizumab in combination with chemotherapy was further established in both the treatment of advanced nonsmall cell lung cancer (NSCLC) as well as metastatic breast cancer. When added to paclitaxel and carboplatin in the treatment of NSCLC, tumor response rates improved from 13% to 30%, and a greater than 2-month improvement in both time to progression and survival were noted. Similarly, in the treatment of metastatic breast cancer, the addition of bevacizumab to a standard weekly paclitaxel regimen yielded an improvement in response rate from 16% to 34% and a greater 28 managedcareoncology Spring 2006

29 than 5-month improvement in time to progression. Both of these clinical trial results were highly statistically significant and showed great improvement over a multitude of trials using various chemotherapy combinations. Bevacizumab recently became compendia listed for the treatment of NSCLC. FDA applications for the use of bevacizumab in the treatment of patients with breast cancer or NSCLC will likely be submitted in the near future. Leading oral TKIs that affect angiogenesis include the recently approved agents sunitinib (Sutent, Pfizer) and sorafenib (Nexavar, Bayer). Sorafenib has been shown to inhibit several targets including Raf kinase as well as platelet derived growth factor receptor (PDGF-R) and the VEGF receptors. In an innovative trial utilizing a randomized discontinuation method, there was a 4-fold improvement in time to progression for sorafenib versus placebo in patients with advanced renal cell cancer. All patients initially received sorafenib, and those that had stable disease at 12 weeks were randomized to either continue sorafenib or receive a placebo. At the time of progression, the placebo patients were allowed to cross over and receive sorafenib. This unique trial design was able to establish that the presence of stable disease was not simply due to tumor characteristics, but in fact was a benefit of the study drug. Larger randomized phase 3 trials also showed significant progression-free survival benefits, with a doubling in this end point (2.8 to 5.5 months). Sorafenib has thus been approved by the FDA for treatment of advanced renal cell cancer, and is administered as an oral 400-mg dose, twice daily, continuously. Bevacizumab has also demonstrated positive clinical results in this disease setting. The introduction of anti- VEGF therapy into the clinic has resulted in a new spectrum of treatment-related toxicity based on these unique mechanisms of action. These toxicities include hypertension, thrombosis, bleeding, proteinuria, and a potential delay in wound healing. Shortly after the approval of sorafenib, the FDA approved sunitinib for renal cell cancer and refractory gastrointestinal stromal tumor (GIST) based on similar positive clinical trial results. Sunitinib also has multiple mechanisms of action, including the inhibition of VEGF-R, PDGF-R, and C-KIT, thus affecting tumor vasculature development and proliferation and endothelial cell proliferation. Clinical trial results to date with sunitinib have shown statistical superiority with regard to response rate, time to progression, and overall survival when compared with interferon. Early clinical trial results showed response rates as high as 40%, and median time to progression has averaged 8 months, with survival extending past 1 year for these advanced patients. In addition to the effects of sunitinib on gastrointestinal stromal tumors, early indications of activity have also been seen in the treatment of breast and colorectal cancer. The introduction of anti-vegf therapy into the clinic has resulted in a new spectrum of treatment-related toxicity based on these unique mechanisms of action. These toxicities include hypertension, thrombosis, bleeding, proteinuria, and a potential delay in wound healing. Healthcare professionals need to be aware of these toxicities so they can be recognized and managed early. Some of the small molecule TKIs currently in development are described in the accompanying table. The inhibition of angiogenesis and the positive effects of this inhibition in the treatment of cancer have now been established in clinical trials, and three new agents have been recently approved by the FDA: one monoclonal antibody, bevacizumab, and two oral agents, Continued on p. 44 managedcareoncology.com 29

30

31 SPRING 2006 issue number:one vol. number: fourteen

32

33 drug and administration compendia Compendia information developed and maintained by In each issue, Managed Care Oncology s Drug & Administration Compendia will highlight a single medication or a group of medications that may be utilized in the management of one of the featured oncology disease states. This section will address such topics as: suggested ICD-9-CM coding possible medication(s) used to treat the conditions, including ancillary medication(s) clinical information regarding the use of the medications listed reimbursement and coding information (how to bill for new medications) HCPCS or CPT coding information current AWP-based pricing the most recent ASP Plus 6% (medicare allowable) possible administration codes that can be utilized with each medication managedcareoncology.com 33

34 Medications currently available to treat renal cell carcinoma include: HCPCS Code Description Current Code Price - Effective Date Code Price (AWP) 1/1/06-3/31/06 ASP + 6% (Medicare Allowable) Administration Code(s) J0207 Amifostine, injection, 500 mg 10/03/05 $ $ , 90766, 90767, 90768, 90774, J1051 Medroxyprogesterone, injection, 50 mg 01/01/05 $6.32 $ J8530 Cyclophosphamide, oral, 25 mg 02/19/03 $2.26 $0.95 J9015 Aldesleukin, per single-use vial 06/03/05 $ $ , 96411, 96413, 96415, 96416, J9060 Cisplatin, powder or solution, per 10 mg 11/01/05 $6.25 $ , 96411, 96413, 96415, 96416, J9062 Cisplatin, 50 mg 11/01/05 $31.25 $ , 96411, 96413, 96415, 96416, J9070 Cyclophosphamide, 100 mg 09/01/01 $5.39 $ , 96411, 96413, 96415, 96416, J9080 Cyclophosphamide, 200 mg 09/01/01 $10.24 $ , 96411, 96413, 96415, 96416, J9090 Cyclophosphamide, 500 mg 09/27/04 $15.80 $ , 96411, 96413, 96415, 96416, J9091 Cyclophosphamide, 1.0 g 09/27/04 $28.45 $ , 96411, 96413, 96415, 96416, J9092 Cyclophosphamide, 2.0 g 09/27/04 $51.20 $ , 96411, 96413, 96415, 96416, J9093 J9094 J9095 J9096 J9097 Cyclophosphamide, lyophilized, 100 mg Cyclophosphamide, lyophilized, 200 mg Cyclophosphamide, lyophilized, 500 mg Cyclophosphamide, lyophilized, 1.0 g Cyclophosphamide, lyophilized, 2.0 g 12/01/01 $6.19 $ , 96411, 96413, 96415, 96416, /01/00 $11.76 $ , 96411, 96413, 96415, 96416, /01/00 $24.68 $ , 96411, 96413, 96415, 96416, /01/00 $49.37 $ , 96411, 96413, 96415, 96416, /27/04 $98.77 $ , 96411, 96413, 96415, 96416, J9190 Fluorouracil, 500 mg 01/19/05 $3.48 $ , 96411, 96413, 96415, 96416, J9200 Floxuridine, 500 mg 01/01/03 $ $60.81 J9213 J9214 Interferon, alfa-2a, recombinant, 3 million units Interferon, alfa-2b, recombinant, 1 million units 02/07/06 $46.34 $ , /06/04 $16.96 $ , J9360 Vinblastine, 1 mg 12/01/01 $3.31 $ , 96411, 96413, 96415, 96416, J9370 Vincristine, 1 mg 09/01/05 $10.00 $ , 96411, 96413, 96415, 96416, J9375 Vincristine, 2 mg 09/01/05 $20.00 $ , 96411, 96413, 96415, 96416, J9380 Vincristine, 5 mg 09/01/05 $50.00 $ , 96411, 96413, 96415, 96416, managedcareoncology Spring 2006

