Clinical Oncology News - September/October 2009 - Digital Edition

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Indications and Important Safety Information for ALIMTA Indications ALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer.

ALIMTA is indicated for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based ďŹ rst-line chemotherapy.

ALIMTA is indicated as a single agent for the treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer after prior chemotherapy.

Limitations of Use: ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer.

Important Safety Information Myelosuppression is usually the dose-limiting toxicity with ALIMTA therapy.

Contraindication: ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed or to any other ingredient used in the formulation.

Warnings and Precautions: Patients must be instructed to take folic acid and vitamin B12 with ALIMTA as a prophylaxis to reduce treatment-related hematologic and GI toxicities.

Pretreatment with dexamethasone or its equivalent has been reported to reduce the incidence and severity of skin rash.

ALIMTA can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia). Reduce doses for subsequent cycles based on hematologic and nonhematologic toxicities.

ALIMTAÂŽ is a registered trademark of Eli Lilly and Company.

PM58001 0709 PRINTED IN USA Š 2009, Lilly USA, LLC. ALL RIGHTS RESERVED.

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ALIMTA should not be administered to patients with a creatinine clearance <45 mL/min. One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drugrelated toxicity following administration of ALIMTA alone.

Caution should be used when administering ibuprofen concurrently with ALIMTA to patients with mild to moderate renal insufďŹ ciency (creatinine clearance from 45 to 79 mL/min). Patients with mild to moderate renal insufďŹ ciency should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives, all patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration. If concomitant administration of an NSAID is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicities.

Patients should not begin a new cycle of treatment unless the ANC is â&#x2030;Ľ1500 cells/mm3, the platelet count is â&#x2030;Ľ100,000 cells/mm3, and creatinine clearance is â&#x2030;Ľ45 mL/min.

Pregnancy Category Dâ&#x20AC;&#x201D;ALIMTA may cause fetal harm when administered to a pregnant woman. Women should be apprised of the potential hazard to the fetus and should be advised to use effective contraceptive measures to prevent pregnancy during treatment with ALIMTA. The effect of third space ďŹ&#x201A;uid, such as pleural effusion and ascites, on ALIMTA is unknown. In patients with clinically signiďŹ cant third space ďŹ&#x201A;uid, consideration should be given to draining the effusion prior to ALIMTA administration.

Drug Interactions: Concomitant administration of nephrotoxic drugs or substances that are tubularly secreted could result in delayed clearance of ALIMTA. See Warnings and Precautions for speciďŹ c information regarding ibuprofen administration.

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Histology Matters with ALIMTA because

EXTENDED SURVIVAL MATTERS. Approved for the 1st-line treatment of advanced nonsquamous NSCLC and now approved for the maintenance treatment of advanced nonsquamous NSCLC. ALIMTA is not indicated for the treatment of patients with squamous cell NSCLC. Myelosuppression is usually the dose-limiting toxicity with ALIMTA therapy.

Within the ALIMTA maintenance trial design, ALIMTA/cisplatin was not included as an induction therapy.

For more information, visit www.ALIMTA.com Use in SpeciďŹ c Patient Populations: It is recommended that nursing be discontinued if the mother is being treated with ALIMTA or discontinue the drug, taking into account the importance of the drug for the mother.

The safety and effectiveness of ALIMTA in pediatric patients have not been established.

Dose adjustments may be necessary in patients with hepatic insufďŹ ciency.

Dosage and Administration Guidelines: Complete blood cell counts, including platelet counts and periodic chemistry tests, should be performed on all patients receiving ALIMTA. Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Modify or suspend therapy according to the Dosage Reduction Guidelines in the full Prescribing Information.

Abbreviated Adverse Reactions (% incidence) for NSCLC 1st-line: The most severe adverse reactions (Grades 3/4) with ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin, respectively, for the 1st-line treatment of patients with advanced non-small cell lung cancer (NSCLC) were neutropenia (15 vs 27); leukopenia (5 vs 8); thrombocytopenia (4 vs 13); anemia (6 vs 10); fatigue (7 vs 5); nausea (7 vs 4); vomiting (6 vs 6); anorexia (2 vs 1); and creatinine elevation (1 vs 1).

Common adverse reactions (all Grades) with ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin, respectively, were nausea (56 vs 53); fatigue (43 vs 45); vomiting (40 vs 36); anemia (33 vs 46); neutropenia (29 vs 38); anorexia (27 vs 24); constipation (21 vs 20); leukopenia (18 vs 21); stomatitis/pharyngitis (14 vs 12); alopecia (12 vs 21); diarrhea (12 vs 13); thrombocytopenia (10 vs 27); neuropathy/sensory (9 vs 12); taste disturbance (8 vs 9); rash/desquamation (7 vs 8); and dyspepsia/heartburn (5 vs 6).

Abbreviated Adverse Reactions (% incidence) for NSCLC Maintenance: The most severe adverse reactions (Grades 3/4) with ALIMTA as a single agent versus placebo, respectively, for the maintenance treatment of patients with locally advanced nonsquamous non-small cell lung cancer (NSCLC) were anemia (3 vs 1); neutropenia (3 vs 0); leukopenia (2 vs 1); fatigue (5 vs 1); nausea (1 vs 1); anorexia (2 vs 0); mucositis/ stomatitis (1 vs 0); diarrhea (1 vs 0); infection (2 vs 0); neuropathy-sensory (1 vs 0). Common adverse reactions (all Grades) with ALIMTA as a single agent versus placebo, respectively, were anemia (15 vs 6); neutropenia (6 vs 0); leukopenia (6 vs 1); increased ALT (10 vs 4); increased AST (8 vs 4); fatigue (25 vs 11); nausea (19 vs 6); anorexia (19 vs 5); vomiting (9 vs 1); mucositis/stomatitis (7 vs 2); diarrhea (5 vs 3); infection (5 vs 2); neuropathy-sensory (9 vs 4); and rash/desquamation (10 vs 3).

Abbreviated Adverse Reactions (% incidence) for NSCLC 2nd-line: The most severe adverse reactions (Grades 3/4) with ALIMTA as a single agent versus docetaxel, respectively, for the 2nd-line treatment of patients with advanced non-small cell lung cancer (NSCLC) were neutropenia (5 vs 40); leukopenia (4 vs 27); thrombocytopenia (2 vs 0); anemia (4 vs 4); fatigue (5 vs 5); nausea (3 vs 2); anorexia (2 vs 3); vomiting (2 vs 1); increased ALT (2 vs 0); increased AST (1 vs 0); and stomatitis/pharyngitis (1 vs 1). Common adverse reactions (all Grades) with ALIMTA as a single agent versus docetaxel, respectively, were fatigue (34 vs 36); nausea (31 vs 17); anorexia (22 vs 24); anemia (19 vs 22); vomiting (16 vs 12); stomatitis/pharyngitis (15 vs 17); rash (14 vs 6); diarrhea (13 vs 24); leukopenia (12 vs 34); and neutropenia (11 vs 45).

For additional safety and dosing guidelines, please see brief summary of Prescribing Information on adjacent page.

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5 5.1

CONTRAINDICATIONS ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed or to any other ingredient used in the formulation.

WARNINGS AND PRECAUTIONS Premedication Regimen Need for Folate and Vitamin B12 Supplementation Patients treated with ALIMTA must be instructed to take folic acid and vitamin B12 as a prophylactic measure to reduce treatment-related hematologic and GI toxicity [see Dosage and Administration (2.3)]. In clinical studies, less overall toxicity and reductions in Grade 3/4 hematologic and nonhematologic toxicities such as neutropenia, febrile neutropenia, and infection with Grade 3/4 neutropenia were reported when pretreatment with folic acid and vitamin B12 was administered.

Corticosteroid Supplementation Skin rash has been reported more frequently in patients not pretreated with a corticosteroid in clinical trials. Pretreatment with dexamethasone (or equivalent) reduces the incidence and severity of cutaneous reaction [see Dosage and Administration (2.3)].

5.2 Bone Marrow Suppression ALIMTA can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia) [see Adverse Reactions (6.1)]; myelosuppression is usually the dose-limiting toxicity. Dose reductions for subsequent cycles are based on nadir ANC, platelet count, and maximum nonhematologic toxicity seen in the previous cycle [see Dosage and Administration (2.4)].

5.3 Decreased Renal Function ALIMTA is primarily eliminated unchanged by renal excretion. No dosage adjustment is needed in patients with creatinine clearance â&#x2030;Ľ45 mL/min. Insufficient numbers of patients have been studied with creatinine clearance <45 mL/min to give a dose recommendation. Therefore, ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min [see Dosage and Administration (2.4)].

One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of ALIMTA alone.

5.4 Use with Non-Steroidal Anti-Inflammatory Drugs with Mild to Moderate Renal Insufficiency Caution should be used when administering ibuprofen concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). Other NSAIDs should also be used with caution [see Drug Interactions (7.1)].

5.5 Required Laboratory Monitoring Patients should not begin a new cycle of treatment unless the ANC is â&#x2030;Ľ1500 cells/mm3, the platelet count is â&#x2030;Ľ100,000 cells/mm3, and creatinine clearance is â&#x2030;Ľ45 mL/min [see Dosage and Administration (2.4)].

5.6 Pregnancy Category D Based on its mechanism of action, ALIMTA can cause fetal harm when administered to a pregnant woman. Pemetrexed administered intraperitoneally to mice during organogenesis was embryotoxic, fetotoxic and teratogenic in mice at greater than 1/833rd the recommended human dose. If ALIMTA is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant. Women should be advised to use effective contraceptive measures to prevent pregnancy during treatment with ALIMTA. [see Use in Specific Populations (8.1)] 5.7 Third Space Fluid The effect of third space fluid, such as pleural effusion and ascites, on ALIMTA is unknown. In patients with clinically significant third space fluid, consideration should be given to draining the effusion prior to ALIMTA administration.

6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reactions rates cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice.

In clinical trials, the most common adverse reactions (incidence â&#x2030;Ľ20%) during therapy with ALIMTA as a single-agent were fatigue, nausea, and anorexia. Additional common adverse reactions (incidence â&#x2030;Ľ20%) during therapy with ALIMTA when used in combination with cisplatin included vomiting, neutropenia, leukopenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation.

Non-Small Cell Lung Cancer (NSCLC)â&#x20AC;&#x201D;Combination with Cisplatin Table 4 provides the frequency and severity of adverse reactions that have been reported in >5% of 839 patients with NSCLC who were randomized to study and received ALIMTA plus cisplatin and 830 patients with NSCLC who were randomized to study and received gemcitabine plus cisplatin. All patients received study therapy as initial treatment for locally advanced or metastatic NSCLC and patients in both treatment groups were fully supplemented with folic acid and vitamin B12.

Table 4: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA plus Cisplatin in NSCLCa ALIMTA/cisplatin Gemcitabine/cisplatin Reaction b (N=839) (N=830) All Grades Grade 3-4 All Grades Grade 3-4 Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) All Adverse Reactions 90 37 91 53 Laboratory Hematologic Anemia 33 6 46 10 Neutropenia 29 15 38 27 Leukopenia 18 5 21 8 Thrombocytopenia 10 4 27 13 Renal Creatinine elevation 10 1 7 1 Clinical Constitutional Symptoms Fatigue 43 7 45 5 Gastrointestinal Nausea 56 7 53 4 Vomiting 40 6 36 6 Anorexia 27 2 24 1 Constipation 21 1 20 0 Stomatitis/Pharyngitis 14 1 12 0 Diarrhea 12 1 13 2 Dyspepsia/Heartburn 5 0 6 0 Neurology Neuropathy-sensory 9 0 12 1 Taste disturbance 8 0c 9 0c Dermatology/Skin Alopecia 12 0c 21 1c Rash/Desquamation 7 0 8 1 a For the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible relationship to ALIMTA. b Refer to NCI CTC Criteria version 2.0 for each Grade of toxicity. c According to NCI CTC Criteria version 2.0, this adverse event term should only be reported as Grade 1 or 2.

No clinically relevant differences in adverse reactions were seen in patients based on histology.

In addition to the lower incidence of hematologic toxicity on the ALIMTA and cisplatin arm, use of transfusions (RBC and platelet) and hematopoietic growth factors was lower in the ALIMTA and cisplatin arm compared to the gemcitabine and cisplatin arm.

The following additional adverse reactions were observed in patients with non-small cell lung cancer randomly assigned to receive ALIMTA plus cisplatin.

Incidence 1% to 5% Body as a Wholeâ&#x20AC;&#x201D;febrile neutropenia, infection, pyrexia General Disordersâ&#x20AC;&#x201D;dehydration Metabolism and Nutritionâ&#x20AC;&#x201D;increased AST, increased ALT Renalâ&#x20AC;&#x201D;creatinine clearance decrease, renal failure Special Sensesâ&#x20AC;&#x201D;conjunctivitis

ALIMTAĺ§&#x17E; (pemetrexed for injection)

ALIMTAĺ§&#x17E; (pemetrexed for injection)

ALIMTAĺ§&#x17E; (pemetrexed for injection) BRIEF SUMMARY. For complete safety, please consult the full Prescribing Information.

1

INDICATIONS AND USAGE

1.1

Nonsquamous Non-Small Cell Lung Cancerâ&#x20AC;&#x201D;Combination with Cisplatin ALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer.

1.2

Nonsquamous Non-Small Cell Lung Cancerâ&#x20AC;&#x201D;Maintenance ALIMTA is indicated for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.

1.3

Nonsquamous Non-Small Cell Lung Cancerâ&#x20AC;&#x201D;After Prior Chemotherapy ALIMTA is indicated as a single agent for the treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer after prior chemotherapy.

1.4

Mesothelioma ALIMTA in combination with cisplatin is indicated for the treatment of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery.

1.5

Limitations of Use ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer. [see Clinical Studies (14.1, 14.2, and 14.3)] 2

DOSAGE AND ADMINISTRATION

2.1

Combination Use with Cisplatin Nonsquamous Non-Small Cell Lung Cancer and Malignant Pleural Mesothelioma The recommended dose of ALIMTA is 500 mg/m2 administered as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle. The recommended dose of cisplatin is 75 mg/m2 infused over 2 hours beginning approximately 30 minutes after the end of ALIMTA administration. Patients should receive appropriate hydration prior to and/or after receiving cisplatin.

See cisplatin package insert for more information.

2.2

Single-Agent Use Nonsquamous Non-Small Cell Lung Cancer The recommended dose of ALIMTA is 500 mg/m2 administered as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle.

2.3

Premedication Regimen Vitamin Supplementation To reduce toxicity, patients treated with ALIMTA must be instructed to take a low-dose oral folic acid preparation or multivitamin with folic acid on a daily basis. At least 5 daily doses of folic acid must be taken during the 7-day period preceding the first dose of ALIMTA; and dosing should continue during the full course of therapy and for 21 days after the last dose of ALIMTA. Patients must also receive one (1) intramuscular injection of vitamin B12 during the week preceding the first dose of ALIMTA and every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the same day as ALIMTA. In clinical trials, the dose of folic acid studied ranged from 350 to 1000 mcg, and the dose of vitamin B12 was 1000 mcg. The most commonly used dose of oral folic acid in clinical trials was 400 mcg [see Warnings and Precautions (5.1)].

Corticosteroid Skin rash has been reported more frequently in patients not pretreated with a corticosteroid. Pretreatment with dexamethasone (or equivalent) reduces the incidence and severity of cutaneous reaction. In clinical trials, dexamethasone 4 mg was given by mouth twice daily the day before, the day of, and the day after ALIMTA administration [see Warnings and Precautions (5.1)].

2.4

Laboratory Monitoring and Dose Reduction/Discontinuation Recommendations Monitoring Complete blood cell counts, including platelet counts, should be performed on all patients receiving ALIMTA. Patients should be monitored for nadir and recovery, which were tested in the clinical study before each dose and on days 8 and 15 of each cycle. Patients should not begin a new cycle of treatment unless the ANC is â&#x2030;Ľ1500 cells/mm3, the platelet count is â&#x2030;Ľ100,000 cells/ mm3, and creatinine clearance is â&#x2030;Ľ45 mL/min. Periodic chemistry tests should be performed to evaluate renal and hepatic function [see Warnings and Precautions (5.5)].

Dose Reduction Recommendations Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Treatment may be delayed to allow sufficient time for recovery.

Upon recovery, patients should be retreated using the guidelines in Tables 1-3, which are suitable for using ALIMTA as a single-agent or in combination with cisplatin.

Table 1: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatinâ&#x20AC;&#x201D;Hematologic Toxicities Nadir ANC <500/mm3 and nadir platelets â&#x2030;Ľ50,000/mm3 75% of previous dose (pemetrexed and cisplatin) Nadir platelets <50,000/mm3 without bleeding regardless of nadir ANC 75% of previous dose (pemetrexed and cisplatin) Nadir platelets <50,000/mm3 with bleeding a, regardless of nadir ANC 50% of previous dose (pemetrexed and cisplatin) a These criteria meet the CTC version 2.0 (NCI 1998) definition of â&#x2030;ĽCTC Grade 2 bleeding.

If patients develop nonhematologic toxicities (excluding neurotoxicity) â&#x2030;ĽGrade 3, treatment should be withheld until resolution to less than or equal to the patientâ&#x20AC;&#x2122;s pre-therapy value. Treatment should be resumed according to guidelines in Table 2.

Table 2: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatinâ&#x20AC;&#x201D;Nonhematologic Toxicities a,b Dose of ALIMTA Dose of Cisplatin (mg/m 2) (mg/m 2) Any Grade 3 or 4 toxicities except mucositis 75% of previous dose 75% of previous dose Any diarrhea requiring hospitalization (irrespective of Grade) or Grade 3 or 4 diarrhea 75% of previous dose 75% of previous dose Grade 3 or 4 mucositis 50% of previous dose 100% of previous dose a NCI Common Toxicity Criteria (CTC). b Excluding neurotoxicity (see Table 3).