35 Two new oral agents have recently been approved to treat renal cell carcinoma. The two drugs, sorafenib (Nexavar, Bayer/Onyx) and sunitinib (Sutent, Pfizer), are both indicated for use in advanced renal cell carcinoma Sorafenib Indications Sorafenib is indicated for the treatment of patients with advanced renal cell carcinoma. Associated ICD-9-CM Codes 189 Malignant Neoplasm of kidney and other and unspecified urinary organs Kidney, except pelvis Billing Instructions For each drug, the following information must appear on the CMS 1500 claim form for reimbursement. Column 24D and Box 19 Column 24D: Indicate the appropriate "J-Code" for the medication administered. In this case utilize J8999 prescription drug, oral, chemotherapeutic, not otherwise specified Box 19: Indicate the full name of the medication administered including strength (if applicable), (e.g., Nexavar 200 mg) as well as the National Drug Code (NDC) on the package used. Column 24F and Column 24G Column 24F: Medication charge Column 24G: Quantity of medication used (number of units) Additional sorafenib Product Information Warnings Nexavar may cause birth defects or fetal loss. Women of child bearing potential should be advised to avoid becoming pregnant while on Nexavar and for at least 2 weeks after stopping treatment. Dosing Information The recommended daily dose of sorafenib is 400 mg (2 x 200-mg tablets) taken orally twice daily. Sorafenib should be taken without food (at least 1 hour before or 2 hours after eating). Treatment should continue until the patient is no longer clinically benefiting from therapy or until unacceptable toxicity occurs. Management of suspected adverse drug reactions may require temporary interruption and/or dose reduction of sorafenib therapy. When dose reduction is necessary, the sorafenib dose may be reduced to 400 mg once daily. If additional dose reduction is required, sorafenib may be reduced to a single 400-mg dose every other day (see PRECAUTIONS in package insert). Box 19 Column 24F NDC Strength Current Code Price (AWP) as of 12/20/ mg tablet $45.14/tablet managedcareoncology.com 35

36 Suggested Dose Modifications for Skin Toxicity Skin Toxicity Grade Occurrence Suggested Dose Modification Grade 1. Numbness, dysesthesia, paresthesia, tingling, painless swelling, erythema, or discomfort of the hands or feet which does not disrupt the patient s normal activities Grade 2. Painful erythema and swelling of the hands or feet and/or discomfort affecting the patient s normal activities Grade 2. Painful erythema and swelling of the hands or feet and/or discomfort affecting the patient s normal activities Any occurrence First occurrence No improvement within 7 days or second or third occurrence Continue treatment with sorafenib and consider topical therapy for symptomatic relief Continue treatment with sorafenib and consider topical therapy for symptomatic relief If no improvement within 7 days, see below Interrupt sorafenib treatment until toxicity resolves to Grade 0 1 If no improvement within 7 days, see below Grade 2. Painful erythema and swelling of the hands or feet and/or discomfort affecting the patient s normal activities Fourth occurrence Discontinue sorafenib treatment Grade 3. Moist desquamation, ulceration, blistering or severe pain of the hands or feet, or severe discomfort that causes the patient to be unable to work or perform activities of daily living Grade 3. Moist desquamation, ulceration, blistering, or severe pain of the hands or feet or severe discomfort that causes the patient to be unable to work or perform activities of daily living First or Second occurrence Third occurrence Interrupt sorafenib treatment until toxicity resolves to Grade 0 1 When resuming treatment, decrease sorafenib dose by one dose level (400 mg daily or 400 mg every other day) Discontinue sorafenib treatment Storage Store at 25 C (77 F). Excursions permitted to C (59 86 F) (see USP-controlled room temperature). Store in a dry place. Sorafenib is available through the REACH program and is not available through retail pharmacies. To receive Nexavar the patient must be enrolled in REACH. Physicians can obtain patient enrollment forms by calling or via the Nexavar website. Once enrolled the drug is shipped directly to the patient s home. Sunitinib Indications Sunitinib is indicated for the treatment of gastrointestinal stromal tumor after disease progression on or intolerance to imatinib mesylate (Gleevec, Novartis). Sunitinib is indicated for the treatment of advanced renal cell carcinoma. Approval for advanced renal cell carcinoma was based on partial response rates and duration of responses. There are no randomized trials of sunitinib demonstrating clinical benefit such as increased survival or improvement in disease related symptoms in renal cell carcinoma. Billing Instructions For each drug, the following information must appear on the CMS 1500 claim form for reimbursement. Column 24D and Box 19 Column 24D: Indicate the appropriate "J-Code" for the medication administered. In this case utilize J8999 NDC Box 19 Strength Prescription drug, oral, chemotherapeutic, NOS or C9399: Unclassified drugs or biologicals (hospital use). Box 19: Indicate the full name of the medication administered including strength (if applicable), (eg, Sutent 50 mg) as well as the NDC on the package used. Column 24F and Column 24G Column 24F: Medication charge Column 24G: Quantity of medication used (number of units) Column 24F Current Code Price (AWP) as of 1/27/ mg capsule $66.80/capsule mg capsule $133.59/capsule mg capsule $267.19/capsule 36 managedcareoncology Spring 2006

37 Additional Product Information Drug Interactions Co-administration of sunitinib with strong inhibitors of the CYP3A4 family may increase sunitinib concentrations. These inhibitors include: - ketoconazole (Nizoral, Janssen) - itraconazole (Sporanox, Janssen) - clarithromycin (Biaxin, Abbott) - atazanavir (Reyataz, Bristol- Myers Squibb) - indinavir (Crixivan, Merck) - nefazodone (Serzone, Bristol- Myers Squibb) - nelfinavir (Viracept, Pfizer) - ritonavir (Norvir, Abbott) - saquinavir (Fortovase / Invirase, Roche) - telithromycin (Ketek, Sanofi-Aventis) - voriconazole (Vfend, Pfizer) Grapefruit may also increase plasma concentrations of sunitinib (see CLINICAL PHARMACOLOGY in package insert). Co-administration of sunitinib with inducers of the CYP3A4 family may decrease sunitinib concentrations (see CLINICAL PHARMACOLOGY in package insert). These inducers include: - dexamethasone (Decadron, Merck) - phenytoin (Dilantin, Pfizer) - carbamazepine (Tegretol, Novartis) - rifampin (Rifadin, Sanofi-Aventis) - rifabutin (Mycobutin, Pfizer) - rifapentine (Priftin, Sanofi-Aventis) - phenobarbital - St. John s Wort St. John s Wort may decrease sunitinib plasma concentrations unpredictably. Patients receiving sunitinib should not take St. John s Wort concomitantly. Sutent dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers (see Dosage and Administration). Dosage and Administration The recommended dose of Sutent for gastrointestinal stromal tumor (GIST) and advanced renal cell carcinoma is one 50-mg oral dose taken once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off. Sutent may be taken with or without food. Dose Modification Dose increase or reduction in 12.5-mg increments is recommended based on individual safety and tolerability. Strong CYP3A4 inhibitors (see Drug Interactions above) may increase sunitinib plasma concentrations. Selection of an alternate concomitant medication with no or minimal enzyme inhibition potential is recommended. A dose reduction for sunitinib to a minimum of 37.5 mg daily should be considered if sunitinib must be co-administered with a strong CYP3A4 inhibitor (see CLINICAL PHARMACOLOGY and PRECAUTIONS, Drug Interactions, in package insert). managedcareoncology.com 37

38 CYP3A4 inducers (see Drug Interactions on previous page) may decrease sunitinib plasma concentrations. Selection of an alternate concomitant medication with no or minimal enzyme induction potential is recommended. A dose increase for sunitinib to a maximum of 87.5 mg daily should be considered if sunitinib must be co-administered with a CYP3A4 inducer. If the dose is increased, the patient should be monitored carefully for toxicity (see CLINICAL PHARMACOLOGY and PRECAUTIONS, Drug Interactions, in package insert). Storage Store at 25 C (77 F); excursions permitted to C (59 86 F) (see USP-controlled room temperature). Sunitinib is available through retail pharmacies. Pharmacies must call (800) once a prescription is received for sunitinib. Sunitinib will then be shipped directly to the pharmacy for dispensing to the patient. References HCPCS Level II Expert, 2004/5/6 Current Procedural Terminology (CPT) 2005/2006 ICD-9-CM for Physicians; Volumes 1 and 2 Drug Bulletin by the Association of Community Cancer Centers The NCCN Drugs and Biologicals Compendium by the National Comprehensive Cancer Network; Version , Kidney Cancer Nexavar and Sutent package inserts The Drug Reimbursement Coding and Pricing Guide by R J Health Systems International, LLC; Volume 3, Number 1; 1st Quarter The information presented in this compendia was supplied by R J Health Systems International, LLC, Wethersfield, CT. 38 managedcareoncology Spring 2006

39 Oncology Related J Codes For roughly a 1 million life healthcare plan, ICORE Healthcare found that claims for 96 HCPCs J codes summed to $65 million, the top 30 codes totaled $56 million (approximately 86% of the J code spend). ICORE Healthcare also found that of these top 30 codes, 23 of them were oncology related codes, which comprised $45 million. It is our belief that these codes should be tracked, so we have complied the following table for your reference: HCPS Code Description FDA-Approved Uses Compendia Approved Uses AWP ASP+6 Administration Code(s) J0881/ J0882 Darbepoetin Alfa Aranesp Anemia in Chronic Kidney Disease (285.21) Anemia in Neoplastic Disease (285.22) Anemia in chronic kidney disease (285.21) Anemia in neoplastic disease (285.22) Anemia, unspecified (285.9) $5.56 $ J0885/ J0886 Epoetin Alfa Procrit Epogen Anemia in Chronic Kidney Disease (285.21) Anemia in Neoplastic Disease (285.22) Neoplasm of uncertain behavior of other lymphatic and hematopoietic tissues (238.7) Anemia in chronic illness (285.2) Anemia, unspecified (285.9) $14.71 $ J2505 Pegfilgrastim Neulasta Diseases of White Blood Cells- Agranulocytosis (288.0) Diseases of white blood cellsagranulocytosis (288.0) $3, $2, J9310 Rifuximab Rituxan Lymphosarcoma and Reticulosarcoma (200._) Other Malignant Neoplasms of Lymphoid and Histocytic Tissue (202._) Rheumatoid Arthritis and other inflammatory Polyarthropathies (714._) Lymphoid leukemia chronic (chronic lymphocytic leukemia) (204.1_) Primary thrombocytopenia (immune or idiopathic throm-bocytopenic purpura) (287.3) Disorders of plasma protein metabolismmacroglobulinemia (waldenstrom macroglobulinemia) (273.3) $ $ C8954 J9263 Oxaliplatin Eloxatin Malignant Neoplasm of Colon (153._) Malignant Neoplasm of Rectum, Rectosigmoid junction, and Anus (154._) Malignant Neoplasm of ovary and other Uterine Adnexa (Advanced Ovarian cancer) (183._) Other Malignant Neoplasms of lymphoid and histocytic tissue (relapsing or refractory non-hodgkin s lymphoma) (202._) $10.65 $ C8954 C8955 J9170 Docetaxel Taxotere Breast cancer: for the treatment of patients with locally advanced or metastatic breast cancer after failure of prior chemotherapy. (174.,175. ) Non-small cell lung cancer: as a single agent for the treatment of patients with locally advanced or metastatic NSCLC after failure of prior platinum-based chemotherapy. Also in combination with cisplatin for the treatment of patients with unresectable locally advanced or metastatic Non-small Cell Lung Cancer who have not previously received chemotherapy for this condition. (162. ) Prostate cancer: in combination with prednisone for the treatment of patients with androgen independent (hormone refractory) metastatic prostate cancer. (185. ) Malignant Neoplasm of Lip (140. ) Malignant Neoplasm of Tongue (141. ) Malignant Neoplasm of major Salivary glands (142. ) Malignant Neoplasm of Gum (143. ) Malignant Neoplasm of floor of Mouth (144. ) Malignant Neoplasm of other and unspecified parts of mouth (145. ) Malignant Neoplasm of Oropharynx (146. ) Malignant Neoplasm of Nasopharynx (147. ) Malignant Neoplasm of Hypopharynx (148. ) Malignant Neoplasm of other and ill-defined sites within the Lip, Oral Cavity, and Pharynx (149. ) Malignant Neoplasm of Esophagus (150. ) Malignant Neoplasm of Stomach (151. ) Malignant Neoplasm of Nasal Cavities, Middle Ear, and Accessory Sinuses (160. ) Malignant Neoplasm of larynx (161. ) Malignant Neoplasm of ovary and other uterine adnexa (183. ) Malignant Neoplasm of bladder (188. ) Malignant Neoplasm of other and ill-defined sites (195. ) Malignant melanoma (172. ) $ $ C8954 managedcareoncology.com 39

40 HCPS Code Description FDA-Approved Uses Compendia Approved Uses AWP ASP+6 Administration Code(s) J9035 Bevacizumab Avastin Malignant Neoplasm of colon (153._) Malignant Neoplasm of rectum, rectosigmoid junction and anus (154._) Malignant Neoplasm of kidney and other and Unspecified Urinary Organs (metastatic renal cell carcinoma) (189._) Malignant Neoplasm of trachea, bronchus, and lung (small-cell, non-squamous lung cancer) (162._) $68.75 $ C8954 C8955 J9217 Leuprolide Acetate Lupron Eligard Advanced prostatic cancer (injection, implant, or depot 7.5, 22.5, and 30 Mg): palliative treatment of advanced prostatic cancer that offers an alternative when orchiectomy or estrogen administration are not indicated or are unacceptable to the patient. (185. ) Endometriosis (depot 3.75 and Mg): management of endometriosis, including pain relief and reduction of endometriotic lesions. Experience is limited to women > 18 years of age treated for <6 months. (617.9) Uterine leiomyomata (fibroids) (depot 3.75 and Mg): concomitantly with iron therapy for the preoperative hematologic improvement of patients with anemia caused by uterine leiomyomata. Experience with leuprolide depot in females has been limited to women > 18 years of age and treated for <6 months. (218.9) Central precocious puberty (CPP) (pediatric injection or depot-ped): treatment of children with CPP. (259.1) Malignant Neoplasm of female breast (174. ) Malignant Neoplasm of male breast (175. ) Malignant Neoplasm of body of uterus (182. ) Malignant Neoplasm of ovary and other uterine adnexa (183. ) $ $ J9355 Trastuzumab Herceptin Breast Cancer: for the treatment of metastatic breast cancer with tumors overexpressing the Human Epidermal Growth Factor Receptor 2 (HER2) protein: 1) as a single agent in patients who have received > 1 chemotherapy regimens; or 2) in combination with paclitaxel in patients who have not received chemotherapy for their metastatic disease. Use only in patients whose tumors have HER2 protein overexpression (174., 175. ) NA $67.90 $ C8954 C8955 J9201 Gemcitabine Hydrochloride Gemzar Breast cancer: gemcitabine in combination with paclitaxel is indicated for the firstline treatment of patients with metastatic breast cancer after failure of prior anthr cycline-containing adjuvant chemotherapy, unless anthracyclines were clinically contraindicated. (174.,175. ) Non-small Cell Lung Cancer: in combination with cisplatin for the first-line treatment of patients with inoperable, locally advanced (stage IIIa or IIIb) or metastatic (stage IV) non-small cell lung cancer. (162. ) Pancreatic cancer: first-line treatment for patients with locally advanced (nonresectable stage II or stage III) or metastatic (stage IV) adenocarcinoma of the pancreas. gemcitabine is indicated for patients previously treated with 5-fluorouracil (5-fu). (157. ) Malignant Neoplasm of gall bladder and extrapepatic bile ducts (156. ) Malignant Neoplasm of retroperitoneum and peritoneum (158. ) Malignant Neoplasm of thymus, heart, and mediastinum (164. ) Malignant Neoplasm of placenta (181. ) Malignant Neoplasm of ovary and other uterine adnexa (183. ) Malignant Neoplasm of testis (186. ) Malignant Neoplasm of other endocrine glands and related structures (194. ) Lymphosarcoma and reticulosarcoma (200. ) Hodgkin s disease (201. ) Other malignant Neoplasms of lymhoid and histiocytic tissue (202. ) Malignant Neoplasm of tongue (141. ) Malignant Neoplasm of major alivary gland (142. ) Malignant Neoplasm of gum (143. ) Malignant Neoplasm of floor of mouth (144. ) $ $ C managedcareoncology Spring 2006