In the event of neurotoxicity, the recommended dose adjustments for ALIMTA and cisplatin are described in Table 3.

Patients should discontinue therapy if Grade 3 or 4 neurotoxicity is experienced.

Table 3: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatinâ&#x20AC;&#x201D;Neurotoxicity Dose of ALIMTA Dose of Cisplatin CTC Grade (mg/m2) (mg/m2) 0-1 100% of previous dose 100% of previous dose 2 100% of previous dose 50% of previous dose Discontinuation Recommendation ALIMTA therapy should be discontinued if a patient experiences any hematologic or nonhematologic Grade 3 or 4 toxicity after 2 dose reductions or immediately if Grade 3 or 4 neurotoxicity is observed.

Renally Impaired Patients In clinical studies, patients with creatinine clearance â&#x2030;Ľ45 mL/min required no dose adjustments other than those recommended for all patients. Insufficient numbers of patients with creatinine clearance below 45 mL/min have been treated to make dosage recommendations for this group of patients [see Clinical Pharmacology (12.3) in the full Prescribing Information].

3

DOSAGE FORMS AND STRENGTHS ALIMTA, pemetrexed for injection, is a white to either light-yellow or green-yellow lyophilized powder available in sterile single-use vials containing 100 mg or 500 mg pemetrexed.

4

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Incidence Less than 1% Cardiovascularâ&#x20AC;&#x201D;arrhythmia General Disordersâ&#x20AC;&#x201D;chest pain Metabolism and Nutritionâ&#x20AC;&#x201D;increased GGT Neurologyâ&#x20AC;&#x201D;motor neuropathy Non-Small Cell Lung Cancer (NSCLC) - Maintenance Table 5 provides the frequency and severity of adverse reactions that have been reported in >5% of 438 patients with NSCLC who received ALIMTA and 218 patients with NSCLC who received placebo. All patients received study therapy immediately following 4 cycles of platinum-based treatment for locally advanced or metastatic NSCLC. Patients in both study arms were fully supplemented with folic acid and vitamin B12.

Table 5: Adverse Reactions in Patients Receiving ALIMTA versus Placebo in NSCLCa ALIMTA Placebo (N=438) (N=218) Reaction b All Grades Grade 3-4 All Grades Grade 3-4 Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) All Adverse Reactions 66 16 37 4 Laboratory Hematologic Anemia 15 3 6 1 Neutropenia 6 3 0 0 Leukopenia 6 2 1 1 Hepatic Increased ALT 10 0 4 0 Increased AST 8 0 4 0 Clinical Constitutional Symptoms Fatigue 25 5 11 1 Gastrointestinal Nausea 19 1 6 1 Anorexia 19 2 5 0 Vomiting 9 0 1 0 Mucositis/stomatitis 7 1 2 0 Diarrhea 5 1 3 0 Infection 5 2 2 0 Neurology Neuropathy-sensory 9 1 4 0 Dermatology/Skin Rash/Desquamation 10 0 3 0 a For the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible relationship to ALIMTA. b Refer to NCI CTCAE Criteria version 3.0 for each Grade of toxicity.

No clinically relevant differences in Grade 3/4 adverse reactions were seen in patients based on age, gender, ethnic origin, or histology except a higher incidence of Grade 3/4 fatigue for Caucasian patients compared to non-Caucasian patients (6.5% versus 0.6%).

Safety was assessed by exposure for patients who received at least one dose of ALIMTA (N=438). The incidence of adverse reactions was evaluated for patients who received â&#x2030;¤6 cycles of ALIMTA, and compared to patients who received >6 cycles of ALIMTA. Increases in adverse reactions (all grades) were observed with longer exposure; however no clinically relevant differences in Grade 3/4 adverse reactions were seen.

Consistent with the higher incidence of anemia (all grades) on the ALIMTA arm, use of transfusions (mainly RBC) and erythropoiesis stimulating agents (ESAs; erythropoietin and darbepoetin) were higher in the ALIMTA arm compared to the placebo arm (transfusions 9.5% versus 3.2%, ESAs 5.9% versus 1.8%).

The following additional adverse reactions were observed in patients with non-small cell lung cancer who received ALIMTA. Incidence 1% to 5% Dermatology/Skinâ&#x20AC;&#x201D;alopecia, pruritis/itching Gastrointestinalâ&#x20AC;&#x201D;constipation General Disordersâ&#x20AC;&#x201D;edema, fever (in the absence of neutropenia) Hematologicâ&#x20AC;&#x201D;thrombocytopenia Renalâ&#x20AC;&#x201D;decreased creatinine clearance, increased creatinine, decreased glomerular filtration rate Special Sensesâ&#x20AC;&#x201D;ocular surface disease (including conjunctivitis), increased lacrimation Incidence Less than 1% Cardiovascularâ&#x20AC;&#x201D;supraventricular arrhythmia Dermatology/Skinâ&#x20AC;&#x201D;erythema multiforme General Disordersâ&#x20AC;&#x201D;febrile neutropenia, allergic reaction/hypersensitivity Neurologyâ&#x20AC;&#x201D;motor neuropathy Renalâ&#x20AC;&#x201D;renal failure Non-Small Cell Lung Cancer (NSCLC)â&#x20AC;&#x201D;After Prior Chemotherapy Table 6 provides the frequency and severity of adverse reactions that have been reported in >5% of 265 patients randomly assigned to receive single-agent ALIMTA with folic acid and vitamin B12 supplementation and 276 patients randomly assigned to receive single-agent docetaxel. All patients were diagnosed with locally advanced or metastatic NSCLC and received prior chemotherapy.

Table 6: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA versus Docetaxel in NSCLCa ALIMTA Docetaxel Reaction b (N=265) (N=276) All Grades Grade 3-4 All Grades Grade 3-4 Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) Laboratory Hematologic Anemia 19 4 22 4 Leukopenia 12 4 34 27 Neutropenia 11 5 45 40 Thrombocytopenia 8 2 1 0 Hepatic Increased ALT 8 2 1 0 Increased AST 7 1 1 0 Clinical Gastrointestinal Nausea 31 3 17 2 Anorexia 22 2 24 3 Vomiting 16 2 12 1 Stomatitis/Pharyngitis 15 1 17 1 Diarrhea 13 0 24 3 Constipation 6 0 4 0 Constitutional Symptoms Fatigue 34 5 36 5 Fever 8 0 8 0 Dermatology/Skin Rash/Desquamation 14 0 6 0 Pruritis 7 0 2 0 c Alopecia 6 1 38 2c a For the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible relationship to ALIMTA. b Refer to NCI CTC Criteria for lab values for each Grade of toxicity (version 2.0). c According to NCI CTC Criteria version 2.0, this adverse event term should only be reported as Grade 1 or 2.

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No clinically relevant differences in adverse reactions were seen in patients based on histology.

Clinically relevant adverse reactions occurring in <5% of patients that received ALIMTA treatment but >5% of patients that received docetaxel include CTC Grade 3/4 febrile neutropenia (1.9% ALIMTA, 12.7% docetaxel).

The following additional adverse reactions were observed in patients with non-small cell lung cancer randomly assigned to receive ALIMTA. Incidence 1% to 5% Body as a Wholeâ&#x20AC;&#x201D;abdominal pain, allergic reaction/hypersensitivity, febrile neutropenia, infection Dermatology/Skinâ&#x20AC;&#x201D;erythema multiforme Neurologyâ&#x20AC;&#x201D;motor neuropathy, sensory neuropathy Renalâ&#x20AC;&#x201D;increased creatinine Incidence Less than 1% Cardiovascularâ&#x20AC;&#x201D;supraventricular arrhythmias Malignant Pleural Mesothelioma (MPM) Table 7 provides the frequency and severity of adverse reactions that have been reported in >5% of 168 patients with mesothelioma who were randomly assigned to receive cisplatin and ALIMTA and 163 patients with mesothelioma randomly assigned to receive single-agent cisplatin. In both treatment arms, these chemonaive patients were fully supplemented with folic acid and vitamin B12.

Table 7: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA plus Cisplatin in MPMa ALIMTA/cisplatin Cisplatin Reaction b (N=168) (N=163) All Grades Grade 3-4 All Grades Grade 3-4 Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) Laboratory Hematologic Neutropenia 56 23 13 3 Leukopenia 53 15 17 1 Anemia 26 4 10 0 Thrombocytopenia 23 5 9 0 Renal Creatinine elevation 11 1 10 1 Creatinine clearance decreased 16 1 18 2 Clinical Eye Disorder Conjunctivitis 5 0 1 0 Gastrointestinal Nausea 82 12 77 6 Vomiting 57 11 50 4 Stomatitis/Pharyngitis 23 3 6 0 Anorexia 20 1 14 1 Diarrhea 17 4 8 0 Constipation 12 1 7 1 Dyspepsia 5 1 1 0 Constitutional Symptoms Fatigue 48 10 42 9 Metabolism and Nutrition Dehydration 7 4 1 1 Neurology Neuropathy-sensory 10 0 10 1 Taste Disturbance 8 0c 6 0c Dermatology/Skin Rash 16 1 5 0 Alopecia 11 0c 6 0c a For the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible relationship to ALIMTA. b Refer to NCI CTC Criteria version 2.0 for each Grade of toxicity except the term â&#x20AC;&#x153;creatinine clearance decreasedâ&#x20AC;? which is derived from the CTC term â&#x20AC;&#x153;renal/genitourinary-otherâ&#x20AC;?. c According to NCI CTC Criteria version 2.0, this adverse event term should only be reported as Grade 1 or 2.

The following additional adverse reactions were observed in patients with malignant pleural mesothelioma randomly assigned to receive ALIMTA plus cisplatin.

Incidence 1% to 5% Body as a Wholeâ&#x20AC;&#x201D;febrile neutropenia, infection, pyrexia Dermatology/Skinâ&#x20AC;&#x201D;urticaria General Disordersâ&#x20AC;&#x201D;chest pain Metabolism and Nutritionâ&#x20AC;&#x201D;increased AST, increased ALT, increased GGT Renalâ&#x20AC;&#x201D;renal failure Incidence Less than 1% Cardiovascularâ&#x20AC;&#x201D;arrhythmia Neurologyâ&#x20AC;&#x201D;motor neuropathy Effects of Vitamin Supplementations Table 8 compares the incidence (percentage of patients) of CTC Grade 3/4 toxicities in patients who received vitamin supplementation with daily folic acid and vitamin B12 from the time of enrollment in the study (fully supplemented) with the incidence in patients who never received vitamin supplementation (never supplemented) during the study in the ALIMTA plus cisplatin arm.

Table 8: Selected Grade 3/4 Adverse Events Comparing Fully Supplemented versus Never Supplemented Patients in the ALIMTA plus Cisplatin arm (% incidence) Fully Supplemented Never Supplemented Patients Patients a Adverse Event (%) (N=168) (N=32) Neutropenia/granulocytopenia 23 38 Thrombocytopenia 5 9 Vomiting 11 31 Febrile neutropenia 1 9 Infection with Grade 3/4 neutropenia 0 6 Diarrhea 4 9 a Refer to NCI CTC criteria for lab and non-laboratory values for each grade of toxicity (Version 2.0).

The following adverse events were greater in the fully supplemented group compared to the never supplemented group: hypertension (11%, 3%), chest pain (8%, 6%), and thrombosis/embolism (6%, 3%).

Subpopulations No relevant effect for ALIMTA safety due to gender or race was identified, except an increased incidence of rash in men (24%) compared to women (16%).

6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of ALIMTA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

These reactions have occurred with ALIMTA when used as a single-agent and in combination therapies.

Gastrointestinalâ&#x20AC;&#x201D;colitis General Disorders and Administration Site Conditionsâ&#x20AC;&#x201D;edema Injury, poisoning, and procedural complicationsâ&#x20AC;&#x201D;Radiation recall has been reported in patients who have previously received radiotherapy Respiratoryâ&#x20AC;&#x201D;interstitial pneumonitis ALIMTAĺ§&#x17E; (pemetrexed for injection)

PV 5206 AMP

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7

DRUG INTERACTIONS

7.1

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Ibuprofen Although ibuprofen (400 mg four times a day) can decrease the clearance of pemetrexed, it can be administered with ALIMTA in patients with normal renal function (creatinine clearance â&#x2030;Ľ80 mL/min). Caution should be used when administering ibuprofen concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min) [see Clinical Pharmacology (12.3) in the full Prescribing Information].

Other NSAIDs Patients with mild to moderate renal insufficiency should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives, all patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration.

If concomitant administration of an NSAID is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicity.

7.2

Nephrotoxic Drugs ALIMTA is primarily eliminated unchanged renally as a result of glomerular filtration and tubular secretion. Concomitant administration of nephrotoxic drugs could result in delayed clearance of ALIMTA. Concomitant administration of substances that are also tubularly secreted (e.g., probenecid) could potentially result in delayed clearance of ALIMTA. 8

USE IN SPECIFIC POPULATIONS

8.1

Pregnancy Teratogenic Effectsâ&#x20AC;&#x201D;Pregnancy Category D [see Warnings and Precautions (5.6)] Based on its mechanism of action, ALIMTA can cause fetal harm when administered to a pregnant woman. There are no adequate and well controlled studies of ALIMTA in pregnant women. Pemetrexed was embryotoxic, fetotoxic, and teratogenic in mice. In mice, repeated intraperitoneal doses of pemetrexed when given during organogenesis caused fetal malformations (incomplete ossification of talus and skull bone; about 1/833rd the recommended intravenous human dose on a mg/m2 basis), and cleft palate (1/33rd the recommended intravenous human dose on a mg/m2 basis). Embryotoxicity was characterized by increased embryo-fetal deaths and reduced litter sizes. If ALIMTA is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to use effective contraceptive measures to prevent pregnancy during the treatment with ALIMTA. 8.3

Nursing Mothers It is not known whether ALIMTA or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ALIMTA, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug for the mother.

8.4

In clinical trials, leucovorin was permitted for CTC Grade 4 leukopenia lasting â&#x2030;Ľ3 days, CTC Grade 4 neutropenia lasting â&#x2030;Ľ3 days, and immediately for CTC Grade 4 thrombocytopenia, bleeding associated with Grade 3 thrombocytopenia, or Grade 3 or 4 mucositis. The following intravenous doses and schedules of leucovorin were recommended for intravenous use: 100 mg/m2, intravenously once, followed by leucovorin, 50 mg/m2, intravenously every 6 hours for 8 days.

The ability of ALIMTA to be dialyzed is unknown.

13

NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity studies have been conducted with pemetrexed. Pemetrexed was clastogenic in the in vivo micronucleus assay in mouse bone marrow but was not mutagenic in multiple in vitro tests (Ames assay, CHO cell assay). Pemetrexed administered at i.v. doses of 0.1 mg/kg/day or greater to male mice (about 1/1666 the recommended human dose on a mg/m2 basis) resulted in reduced fertility, hypospermia, and testicular atrophy.

17

PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling.

Patients should be instructed to read the patient package insert carefully.

17.1 Need for Folic Acid and Vitamin B12 Patients treated with ALIMTA must be instructed to take folic acid and vitamin B12 as a prophylactic measure to reduce treatment-related hematologic and gastrointestinal toxicity [see Dosage and Administration (2.3)].

17.2 Low Blood Cell Counts Patients should be adequately informed of the risk of low blood cell counts and instructed to immediately contact their physician should any sign of infection develop including fever. Patients should also contact their physician if bleeding or symptoms of anemia occur.

17.3 Gastrointestinal Effects Patients should be instructed to contact their physician if persistent vomiting, diarrhea, or signs of dehydration appear.

17.4 Concomitant Medications Patients should be instructed to inform the physician if they are taking any concomitant prescription or over-the-counter medications including those for pain or inflammation such as non-steroidal anti-inflammatory drugs [see Drug Interactions (7.1)].

17.5 FDA-Approved Patient Labeling Patients should be instructed to read the patient package insert carefully.

To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088, or www.fda.gov/medwatch.

Pediatric Use The safety and effectiveness of ALIMTA in pediatric patients have not been established.

8.5

Geriatric Use ALIMTA is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Renal function monitoring is recommended with administration of ALIMTA. No dose reductions other than those recommended for all patients are necessary for patients 65 years of age or older [see Dosage and Administration (2.4)].

In the initial treatment non-small cell lung cancer clinical trial, 37.7% of patients treated with ALIMTA plus cisplatin were â&#x2030;Ľ65 years and Grade 3/4 neutropenia was greater as compared to patients <65 years (19.9% versus 12.2%). For patients <65 years, the HR for overall survival was 0.96 (95% CI: 0.83, 1.10) and for patients â&#x2030;Ľ65 years the HR was 0.88 (95% CI: 0.74, 1.06) in the intent-to-treat population.

In the maintenance non-small cell lung cancer trial, 33.3% of patients treated with ALIMTA were â&#x2030;Ľ65 years and no differences were seen in Grade 3/4 adverse reactions as compared to patients <65 years. For patients <65 years, the HR for overall survival was 0.74 (95% CI: 0.58, 0.93) and for patients â&#x2030;Ľ65 years the HR was 0.88 (95% CI: 0.65, 1.21) in the intent-to-treat population.

In the non-small cell lung cancer trial after prior chemotherapy, 29.7% patients treated with ALIMTA were â&#x2030;Ľ65 years and Grade 3/4 hypertension was greater as compared to patients <65 years. For patients <65 years, the HR for overall survival was 0.95 (95% CI: 0.76, 1.19), and for patients â&#x2030;Ľ65 years the HR was 1.15 (95% CI: 0.79, 1.68) in the intent-to-treat population.

The mesothelioma trial included 36.7% patients treated with ALIMTA plus cisplatin that were â&#x2030;Ľ65 years, and Grade 3/4 fatigue, leukopenia, neutropenia, and thrombocytopenia were greater as compared to patients <65 years. For patients <65 years, the HR for overall survival was 0.71 (95% CI: 0.53, 0.96) and for patients â&#x2030;Ľ65 years, the HR was 0.85 (95% CI: 0.59, 1.22) in the intent-to-treat population.