41 HCPS Code Description FDA-Approved Uses Compendia Approved Uses AWP ASP+6 Administration Code(s) J9045 Carboplatin Paraplatin Advanced ovarian carcinoma: (183. ) Initial treatment: for the Initial treatment of advanced ovarian carcinoma in established combination with other approved chemotherapeutic agents. One established combination regimen consists of carboplatin and cyclophosphamide. Secondary treatment: for the palliative treatment of patients with ovarian carcinoma recurrent after prior chemotherapy, including patients who have been previously treated with cisplatin. Malignant Neoplasm of other and unspecified parts of Mouth (145. ) Malignant Neoplasm of oropharynx (146. ) Malignant Neoplasm of nasopharynx (147. ) Malignant Neoplasm of hypopharynx (148. ) Malignant Neoplasm of Neoplasm of other and ill-defined sites within the lip, oral cavity, and pharynx (149. ) Malignant Neoplasm of esophagus (150. ) Malignant Neoplasm of nasal cavities, middle ear, and accessory sinuses (160. ) Malignant Neoplasm of retroperitoneum and peritoneum (158. ) Malignant Neoplasm of larynx (162. ) Malignant Neoplasm of trachea, bronchus, and lung (162. ) Malignant melanoma of skin (172. ) Malignant Neoplasm of femal breast (174. ) Malignant Neoplasm of male breast (175. ) Malignant Neoplasm of cervix uteri (180. ) Malignant Neoplasm of body of uterus (182. ) Malignant Neoplasm of ovary and other uterine adnexa (183. ) Malignant Neoplasm of testis (186. ) Malignant Neoplasm of bladder (188. ) Malignant Neoplasm of brain (191. ) Malignant Neoplasm of other endocrine glands and related structures (194. ) Malignant Neoplasm of other and ill-defined sites (195. ) Secondary malignant Neoplasm of respiratory and digestive systems (197. ) Malignant Neoplasm without specification of site (199. ) Lymphosarcoma and reticulosarcoma (200. ) Hodgkin s disease (201. ) Other malignant Neoplasms of lymphoid and histiocytic tissue (202. ) Wilm s tumor (189.0) $85.10 $ C8954 J3487 Zoledronic Acid Zometa Hypercalcemia (275.42) Multiple myeloma (203.0) Bone and bone marrow (198.5) Bone and bone marrow (198.5) Multiple myeloma (203.0_) Hypercalcemia (275.42) Disorder of bone and cartilage, unspecified (733.90) $ $ C8954 J9265 Paclitaxel Onxol Taxol Onxol : Malignant Neoplasm of ovary and other uterine adnexa (183._) Malignant Neoplasm of female breast (174._) Malignant Neoplasm of male breast (175._) Taxol : Maligant Neoplasm of ovary and other uterine adnexa (183._) Malignant Neoplasm of female breast (174._) Malignant Neoplasm of male breast (175._) Malignant Neoplasm of trachea, bronchus, and lung (162._) Kaposi s sarcoma (176._) Malignant Neoplasm of trachea, bronchus, and lung (small cell lung cancer) (162._) Malignant Neoplasm of bladder (bladder cancer) (188._) Malignant Neoplasm of uterus (endometreal cancer) (182.0) Malignant Neoplasm of esophagus (esophageal cancer) (150._) Malignant Neoplasm of prostate (prostate cancer) (185._) Malignant Neoplasm of stomach (gastric cancer) (151._) Malignant Neoplasm of testis (testicular cancer) (186._) Malignant Neoplasm of lip (head and neck ) (140._) Malignant Neoplasm of tongue (head and neck) (141._) Malignant Neoplasm of major salvary glands (head and neck) (1421._) $ $ C8954 C8955 managedcareoncology.com 41

42 HCPS Code J9265 Cont. Description FDA-Approved Uses Compendia Approved Uses AWP ASP+6 Malignant Neoplasm of Gum (Head and Neck) (143._) Malignant Neoplasm of floor of Mouth (Head and Neck) (144._) Malignant Neoplasm of other and unspecified parts of Mouth (Head and Neck) (145._) Malignant Neoplasm of Oropharynx (Head and Neck) (146._) Malignant Neoplasm of Nasopharynx (Head and Neck) (147._) Malignant Neoplasm of Hypopharynx (Head and Neck) (148._) Malignant Neoplasm of other and illdefined sites within the Lip, Oral Cavity, and Pharynx (Head and Neck) (149._) Malignant Neoplasm of Nasal Cavities, Middle Ear, and accessory Sinuses (Head and Neck) (160._) Malignant Neoplasm of Larynx (Head and Neck) (161._) Malignant Neoplasm of other ill defined sites-head, Face and Neck (Head and Neck) (195.0) Malignant Neoplasm of Retroperitoneum and peritoneum-specific parts of Peritoneum (peritoneal) (158.8) Malignant Neoplasm of Retroperitoneum and Peritoneum-peritoneum, unspecified (Peritoneal) (158.9) Malignant Neoplasm of Ovary and other Uterine Adnexa Fallopian tube (Fallopian tube) (183.2) Malignant Neoplasm of Cervix Uteri (Cervix) (180._) Malignant Neoplasm without specification of site-disseminated (Cancer of Unknown Primary) (199.0) Malignant Neoplasm without specification of site-other (Cancer of Unknown Primary) (199.1) Administration Code(s) J2469 Palonosetron Hydrochloride Aloxi Symptoms involving digestive systemnausea with vomiting (787.01) Symptoms involving digestive systemnausea with vomiting (787.01) Symptoms involving digestive systemvomiting alone (787.03) Certain adverse effects not elsewhere classified-unspecified adverse effect of drug, medicinal and biological substance (995.2) $37.20 $ C8950 J9206 Irinotecan HCL Camptosar Metastatic Carcinoma of the Colon or Rectum: first-line therapy in combination with 5-fluorouracil (5-fu) and leucovorin for patients with metastatic colon or rectal carcinomas. It is also indicated for the treatment of metastatic carcinoma of the colon or rectum in patients whose disease has recurred or progressed following initial 5-fu-based therapy. (153.,154. ) Malignant Neoplasm of trachea, bronchus, and lung (162. ) Malignant Neoplasm of cervix uteri (180. ) Malignant Neoplasm of stomach (151. ) Malignant Neoplasm of brain (191. ) $ $ C8954 C8955 J9055 Cetuximab Erbitux Metastatic Colorectal Carcinoma: used in combination with irinotecan for the treatment of epidermal growth factor receptor (EGFR)-expression, metastatic colorectal carcinoma in patients who are refractory to irinotecan-based chemotherapy; as a single agent for the treatment of EGFR-expressing, metastatic colorectal carcinoma in patients who are intolerant to irinote can-based chemotherapy. (153.,154. ) NA $60.00 $ C8954 C managedcareoncology Spring 2006

43 FDA-Approved Uses Compendia Approved Uses AWP ASP+6 Administration Code(s) J0180 Agalsidase Beta Fabrazyme Lipidoses- Fabry s disease (272.7) NA $ $ C8950 C8951 J1950 (3.75mg) Leuprolide Acetate Lupron Leiomyoma of Uterus (218.9) Endometriosis, site unspecified (617.9) Malignant Neoplasm of Female Breast (174._) Malignant Neoplasm of Prostate (185) Endometriosis (617._) $ $ J9305 Pemetrexed Disodium Alimta Malignant Neoplasm of pleura (163._) Malignant Neoplasm of trachea, bronchus, and lung (162._) NA $51.22 $ C8954 J9041 Bortezomib Velcade Multiple myeloma and immunoproliferative Neoplasmsmultiple myeloma (203.0_) Malignant Neoplasms of Lymphoid and Histiocytic tissue (Mantle Cell Lymphoma) (202.8) $38.39 $ C8953 J9001 Doxorubicin Hydrocloride Liposome Doxil Malignant Neoplasm of ovary and other uterine adnexa (183._) Kaposi s sarcoma (176._) Malignant Neoplasm of Female Breast (Refractory breast cancer) (174._) Malignant Neoplasm of Male Breast (Refractory Breast Cancer) (175._) Multiple Myeloma and Immunoproliferative Neoplasms-Multiple Myeloma (Multiple Myeloma) (203.0) $ $ C8954 C8955 J1626 Granisetron Hydrochloride Kytril Symptoms involving digestive systemnausea with vomiting (787.01) Symptoms involving Digestive System- Nausea with vomiting (787.01) Symptoms involving Digestive Systemvomiting alone (787.03) Certain adverse effects not elsewhere classified-unspecified adverse effect of drug, medicinal and biological substance (995.2) $12.03 $ C8952 C8950 J1440 (300 mcg) J1441 (480 mcg) Filgrastim Neupogen Agranulocytosis (288.0) Other specified disease of white blood cells (288.8) Myeloid leukemia (205._) Monocytic leukemia (206._) Other specified leukemia (207._) Leukemia of unspecified cell typeacute-in remission (208.01) Other lymphatic and hematopoietic tissues (238.7) Agranulocytosis (288.0) $ (J1440) $ (J1441) $ (J1440) $ (J1441) C8950 C8952 managedcareoncology.com 43

44 Improving Value (continued from p.15) health plans healthcare affordability issues while maintaining a reasonable profitability level for the providers practices. A key component to the successful functioning of such a servicebased type of system would be an incentive where the solution is centered on the provider to produce the best outcomes at an efficient cost. The shift initiated by Medicare s ASP+6% is evidence that the industry is trending in the direction of a reimbursement strategy that is weighted toward providing more reimbursement for the service component as opposed to the drug component. This comes as no surprise since service-based reimbursement strategies are logical and used by managed care to reimburse providers outside of the oncology specialty. Service-based reimbursement is fair and reasonable; however, a wholesale change in reimbursement methodologies is required to ensure that the market is ready for this as the industry continues to focus on the healthcare affordability issues in the United States. Pipeline Report (continued from p.29) sorafenib and sunitinib. The early promise with these therapies seems to be a realization; however, many more clinical trials are needed to better understand how best to combine these agents with chemotherapeutics. Furthermore, it is likely that multiple tumor types will be sensitive to the utilization of angiogenesis inhibitors. Anti-VEGF TKI Pharmaceutical Company Howard A. Skip Burris III, MD, is currently serving as Director of Drug Development at The Sarah Cannon Research Institute in Nashville, TN, where he is also an Associate with Tennessee Oncology, PLLC. He currently serves on the ASCO Board of Directors and is a member of the ASCO Ethics committee. Target PTK-787 Novartis VEGFR-1-2, and PDGFR ZD6474 (Zactima) Astra Zeneca VEGFR-2, and EGFR AZD2171 Astra Zeneca VEGFR-1 and-2 AEE788 Novartis VEGFR-2, EGFR AMG706 Amgen VEGFR-1,-3 and PDGFR GW GlaxoSmithKline VEGFR-1,-2,-3, and PDGFR CP-547,632 OSI/Pfizer VEGFR-2 Mike Waterbury is Vice President for Healthcare Services at Oxford Health Plans, LLC, A United Healthcare Company. United Healthcare provides a full spectrum of consumer-oriented health benefit plans and services, and arranges access to quality, affordable care with more than 470,000 physicians and care professionals and 4,600 hospitals across America, including more than 55,000 physicians and 380 hospitals in New York, New Jersey, and Connecticut. Oxford Health Plans merged with United- Healthcare in July managedcareoncology Spring 2006

45

46 regulatory and reimbursement for Office-Based Drug Infusion Payment? by Roberta L. Buell, VP, Patient & Provider Services, P4 Healthcare, LLC. In 2003, Congress passed the Medicare Prescription Drug Improvement and Modernization Act, sometimes referred to as MMA. While most private payers know about MMA as it pertains to prescription drug coverage, there are many aspects of MMA that effect the way Medicare pays for officebased infusion services with which payers are unfamiliar. The questions that private payers may need to answer include the following: What is the history and background of the MMA payment change? How has this MMA payment change impacted office-based infusion services? How can private payors maximize the benefits of this payment change without changing the positives of the in-office delivery system? History and Background Medicare changed their physician payment system for all physicians in This payment system, called the Resourcebased Relative Value System (RBRVS), was also adopted by many other payers within a few years of the reform in Medicare fees. While the payment to medical oncologists for cognitive services was and is the same as for other physicians under the fee schedule, office-based infusion services differed in the following ways: Drug administration services were not paid in a manner consistent with the costs of doing business. An integral part of the RBRVS fee schedule is the relative values for practice expense. Practice expense includes the overhead, nursing time, and supplies of performing a specific procedure. All payment values in the fee schedule, including practice expense, are relative to a A 2003 practice expense of 0.69 is equal to the expense of providing an intermediate office visit (99213). The expense of providing that service, in terms of overhead, is fairly low. In 2003, the practice expense relative values for some infusion services were clearly not capturing expenses relative to a as the following table demonstrates: 46 managedcareoncology Spring 2006

47 Code Description 2003 Number PE RVUs Code RVUs Therapeutic infusion up to 1 hour Therapeutic infusion, next 1 8 hours Chemotherapeutic injection, SC or IM Chemotherapy, IV push Chemotherapy, up to 1 hour Chemotherapy, initiation of a prolonged infusion Many office services were bundled into payment, so there was no reimbursement for those services. There were other services that took a significant amount of office time, and these services could not be paid on the date of any other service by Medicare or not at all. This was a cost absorbed by the clinic. These services included: subcutaneous (SC) and intramuscular (IM) injections of therapeutic drugs; intravenous (IV) pushes of therapeutic drugs; and flushes of vascular access devices. Drug payment in was at 95% of average wholesale price (AWP) and had been maintained at that level to compensate for poor overhead payments. Drugs had become 70% 80% of practice revenues according to MedPac and our own practice surveys. Margins between provider cost and AWP had widened as generics came into the oncology marketplace. Medicare payments for chemotherapy increased 27%, and payments for red blood cell factors increased 51% in 2003 according to MedPac. 1 supported by better payment for practice expense of infusion service. To accomplish this, the Act mandated the following: A two-year transition period, which would give the American Medical Association time to build a new coding system for drug administration services. This transition meant that there would be a 32% increase and 3% increase in drug administration conversion factors in 2004 and 2005, respectively. New CPT codes would be developed and released in A one-year transition to a new drug pricing scheme based on average selling price (ASP). Medicare would pay cost plus 6% in a new surrogate allowable of ASP, plus 6%. The ASP is submitted by the manufacturer on a quarterly basis. If this cost seems too high to Medicare regulators, it is compared to widely available market price (WAMP) or average manufacturers price (AMP). In July 2006, Medicare will introduce a Competitive Acquisition Program (CAP) for practices that choose not to buy and bill for drugs. A minority of medical MMA changes and their impact on office-based infusion services The MMA mandated that office-based infusion reimbursement should shift from drug margins to a service model oncology practices (our last survey showed 7%) is seriously considering this option. Other specialty infusion clinics may also find this option more favorable. Has this payment system worked for Medicare now that the transition is over? From Medicare s vantage point, this new payment system probably has worked well. Drug costs grew at a much slower rate in 2004, according to MedPac; 1 chemotherapy increased only 4% with red blood cell factors increasing only 17%. Due to ASP implementation, the rate of drug cost growth in 2005 will probably be negative. The government may have gained control over its Part B drug costs just in time for implementation of the new prescription drug benefit. But, are office-based infusion services paid at a fairer rate and does this balance out the impact of the new drug pricing? The answers to this are sort of, kind of, maybe, and the jury is still out. Here are some reasons we do not believe that providers can support community-based infusion services: In 2005 and 2006, Medicare has provided medical oncologists with an additional payment ($130 and $23, respectively) for voluntary participation in a Demonstration Project. No other specialty is being paid for performance. These payments mask the actual financial impact of the changes in the payment system for drugs and services and the balance of the two. Fiscal year 2006 might tell the tale as the Demonstration Project payment has been reduced (an indeterminate aggregate amount for all practices) by $107 per episode. Certain definition changes in the drug administration coding have significantly lowered payments for some services and increased administrative costs for coding. Brace yourself, reader a lot of these coding rules are boring, but they should be understood for their managedcareoncology.com 47