8.6

Patients with Hepatic Impairment There was no effect of elevated AST, ALT, or total bilirubin on the pharmacokinetics of pemetrexed [see Clinical Pharmacology (12.3) in the full Prescribing Information].

Dose adjustments based on hepatic impairment experienced during treatment with ALIMTA are provided in Table 2 [see Dosage and Administration (2.4)].

8.7

Patients with Renal Impairment ALIMTA is known to be primarily excreted by the kidneys. Decreased renal function will result in reduced clearance and greater exposure (AUC) to ALIMTA compared with patients with normal renal function [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) in the full Prescribing Information]. Cisplatin coadministration with ALIMTA has not been studied in patients with moderate renal impairment.

8.8

Gender In the initial treatment non-small cell lung cancer trial, 70% of patients were males and 30% females. For males the HR for overall survival was 0.97 (95% CI: 0.85, 1.10) and for females the HR was 0.86 (95% CI: 0.70, 1.06) in the intent-to-treat population.

In the maintenance non-small cell lung cancer trial, 73% of patients were males and 27% females. For males the HR for overall survival was 0.78 (95% CI: 0.63, 0.96) and for females the HR was 0.83 (95% CI: 0.56, 1.21) in the intent-to-treat population.

In the non-small cell lung cancer trial after prior chemotherapy, 72% of patients were males and 28% females. For males the HR for overall survival was 0.95 (95% CI: 0.76, 1.19) and for females the HR was 1.28 (95% CI: 0.86, 1.91) in the intent-totreat population.

In the mesothelioma trial, 82% of patients were males and 18% females. For males the HR for overall survival was 0.85 (95% CI: 0.66, 1.09) and for females the HR was 0.48 (95% CI: 0.27, 0.85) in the intent-to-treat population.

8.9

Race In the initial treatment non-small cell lung cancer trial, 78% of patients were Caucasians, 13% East/Southeast Asians, and 9% others. For Caucasians, the HR for overall survival was 0.92 (95% CI: 0.82, 1.04), for East/Southeast Asians the HR was 0.86 (95% CI: 0.61, 1.21), and for others the HR was 1.24 (95% CI: 0.84, 1.84) in the intent-to-treat population.

In the maintenance non-small cell lung cancer trial, 65% of patients were Caucasians, 23% East Asian, and 12% others.

For Caucasians the HR for overall survival was 0.77 (95% CI: 0.62, 0.97), for East Asians was 1.05 (95% CI: 0.70, 1.59) and for others the HR was 0.46 (95% CI: 0.26, 0.79) in the intent-to-treat population.

In the non-small cell lung cancer trial after prior chemotherapy, 71% of patients were Caucasians and 29% others. For Caucasians the HR for overall survival was 0.91 (95% CI: 0.73, 1.15) and for others the HR was 1.27 (95% CI: 0.87, 1.87) in the intent-to-treat population.

In the mesothelioma trial, 92% of patients were Caucasians and 8% others. For Caucasians, the HR for overall survival was 0.77 (95% CI: 0.61, 0.97) and for others the HR was 0.86 (95% CI: 0.39, 1.90) in the intent-to-treat population.

Literature revised July 2, 2009

Eli Lilly and Company Indianapolis, IN 46285, USA

10

OVERDOSAGE There have been few cases of ALIMTA overdose. Reported toxicities included neutropenia, anemia, thrombocytopenia, mucositis, and rash. Anticipated complications of overdose include bone marrow suppression as manifested by neutropenia, thrombocytopenia, and anemia. In addition, infection with or without fever, diarrhea, and mucositis may be seen. If an overdose occurs, general supportive measures should be instituted as deemed necessary by the treating physician.

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PRN

CLINICAL ONCOLOGY NEWS â&#x20AC;˘ SEPTEMBER/OCTOBER 2009

Research

Government-Funded Initiative Meets With Skepticism Recently, the Obama administration committed to spending $1.1 billion on comparative effectiveness research (CER).

The funds should start flowing next spring, which is good news, but the medical community has expressed mixed feelings about the initiative.

The funds will be allocated in the form of grants from the Department of Health and Human Services (HHS), the National Institutes of Health (NIH) and the Agency for Healthcare Research and Quality (AHRQ).

Everyone agrees that, in the age of budget constraints, health care spending must be kept in check.

But they also worry that it may be impossible to sort through the huge volume of evidence to arrive at a completely accurate and impartial conclusion on any topicâ&#x20AC;&#x201D;with the task made even more difficult by the ambitious array of therapeutic areas to be tackled under very tight timelinesâ&#x20AC;&#x201D;and that any conclusion favoring one treatment may well lead to other treatments being barred.

â&#x20AC;&#x2DC;[Comparative effectiveness research] isnâ&#x20AC;&#x2122;t about denying treatments; itâ&#x20AC;&#x2122;s about making sure all types of patients are appropriately treated.â&#x20AC;&#x2122; â&#x20AC;&#x201D;Sheldon Greenfield, MD

John I. Allen, MD, clinical associate professor of medicine, University of Minnesota, Minneapolis, noted that most people are â&#x20AC;&#x153;on boardâ&#x20AC;? with the concept of evidence-based medicine. â&#x20AC;&#x153;But I think skepticism comes from the fact that itâ&#x20AC;&#x2122;s an extraordinarily complicated and costly proposition to arrive at evidencebased medicine in general, and to arrive at decisions about every area of medicine at once will compound the complexity and cost to an unobtainable level,â&#x20AC;?

Dr. Allen said. â&#x20AC;&#x153;Weâ&#x20AC;&#x2122;re concerned that this is going to be superficial and not reflect the complexity of realworld patient care. Weâ&#x20AC;&#x2122;re also concerned that comparative effectiveness analysis will lead to decisions that might restrict choices for patient care and development of new technologies and treatments.â&#x20AC;?

Douglas Blayney, MD, president of the American Society of Clinical Oncology (ASCO), in Alexandria, Va., expressed a similar view. â&#x20AC;&#x153;I think that it is valuable to call attention to the fact that comparative effectiveness research is important for doctorsâ&#x20AC;&#x2122; and patientsâ&#x20AC;&#x2122; decision making,â&#x20AC;? Dr. Blayney said. â&#x20AC;&#x153;But, in general, ASCO also wants to have the decision making remain in the hands of physicians and patients.â&#x20AC;?

The Top 100 The initiative is part of the rolling out of the American Recovery and Reinvestment Act of 2009. The legislation, signed into law on Feb. 17 by President Barack Obama, allocated $400 million to the Office of the Secretary of the HHS, $400 million to the NIH and $300 million to the AHRQ for CER.

Reinvestment Act of 2009 called for the Institute of Medicine (IOM) to form a committee to recommend priorities for the funding of CER. The IOM solicited input from the public, health care professionals and medical organizations before voting on the results and recommending 100 priorities, which can be found at www.iom.edu/CMS/3809/63608/71025.aspx.

â&#x20AC;&#x2DC;Letâ&#x20AC;&#x2122;s make sure thereâ&#x20AC;&#x2122;s no hidden issues here. Letâ&#x20AC;&#x2122;s make sure thereâ&#x20AC;&#x2122;s no subterfuge for rationing drugs, or for funding your research.â&#x20AC;&#x2122; â&#x20AC;&#x201D;Gary Lyman, MD, MPH

The law also called for the creation of the Federal Coordinating Council for Comparative Effectiveness Research, whose objectives are outlined in a June 30 report to the president and Congress, available at www. hhs.gov/recovery/programs/cer/cerannualrpt.pdf. The councilâ&#x20AC;&#x2122;s report sketched out a framework for arriving at priorities for research, investment of human and scientific capital, assembly of data and infrastructure, and dissemination and translation of CER. Additionally, the American Recovery and

Table. Oncology Priorities Recommended To Receive Funding for Comparative Effectiveness Research Oncology Effectiveness of imaging technologies in diagnosing, staging and monitoring patients with cancer, including positron emission tomography, magnetic resonance imaging (MRI) and CT Effectiveness of film-screen or digital mammography alone and mammography plus MRI in community practiceâ&#x20AC;&#x201C;based screening for breast cancer in high-risk women of different ages, risk factors, and race or ethnicity Effectiveness of management strategies for localized prostate cancer (e.g., active surveillance, radical prostatectomy [conventional, robotic and laparoscopic], and radiotherapy [conformal, brachytherapy, proton-beam and intensity-modulated radiotherapy]) on survival, recurrence, side effects, quality of life and costs Effectiveness of surgical resection, observation or ablative techniques on disease-free and overall survival, tumor recurrence, quality of life and toxicity in patients with liver metastases Effectiveness of genetic and biomarker testing and usual care in preventing and treating breast, colorectal, prostate, lung, and ovarian cancers, and possibly other clinical conditions for which promising biomarkers exist.

Cancer was one of the 14 priority conditions set out by the HHS Secretary in 2008. Hence it is emphasized in the IOM report (Table), as well as in the Council report. â&#x20AC;&#x153;The report is meant to address the fear that if one treatment comes out ahead, the other treatments will be denied,â&#x20AC;? remarked Sheldon Greenfield, MD, professor of medicine at University of California, Irvine, and co-chair of the IOM committee that produced the report. â&#x20AC;&#x153;If one treatment is found to work well, and another treatment works only somewhat better, then both treatments will be available. CER isnâ&#x20AC;&#x2122;t about denying treatments, itâ&#x20AC;&#x2122;s about making sure all types of patients are appropriately treated.â&#x20AC;?

AHRQ is expected to publish solicitations for research projects in fall 2009, and funding will commence in spring 2010. The agency announced that it is suspending the appeals procedure for investigators applying for grants â&#x20AC;&#x153;due to the time sensitivity of the Recovery Act granting process.â&#x20AC;? At press time, neither the HHS nor the NIH had revealed when grant solicitations would be made or when funding will start to flow.

What Does This Mean for You? While the particulars of the grant solicitations are being worked out, there is little for clinicians across the country to do but wait. Gary Lyman, MD, MPH, examined oncology CER in the July issue of Cancer Investigation (2009;27:593-597). In the article, Dr. Lyman, editor-in-chief of the journal, chair of four ASCO guidelines committees and a member of the FDAâ&#x20AC;&#x2122;s Oncology Drug Advisory Committee, lays out how systematic reviews, prospective clinical trials, longitudinal registries, comparative effectiveness simulations and clinical practice guidelines can deliver the apparent intent of the Obama initiative, which is to optimally inform clinical decisions. â&#x20AC;&#x153;But first, we have to carefully define what comparative effectiveness research is,â&#x20AC;? said Dr. Lyman, who is also professor of medicine and director of Health Services, Effectiveness and Outcome Research at Duke University School of Medicine and Duke Comprehensive Cancer Center, in Durham, N.C. â&#x20AC;&#x153;And No. 2, letâ&#x20AC;&#x2122;s make sure thereâ&#x20AC;&#x2122;s no hidden issues here,â&#x20AC;? he said. â&#x20AC;&#x153;Letâ&#x20AC;&#x2122;s make sure thereâ&#x20AC;&#x2122;s no subterfuge for rationing drugs, or for funding your research.â&#x20AC;? â&#x20AC;&#x201D;Rosemary Frei, MSc

A

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FDA NEWS

CLINICAL ONCOLOGY NEWS â&#x20AC;˘ SEPTEMBER/OCTOBER 2009

Folotyn Approved for PTCL T

he FDA has granted accelerated approval for pralatrexate injection (Folotyn, Allos Therapeutics) for use as a single agent for patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). This is the only drug approved

for this indication.

The approval was based on results from PROPEL (Pralatrexate in patients with Relapsed Or refractory Peripheral T-cell Lymphoma), an open-label, singlearm, multicenter, international clinical

Your Letters Response to Dr. Engâ&#x20AC;&#x2122;s Editorial Dr. Eng:

I

read your editorial in Clinical Oncology News on the NSABP C-08 trial. I think the biggest problem is the assumption that bevacizumab will have some predefined effect on microscopic disease postâ&#x20AC;&#x201C;primary resection. I know of no other pure adjuvant trials with bevacizumabâ&#x20AC;&#x201D;just in patients with macroscopic disease and in patients with residual disease as a maintenance therapy, i.e., the ATLAS trial in NSCLC [non-small cell lung cancer]. Your points are well taken regarding lack of utilization of CEA (carcinoembryonic antigen) or CT (computed tomography) scans, which NCI and CTEP would have not allowed. I guess AVANT will decide if bevacizumab has any role in stage II or III adjuvant therapy in colon cancer. Iâ&#x20AC;&#x2122;m more interested in the drugâ&#x20AC;&#x2122;s role in the neoadjuvant setting in patients with measurable disease with subset stratification based on MSI [microsatellite instability] and/or 18q loss of heterozygosity, which is important in stage II colon cancer.

I believe that small Phase II trials that test both RECIST and genomic response in the neoadjuvant setting is the best way to â&#x20AC;&#x153;testâ&#x20AC;? whether one should embark on bigger trials and how to do so in a genomically clever fashion.

Regards, Anthony F. Provenzano, MD Chief of Oncology Lawrence Hospital Center Bronxville, N.Y.

TM

ADVISORY BOARD

Gastrointestinal Cancer Edward Chu, MD Cathy Eng, MD Leonard Saltz, MD

Bioethics

Gastrointestinal Cancer and Sarcoma

Joseph P. DeMarco, PhD Paul J. Ford, PhD

Ephraim Casper, MD

Community Oncology

Ronald M. Bukowski, MD

Michael J. Fisch, MD, MPH John W. Finnie, MD

Gynecologic Cancer

Hematologic Malignancies

Lung, and Head and Neck Cancers

Jennifer R. Brown, MD, PhD Agnes Y.Y. Lee, MSc, MD Richard Stone, MD

Edward S. Kim, MD

Oncology Nursing Betty Ferrell, RN, PhD

Pharmacy

Genitourinary Cancer

Maurie Markman, MD

David Bronstein, Editorial Director, Hospital Group Robin B. Weisberg, Manager, Copyediting Services Elizabeth Zhong, Associate Copy Chief

SALES STAFF Thomas Ciriacks, Group Publication Director thomasc@mcmahonmed.com Julianna Dawson, Associate Publication Director jdawson@mcmahonmed.com

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William S. Breitbart, MD Steven D. Passik, PhD Joseph V. Pergolizzi Jr., MD Russell K. Portenoy, MD Charles F. von Gunten, MD

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MCMAHON PUBLISHING Raymond E. McMahon, Publisher & CEO, Managing Partner Van Velle, President, Partner

Solid Tumors

EDITORIAL STAFF

Bone Metastases

Kate Oâ&#x20AC;&#x2122;Rourke, Editor korourke@mcmahonmed.com

Allan Lipton, MD

Breast Cancer

Sarah Tilyou, Senior Editor smtilyou@mcmahonmed.com

Andrew Seidman, MD James Prudden, Group Editorial Director

pralatrexate injection. Median duration of response was 287 days, or 9.4 months (range, 1-503 days). Of the 109 evaluable patients, 13 had duration of response greater than or equal to 14 weeks (range, 98-503 days). The most common grade 3/4 adverse events were thrombocytopenia (33%), mucositis (21%), neutropenia (20%) and anemia (17%).

The median number of prior systemic therapies was three. Approximately 25% of patients did not have evidence of response to any previous therapy, and 63% did not have evidence of response to their most recent prior therapy before entering the trial. The initial response assessment was scheduled at the end of the first cycle. Of the responders, 66% responded within cycle 1. The median time to first response was 45 days (range, 37-349 days).

Clinical benefit such as improvement in progression-free survival or overall survival has yet to be demonstrated.

Because pralatrexate injection can harm a fetus, women should avoid becoming pregnant while being treated with this drug and pregnant women should be informed of the potential risk.

McMahon Publishing is a 37-year-old, family-owned medical publishing and medical education company. McMahon publishes seven clinical newspapers, seven special editions, and continuing medical education and custom publications.

Copyright Š 2009 by McMahon Publishing, New York, NY 10036. All rights reserved. Clinical Oncology News (ISSN 1933-0677) is published monthly for $70.00 per year by McMahon Publishing. Postage paid at New York, NY, and at additional mailing offices. www.mcmahonmed.com POSTMASTER: Please send address changes to Clinical Oncology News, 545 W. 45th St., 8th Floor, New York, NY 10036.

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Lung Cancer, Emesis

Polly E. Kintzel, PharmD Melvin E. Liter, MS, PharmD

Mary Lou Bowers, MBA Barbara Constable, RN, MBA Rhonda M. Gold, RN, MSN

trial. PROPEL enrolled 115 patients with relapsed or refractory PTCL; of these 109 were considered evaluable. Patients were considered evaluable if they received at least one dose of the drug, their diagnosis of PTCL was confirmed by independent pathology review, and they had relapsed or refractory disease after at least one prior treatment. Patients were treated with pralatrexate injection at 30 mg/m2 once weekly by IV push over three to five minutes for six weeks in seven-week cycles until disease progression or unacceptable toxicity. Additionally, patients received 1 mg of vitamin B12 intramuscularly every eight to 10 weeks and 1 to 1.25 mg of folic acid orally on a daily basis.

The primary efficacy end point was overall response rate as assessed by International Workshop Criteria (IWC).

The key secondary efficacy end point was duration of response. Response assessments were scheduled at the end of the first cycle and then every other cycle (every 14 weeks). Duration of response was measured from the first day of documented response to disease progression or death. Response and disease progression were evaluated by independent central review using the IWC. The trial revealed that of the 109 evaluable patients, 29 (27%) responded to

Thomas Ciriacks, Vice President, Medical Education Matthew McMahon, General Manager, Partner Lauren Smith, Michael McMahon, Michele McMahon Velle, Rosanne C. McMahon, Partners

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7

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PRN

CLINICAL ONCOLOGY NEWS â&#x20AC;˘ SEPTEMBER/OCTOBER 2009

CareFusionâ&#x20AC;&#x2122;s Focus:

Medical Devices Supporting Patient Care and Safety

Did you receive the August Digital Exclusive issue of Clinical Oncology News?