48 negative provider impact. We call these rules more coding, less money. All allowables are average Medicare payments for In 2004, you could bill two full-price initial drug administration codes not now. For example, if you billed an hour of hydration before chemo and no supportive care drugs, you were paid a national average of $117; now you are paid about $20 on average AND that s if you hydrate for over 30 minutes. In 2004, an intravenous push was a push and an intravenous infusion was an infusion. The CPT coding rule now is that any INFUSION of 15 minutes or less is a PUSH. Therefore, if a pre-chemo supportive care infusion takes 10 minutes, you get paid about $26 for it, whereas you used to be paid $117 in Some things are just plain wrong. If you put two drugs in a bag and infuse them for 20 minutes, it is billed to and paid at (according to correspondence from the AMA) or $25, but if you infuse the same mix for 10 minutes, it is a push and is paid at about $27. You are supposed to be able to bill by the drug, not by the infusion time. This is untrue. If you bill three drugs in a bag of fluids for 2 hours, you get 1 hour of drug at a highly reduced rate (one = about $25). There are drugs that are currently underwater (paid less than practice cost) and, if 100% of the allowable is not paid by insurance, the patient goes to the hospital for IV therapy. The Office of Inspector General found that practices on average purchased 35 of 39 drugs 1 above Medicare reimbursement. Common drugs like paclitaxel, carboplatin, and pamidronate have experienced more than 80% reimbursement decreases from Medicare over the past year. What you can learn from Medicare drug administration payment Eighty percent of all cancer infusions take place in the community setting. Taking this into consideration, 2006 may be a watershed year for communitybased infusion clinics depending upon private payer adoption of MMA changes. Anecdotal evidence tells us that more Medicare patients are going from the community setting to the hospital for some infusion therapies. While the Medicare payment system is somewhat indifferent to this shift, private insurance companies may still pay hospitals a percentage of charges or AWPbased drug carve outs. What can you do to avoid the shifting of patients to the hospital? Pay for drugs at something above ASP +6%: The ASP system is flawed for a number of reasons (wholesaler discounts are included, large hospital purchasers are included, etc.) Moreover, drug price increases are not reflected for over 6 months. If you want your patients to stay out of the hospital setting, office-based cancer or infusion practices cannot be paid at less than cost. Pay infusion clinics an additional facility fee. The AMA has now excluded supply coding for drug administration to all payers. The RVUs in most drug administration codes do not pay for the facility costs of drug acquisition, mixing, supplies, and capital costs. If you want to preserve this setting for infusions, this payment is a good idea. If you use specialty pharmacy to deliver drugs to the office, pay a higher conversion factor for the administration of these drugs. You want your cancer patients to have access to care in their community setting. Again, drug administration payment is often not lucrative. As someone who has worked with community cancer practices for almost 15 years, I believe that officebased infusion clinics are an efficient, convenient delivery system. To preserve the positive aspects of this access to care, we must ensure that their payment is fair enough to keep access alive. Roberta L. Buell is Vice President, Patient & Provider Services, P4 Healthcare, LLC. and a recognized expert in oncology reimbursement. Reference 1. MedPac. Effects of Medicare changes on oncology services. January managedcareoncology Spring 2006

49 calendar events of The list of events that follows provides the dates and locations of upcoming meetings, workshops, and conferences of interest to managed care oncology professionals. June 02 ASCO Annual Meeting Atlanta, GA 04 National Medicaid Congress Washington, DC 07 Therapeutic Alliances-Oncology Atlanta, GA 07 PBMs & Generic Manufacturers Trends, Tools, and Alignment New York, NY 15 6th International Conference on The Adjuvant Therapy of Malignant Melanoma Stockholm, Sweden Billing and Reimbursement Conference Orlando, FL 28 The 8th World Congress on Gastrointestinal Cancer Barcelona, Spain July 13 Southern Association for Oncology 19th Annual Meeting Ponte Vedra, FL 27 3rd Interamerican Breast Cancer Conference Cancun, Mexico August 11 Cancer in Women Cruise Vancouver, British Columbia, Canada September 13 3rd Annual Meeting of the Society of Melanoma Research: Perspectives in Melanoma X Noordwijk, Netherlands 13 Health Management Congress Las Vegas, NV 28 Chicago Supportive Oncology Conference Chicago, IL 28 10th Annual Joint Cancer Conference of the Florida Universities Palm Beach, FL October 04 AMCP 2006 Educational Conference Chicago, IL 08 NCRI Cancer Conference Birmingham United, Kingdom 13 3rd Annual icore Oncology Summit Location TBD 19 Oncology Congress New York, NY Lymphoma & Myeloma New York, NY November 08 Chemotherapy Foundation Symposium New York, NY 09 SIO Third International Conference: Multi-disciplinary Advances in Integrative Oncology Boston, MA 15 11th Annual Meeting of the Society for Neuro-Oncology Orlando, FL December 03 Disease Management Leadership Forum Denver, CO 03 ASHP Midyear Clinical Meeting Anaheim, CA managedcareoncology.com 49

50 trial clinical update by John W. Mucenski, BS, PharmD, Director of Pharamacy Operations, UMPC Cancer Centers In order to provide the most up-to-date and efficacious care to their patients, oncologists must be aware of the emerging pharmacotherapeutic agents and therapies assessed in clinical trials. The trials reviewed here evaluated investigational agents and regimens for the treatment of ovarian, breast, lung, pancreatic, colorectal, and renal cancer. The purpose, methods, results, and conclusions of each study are reported, and managed care implications are presented. Title: Intraperitoneal cisplatin and paclitaxel in ovarian cancer Authors: Armstrong DK, Bundy B, Wenzel L, et al. Reference: N Engl J Med. 2006;354(1): Purpose: Gynecologic Oncology Group (GOG) phase 3 trial comparing intravenous (IV) paclitaxel plus cisplatin with intravenous paclitaxel plus intraperitoneal (IP) cisplatin and paclitaxel in patients with stage III ovarian cancer. Methods: Patients with no residual ovarian masses >1 cm following surgery were randomly assigned to receive 135 mg/m 2 of IV paclitaxel over 24 hours followed by either 75 mg/m 2 of IV cisplatin on day 2 (IV group) or 100 mg/m 2 of IP cisplatin on day 2 and 60 mg/m 2 of IP paclitaxel on day 8 (IP group). Treatment was given on an every 3 week basis for 6 cycles. Primary end points included progression-free survival (PFS) and overall survival (OS). Quality of life was also assessed. Results: A total of 210 eligible women were randomly assigned to receive the IV therapy and 205 were assigned to IP therapy. 174/210 (83%) of the patients in the IV group received all 6 cycles of the assigned therapy in comparison to 86/205 (42%) in the IP group. The median duration of follow-up was 48.2 months in the IV group and 52.6 months in the IP group. Median PFS was 18.3 months in the IV group and 23.8 months in the IP group (P=.05 by the logrank test). The median duration of overall survival was 49.7 months in the IV-treated group and 65.6 months in the IP-treated group (P=.03 by the log-rank test). Quality of life was significantly worse in the IP-treated group secondary to an increase in Grade 3 and 4 pain, fatigue and hematologic, gastrointestinal, metabolic and neurological toxic effects when compared to those patients treated with the IV therapy. Conclusions: The authors concluded that IV paclitaxel plus IP cisplatin and paclitaxel improves survival in patients with optimally debulked stage III ovarian cancer when compared to IV paclitaxel and cisplatin. Potential Next Step: A comparative trial of the IP regimen used in this trial versus the most effective IV therapy for women with this type of ovarian cancer carboplatin and paclitaxel. 50 managedcareoncology Spring 2006