Visit www.clinicaloncology.com

for ventilator-associated pneumonia.

Diversified Line of Products CareFusion, whose international headquarters is located here, also markets the V. Mueller line of surgical instruments; monitoring and diagnostic products for neurology; products for interventional medicine; ChloraPrep, which helps reduce surgical site and bloodstream infections;

and MedMined, an infection surveillance software service that oversees the threat of hospital-acquired infections and helps hospitals refine their practices to avoid them.

CareFusion has plans to introduce nearly 40 new products in the next 18 months. â&#x20AC;&#x153;Some of our new offerings will connect existing products, such as Pyxis and MedMined, to further enhance safety and help hospitals measurably

improve the care they deliver.â&#x20AC;? â&#x20AC;&#x153;We are in business in many parts of the world,â&#x20AC;? Mr. Mazzola said. â&#x20AC;&#x153;Although these markets can be very different, many of the challenges hospitals face are really the same. Adaptation and sensitivity to these local markets come into play, but patient safety and improving patient care are important everywhere.â&#x20AC;? â&#x20AC;&#x201D;Staff

Committed to Cancer Research

National Cancer Institute

San Diegoâ&#x20AC;&#x201D;The biggest medical company youâ&#x20AC;&#x2122;ve never heard of is ready to lose its anonymity.

Although CareFusion Corporation is brand new, it already employs more than 15,000 people globally who do business in 120 different countries. Its mature product lines and newer offerings are focused on improving patient care and safety.

Jim Mazzola, senior vice president of marketing and communication, explained, â&#x20AC;&#x153;The parent company, Cardinal Health, is primarily a North American distribution business, while CareFusion is primarily a global medical device business. We determined that these very different businesses would both be better positioned in their respective markets if they were separate and could therefore invest independently to grow.â&#x20AC;?

CareFusionâ&#x20AC;&#x2122;s product lines already are well known and widely used in hospitals worldwide. â&#x20AC;&#x153;They run the gamut from surgical instruments, to ventilators, to IV infusion pumps,â&#x20AC;? Mr. Mazzola explained. One example is Pyxis, â&#x20AC;&#x153;an automated dispensing and patient identification system that secures pharmaceuticals on the nursing floor, cutting down the time it takes to deliver drugs to where they are neededâ&#x20AC;&#x201D;at the patientâ&#x20AC;&#x2122;s bedside.â&#x20AC;? The system greatly reduces the possibility of medication errors, an important consideration given the extent of annual adverse drug events among hospitalized patients.

Alaris is CareFusionâ&#x20AC;&#x2122;s line of infusion pumps. Among its many innovations, â&#x20AC;&#x153;Alaris introduced â&#x20AC;&#x2DC;guardrails safety software,â&#x20AC;&#x2122; which allows hospitals to set parameters for medication infusions. If a nurse accidentally enters a value that is above or below the recommended dosageâ&#x20AC;&#x201D;for example, 2.0 is entered as 20.0â&#x20AC;&#x201D;it will stop the infusion.â&#x20AC;?

CareFusion also markets AVEA and Pulmonetic Systems, a line of ventilation and respiratory products, and will shortly introduce a full-function ventilator that weighs only 9 lb. The EnVe Palmtop Ventilator, or PTV, is an advance in patient care and safety because it allows the patient to be moved without having to be switched from a bedside ventilator to a transport ventilator. Studies have found that changing ventilators increases the risk

CCR Clinical Trials at NIH

A

re you looking for more options for your patients? NCIâ&#x20AC;&#x2122;s Center for Cancer Research (CCR) conducts more than 150 clinical trials at the National Institutes of Health (NIH) in Bethesda, Md. In the state-ofthe-art NIH Clinical Center, the latest innovations in medicine are put into practice every day.

CCR is currently conducting trials for many types of cancer including: â&#x20AC;˘ Prostate Cancer â&#x20AC;˘ Lung Cancer â&#x20AC;˘ Thymoma â&#x20AC;˘ Pediatric Sarcoma â&#x20AC;˘ Kidney Cancer â&#x20AC;˘ Brain Cancer

To learn whether your patients may be eligible, visit

bethesdatrials.cancer.gov or call 1-888-NCI-1937 (1-888-624-1937)

9

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SWOG S0777 CURRENTLY ENROLLING

A Phase III Study for Patients With Previously Untreated Multiple Myeloma Study Coordinator Brian Durie, MD, Cedars-Sinai Medical Center, Los Angeles, CA

Primary Objective To compare progression-free survival (PFS) with lenalidomide plus low dose dexamethasone (Ld) versus lenalidomide, bortezomib, and low dose dexamethasone (LBd) in patients with previously untreated multiple myeloma without an intent for immediate stem cell transplantation

Secondary Objectives 1. To evaluate the role of MRI scan in assessment of stage and response to therapy 2. To correlate Gene Expression Profiling and single nucleotide polymorphisms with prognosis and outcomes

Key Eligibility Criteria â&#x20AC;˘ Newly diagnosed multiple myeloma with no prior chemotherapy â&#x20AC;˘ Adequate bone marrow function â&#x20AC;˘ Zubrod Performance Status 0-3 â&#x20AC;˘ Creatinine clearance >30 mL/min

Induction

Study Design

Treatment A (Ld)

Enrollment N=440

â&#x20AC;˘ Lenalidomide 25 mg po once daily, days 1-21 each cycle a,b â&#x20AC;˘ Dexamethasone 40 mg po once weekly, days 1, 8, 15, and 22 each cycle c â&#x20AC;˘ Aspirin 325 mg po once daily, continuously Up to 6 cycles, 28 days eachb Patients in both arms considering autologous stem cell transplantation following relapse should undergo stem cell collection after the second cycle of treatment.

Treatment B (LBd) â&#x20AC;˘ Lenalidomide 25 mg po once daily, days 1-14 each cycle a,b â&#x20AC;˘ Dexamethasone 20 mg po once daily, days 1, 2, 4, 5, 8, 9, 11, and 12 each cyclec â&#x20AC;˘ Bortezomib 1.3 mg/m2 intravenously once daily, days 1, 4, 8, and 11 each cyclea â&#x20AC;˘ Aspirin 325 mg po once daily, continuously â&#x20AC;˘ HSV prophylaxis per institutional standard Up to 8 cycles, 21 days eachb

Maintenance Treatment (Ld) â&#x20AC;˘ Lenalidomide 25 mg po once daily, days 1-21 each cycle a,b â&#x20AC;˘ Dexamethasone 40 mg po once daily, days 1, 8, 15, and 22 each cycle c â&#x20AC;˘ Aspirin 325 mg po once daily, continuously 28-day cycles; until progression

Long-term Follow-up Phase Patients followed for survival for 6 years

a Patients

experiencing bortezomib- and/or lenalidomide-related â&#x2030;ĽGrade 3 non-hematologic or Grade 4 hematologic toxicity will have their dose held until toxicity has resolved to Grade 1 or better, and then will have their dose reduced 1 level from the previous dose received. b If serum creatinine is â&#x2030;Ľ2 mg/dL prior to the first cycle, a reduced dose of lenalidomide of 5 mg/day is recommended. c Induction dose reduction of dexamethasone is not allowed. In the event of Grade 3 or Grade 4 gastrointestinal bleeding or severe diabetes, dexamethasone must be discontinued.

For more information contact www.clinicaltrials.gov (NCT00644228), www.swog.org, -ORthe National Cancer Institute Cancer Trials Support Unit (888) 823-5923 (ctsucontact@westat.com) Funding and editorial support for trial recruitment materials provided by Celgene Corporation.

09/09

CELG09152T

Note: This study is supported by the National Cancer Institute Cancer Trials Support Unit (CTSU). Institutions not aligned with SWOG will participate through the CTSU mechanisms.

Funding for this trial provided

by Celgene Corporation, Millennium: The Takeda Oncology Company, and the National Cancer Institute.

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Newly Diagnosed Myeloma Once a patient has been diagnosed with MM and the decision to initiate treatment has been made, clinicians should make every effort to enroll patients in clinical trials. For those not enrolled in a clinical trial, the first critical step is to determine whether the patient is eligible for autologous stem cell transplant (ASCT) and is willing to undergo the procedure trial (Figure).1 Traditionally, eligibility has been based on age, reflecting the results of randomized clinical trials (RCTs); however, existing data support the use of ASCT in selected older patients.2 Thus, the decision to undergo ASCT must be based on the patientâ&#x20AC;&#x2122;s physiologic age and preferences. The criteria used for assessing response to treatment and likelihood for relapse after successful therapy has been revised to incorporate recent advances, such as the free light chain assay (Table 1).3

INITIAL TREATMENT If the patient is considered a potential candidate for ASCT, initial therapy is aimed at maximizing disease control with the least toxicity. Traditionally, this has included 4 to 6 months of treatment with one or more commonly used regimens, followed by stem cell collection and high-dose therapy.4-7 The long-term impact of initial therapy on the outcome of ASCT remains undefined, with individuals refractory to initial therapy obtaining as much benefit from ASCT as those who have responded to the initial regimen.8 In this scenario, the 5 important attributes for initial therapy are as follows: 1. effectively controlling disease and minimizing early mortality, thereby providing the maximum possibility of reaching an ASCT; 2. minimizing possible toxicity; 3. administering therapy with the least negative impact on quality of life; 4. minimizing the impact on the ability to collect stem cells; and 5. continuing therapy with minimal modificationâ&#x20AC;&#x201D;given the lack of a survival advantage for early ASCTâ&#x20AC;&#x201D;if a decision is made to delay ASCT. The introduction of newer agents has shifted the initial approach from the traditional regimens of singleagent dexamethasone or a combination of vincristine, doxorubicin, and dexamethasone (VAD) to 1 of 3 regimens: the combination of the thalidomide analogue lenalidomide (Revlimid, Celgene) and low-dose dexamethasone; thalidomide and dexamethasone (TD); or bortezomib (Velcade, Millennium Pharmaceuticals) and dexamethasone.

Various clinical trials in patients newly diagnosed

2

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F\b dVYY NY`\ OR Nba\ZNaVPNYYf R[aR_RQ V[a\ N Q_NdV[T a\ dV[ N[ V=\Q a\bPU

with MM provide support for this approach. In 2 Phase III trials, TD compared with dexamethasone alone was associated with increased response rates and longer time to progression (TTP), but toxicities, especially thrombotic events, were higher with the combination.6,9 The combination also has been compared with the VAD regimen and has been found to have a superior response rate.10 Several trials also examined the addition of thalidomide to chemotherapy regimens demonstrating attainment of deeper responses, at least prior to SCT. Lenalidomide in combination with dexamethasone was studied in Phase II and III trials, and long-term follow-up demonstrates a 2-year survival rate greater than 90%. In comparison with dexamethasone alone, the combination imparts a higher response rate and longer progression-free survival (PFS). Another Phase III trial compared lenalidomide and high-dose (standard) dexamethasone with lenalidomide and low-dose (weekly) dexamethasone. This study demonstrated improved survival, despite a lower response rate, for patients treated with lowerdose dexamethasone, effectively eliminating highdose dexamethasone treatment from the setting of newly diagnosed disease.11 Lenalidomide has been studied in combination with alkylators or anthracyclines, as well as other novel agents, in multiple Phase I and II studies.12-15 The combination of bortezomib and dexamethasone has been examined in the setting of newly diagnosed MM in several clinical trials, with high response rates and excellent safety.16 This combination has been compared with VAD as induction therapy prior to SCT in a Phase III trial, with deeper responses and reduced need for tandem ASCT, as well as improved PFS after SCT.17 The exciting results seen with the novel agents raised the question of whether these agents in combination can further enhance the up-front treatment of myeloma. The combination of bortezomib, thalidomide, and dexamethasone (VTD) was compared with TD in a Phase III trial. VTD resulted in significantly higher response rates and deeper responses, which translated into an improved PFS following SCT.18 Subsequently, lenalidomide has been combined with bortezomib and dexamethasone (VRD), resulting in a 100% response rate with very good partial response (VGPR) or better in nearly two-thirds of the patients.19 To maximize the initial treatment, the EVOLUTION (Evaluation of VELCADE, dexamethasOne, and Lenalidomide with or without cyclophosphamide Using Targeted Innovative ONcology strategies in the treatment of front-line multiple myeloma) trial added cyclophosphamide to the VRD combination and reported a 100% response rate with high

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F\b N_R ]_R_RTV`aR_RQ a\ _RPRVcR

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Transplant-Ineligible

Transplant-Eligible

MPT or MPV x 12 cycles

Induction Therapy a Lenalidomide-Low-dose Dexamethasone Bortezomib-Dexamethasone Thalidomide-Dexamethasone

Collect stem cells after 4 cycles of induction

Option 1

Option 2

Autologous stem cell transplant

Continue induction therapy

Second transplant or maintenance thalidomide if not in complete response or very good partial response after first transplant

Continue until maximum response or indefinite based on adverse effects

Figure. Approach to patient with newly diagnosed MM. a

Bortezomib-containing regimens preferred in patients with high-risk myeloma based on adverse cytogenetics, and in patients with renal failure. Combination regimens such as VRD and VTD may be considered outside a clinical trial in patients in whom rapid response is required due to disease-related complications or aggressive disease.

MM, multiple myeloma; MPT, melphalan-prednisone-thalidomide; MPV, melphalan-prednisone-bortezomib; VRD, bortezomib-dexamethasone-lenalidomide; VTD, bortezomib-dexamethasone-thalidomide Based on reference 1.

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

3

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VGPR rates after a median of 4 cycles of therapy. 20 Similarly, liposomal doxorubicin has been added to the VRD combination in the setting of newly diagnosed myeloma. 21 The overall response rate (ORR) was 97%, including 62% VGPRs. The long-term impact of these highly active regimens is not clear and longer follow-up will be required to delineate their effect on the natural history of the disease.

ROLE

OF

ASCT

Several RCTs have indicated that ASCT improves the outcome of patients with MM, whereas others have suggested no benefit for ASCT, especially in patients responsive to initial therapy. 22-24 In the IFM94 and Myeloma VII trials, previously untreated patients younger than age 65, were randomly assigned to receive either conventional chemotherapy (CCT) or ASCT. Patients receiving ASCT had a superior response rate, event-free survival (EFS), and overall survival (OS) compared with those receiving CCT. 22,23 In contrast, MAG91 demonstrated improved EFS and time without symptoms, treatment, and toxicity (TWiSTT) with ASCT, but no improvement in OS, in patients younger than age 65. 25 Similarly, the Intergroup study S9321 showed that patients with untreated MM randomly assigned to either ASCT or CCT, with further randomization of responding patients to interferon maintenance or no maintenance, did not reveal any OS benefit. 26 The Spanish cooperative group PETHEMA conducted a randomized trial comparing ASCT with CCT in patients who responded to initial therapy and demonstrated higher complete response (CR) rates with ASCT but no differences in PFS or OS. 24 In the MAG90 trial, patients were randomly assigned to receive ASCT after 3 to 4 cycles of initial therapy, or to continue CCT, with ASCT done at time of first relapse or if the patient became refractory to initial therapy. 27 Although the OS was similar in this study, TWiSTT was significantly better for the early ASCT group.

SCT in MM involves collection of peripheral blood stem cells, using either granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor alone or following initial priming with cyclophosphamide, and collection during recovery.

Purging of tumor cells from the stem cell collection, using various selection methods, has not translated into any improvement, likely reflecting the disease biology and the inability of the conditioning therapy to completely eradicate the tumor clone. The most widely used conditioning regimen is that of melphalan 200 mg/m2, based on results of the IFM95-02 trial, in which patients were randomly assigned to receive

4

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

either 8 Gy total body irradiation (TBI) plus 140 mg/m2 melphalan, or 200 mg/m2 melphalan alone. 28 Patients receiving only melphalan had a faster recovery of neutrophils and platelets, and milder mucositis, without any effect on EFS or OS. Ongoing trials are attempting to improve melphalan conditioning by increasing the melphalan dose (alone or in combination with cytoprotectants such as amifostine), adding skeletal targeted radioisotopes such as samarium or holmium, using skeletal targeted TBI, or adding novel agents such as bortezomib.

The role of ASCT in the treatment of MM continues to evolve in the era of novel agents. The high response rates seen with the new combination regimens incorporating novel agents have brought the role of SCT into question once again. Recent studies have shown that even with the high response rates obtained with the novel agent combinations, SCT provides additional tumor reduction. Whether this can be replaced by additional cycles of novel agent combinations remains to be studied. However, MM remains an incurable disease and in the absence of randomized trials demonstrating lack of benefit with SCT, it still should be considered a part of the therapeutic armamentarium for MM. Ongoing trials are examining the best way to integrate these treatment modalities to provide maximum benefit to patients.

ROLE

OF

SECOND ASCT

The concept of a second transplant was introduced to examine if further consolidation can be achieved with additional cycles of ASCT. Three RCTs have assigned previously untreated patients to a single or double transplant. The IFM94 trial showed a slight improvement in the combined CR and VGPR rate with double transplant (50% vs 42%), but at 7 years, EFS (20% vs 10%) and OS (42% vs 21%) doubled with the second ASCT. 29 The benefit of a second transplant was, for the most part, restricted to individuals failing to achieve a VGPR after first transplant (OS at 7 years of 43%, vs 11%). This is particularly relevant, given that a significant proportion of patients undergoing induction therapy with novel agents achieve a VGPR state after the initial ASCT, thus negating the need for a second ASCT. In the Bologna 96 trial, the addition of a second ASCT prolonged EFS by 12 months and TTP by 17 months, with a projected OS at 6 years of 44% for single transplant and 63% for double transplant.30 Again, patients who failed to achieve a CR or VGPR after the first ASCT obtained the maximum benefit from the second cycle of ASCT. In the MAG95 clinical trial, patients were randomly assigned to receive single or double ASCTs and then further randomized

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Table 1. Response Criteria for MM Response Subcategory

Response Criteria

CR

â&#x20AC;˘ Negative immunofixation on the serum and urine and â&#x20AC;˘ Disappearance of any soft tissue plasmacytomas and â&#x20AC;˘ <5% plasma cells in bone marrow

Stringent CR

â&#x20AC;˘ Normal FLC ratio and

(CR as above plus)

â&#x20AC;˘ Absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence

VGPR

â&#x20AC;˘ Serum and urine M-component detectable by immunofixation but not on electrophoresis or â&#x20AC;˘ â&#x2030;Ľ90% reduction in serum M-component plus urine M-component <100 mg/24 h

PR

â&#x20AC;˘ â&#x2030;Ľ50% reduction of serum M-protein and reduction in 24-h urinary M-protein by â&#x2030;Ľ90% or to <200 mg per 24 h â&#x20AC;˘ If the serum and urine M-protein are unmeasurable, a â&#x2030;Ľ50% decrease in the difference between involved and uninvolved FLC levels is required in place of the M-protein criteria â&#x20AC;˘ If serum and urine M-protein are unmeasurable, and serum FLC assay is also unmeasurable, â&#x2030;Ľ50% reduction in bone marrow plasma cells is required in place of M-protein, provided baseline percentage was â&#x2030;Ľ30% â&#x20AC;˘ In addition to the above criteria, if present at baseline, â&#x2030;Ľ50% reduction in the size of soft tissue plasmacytomas is also required

SD

â&#x20AC;˘ Not meeting criteria for CR, VGPR, PR, or PD

PD

Increase of 25% from baseline in: â&#x20AC;˘ Serum M-component (absolute increase must be â&#x2030;Ľ0.5 g/dL) and/or â&#x20AC;˘ Urine M-component (absolute increase must be â&#x2030;Ľ200 mg/24 h) and/or â&#x20AC;˘ Only in patients without measurable serum and urine M-protein levels: the difference between involved and uninvolved FLC levels (absolute increase must be >10 mg/dL) â&#x20AC;˘ Bone marrow plasma cell percentage (absolute % must be 10%) â&#x20AC;˘ Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas â&#x20AC;˘ Development of hypercalcemia (corrected serum calcium >11.5 mg/dL) that can be attributed solely to the plasma cell proliferative disorder

Relapse from CR

â&#x20AC;˘ Reappearance of serum or urine M-protein by immunofixation or electrophoresis or â&#x20AC;˘ Development of â&#x2030;Ľ5% plasma cells in the bone marrow or â&#x20AC;˘ Appearance of any other sign of progression (ie, new plasmacytoma, lytic bone lesion, or hypercalcemia)

CR, complete response; FLC, free light chain; MM, multiple myeloma; PD, progressive disease; PR, partial response; SD, stable disease; VGPR, very good partial response Based on reference 3.

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5

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F\b N_R ]_R_RTV`aR_RQ a\ _RPRVcR

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to selected or unselected CD34-positive cells. 31 The study again confirmed an OS advantage for this approach. However, the proportion of patients not achieving VGPR with the first SCT has decreased considerably in the current era, given the high response rates with novel agents prior to the SCT. As a result, it is not clear how beneficial a second SCT is in the era of effective novel agents.

MAINTENANCE THERAPY AFTER ASCT ASCT clearly improves response rates in patients with newly diagnosed MM compared with conventional therapy, but patients invariably relapse. Various trials have attempted to maintain the ASCT response through maintenance approaches. A small RCT of interferon alfa 3 x 106 units/m2 subcutaneously 3 times weekly following initial ASCT suggested a modest improvement in EFS. 32 In IFM99-02, patients with standard-risk MM (β2-microglobulin [B2M] <3 mg/L, and no chromosome 13 deletion) were randomly assigned to receive no maintenance, pamidronate, or pamidronate plus thalidomide 2 months after tandem ASCT. 33 The response rates were significantly higher for the thalidomide arm; this translated into an improved EFS of 52%, compared with 36% with no maintenance and 37% with pamidronate alone. The 4-year estimated survival from diagnosis was higher with thalidomide (87%) compared with no maintenance (77%). In an Australian trial, patients were randomized to receive prednisolone with or without thalidomide. 34 After a median follow-up of 3 years, the 3-year PFS rates were 42% and 23%, and the OS rates were 86% and 75% in the thalidomide and control groups, respectively. More importantly, there was no difference in survival between the groups when followed after disease progression (79% vs 77%), negating concern that maintenance therapy may alter natural history of disease. Additional studies have examined the role of thalidomide maintenance; a PFS advantage has been noted for thalidomide following SCT in all studies, with survival advantage seen in 4 of 5 studies. An ongoing large study (Cancer and Leukemia Group B) is evaluating lenalidomide as maintenance after single ASCT. Maintenance approaches have been attempted with bortezomib; however, long-term data are lacking. The HOVON 65 trial randomized patients to bortezomib, doxorubicin, dexamethasone (PAD) or VAD followed by maintenance with bortezomib or thalidomide, respectively.

Early data show improvement in the response rates with PAD. 35 Other approaches for post-transplant maintenance have included immunotherapeutic strategies, such as dendritic cell vaccines. Long-term

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results of these trials should be evaluated before this is adopted into routine practice.

ALLOGENIC STEM CELL TRANSPLANT Although allogeneic stem cell transplant (alloSCT) has been shown to mediate a potentially curative graftversus-myeloma effect, it also is associated with a high level of toxicity.36 Most of the initial reports on the use of allogeneic approaches have come from small studies or from transplant registries. In a retrospective case-matched analysis from the European Blood and Marrow Transplant Registry, patients treated with allogeneic bone marrow transplant (allo-BMT) were compared with a similar group of patients who received ASCT.37 The OS was significantly better for the ASCT arm than for the allo-BMT arm, with median survival of 34 and 18 months, respectively. The poorer survival in allo-BMT patients could be attributed mostly to the higher treatmentâ&#x20AC;&#x201C;related mortality (41% vs 13%).

Among patients surviving the first year, there was a trend for better OS and EFS for allo-BMT. The use of nonmyeloablative SCT is intended to curb treatmentâ&#x20AC;&#x201C;related mortality by depending more on the anti-tumor effect of the graft than on the initial cytoreduction achieved by the conditioning regimen. The IFM99-03/99-04 trials included patients with high-risk myeloma (B2M level >3 mg/L and chromosome 13 deletion at diagnosis). 38 In IFM99-03, 65 patients with an HLA-identical sibling donor were assigned to receive reduced-intensity conditioning (RIC) alloSCT; in IFM99-04, 219 patients without an HLA-identical sibling donor were assigned to undergo a second ASCT. The investigators found that RIC-alloSCT was associated with an inferior outcome compared with tandem ASCT. In an Italian trial, 108 patients younger than age 65 with newly diagnosed MM received standard ASCT, followed by low-dose TBI conditioning and HLA-matched sibling peripheral blood SCT (median of 2-4 months from ASCT), then mycophenolate mofetilâ&#x20AC;&#x201C;cyclosporine graft-versus-host disease prophylaxis, and finally a second ASCT. 39 At a median follow-up of 3 years, treatmentrelated mortality was 11% for the alloSCT group versus 4% for the double ASCT group; CR rate was 46% versus 16%; OS was 84% versus 62% (P=0.003); and PFS was 75% versus 41% (P=0.00008). This trial had several shortcomings, however, and the results cannot be generalized.

PATIENTS NOT ELIGIBLE

FOR

TRANSPLANT

Patients not eligible to receive a transplant constitute a sizable proportion of patients, given that nearly two-thirds of individuals with MM are older than age

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65 at diagnosis.40 For decades, melphalan and prednisone (MP) have been the mainstays of therapy for patients not eligible for SCT. A meta-analysis of multiple randomized trials failed to demonstrate any benefit for combination regimens compared with MP. In a Phase III clinical trial, Italian investigators examined the addition of thalidomide to MP.41 Patients older than 65 years with newly diagnosed MM, or younger than age 65 and ineligible for SCT, were randomly assigned to receive MP (melphalan 4 mg/m2, days 1-7, and prednisone 40 mg/m2, days 1-7) or MP plus thalidomide 100 mg daily (MPT) for 6 cycles. Patients in the MPT arm continued on maintenance thalidomide after the 6 cycles until relapse. At 6 months from initiation of therapy, 76% of patients in the MPT arm had a response (CR or partial), compared with 47.6% in the MP arm. With comparable follow-up, the EFS at 2 years doubled with the addition of thalidomide to MP (54% vs 27%), with those older than age 70 deriving similar benefit as the younger patients. Grade 3 and 4 adverse events (AEs), however, nearly doubled with the addition of thalidomide (48% for MPT vs 25% for MP) and 11 patients had toxicity-related deaths in the MPT group, compared with 6 patients in the MP group. Deep vein thrombosis was the most common grade 3/4 AE in the MPT group, with 13 of the first 65 patients developing the condition. After introduction of enoxaparin prophylaxis, however, 2 of the remaining 64 patients developed thrombosis. A second clinical trial, conducted in France (IFM99-06) randomly assigned patients aged 65 to 75 to receive MP (12 cycles at 6-week intervals), MPT (maximum tolerated thalidomide dose, up to 400 mg/d), or MEL100 (induction therapy with VAD x 2, cyclophosphamide 3 g/m2-based mobilization, and 2 courses of melphalan 100 mg/m2 with stem cell support).42 A CR or VGPR was seen in 9%, 64%, and 58% of patients in the MP, MPT, and MEL100 groups, respectively; at a median follow-up of 32.2 months, the corresponding PFS rates were 17.2, 29.5, and 19 months. The median OS rates were 30.3 months, not reached at 56 months, and 38.6 months in the MP, MPT, and MEL100 groups, respectively. Another French trial specifically examined this question in a group of older patients (>75 years) and was able to demonstrate improved PFS and OS with addition of thalidomide.43 There have been 5 randomized studies comparing MPT with MP, including the 3 mentioned above. The trials have consistently demonstrated a PFS advantage for addition of thalidomide, with 2 of the 5 showing an improvement in OS as well. Based on these results, the recommendation for patients ineligible for SCT is to add 100 mg per day of thalidomide to the MP

F\b dVYY NY`\ OR Nba\ZNaVPNYYf R[aR_RQ V[a\ N Q_NdV[T a\ dV[ N[ V=\Q a\bPU

regimen and limit the therapy to 12 months. Patients should be given daily aspirin for thromboprophylaxis, and clinicians should limit the use of lowâ&#x20AC;&#x201C;molecularweight heparin or warfarin anticoagulation to patients at higher risk for thrombosis.

The role of bortezomib in combination with MP was examined in the large Phase III VISTA (VELCADE as Initial Standard Therapy in multiple myeloma: Assessment with melphalan and prednisone) trial, in which patients with previously untreated MM who were not candidates for ASCT were randomly assigned to receive bortezomib plus MP (VMP) or MP alone.44 Patients in the VMP arm received IV bortezomib 1.3 mg/m2 twice per week (weeks 1, 2, 4, and 5) for 4 cycles of 6 weeks (8 doses per cycle), followed by once per week (weeks 1, 2, 4, and 5) for 5 cycles of 6 weeks (4 doses per cycle) in combination with oral melphalan 9 mg/m2 and prednisone 60 mg/m2 once daily on days 1 to 4 of each cycle. Patients in the MP arm received MP once daily on days 1 through 4 for 9 cycles of 6 weeks. Both the median TTP and OS at 2 years were significantly better in the VMP group: TTP, 24 months with VMP versus 16.6 months with MP; OS at 2 years, 82.6% with VMP versus 69.5% with MP. MP also has been studied in combination with lenalidomide; Phase II results are promising, and a Phase III trial comparing this regimen with MPT is ongoing. 45 Both thalidomide and bortezomib have been combined with MP in this population (VMPT). Palumbo et al randomized 450 newly diagnosed MM patients aged 65 or older to VMPT (n=221) or VMP (n=229). Patients were treated with nine 5-week cycles of VMPT (bortezomib 1.3 mg/m2, days 1, 8, 15, and 22; melphalan 9 mg/m2, days 1-4; prednisone 60 mg/m2, days 1-4 and thalidomide 50 mg, days 1-35) or VMP. The weekly administration of bortezomib resulted in significantly less neuropathy compared with standard administration schedule. Addition of thalidomide resulted in a higher response rate (84% vs 78%) and increased depth of response (CR + VGPR 51% vs 42%).46

Management of Relapsed MM The key determinants of the approach to the patient with relapsed disease depend on types of previous therapy and response, duration of response to previous therapy, and presence of high-risk cytogenetic features. Patients relapsing on initial therapy or within 12 months of ASCT, and those with the high-risk genetic abnormalities should be considered at high risk for early mortality. Patients without any of these high-risk features have several options for treatment at first relapse. ASCT remains an option for those with or without previous ASCT, as long as they are considered

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Table 2. Options for Relapsed MM Bortezomib Âą dexamethasone Lenalidomide Âą dexamethasone Melphalan, prednisone (Âą thalidomide, lenalidomide, or bortezomib) Cyclophosphamide, prednisone Vincristine, adriamycin, dexamethasone Thalidomide Âą dexamethasone Bortezomib, doxorubicin HCl liposome injection (Âą dexamethasone) Bortezomib, thalidomide (or lenalidomide), dexamethasone Cyclophosphamide, thalidomide (or lenalidomide), dexamethasone Dexamethasone (pulse dose) DT-PACE (Âą bortezomib) DT-PACE, dexamethasone, thalidomide, cisplatin, adriamycin, cyclophosphamide, etoposide; MM, multiple myeloma

eligible for transplant. Retrospective studies support the use of a second ASCT in patients with relapsed disease. Nontransplant approaches can involve the use of a single active agent or combinations of active agents that have been studied in different clinical trials. A compilation of the regimens that have been evaluated in different clinical trials is presented in Table 2. As with newly diagnosed MM, inclusion of patients in clinical trials of new agents is recommended for patients with relapsed MM. Outside of a clinical trial, repeating the initial therapy is favored, as long it was tolerated without significant toxicity. Studies into the natural history of MM point toward decreasing response duration, with each relapse reflecting increasingly acquired drug resistance.47 Two of the most promising drugs undergoing clinical trials in this setting include the IMiD pomalidomide, in development by Celgene, and the proteosome inhibitor carfilzomib, in development by Proteolix.

The Phase II trial of pomalidomide and dexamethasone enrolled 60 patients with relapsed MM who had received 1 to 3 prior regimens. The ORR was 58%, including a 25% VGPR, and the regimen was very well tolerated, with a manageable toxicity profile. The

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response rate among patients who were previously refractory to lenalidomide was 29%, demonstrating nonoverlapping mechanisms of action.48 The Phase II trial of carfilzomib, a proteasome inhibitor, enrolled 31 patients with relapsed MM, who had had 3 or fewer prior therapies. The responses were relatively rapid, occurring within 2 cycles; the ORR was 36%, and response was higher among those without previous exposure to bortezomib.49 Other agents being evaluated in ongoing clinical trials are listed in Table 3. Two classes of drugs are of particular interest and are being explored in Phase III trials in combination with novel agents.

These include the histone deacetylase (HDAC) inhibitors and the heat-shock protein (Hsp) inhibitors. The HDAC inhibitor vorinostat is in a Phase III trial in combination with bortezomib based on in vitro synergy and encouraging results from Phase II trials of the combination. Similarly, the Hsp inhibitor tanespimycin (Kosan Biosciences) is in a Phase III trial in combination with bortezomib based on promising results from a Phase II trial. 50 The HDAC inhibitors are also undergoing Phase I/II testing in combination with lenalidomide.14,15

Patients With High-Risk Features at Diagnosis Patients with cytogenetic deletions 13 and 17p and translocations (t)4;14 or 14;16 on fluorescence in situ hybridization tests; cytogenetic hypodiploidy, plasma cell labeling index greater than 3%; and B2M greater than 5.5 tend to have very short response duration with ASCT and should be considered for clinical trials evaluating novel drug combinations. 51 The outcome of these patients with newer induction therapy regimens, however, is not well studied; there are emerging data that bortezomib and lenalidomide may overcome some of these poor prognostic features. In the newly diagnosed setting, bortezomib appears to overcome the adverse impact of del 13 and t(4;14) translocation, based on the results from Phase II and III studies. 52,53 In the context of lenalidomide therapy, newly diagnosed patients with high-risk cytogenetic abnormalities had inferior outcome compared with standard-risk patients in one study, 54 but this finding was not replicated in another study with a relapsed population. 55 In most of the studies that have been conducted, the adverse effect of 17p deletion did not appear to be affected by the novel agents. Patients with these abnormalities should consider novel approaches with lenalidomide and/or bortezomib-containing regimens, and should delay the use of ASCT until relapse. However, recent

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data have suggested that patients with t(4;14) with low B2M and normal hemoglobin may have a better than expected outcome, again highlighting the heterogeneity of the disease. 56 Selected patients also may be candidates for clinical trials with nonmyeloablative SCT.

Supportive Care BISPHOSPHONATES The widespread use of bisphosphonates stems from early trials demonstrating a benefit for pamidronate in reducing skeletal events in patients with MM. The duration of therapy with bisphosphonates and the frequency of administration have been revisited as a result of the increasing recognition of osteonecrosis of the jaw (ONJ) as a complication of the therapy. Although zoledronic acid has been associated with a higher risk for ONJ, pamidronate also can lead to this side effect, with the risk correlating to the duration of therapy. Mayo Clinic has developed a consensus statement regarding the use of bisphosphonates in MM, and the American Society of Clinical Oncology has revised its guidelines to reflect the concerns regarding ONJ. 57,58

ANEMIA Anemia is common in patients with MM and is multifactorial in origin. Typically, effective therapy is associated with improvement in hemoglobin.