51 Managed Care Implications: These results may cause a shift in practice patterns in regards to treating this disease. The toxicity of IP therapy may become a significant issue especially if hospitalization rates are increased. At 4 years, DFS was 85% for patients treated with H compared with 67% in those women treated with chemotherapy alone Title: Doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab as adjuvant therapy for patients with HER-2 positive operable breast cancer. Combined analysis of the NSABP B13/NCCTG N931. Authors: Romond E, Perez E, Bryant J, et al. Reference: Proceedings of the 41st Annual Meeting of the American Society of Clinical Oncology; 2005; Orlando, Fla. Purpose: The value of trastuzumab has been proven in women with HER-2 positive breast cancer in the metastatic setting. The utilization of this agent in the adjuvant setting had yet to be evaluated. Toxicity, particularly cardiac, would be closely evaluated. Methods: Two large phase 3 randomized clinical trials completed in the United States were analyzed together. Both evaluated trastuzumab in the adjuvant setting in over 3,000 women with HER-2 positive early breast cancer. The patients in these trials were node-positive or highrisk node-negative patients and had received no prior anthracycline or taxane therapy. Researchers compared the combination of doxorubicin and cyclophosphamide (AC) followed by paclitaxel (T) with or without trastuzumab (H). In both studies, AC was administered every 3 weeks for 4 cycles followed by T administered every 3 weeks for 4 cycles or weekly for 12 weeks with or without H. H was given weekly for 1 year. The primary end points of the studies were overall survival (OS) and disease-free survival (DFS). Results: At 4 years, DFS was 85% for patients treated with H compared with 67% in those women treated with chemotherapy alone. This result was highly statistically significant, equating to a 52% decrease in recurrence for the patients treated with H. Differences in congestive heart failure or cardiac deaths were <4% in the H arm versus the chemotherapy-only arm. Conclusion: One year of treatment with trastuzumab after adjuvant chemotherapy significantly improves disease-free survival among women with HER-2 positive breast cancer. The toxicity of the new regimen, namely cardiac, is acceptable. Managed Care Implications: This type of adjuvant therapy will likely become the cornerstone of treatment for this specific subset of breast cancer patients. Title: Vinorelbine plus cisplatin vs. observation in resected nonsmall cell lung cancer Authors: Winton T, Livingston R, Johnston D, et al. Reference: New Engl J Med. 2005;352(25): Purpose: Results from earlier studies regarding the benefit of adjuvant therapy in the treatment of non-small cell lung cancer (NSCLC) have been mixed, particularly when using older chemotherapeutic agents. Newer agents such as vinorelbine, gemcitabine, and taxanes, when coupled with a platinum derivative, have significantly increased response and overall survival rates as compared to previous regimens in advanced (metastatic) NSCLC. The purpose of this study was to determine whether adjuvant vinorelbine and cisplatin prolongs overall survival among patients with completely resected early-stage NSCLC. managedcareoncology.com 51

52 Methods: This randomized, phase 3 study assigned 240 patients to observation alone and 242 to chemotherapy. The groups were evenly matched with regards to pathologic stage of disease, performance status, age, sex and disease type. Within 6 weeks after surgery, eligible patients were randomized to one of the two treatment arms of the study. Those receiving chemotherapy were administered cisplatin 50 mg/m 2 on days 1 and 8 every 4 weeks for 4 cycles and 25 mg/m 2 of vinorelbine administered on a weekly basis for 16 weeks. The primary end point was overall survival (OS). Secondary end points included recurrence-free survival and the safety, toxicity, and quality of life associated with this particular chemotherapy regimen. Results: Overall survival was prolonged in the chemotherapy-treated group as compared to the observation group (94 months vs 73 months; P=.04) as well as relapse-free survival (not reached vs 46.7 months; P<0.001). Five-year survival also favored the administration of chemotherapy (69% vs 54%; P=.03). As expected, toxicity was higher in the chemotherapytreated group, with the most common effects being fatigue, nausea, anorexia, vomiting, and neuropathy. Conclusion: The authors concluded that adjuvant chemotherapy has acceptable toxicity and prolongs disease-free and overall survival in patients with completely resected early-stage NSCLC. Managed Care Implications: This may lead to a large new patient population now being treated with chemotherapy. Title: Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup 52 managedcareoncology Spring 2006

53 Trial C9741/Cancer and Leukemia Group B Trial 9741 Authors: Citron ML, Berry DA, Cirrincione C, et al. Reference: J Clin Oncol. 2003;21: Purpose: Human cancers usually grow by non-exponential kinetics. Regrowth of cancer cells between cycles of chemotherapy is more rapid in this model versus exponential models. It has been hypothesized that the more frequent administration of chemotherapy would be a more effective means of minimizing residual tumor burden. This objective could be accomplished by utilizing a dose-dense treatment schedule. Methods: A total of 2005 women were randomly assigned to receive one of four chemotherapy regimens. All patients were treated with 4 cycles of chemotherapy consisting of doxorubicin (A) 60 mg/m 2, cyclophosphamide (C) 600 mg/m 2, and paclitaxel (T) 175 mg/m2. The treatment regimens were: I. Sequential A x 4 followed by T x 4 followed by C x 4 given every 3 weeks (therapy over 33 weeks) II. Seqential A x 4 followed by T x 4 followed by C x 4 given every 2 weeks with filgrastim (therapy over 22 weeks) III. Concurrent AC x 4 followed by T x 4 given every 3 weeks (therapy over 21 weeks) IV. Concurrent AC x 4 followed by T x 4 given every 2 weeks with filgrastim (therapy over 14 weeks) Outcomes included disease-free survival (DFS), overall survival (OS), and the toxicity of the four regimens. Results: Dose-dense treatment improved the primary end point, DFS (RR=0.74; P=.010) and OS (RR=0.69; P=.013). Four-year DFS was 82% in the dose-dense regimen and 75% for the other regimens. Toxicity was reduced in the dosedense group treated with filgrastim. Conclusion: Dose density improves the clinical outcome significantly. Managed Care Implications: Further evaluation over time will determine the place of dose-dense therapy for the treatment of adjuvant breast cancer. Many physicians continue to treat with standard sequential therapy, which may be less costly if the routine use of white cell growth factors may be avoided. Title: Erlotinib plus gemcitabine compared to gemcitabine alone in patients with advanced pancreatic cancer. A phase III trial of the National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG). Authors: Moore MJ, Goldstein D, Hamm J, et al. Reference: Proceedings of the 41st Annual Meeting of the American Society of Clinical Oncology; 2005; Orlando, Fla. Purpose: Gemcitabine has been the standard treatment option for patients with advanced pancreatic cancer since Survival rates in this patient population remain extremely poor. Erlotinib is a new drug that acts in part by inhibiting tyrosine kinase, an enzyme associated with the epidermal growth factor receptor (EGFR), which stimulates cell division. Patients with pancreatic cancer frequently have elevated levels of EGFR. This combination therapy may lead to improved survival in patients with advanced pancreatic cancer. Methods: Patients with advanced pancreatic cancer who had not yet received systemic chemotherapy other than that given with radiation therapy were eligible. EGFR status was not required for entry in the study. Patients were randomized to receive gemcitabine 1000 mg/m 2 IV, initially weekly, for 7 of 8 weeks followed by weekly therapy every 3 of 4 weeks with either erlotinib 100 mg or 150 mg orally per day or placebo. Patients had imaging studies performed every 8 weeks to assess response to the therapy. The primary end points were overall survival (OS) and progression-free survival (PFS). Results: A total of 569 patients (285 gemcitabine/erlotinib and 284 gemcitabine/placebo) were entered onto the study. A response rate (complete response, partial response, or stable disease) was achieved in 57% of those patients treated with the combination in comparison to 49% of those treated with the single agent gemcitabine. Median survival (6.37 months vs 5.91 months) and 1-year survival (24% vs 17%) also favored the erlotinib-treated group. Progressionfree survival was also improved in the erlotinib group (HR=0.76, P=.003). An increase in grades 1 and 2 rash and diarrhea was noted in those patients treated with erlotinib. No difference in quality of life score was noted between the two groups. Conclusion: The addition of erlotinib to gemcitabine significantly improves overall survival and progression-free survival in patients with advanced pancreatic cancer. Managed Care Implications: These results may cause a shift in practice from IV therapy alone to IV and oral therapy. Patients solely responsible for the procurement of any oral therapy may be unable to be treated in this manner. managedcareoncology.com 53