Although clinicians have used erythropoietic agents in a limited manner, the most recent guidelines have placed increasing restrictions on their use. Concurrent use of erythropoietin in patients taking lenalidomide or thalidomide increases the risk for thrombosis.

Mayo Clinicâ&#x20AC;&#x2122;s approach is to avoid using erythropoietin in patients with MM, unless hemoglobin does not improve with effective therapy. The target for hemoglobin is 10 to 11 g/dL.

HYPERCALCEMIA Usually seen in the setting of uncontrolled MM, hypercalcemia can be managed with conservative measures, including aggressive hydration and use of loop diuretics. Bisphosphonates can allow for the long-term stable control of hypercalcemia.

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Table 3. Novel Drugs Undergoing Clinical Trials in Myeloma IMiDâ&#x20AC;&#x201D;pomalidomide (Celgene) New proteasome inhibitorâ&#x20AC;&#x201D;carfilzomib (Proteolix) Histone deacetylase inhibitorsâ&#x20AC;&#x201D;vorinostat (Zolinza, Merck); panabinostat (Novartis) Monoclonal antibodiesâ&#x20AC;&#x201D;neural cell adhesion molecule (CD56), interleukin-6 Hsp-90 inhibitorsâ&#x20AC;&#x201D;tanespimycin (Kosan); retaspimycin (Infinity Pharmaceuticals) PI3k/Akt pathway inhibitorâ&#x20AC;&#x201D;perifosine (Keryx Biopharmaceuticals) Farnesytransferase inhibitorâ&#x20AC;&#x201D;tipifarnib (Zarnestra, Johnson & Johnson) Bcl2 inhibitorsâ&#x20AC;&#x201D;ABT737, obatoclax Anti-VEGF agentsâ&#x20AC;&#x201D;sorafenib (Nexavar, Bayer); sunitinib (Sutent, Pfizer) mTOR inhibitorsâ&#x20AC;&#x201D;everolimus (Afinitor, Novartis); temsirolimus (Toricel, Wyeth)

steroidal anti-inflammatory drugs and, rarely, coexistent amyloidosis or light chain deposition disease.

Renal insufficiency in MM should be managed aggressively because renal function can either completely recover or improve significantly in some patients.

Aggressive hydration as well as management of hypercalcemia and hyperuricemia is imperative. The role of plasmapheresis is controversial, but it is likely to benefit patients with high levels of free light chains.

Prompt institution of antimyeloma therapy is important to prevent further deterioration of, and possibly ensure improvement of, renal function. Patients with advanced renal failure will require dialysis support.

VERTEBRAL COMPRESSION FRACTURES RENAL FAILURE Renal impairment of varying degrees is present in nearly 20% of patients diagnosed with MM. Renal insufficiency in MM is multifactorial in etiology and may be the result of one or more factors, including cast nephropathy, hypercalcemia, hyperuricemia, dehydration, hyperviscosity, medications such as non-

Vertebral compression fractures contribute to significant morbidity in patients with MM, and vertebroplasty and kyphoplasty have a definite role in its management. These procedures decrease the pain and improve the spinal deformities associated with compression fractures. However, RCTs are required to define the precise role of these interventions.

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0YV[VPNY <[P\Y\Tf ;Rd` 3V_`a 9\\X N OVZ\[aUYf R [Rd`YRaaR_ aUNa P\[aNV[` [Rd QVTVaNY P\[aR[a [\a S\b[Q V[ aUR ]_V[a RQVaV\[ \S 0YV[<[P

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23. Child JA, Morgan GJ, Davies FE, et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med. 2003;348(19):1875-1883, PMID: 12736280.

24. Blade J, Rosinol L, Sureda A, et al. High-dose therapy intensification compared with continued standard chemotherapy in multiple myeloma patients responding to the initial chemotherapy: longterm results from a prospective randomized trial from the Spanish cooperative group PETHEMA. Blood. 2005;106(12):3755-3759, PMID: 16105975.

25. Fermand JP, Katsahian S, Divine M, et al. High-dose therapy and autologous blood stem-cell transplantation compared with conventional treatment in myeloma patients aged 55 to 65 years: long-term results of a randomized control trial from the Group Myelome-Autogreffe. J Clin Oncol. 2005;23(36):9227-9233, PMID: 16275936.

26. Barlogie B, Kyle RA, Anderson KC, et al. Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma: final results of phase III US Intergroup Trial S9321.

J Clin Oncol. 2006;24(6):929-936, PMID: 16432076.

27. Fermand JP, Ravaud P, Chevret S, et al. High-dose therapy and autologous peripheral blood stem cell transplantation in multiple myeloma: up-front or rescue treatment? Results of a multicenter sequential randomized clinical trial. Blood. 1998;92(9):3131-3136, PMID: 9787148.

28. Moreau P, Facon T, Attal M, et al. Comparison of 200 mg/m2 melphalan and 8 Gy total body irradiation plus 140 mg/m2 melphalan as conditioning regimens for peripheral blood stem cell transplantation in patients with newly diagnosed multiple myeloma: final analysis of the Intergroupe Francophone du Myelome 9502 randomized trial. Blood. 2002;99(3):731-735, PMID: 11806971.

F\b dVYY NY`\ OR Nba\ZNaVPNYYf R[aR_RQ V[a\ N Q_NdV[T a\ dV[ N[ V=\Q a\bPU

29. Attal M, Harousseau JL, Facon T, et al. Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med. 2003;349(26):2495-2502, PMID: 14695409.

30. Cavo M, Tosi P, Zamagni E, et al. Prospective, randomized study of single compared with double autologous stem-cell transplantation for multiple myeloma: Bologna 96 Clinical Study. J Clin Oncol.

2007;25(17):2434-2441, PMID: 17485707.

31. Fermand JP. MAG studies (1985-2005), 10th International Myeloma Workshop, Sydney, April 2005. http://myeloma.org/pdfs/ Sydney2005_Fermand_P8.pdf. Accessed September 23, 2009.

32. Cunningham D, Powles R, Malpas J, et al. A randomized trial of maintenance interferon following high-dose chemotherapy in multiple myeloma: long-term follow-up results. Br J Haematol.

1998;102(2):495-502, PMID: 9695964.

33. Attal M, Harousseau JL, Leyvraz S, et al. Maintenance therapy with thalidomide improves survival in patients with multiple myeloma.

Blood. 2006;108(10):3289-3294, PMID: 16873668.

34. Spencer A, Prince HM, Roberts AW. Consolidation therapy with low-dose thalidomide and prednisolone prolongs the survival of multiple myeloma patients undergoing a single autologous stemcell transplantation procedure. J Clin Oncol. 2009;27:1788-1793, PMID: 19273705.

35. Sonneveld P, van der Holt B, Schmidt-Wolf IGH, et al. Analysis of HOVON-65/GMMG-HD4 randomized Phase III trial comparing bortezomib, adriamycin, dexamethasone (PAD) vs VAD as induction treatment prior to high dose melphalan (HDM) in patients with newly diagnosed multiple myeloma (MM). ASH Annual Meeting Abstracts. Blood. 2008;112:653.

36. Tricot G, Vesole DH, Jagannath S, Hilton J, Munshi N, Barlogie B. Graft-versus-myeloma effect: proof of principle. Blood.

1996;87(3):1196-1198, PMID: 8562947.

37. Bjorkstrand BB, Ljungman P, Svensson H, et al. Allogeneic bone marrow transplantation versus autologous stem cell transplantation in multiple myeloma: a retrospective case-matched study from the European Group for Blood and Marrow Transplantation.

Blood. 1996;88(12):4711-4718, PMID: 8977265.

38. Garban F, Attal M, Michallet M, et al. Prospective comparison of autologous stem cell transplantation followed by dose-reduced allograft (IFM99-03 trial) with tandem autologous stem cell transplantation (IFM99-04 trial) in high-risk de novo multiple myeloma.

Blood. 2006;107(9):3474-3480, PMID: 16397129.

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

11

* 0YVPX UR_R a\ Pb`a\ZVgR f\b_ `bO`P_V]aV\[ F\b N_R ]_R_RTV`aR_RQ a\ _RPRVcR

0YV[VPNY <[P\Y\Tf ;Rd` 3V_`a 9\\X N OVZ\[aUYf R [Rd`YRaaR_ aUNa P\[aNV[` [Rd QVTVaNY P\[aR[a [\a S\b[Q V[ aUR ]_V[a RQVaV\[ \S 0YV[<[P

39. Bruno B, Rotta M, Patriarca F, et al. A comparison of allografting with autografting for newly diagnosed myeloma. N Engl J Med. 2007;356(11):1110-1120, PMID: 17360989.

40. Kyle RA, Rajkumar SV. Multiple myeloma. N Engl J Med. 2004;351(18):1860-1873, PMID: 15509819.

41. Palumbo A, Bringhen S, Caravita T, et al. Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: a randomised controlled trial. Lancet.

2006;367(9513):825-831, PMID: 16530576.

42. Facon T, Mary JY, Hulin C, et al. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06). Lancet.

2007;370(9594):1209-1218, PMID: 17920916.

F\b dVYY NY`\ OR Nba\ZNaVPNYYf R[aR_RQ V[a\ N Q_NdV[T a\ dV[ N[ V=\Q a\bPU

patients with relapsed and refractory multiple myeloma (MM).

ASH Annual Meeting Abstracts. Blood. 2008;112(11):864.

50. Richardson PG, Chanan-Khan A, Lonial S, et al. Tanespimycin plus bortezomib in patients with relapsed and refractory multiple myeloma: final results of a phase I/II study. J Clin Oncol.

2009;27(15 suppl):Abstract 8503.

51. Gertz MA, Lacy MQ, Dispenzieri A, et al. Clinical implications of t(11;14)(q13;q32), t(4;14)(p16.3;q32), and -17p13 in myeloma patients treated with high-dose therapy. Blood. 2005;106(8): 2837-2840, PMID: 15976175.

52. Jagannath S, Richardson PG, Sonneveld P, et al. Bortezomib appears to overcome the poor prognosis conferred by chromosome 13 deletion in phase 2 and 3 trials. Leukemia.

2007;21(1):151-157, PMID: 17096017.

43. Hulin C, Facon T, Rodon P, et al. Efficacy of melphalan and prednisone plus thalidomide in patients older than 75 years with newly diagnosed multiple myeloma: IFM 01/01 trial. J Clin Oncol.

2009;27(22):3664-3670, PMID: 19451428.

53. San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma.

N Engl J Med. 2008;359(9):906-917, PMID: 18753647.

44. San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma.

N Engl J Med. 2008;359(9):906-917, PMID: 18753647.

54. Kapoor P, Kumar S, Fonseca R, et al. Impact of risk stratification on outcome among patients with multiple myeloma receiving initial therapy with lenalidomide and dexamethasone. Blood.

2009;114(3):518-521, PMID: 19324902.

45. Palumbo A, Falco P, Corradini P, et al. Melphalan, prednisone, and lenalidomide treatment for newly diagnosed myeloma: a report from the GIMEMA Italian Multiple Myeloma Network. J Clin Oncol.

2007;25(28):4459-4465, PMID: 17785703.

46. Palumbo AP, Bringhen S, Rossi D, et al. A phase III study of VMPT versus VMP in newly diagnosed elderly myeloma patients. J Clin Oncol. 2009;27(15 suppl):Abstract 8515.

47. Kumar SK, Therneau TM, Gertz MA, et al. Clinical course of patients with relapsed multiple myeloma. Mayo Clin Proc.

2004;79(7):867-874, PMID: 15244382.

48. Lacy MQ, Hayman SR, Gertz MA, et al. Pomalidomide (CC4047) plus low-dose dexamethasone (pom/dex) is highly effective therapy in relapsed multiple myeloma. ASH Annual Meeting Abstracts. Blood. 2008;112(11):866.

49. Jagannath S, Vij R, Stewart KA, et al. Initial results of PX-171-003, an open-label, single arm, Phase II study of carfilzomib (CFZ) in

12

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55. Reece D, Song KW, Fu T, et al. Influence of cytogenetics in patients with relapsed or refractory multiple myeloma treated with lenalidomide plus dexamethasone: adverse effect of deletion 17p13. Blood. 2009;114(3):522-525, PMID: 19332768.

56. Moreau P, Attal M, Garban F, et al. Heterogeneity of t(4;14) in multiple myeloma. Long-term follow-up of 100 cases treated with tandem transplantation in IFM99 trials. Leukemia.

2007;21(9):2020-2024, PMID: 17625611.

57. Kyle RA, Yee GC, Somerfield MR, et al. American Society of Clinical Oncology 2007 clinical practice guideline update on the role of bisphosphonates in multiple myeloma. J Clin Oncol.

2007;25(17):2464-2472, PMID: 17515569.

58. Lacy MQ, Dispenzieri A, Gertz MA, et al. Mayo Clinic consensus statement for the use of bisphosphonates in multiple myeloma.

Mayo Clinic Proc. 2006;81(8):1047-1053, PMID: 16901028.

* 0YVPX UR_R a\ Pb`a\ZVgR f\b_ `bO`P_V]aV\[ F\b N_R ]_R_RTV`aR_RQ a\ _RPRVcR

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SUPPORTIVE CARE

CLINICAL ONCOLOGY NEWS â&#x20AC;˘ SEPTEMBER/OCTOBER 2009

Pain Management

Onsolis Comes With First Opioid REMSâ&#x20AC;&#x201D;and Some Rancor

Onsolis should not be substituted by or for any other fentanyl products. â&#x20AC;&#x153;Onsolis can provide strong pain relief to patients who are opioid tolerant. But for patients who are not opioid tolerant, it can lead to overdose, sudden serious breathing difficulties and death,â&#x20AC;? said Bob Rappaport, MD, director, Division of Anesthesia, Analgesia and Rheumatology Products in the FDAâ&#x20AC;&#x2122;s Center for Drug Evaluation and Research (CDER). â&#x20AC;&#x153;For this reason, Onsolis should be prescribed only under the safeguards provided by the FDA-required REMS and by health care professionals knowledgeable about Onsolis and the use of potent opioid medications.â&#x20AC;?

fits-allâ&#x20AC;? plan for all opioids, given that the product is a short-acting medication. â&#x20AC;&#x153;The REMS for Onsolis was specifically tailored to that drug and should not be viewed as a model REMS for long-acting and extended-release opioid products,â&#x20AC;? said Douglas Throckmorton, MD, deputy director of CDER. â&#x20AC;&#x153;Developing the comprehensive REMS for these other products is a complex undertaking. We will take the time necessary to review all of the public comments and will proceed in a deliberate manner toward the mutual goals of patient access and patient protection.â&#x20AC;? â&#x20AC;&#x153;The chief concern for oral membrane fentanyl products is the fact that patients need to be opioid tolerant,â&#x20AC;? said Dr. Finn. â&#x20AC;&#x153;Thatâ&#x20AC;&#x2122;s not the concern for long-acting products. There are different safety concerns for the two products so they have to be different kinds of REMS.â&#x20AC;?

FOCUS

APS Frustration

The Onsolis Full Ongoing Commitment to User Safety (FOCUS) program will include a prescriber/pharmacy training program, educational materials and patient counseling calls to ensure they understand how to properly use the drug. The hot-button component of FOCUS, however, is the restricted distribution program.

â&#x20AC;&#x153;The FDA has held a series of meetings with stakeholders, including a large public meeting, and also has solicited written public comments to hear more about how to develop this REMS,â&#x20AC;? said the FDA in a statement announcing the Onsolis approval. In a July 24 letter from APS president Charles E. Inturrisi, PhD, to Dr. Rappaport, the APS

â&#x20AC;&#x153;There is a restricted distribution program that the FDA has required but we donâ&#x20AC;&#x2122;t see that being in any way an obstacle to the proper patients receiving the product,â&#x20AC;? said Andrew Finn, MD, executive vice president of product development for BioDelivery Sciences, in a July 17 teleconference. â&#x20AC;&#x153;The product will be delivered to a courier service, and thatâ&#x20AC;&#x2122;s the way it will be delivered to the patient directly. We think thatâ&#x20AC;&#x2122;s a positive.â&#x20AC;? â&#x20AC;&#x153;We donâ&#x20AC;&#x2122;t see it [the REMS] affecting the long-term sales of this product,â&#x20AC;? agreed BioDelivery Sciences CEO Mark Sirgo in the same teleconference. â&#x20AC;&#x153;We actually think this educational process will drive usage, and do it in an appropriate way by making sure the product gets to appropriate patients.â&#x20AC;?

The FDA was quick to point out that the REMS for Onsolis was not a â&#x20AC;&#x153;one-size-

acknowledged the opportunity to present its recommendations to the agency, but added that it was â&#x20AC;&#x153;surprised and disappointedâ&#x20AC;? that the Onsolis REMS was â&#x20AC;&#x153;in stark contrast to many of the stakeholder suggestions made.â&#x20AC;? â&#x20AC;&#x153;We [the APS] are concerned with the well-documented issues of misuse, abuse and overdose deathsâ&#x20AC;&#x201D;particularly in [young people]â&#x20AC;&#x201D;but we advocate for a rational approach that will minimize secondary, unintended consequences such as restriction of access to proper pain care,â&#x20AC;? said Edward Michna, MD, APS Public Policy Committee co-leader. â&#x20AC;&#x153;Of concern, in particular, are the already underserved communities.â&#x20AC;?

One of the concerns of the APS is that REMS will not be required for all opioids. â&#x20AC;&#x153;We do want to emphasize again our belief that opiate-induced dangers and

The approval of a new opioid pain reliever for the treatment of some cancer patients with breakthrough pain may seem on the surface as simply a step forward in pain pharmacotherapy.