54 Title: OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-go fashion in advanced colorectal cancer a GERCOR study Authors: Tournigand C, Cervantes A, Figer A, et al. Reference: J Clin Oncol. 2006; 24: Purpose: The combination of leucovorin (LV), fluroruacil (FU), and oxaliplatin (OX) is a standard first-line therapy in patients with advanced colorectal cancer. Cumulative neurotoxicity secondary to oxaliplatin often necessitates therapy to be stopped even in patients who are responding. This study evaluated the effectiveness of intermittent oxaliplatin therapy versus standard continuous therapy. Methods: Patients previously untreated in the metastatic setting were randomized to receive one of two treatment regimens: Arm A, FOLFOX4; or Arm B, FOLFOX7. FOLFOX4 consisted of a 2-hour infusion of LV (200 mg/m 2 ) followed by bolus FU (400 mg/m 2 ) and a 22-hour FU infusion (600 mg/m 2 ) for 2 consecutive days every 2 weeks with OX (85 mg/m 2 ) as a 2-hour infusion on day 1. Treatment was continued until disease progression or drug toxicity. The OPTIMOX1 arm (Arm B) consisted of 6 cycles of FOLFOX7. A 2-hour LV infusion a majority of patients received second-line chemotherapy upon progression of disease and fewer received third-and fourth-line therapy. (200 mg/m 2 ) was followed by a 46-hour FU infusion (2400 mg/m 2 ) every 2 weeks with OX (130 mg/m 2 ) as a 2-hour infusion on day 1. This was followed by 12 weeks of maintenance therapy consisting of LV (400 mg/m 2 ) over 2 hours followed by a 400 mg/m 2 bolus of FU and a 46-hour infusion of 3000 mg/m 2 of FU. FOLFOX7 was then resumed for an additional 6 cycles. The primary end point of the study was duration of disease control (DDC). It is important to note that a majority of patients received second-line chemotherapy upon progression of disease and fewer received third-and fourthline therapy. Results: A total of 620 patients (Arm A, 311; Arm B, 309) were eligible for evaluation. Response rates were 58.5% in Arm A and 59.2% in Arm B. The median DDC was comparable in both arms (9.0 months in Arm A vs 10.6 months in Arm B; P=.89). Median progression free survival was 9.0 months in Arm A versus 8.7 months in Arm B (P=.47), and median survival was 19.3 months in the FOLFOX4-treated patients versus 21.2 months in the FOLFOX7- patients (P=.49). Toxicity was similar during the oxaliplatin portion of therapy but decreased in the patients receiving maintenance LV/FU when compared to those who continued to receive oxaliplatin. Only 40.1% of patients in Arm B received FOLFOX7 reinduction. The major reasons for not receiving this therapy were death, early disease progression, or chemotherapy-related toxicity. Conclusion: Oxaliplatin can be safely stopped after 6 cycles in a FOLFOX regimen. Further study is needed to evaluate the role of oxaliplatin reinduction. Managed Care Implications: Fewer cycles of oxaliplatin therapy may be needed when treating patients with first-line therapy for advanced colorectal cancer leading to a decrease in drug-induced toxicity. Title: Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor (VEGF) receptor and platelet-derived growth factor (PDGF) receptor, in patients with metastatic renal cell carcinoma Authors: Motzer RJ, Michaelson MD, Redman BG, et al. Reference: J Clin Oncol. 2006;24: managedcareoncology Spring 2006

55 Purpose: Renal cell carcinoma (RCC) is characterized by a loss of tumor suppressor gene activity resulting in the over-expression of pro-angiogenic growth factors such as VEGF and PDGF. SU11248, or sunitinib, is an oral small molecule inhibitor with high binding affinity to both VEGF and PDGF receptors. This study was designed to assess the clinical efficacy and safety of this compound in patients with cytokine-refractory (interferon, interleukin 2) RCC. Methods: Patients with metastatic RCC who had progressed on firstline cytokine therapy were enrolled in this multicenter phase 2 study. Sunitinib was administered at a dose of 50 mg orally once a day for 4 weeks, followed by 2 weeks off. Cycles were repeated every 6 weeks. The primary end point of the study was overall response rate (ORR) via the RECIST criteria with time to progression (TTP) and drug safety as secondary end points. Results: Sixty three (63) patients were enrolled in the study. A partial response was achieved in 25 (40%) of the patients treated, with stable disease (no progression for 3 months) noted in another 17 patients (27%). Median time to progression for the 63 patients was 8.7 months with a median survival of 16.4 months. Of the 25 patients who achieved a A response rate was achieved in 57% of those patients treated with the combination in comparison to 49% of those treated with the single agent gemcitabine. partial response, 8 remain on therapy and are progression-free at 21+ to 24+ months from the start of therapy. The median duration of treatment was 9 months. The most common adverse reaction was fatigue, which was graded at a level 3 in 11% of the patients. Grade 3 to 4 laboratory abnormalities included lymphopenia without infection and elevated serum lipase without clinical signs and symptoms of pancreatitis. Conclusion: Sunitinib, an oral multitargeted receptor tyrosine kinase inhibitor, demonstrates anti-tumor activity in metastatic RCC as secondline therapy. This is a setting where no effective systemic therapy is currently available. The toxicity profile is acceptable. Managed Care Implications: Sunitinib was recently FDA approved for the treatment of advanced RCC in patients based on this study. No phase 3 data are currently available. Sorafenib, an oral multikinase inhibitor, has also been approved by the FDA for treatment of advanced RCC based on improved progressionfree survival versus placebo in phase 3 clinical trials. John W. Mucenski, BS, PharmD, is the Director of Pharmacy Operations for the UMPC Cancer Centers in southwestern Pennsylvania. He oversees the operation of over 25 private practice offices and four cancer centers. managedcareoncology.com 55

56 references resources & The resource guide that follows features oncology-related links and Web sites that may be of use to the reader in daily practice.* American Cancer Society. American Society of Clinical Oncology (ASCO). A nonprofit organization, ASCO supports cancer research, especially patient-oriented clinical research ASP Drug Pricing Files. Provided by the Centers for Medicare and Medicaid Services, this site features average sales price (ASP) drug pricing files as well as National Drug Code-Healthcare Common Procedure Coding System (NDC-HCPCS) crosswalk files. McrPartBDrug AvgSalesPrice/ 02_aspfiles.asp List of FDA Approved Oncology Drugs with Approved Indications. druglistframe.htm MEDLINE. Authoritative information from the National Library of Medicine (NLM), the National Institutes of Health (NIH), and other organizations. MEDLINE has more than 10 million journal article references and abstracts dating back to the early 1960s. query.fcgi National Cancer Institute (NCI). NCI conducts and supports research, training, health information dissemination, and other programs with respect to the cause, diagnosis, prevention, and treatment of cancer, rehabilitation from cancer, and the continuing care of cancer patients and the families of cancer patients. OncoLink. From the University of Pennsylvania, OncoLink provides information on different types of cancer, treatment options, coping resources, clinical trials, and more. Oncology Online. A site dedicated to improving cancer diagnosis and treatment by providing clinicians fast and free access to authoritative medical databases, news, expert Q&As, and more. ClinicalTrials.gov. This Web site was developed by the National Library of Medicine (NLM) and is presented as a service of the U.S. National Institutes of Health (NIH). Oncology-related clinical trial information can be found here. Reimbursement Coding and Pricing. This site provides comprehensive Healthcare Common Procedure Coding System/Current Procedural Terminology (HCPCS/CPT) reimbursement coding and pricing information. National Comprehensive Cancer Network (NCCN). World Oncology Network (WON). The WON Web site is a resource for practicing oncologists and hematologists throughout the world. As an ongoing service to our readership, OnCore will accept questions and print selected responses in future issues. Please submit questions or requested future topics at: /questions *Note: OnCore Healthcare, LLC does not endorse or verify the information presented. 56 managedcareoncology Spring 2006

57

58 thank you Advertising Index IFC Roche Pharmaceuticals Page MGI Pharma, Inc. Page Watson Pharmaceuticals, Inc. Page Abraxis Oncology Pages 9,45, ICORE Healthcare, LLC IBC Watson Pharmaceuticals, Inc. BC Amgen 58 managedcareoncology Spring 2006

59

60 Recombinant DNA Technology The injection of recombinant DNA into a single cell allows the cell to add new DNA to its own genetic information. This basic technique for transferring genetic material is used in many areas of pioneering research to evaluate the function of potential therapeutic products. customer-oriented patient-focused science-driven Over the past two decades, Amgen has built a reputation as a science-driven company dedicated to improving people s lives. In order to succeed, we rely heavily on our valued customers. It s through our customers that we re able to deliver the benefits of our science to patients. Amgen. Committed to our customers. Committed to our science. Committed to dramatically improving people s lives Amgen. All rights reserved. MC Amgen One Amgen Center Drive Thousand Oaks, CA