The FDAâ&#x20AC;&#x2122;s approval of the pain drug Onsolis, however, is replete with backstory and the potential for ongoing controversy, as the agent is the first in the opioid drug class to come with a Risk Evaluation and Mitigation Strategy (REMS), an FDAmandated plan for minimizing risks associated with taking a drug.

The Onsolis REMSâ&#x20AC;&#x201D;and most likely the risk plans for all opioids for which they will be requiredâ&#x20AC;&#x201D;will include a restricted distribution program under which prescribers, pharmacies and patients would have to register in order to prescribe, dispense and receive Onsolis, respectively.

The drug will be delivered directly to the patientâ&#x20AC;&#x2122;s home and is restricted in physician offices and hospitals in order to reduce the risk for diversion. This, and several other aspects of REMS, have come under fire from groups like the American Pain Society (APS), which feels that many of the recommendations it made regarding REMS during its development process were ignored by the FDA. Empowered by the Food and Drug Administration Amendments Act of 2007 to require drugs to carry REMS, the FDA first acknowledged in February that it would ask 24 manufacturers of longacting and extended-release opioids to develop such risk management plans for their products. Each of these agents is formulated with one of the following active ingredients: fentanyl, hydromorphone, methadone, morphine, oxycodone and oxymorphone.

Onsolis (fentanyl buccal soluble film, Meda AB, BioDelivery Sciences) is indicated for the management of breakthrough pain in adult patients with cancer (aged â&#x2030;Ľ18 years) already taking and tolerant of opioids for their chronic cancer pain. The focus of a clinical trial program involving more than 300 patients and 90,000 administered doses, Onsolis is slated for launch in the fourth quarter of 2009.

Although Onsolis is a short-acting agent, it was required to include a REMS because of safety concerns with fentanyl products. An opioid analgesic, fentanyl is a Schedule II controlled substance with substantial potential for misuse and abuse. Onsolis will carry a boxed warning on its label, stating it should not be used to treat migraines, dental or postoperative pain or by patients taking opioids on an intermittent basis. The required labeling will stress that, given substantial differences between the pharmacokinetic profile of Onsolis and other fentanyl products that affect the degree of drug absorption,

the REMS to address them share many features across the opiate drug classâ&#x20AC;&#x201D; regardless of their route of administration, onset of action and potency,â&#x20AC;? the APS president wrote in the letter.

If the REMS do not cover all opioids, â&#x20AC;&#x153;you will probably drive prescribing to the uncovered class,â&#x20AC;? said Dr. Michna.

The following issues were among those described in the APS letter regarding the â&#x20AC;&#x153;stringent and complicatedâ&#x20AC;? Onsolis REMS. Registry requirements. â&#x20AC;&#x153;The attempted reassurance in the announcement that after patient, prescriber and dispenser are all found to be registered the drug should be delivered within five business days may give small comfort to the cancer patient without intravenous access in need of rapid analgesia (from for example, dressing changes) several times a day,â&#x20AC;? wrote the APS, â&#x20AC;&#x153;particularly if the patient happens to be located in a place where distribution is restricted like a hospital.â&#x20AC;?

Restricted distribution. â&#x20AC;&#x153;Not allowing hospital and institutional pharmacies to stock these medications for immediate use â&#x20AC;Ś denies patients and prescribers access to medications that may for these clinical situations be the best alternative,â&#x20AC;? according to the APS. Patient education. Although medication guides are â&#x20AC;&#x153;worthwhile educational efforts,â&#x20AC;? they are not an adequate replacement for a knowledgeable pharmacist or clinician, according to the APS. â&#x20AC;&#x153;Many patients suffering from cancerrelated pain are cognitively impaired, particularly at the end of life, which makes counseling and education of a patient, let alone a counseling call, difficult or impossible.â&#x20AC;?

The APS urged the FDA to once again be open to stakeholder input, especially from pain and palliative care groups, to ensure the â&#x20AC;&#x153;unintended consequencesâ&#x20AC;? of implementing REMS are reduced. â&#x20AC;&#x153;It would indeed be tragic if the very patients that these products were developed and approved for were denied access to their specific therapeutic qualities,â&#x20AC;? the letter concluded.

Making it clear that he was speaking as an individual and not on behalf of the APS, Dr. Michna said he believes the REMS will limit access to Onsolis. â&#x20AC;&#x153;I have spoken to many physicians about this and no one is going to be certified for this med,â&#x20AC;? he said.

Actiq (transmucosal fentanyl citrate, Cephalon) and Fentora (fentanyl buccal tablet, Cephalon), two other fentanylbased products, will also include REMS, both of which are purported to be similar in nature to the Onsolis risk plan. â&#x20AC;&#x201D;Donald M. Pizzi

11

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ADVERTISEMENT

Advances in monoclonal antibody technology Immunogenicity and monoclonal antibodies While the development of therapeutic monoclonal antibodies has advanced the practice of medicine dramatically, immunogenicity remains an important clinical problem in oncology.1,2 The acute symptoms of a hypersensitivity reaction may include rash, ďŹ&#x201A;ushing, urticaria, dyspnea, fever, bronchospasm, edema, and hypotension.3,4 Occasionally, patients experience life-threatening anaphylaxis requiring emergency medical interventions; and rarely death.2,3,5 Further, immune reactions sometimes require discontinuation of treatment, potentially leading to an adverse impact on therapy outcomes.2 Repeated exposure to the foreign proteinâ&#x20AC;&#x201C;containing monoclonal antibody increases the risk for the immune-mediated reactions and may lead to the formation of neutralizing antibodies.1,6

Monoclonal antibodies over time The ďŹ rst therapeutic monoclonal antibody was introduced clinically in the early 1980s and was composed of 100% murine protein. While monoclonal antibodies of murine origin displayed clinical activity, their usefulness was limited by the substantial immunogenicity inherent in the foreign protein. By 1997, recombinant DNA technology had advanced to a point where it was possible to create chimeric monoclonal antibodies, reducing the amount of murine protein to approximately 35%. Since that time, a number of chimeric monoclonal antibodies have been approved in oncology.3,7

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In the last decade, new technologies have allowed the development of monoclonal antibodies containing 100% human protein.1 A variety of fully human monoclonal antibodies have been evaluated in clinical trials.1,6 Although any protein has the potential to elicit an immune response, a fully human monoclonal antibody is anticipated to contain fewer sites that might be considered foreign.6

No monoclonal antibody is immune to immune reactions Four important molecular features of therapeutic monoclonal antibodies may contribute to immunogenicity: Allotypic differences: Individual polymorphisms in the constant region of monoclonal antibodies may induce an immune response in patients that is speciďŹ c to the constant region of the therapeutic monoclonal antibody.8,9 Idiotypic differences: Differences in the variable region of a therapeutic monoclonal antibody, or idiotype, may lead to the production of antibodies speciďŹ c to this region of the therapeutic monoclonal antibody.8,10,11 Foreign protein content: Murine amino acid sequences may be recognized as foreign, leading to the production of antibodies speciďŹ c to the foreign component of certain chimeric monoclonal antibodies.1,6,7,10 Production method: The commercial production of a monoclonal antibody may modify protein structure or introduce abnormal glycosylation patterns, creating a molecule that is recognized as foreign; some patients may have preexisting antibodies to these sugars or other components created during the manufacturing process.

Patients exposed to these factors may experience unexpected allergic reactions even on ďŹ rst administration of the monoclonal antibody.5,12

Amgen Oncology: improving monoclonal antibody technology Amgen Oncology is focused on developing novel therapeutics to help address medical needs. We are currently exploring the potential of fully human monoclonal antibodies in multiple therapeutic areas. For more information, please visit www.Amgen.com.

Multiple Pathways Singular Vision

References: 1. Weiner LM. J Immunother. 2006;29:1-9. 2. Schwartzberg LS, Stepanski EJ, Fortner BV, Houts AC. Support Care Cancer. 2008;16:393-398. 3. Kang SP, Saif MW. J Support Oncol. 2007;5:451-457.

4. NCI Common Terminology Criteria for Adverse Events v3.0, August 9, 2006. http://ctep.cancer.gov/ protocolDevelopment/electronic_applications/docs/ctcaev3.pdf. Accessed August 5, 2009. 5. Chung CH, Mirakhur B, Chan E, et al. N Engl J Med. 2008;358:1109-1117. 6. Jakobovits A, Amado RG, Yang X, et al. Nat Biotechnol. 2007;25:1134-1143. 7. Oldham RK, Dillman RO. J Clin Oncol.

2008;26:1774-1777. 8. Reinsberg J. In: Albitar M, ed. Methods in Molecular Biology, vol 378: Monoclonal Antibodies: Methods and Protocols. Totowa, NJ: Humana Press Inc; 2007.

9. Pandey JP. Vaccine. 2001;19:613-617. 10. Klee GG. Arch Pathol Lab Med. 2000;124:921-923. 11. Rajewsky K, Takemori T. Ann Rev Immunol. 1983;1:569-607.

12. Peeters M, Balfour J, Arnold D. Aliment Pharmacol Ther. 2008;28:269-281. Š2009 Amgen. All rights reserved.

7-09 44246

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F\b dVYY NY`\ OR Nba\ZNaVPNYYf R[aR_RQ V[a\ N Q_NdV[T a\ dV[ N[ V=\Q a\bPU

POLICY & MANAGEMENT

CLINICAL ONCOLOGY NEWS â&#x20AC;˘ SEPTEMBER/OCTOBER 2009

Health Care

RED FLAGS continued from page 1

compliance than I am about potential audits, surveys or â&#x20AC;&#x2DC;out-rightâ&#x20AC;&#x2122; government intrusion into practices â&#x20AC;Ś I donâ&#x20AC;&#x2122;t think many private practices have spent a lot of time other than concern, but I might be wrong on this issue.â&#x20AC;?

The HIPAA of 1996 made protecting the privacy of patients a top priority for hospitals, health care providers, insurance companies and other entities.

Now, the Federal Trade Commission (FTC), which promulgated the rule, hopes the Red Flags Rule will combat a potentially even greater threat to patients: identity theft.

At the heart of the FTCâ&#x20AC;&#x2122;s Identity Theft Red Flags Rule program is the agencyâ&#x20AC;&#x2122;s assertion that physicians, by accepting credit cards and deferring payments, are â&#x20AC;&#x153;creditorsâ&#x20AC;? or â&#x20AC;&#x153;financial institutions,â&#x20AC;? and therefore are covered under banking regulations regarding consumer privacy. The program mandates that medical practices must create and institute programs that are appropriate to their size and operation, with the goal of identifying and detecting patterns, practices and activities that indicate the possible breach of privacy of patient data. The FTC calls such breaches â&#x20AC;&#x153;red flags.â&#x20AC;?

Identity thieves are increasingly focused on stealing medical records, which contain not only Social Security and credit card numbers, billing addresses and dates of birth, but also insurance and personal health information.

Thieves can use this information not only to obtain goods, open accounts and more, but also to seek medical care in the victimâ&#x20AC;&#x2122;s name, ultimately corrupting the victimâ&#x20AC;&#x2122;s true medical history and records and sometimes receiving care for which the victim is billed. According to the FTC, 4.5% of the annual 8.3 million victims of identity theft had their medical information plundered.

However, the rule comes at a time when many medical practices are no longer accepting credit cards. A recent survey of more than 202,000 physiciansâ&#x20AC;&#x2122; offices

by SK&A Informational Services, found that the number that had stopped taking plastic rose to 33%, from 28% in 2008.

One reason: transaction fees, typically 3% to 4% per charge, that practices must pay credit card companies.

Physician Lobby Fought the Law ...

In early 2009, the American Medical Association submitted a detailed argument to the FTC against the red flags regulation. The group objected to the proposed rule on several grounds, claiming that: â&#x20AC;˘ Physicians should not be considered creditors because they submit claims to health insurance carriers, who

should be considered the creditors; â&#x20AC;˘ Physicians already have devoted substantial resources to complying with privacy and security requirements of HIPAA; and â&#x20AC;˘ The mandate could have unintended consequences, such as physicians demanding payment up front or abandoning the practice of medicine altogether.

... But the Law Won However, the FTC dismissed those concerns. Although the agency acknowledged that the primary responsibility of physicians is to provide

health care, they also conduct businesses that provide services for which payment may be deferred. The FTC also said the red flags rule comple ments, not duplicates, HIPAAâ&#x20AC;&#x2122;s data security requirements.

Nor should the measure impose significant burdens on providers, especially those â&#x20AC;&#x153;in a low-risk environment,â&#x20AC;? because it is designed to be flexible and â&#x20AC;&#x153;tailored,â&#x20AC;? said Eileen Harrington, acting director of the FTCâ&#x20AC;&#x2122;s Bureau of Consumer Protection.

Ms. Harrington noted that many simple protections already are in place in physiciansâ&#x20AC;&#x2122; offices, such as checking

photo identification cards, training staff to detect fraud, restricting access to patient files and monitoring for suspicious activity in patient accounts.

George Kovach, MD, medical director of Iowa Cancer Specialists, said that protecting against identify theft wasnâ&#x20AC;&#x2122;t necessarily hard to do. â&#x20AC;&#x153;The rule is more of nuisance,â&#x20AC;? Dr. Kovach said. â&#x20AC;&#x153;I would like clear direction from the government as to what they would like us to do and we are not getting it.â&#x20AC;?

Legal Viewpoint Mark F. Weiss, an attorney with the see RED FLAGS, page 16

15

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16

POLICY & MANAGEMENT

CLINICAL ONCOLOGY NEWS â&#x20AC;˘ SEPTEMBER/OCTOBER 2009

Health Care

RED FLAGS continued from page 15

Advisory Law Group, a California firm with offices in Los Angeles and Santa Barbara, said clinicians need to understand that compliance goes handin-hand with fidelity to HIPAA. â&#x20AC;&#x153;HIPAA and other patient confidentiality rules exist to protect the secrecy of patientsâ&#x20AC;&#x2122; health care information; compliance with the red flags rule will help prevent an individualâ&#x20AC;&#x2122;s health care records from becoming polluted with an imposterâ&#x20AC;&#x2122;s data,â&#x20AC;? Mr. Weiss said.

The rule presents a series of steps to determine whether or not a practice is actually covered, Mr. Weiss said. Because the penalties for noncompliance can be severe, implementing a program to prevent identity theft as required by the measure makes sense.

Some medical groups use outside billing services, so groups need to coordinate their programs with

The Nov. 1 deadline is the third extension of the Red Flags Rule program given to medical practices, as few seem to have established programs and many appear to be unaware of the mandate.

the billing service, Mr. Weiss said. â&#x20AC;&#x153;However, as the group is responsible for compliance, the process cannot simply be outsourced to the billing service and then forgotten.â&#x20AC;?

According to Mr. Weiss, â&#x20AC;&#x153;security breachesâ&#x20AC;? are not the only thing to fear: Problems could stem from the simple fact of not establishing or implementing a program.

What happens if physicians do not comply? â&#x20AC;&#x153;The penalty can be as high as $2,500 for each â&#x20AC;&#x2DC;knowing violation,â&#x20AC;&#x2122; â&#x20AC;? he said. â&#x20AC;&#x153;A groupâ&#x20AC;&#x2122;s noncompliance might be global and not just limited to a single instance, so it is conceivable that their liability or one violation might result, upon further investigation, into liability for many penalties.â&#x20AC;?

Advice From an ID Theft Specialist In the minds of specialists who deal with solutions to identity theft, businessesâ&#x20AC;&#x201D;including medical practicesâ&#x20AC;&#x201D; can hardly go far enough to protect customers, clients and in this case, patients.

Harry Perret, a certified identity theft risk management specialist and executive director of the consulting firm Prevention Benefits, suggested

medical providers hire a specialist to fully protect their practice and comply with the rule, as other businesses have been doing for years. â&#x20AC;&#x153;The liabilities follow the data, and leave the doctors at risk,â&#x20AC;? Mr. Perret said.

Medical offices are required to have a written policy on how to handle nonpublic information (NPI) and personally identifiable

information (PII). All employees must be trained on this policy with documentation of training in their human resources files. An officer must be appointed to be in charge of NPI and PII. Finally, the vendors of the offices must have policies in place in the event there is a data breach, according to Mr. Perret.

Regardless of the means to getting there, the regulation should be taken seriously, and for good

reason, Mr. Perret said. â&#x20AC;&#x153;Medical identity theft is the fastest growing type,â&#x20AC;? he said, â&#x20AC;&#x153;with both financial and potentially lifethreatening results.â&#x20AC;? â&#x20AC;&#x201D;Audrey Andrews

Breakthrough cancer pain

Closing the Gap by

Opening the Dialogue Although breakthrough cancer pain is becoming more widely recognized among healthcare professionals as a serious healthcare problem, there is still a gap between identifying it and actually treating it. This gap may be due partly to the variable and complicated nature of breakthrough cancer pain itself. But, more likely, this gap can be attributed to the limited dialogue that exists between the patient and the clinician.

Patient-related barriers to the conversation Identifying and addressing the patient-related barriers to the dialogue about pain and talking about them proactively with patients is a positive step toward effectively managing breakthrough cancer pain. In actual clinical practice, translating a patientâ&#x20AC;&#x2122;s description of various breakthrough cancer pain episodesâ&#x20AC;&#x201D; often described as â&#x20AC;&#x153;burning, aching, sharp, searing, throbbing, excruciating, relentless, or intolerableâ&#x20AC;?1,2â&#x20AC;&#x201D;into effective pain management can be challenging. It is a process that requires an open dialogue.

Barriers to the dialogue may manifest themselves in a number of ways. For instance, patients may fail to report breakthrough cancer pain to their healthcare provider for emotional or personal reasons and do not want to complain or bother the doctor.1,3

Some patients believe that an admission of pain indicates a worsening of their disease.1 Other patients may be reluctant to distract the physician from treating the cancer.1 Many patients have a fear of drug addiction and do not want to be thought of as addicts.2 They are afraid to use opioids,1,3 often failing to fill prescriptions. Concern about unmanageable side effectsâ&#x20AC;&#x201D;such as mental confusion and analgesic addictionâ&#x20AC;&#x201D;may be an issue for some patients.4 Also, some patients may be unable to assess pain levels or understand treatment regimens.

Most patients and caregivers do not understand the difference between persistent and breakthrough cancer pain or the difference between the types of medications used to treat them.5 This lack of knowledge causes a disconnect that can influence the way a patient takes pain medication.5 For example, a patient with chronic pain may decide not to take extra medicine during episodes of increased pain (breakthrough cancer pain) because he/she is concerned about the number of pills taken per day.5 One survey of 40 patients with terminal cancer found that 60% believed that being given drugs for pain was harmful to them and that they should refrain from taking such therapy too often.3

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A D V E R T I S E M E N T

Starting the right conversation

Patient dialogue tools can facilitate discussion

There are several ways to open the dialogue with your patients to help reassure, educate, and empower them to openly discuss their pain and medication.

Consider sharing the following statements with patients to help them take charge of their pain and symptom management. For instanceâ&#x20AC;&#x201D;

There are numerous resources available that are designed to facilitate the discussion, but how you approach the subject also plays an important role.

Try using a simple set of numeric scales to help patients express the magnitude of their pain.1 Consider asking patients open-ended questions1 such as, â&#x20AC;&#x153;What is your average pain?â&#x20AC;? and, â&#x20AC;&#x153;What is your worst pain?â&#x20AC;? to help determine if the pain is breakthrough cancer pain. Also ask, â&#x20AC;&#x153;How often

If your patients seem afraid to complain, say: not have to suffer in pain from cancer pain arenâ&#x20AC;&#x2122;t working not mean I have stopped treating the cancer If your patients are reluctant to take medication, you might say: not wait until your cancer pain is â&#x20AC;&#x153;unbearableâ&#x20AC;? to take your medication prescribed pain medication believe you will really need them For your patients who fear drug addiction, try saying something like: are not considered drug addicts

things you want or need to do?â&#x20AC;? to help understand how breakthrough cancer pain impacts their quality of life.

Discussion leads to actionable information Breakthrough cancer pain is challenging to treat and can be difficult for the patient, the family, and loved ones. It is important for patients and healthcare providers to develop an open and honest dialogue to determine the extent of breakthrough cancer pain and to make informed treatment decisions. Armed with the right tools and information, healthcare providers can offer patients the comfort and relief they need.

Next in the Series: â&#x20AC;&#x153;Knowing Your Options Can Help Keep It Under Controlâ&#x20AC;?

References: 1. Cleeland CS. The impact of pain on the patient with cancer. Cancer.

1984;54(11 suppl):2635-2641. 2.

exactly as prescribed 3. opioids among patients with metastatic cancer during the last year of life.

J Pain Symptom Manage 4.

Cancer 5. in the comprehensive management of pain. Pain Practitioner

Š2009 MEDA Pharmaceuticals Inc. All rights reserved. Printed in the USA. 08/09 BEM9033

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18

SUPPORTIVE CARE

CLINICAL ONCOLOGY NEWS â&#x20AC;˘ SEPTEMBER/OCTOBER 2009

Bone Metastases

RADIOACTIVE DRUG continued from page 1

Cancer Center in New York. â&#x20AC;&#x153;Furthermore, medical isotope providers are telling us to expect continued shortages of technetium-99m.â&#x20AC;?

Historically inexpensive, technetium-99m (Tc-99m) emits low radiation, has a convenient six-hour half-life and gives off a level of energy that can be optimized by gamma cameras. As a result, the radioisotope has a wide range of diagnostic uses. It can easily be attached to a wide variety of compounds and is used to identify obstructions in the kidneys, visualize gastric emptying, gauge cardiac function and measure blood flow in the brain.

In oncology, Tc-99m has two primary uses. One application is in bone scans to identify metastases; the other is to measure the ejection fraction of the heart in patients who are receiving cardiotoxic chemotherapy. A small amount of Tc-99m also is used as a tracer in sentinel lymph node procedures. â&#x20AC;&#x153;It is in many respects an ideal radioisotope,â&#x20AC;? said Michael M. Graham, MD, PhD, president of the Society of Nuclear Medicine, and professor of radiology and director of nuclear medicine at the University of Iowa Carver College of Medicine, in Iowa City.

Dr. Graham explained that it can be used to look at the function of an organ system, not just anatomy.

But the once common isotope has become scarce.

Tc-99m is made from another isotope called molybdenum-99 (Mo-99). Molybdenum is created by placing uranium-235 into the core of a nuclear reactor. The fission of the uranium-235 atom breaks it into two fragments, one of which, Dr. Graham explained, is Mo-99. â&#x20AC;&#x153;As you can imagine, the fuel element is extraordinarily radioactive. So, this has to be done in a remote processing facility, and there are a fairly limited number of these facilities around,â&#x20AC;? he said.

Historically, about 80% of the United Statesâ&#x20AC;&#x2122; molybdenum came from two reactors, the Chalk River reactor in Ontario, Canada, and the Petten reactor in the Netherlands, Dr. Graham said. But in May, the Chalk River reactor was shut down because of safety concerns. Then this summer, the Petten reactor shut down for scheduled maintenance. Now the only sources are reactors in South Africa and Australia, which typically produce 15% of the worldâ&#x20AC;&#x2122;s supply, said Dr. Graham.

The Impact David Mankoff, MD, PhD, professor of radiology, medicine and bioengineering at the University of Washington in Seattle, is seeing an impact of the shortage. â&#x20AC;&#x153;The shortage will sometimes limit the number of studies that can be done in a particular day. We have had to set up a system of reviewing and, when necessary, triaging studies when this happens, so that the

Chalk River Labs seen from the Ottawa River, in Canada. In May, the Chalk River reactor, a source of Tc-99m, was shut down out of safety concerns.

most urgent tests get done,â&#x20AC;? he said.

Patients seeking elective tests, including some cancer patients, sometimes have short delays in their studies. â&#x20AC;&#x153;Technetium-99m is fairly heavily used in oncology, but [only] in a few specific indications, for example bone scans, and most of them tend not to be emergencies. Fortunately, so far, the delays have been short; nevertheless, delays in diagnostic scans can cause delays in treatment and should be avoided whenever possible.â&#x20AC;?

â&#x20AC;&#x2DC;The shortage will sometimes limit the number of studies that can be done in a particular day.â&#x20AC;&#x2122; â&#x20AC;&#x201D;David Mankoff, MD, PhD

Homer Macapinlac, MD, professor and chair of the Department of Nuclear Medicine at the University of Texas M.D. Anderson Cancer Center, in Houston, said his facility has seen the supply drop 20%. Its supplier does not rely solely on the Canadian reactor, he said.

Dr. Macapinlac has worked with his supplier to get advance warning of shortages, which can help with planning. Additionally, he has reduced dosing in some scans.

Dr. Macapinlac said such scans take longer, making them less comfortable and inconvenient for patients.

The cost of Tc-99m has also skyrocketed, Dr. Graham said. â&#x20AC;&#x153;In the past, the average cost at our university was about $20 per dose. The price has doubled in the last few months. With additional shortages, it is likely to go higher. The problem is that the margin on these studies is remarkably slim. With the prior arrangement, we were barely breaking even. Now this tips us over the edge.â&#x20AC;?

For patients needing tests, there are some alternatives but they can have drawbacks. For example, a fullbody CAT scan can be used to do a bone scan; however, it involves a much higher radiation dose than Tc-99m

and has a lower sensitivity, Dr. Graham said.

Dr. Macapinlac said he is using thallium, a different radioactive tracer, in patients who need myocardial perfusion imaging. â&#x20AC;&#x153;We might not be able to do the scan as optimally as weâ&#x20AC;&#x2122;d like, and we certainly do not like to switch techniques, but we need to deal with this on a daily or weekly basis,â&#x20AC;? he said.

Waiting for a Solution Dr. Graham said the Tc-99m shortage was not unexpected. About a decade ago, Canada announced it would build two new reactors to supply the worldâ&#x20AC;&#x2122;s need for medical isotopes while replacing the production of the aging reactors. â&#x20AC;&#x153;That was supposed to be the solution for the whole world. Everybody was sort of standing back and saying, â&#x20AC;&#x2DC;letâ&#x20AC;&#x2122;s let Canada do it.â&#x20AC;&#x2122; But those reactors have a critical design flaw that makes it essentially impossible, or financially unfeasible, for them to fix,â&#x20AC;? Dr. Graham said.

Now, some are trying to bring the solution to the United States.

On July 21, Rep. Edward J. Markey (D-Mass.) introduced a bill called the American Medical Isotopes Production Act of 2009, which calls for the creation of a program to evaluate and support production of Mo-99 in this country for medical use. Dr. Macapinlac called the bill â&#x20AC;&#x153;our best hope to have a lasting solution to this [shortage].â&#x20AC;?

On Sept. 9, several experts, including Dr. Larson, testified on behalf of the bill to the House Committee on Energy and Commerce. â&#x20AC;&#x153;The recent shutdown of NRU reactor at Chalk River in Canada has disrupted supplies of this important isotope to our clinic and to other hospitals in the northeastern United States,â&#x20AC;? Dr. Larson said. â&#x20AC;&#x153;At present, we have the acute exacerbation of a chronic problem with technetium-99m supplies that is the result of an unhealthy dependency on reactors in other countries whose operational life expectancy is unpredictable.

The development of a reliable domestic supply of technetium-99m is good public policy.â&#x20AC;? â&#x20AC;&#x201D;David Jakubiak

CareFusion Launches Jazz Festival Series

C

areFusion created the CareFusion Jazz Festival Series to support the launch of this new company and recognize individuals and organizations working to improve patient care.

The new medical technology company combines its proven technologies with information to help measurably improve the delivery of patient care. The Jazz Festival Series comprises some of the largest and oldest jazz festivals in the world, attracting both big-name and upand-coming artists. â&#x20AC;&#x153;There is a clear connection between jazz and medicine that provides the perfect

opportunity to launch our new brand, raise funds for and awareness of patient safety and help support and preserve the arts,â&#x20AC;? said David Schlotterbeck, CEO of CareFusion. â&#x20AC;&#x153;Both jazz and the practice of medicine embrace innovation, performance and change. Jazz is also used to teach listening skills to medical students and resonates with our customers.â&#x20AC;? (The connection between jazz and medicine is also made at mcmahonjazzmedicine.com, a sister publication of this newsmagazine, which celebrates the improvisational nature of creative art and the practice of medicine.)

The CareFusion Jazz Festival Series schedule includes: George Weinâ&#x20AC;&#x2122;s CareFusion Jazz Festival 55 (Newport, R.I.), Aug. 7â&#x20AC;&#x201C;9, 2009, completed Chicago Jazz Festival presented by CareFusion, Sept. 4â&#x20AC;&#x201C;6, 2009, completed CareFusion Presents Dizzyâ&#x20AC;&#x2122;s Den at the Monterey Jazz Festival, Sept. 18â&#x20AC;&#x201C;20, 2009, completed CareFusion Manly Jazz Festival (Australia), Oct. 3â&#x20AC;&#x201C;5, 2009, completed CareFusion Jazz Festival Paris, Oct. 16â&#x20AC;&#x201C;24, 2009

CareFusion New York Jazz Festival, June 2010 (exact dates TBD) As part of the Festival Series, CareFusion will broadcast the performances of selected festival artists live to hospitals. Caregivers and administrators from hospitals across the United States, Europe and Australia will also be invited to special VIP events at the festivals to raise funds and awareness for a new health care safety campaign named â&#x20AC;&#x153;Rhythm of Care,â&#x20AC;? which brings together organizations and people from health care to promote best practices.

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PRINTER-FRIENDLY VERSION AT CLINICALONCOLOGY.COM

Management of

Cutaneous T-Cell Lymphoma FREDERICK LANSIGAN, MD Assistant Professor of Medicine Hematology and Oncology Norris Cotton Cancer Center Dartmouth-Hitchcock Medical Center Lebanon, New Hampshire

FRANCINE M. FOSS, MD Professor of Medicine Hematological Malignancies Medical Oncology Yale Cancer Center New Haven, Connecticut

C

utaneous T-cell lymphoma (CTCL) is a heterogeneous group of lymphoproliferative diseases characterized by infiltration of the skin by malignant T-cells, comprises approximately 4%

of the non-Hodgkinâ&#x20AC;&#x2122;s lymphomas in the United States.

The classification of cutaneous lymphomas describes several subtypes of CTCL: mycosis fungoides (MF), its variants, and the SĂŠzary syndrome (SS), which comprise 44% of cases; the CD30+ lymphomas, such as anaplastic large cell lymphoma of the skin and lymphomatoid papulosis; and aggressive forms of peripheral T-cell lymphoma (PTCL), including PTCLunspecified, panniculitic T-cell lymphoma, and natural killer (NK)/T-cell lymphomas of the skin.1 According to a recent review of the SEER (Surveillance, Epidemiology and End Results) database and other registries, the incidence of CTCL is on the rise. It is estimated that 6.4 per 1 million people will be diagnosed with CTCL annually.2 Patients with early-stage disease frequently have an indolent clinical course; however, those with advanced stages have a shortened survival. An accepted treatment approach has been to delay traditional chemotherapy, which can cause excessive toxicity without durable benefit.

More conservative treatment strategies in the initial management of CTCL have led to the development of newer biologic and targeted therapies.

MF, the most common form of CTCL, is considered a more indolent form of the disease, whereas SS is a more aggressive leukemic form with both blood and skin involvement. The skin manifestations of CTCL are multiple and include patches or plaques, cutaneous tumors, ulcerations or fissuring of the skin, patchy or diffuse erythroderma, and exfoliation.

Generally, early-stage MF evolves slowly from patch-plaque disease to more aggressive forms, including cutaneous tumors, erythroderma, and visceral involvement. The diagnoses of MF and SS are based on the presence of characteristic malignant T-cells with cerebriform or convoluted nuclear contours in the epidermis and dermis. The malignant cells may occur in clusters with a perinuclear halo, called a Pautrierâ&#x20AC;&#x2122;s microabscess. In earlystage disease, infiltration may be minimal and diagnosis may be based on immunophenotypic features of the T-cells, including loss of normal antigen expression or the presence of clonal T-cell receptors in genotypic analysis.

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

Clinical Staging and Prognosis of MF and SS Staging of patients with MF and SS is essential both for its prognostic value and for decisions in management. The most commonly used staging system for MF/SS is based on a tumor-node-metastasis-blood (TNMB) classification (Table 1).3 When MF is grouped by stage, patients with patchplaque disease (stages IA, IB, and IIA) have an excellent survival of more than 12 years; those with tumors or erythroderma (stages IIB/III) have a median survival of approximately 4 years; and those with stage IV, which includes patients with lymph node or visceral involvement, have a median survival of less than 3 years.4 Similarly, SS has a median survival of less than 3 years.5,6 Many patients die not from their disease but from infectious complications, which are likely due to impaired immunity, as well as immunosuppressive effects of systemic therapies.

Treatment Decisions about initial or subsequent therapies should be made based on disease stage, overall prognosis, and quality of life for the patient. For early-stage patients in whom remission is likely, the goal should be to avoid long-term treatment-related toxicities; for patients with aggressive disease, approaches often include skin-directed as well as systemic therapies, including biologic or targeted therapy. For younger patients with highly refractory or advanced disease, allogeneic stem cell transplantation provides a potentially curative treatment. The sequence of treatment frequently depends on the experience of the treating physicians and institution, as well as patient preference. Treatment algorithms for MF/SS include combined or sequential therapies with multiple skin-directed and systemic agents (Table 2).7

Skin-Directed Therapies Patients with early-stage MF often present with disease limited to the

C L I N I C A L O N CO LO GY N E WS â&#x20AC;˘ S E P T E M B E R /O C TO B E R 2 0 0 9

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Table 1. Tumor-Node-Metastasis-Blood Classification And Clinical Staging System for Mycosis Fungoides

N

M

T1: Limited Patch/ Plaque (<10% BSA)

N0: Nodes clinically uninvolved

M0

IA

N1: Nodes enlarged, histologically uninvolved

M0

IIA

N2â&#x20AC;&#x201C;3: Nodes clinically normal (N2) or enlarged (N3), histologically involved

M0

IVA

N0â&#x20AC;&#x201C;3: Visceral involvement

M1

IVB

T2: Generalized Patch/Plaque (â&#x2030;Ľ10% BSA)

T3 Tumor

T4 Erythroderma

IB

IIB

IIIA IIIB

B: Classification not incorporated in the clinical stage B0: Absence of significant peripheral blood SĂŠzary cells B1: Presence of significant peripheral blood SĂŠzary cells BSA, body surface area Adapted from reference 3.

skin without systemic involvement, that is, patch-plaque disease. These patients usually have an intact cellular immune response, so that treatment with skin-directed agents often is sufficient to induce clearing of disease and can produce effective long-term responses in roughly 60% of cases.

Intermediate- and high-potency topical corticosteroids produce clinical remission in 25% to 63% of patients, but the duration of benefit may be short.8 Long-term use of topical steroids, especially over a large body surface area, can suppress endogenous cortisol secretion in approximately 15% of patients treated, and can cause cutaneous atrophy. Oral corticosteroids also are effective; however, they can cause the unwanted side effects of osteoporosis, adrenal suppression, altered glucose metabolism, and steroid-induced myopathies.

Topical nitrogen mustard (mechlorethamine; Mustargen, Ovation), an alkylating agent that damages cellular DNA and induces apoptosis, is available in an ointment-based preparation and can be very effective in palliating skin lesions in patients in all stages of disease, even when systemic treatment for CTCL is being administered. It has been shown to produce complete response (CR) rates of 26% to 76% in stage I disease, and 22% to 49% in stage III disease.9 Some patients with stage IA disease may be cured; however, relapses are frequent even when therapy is continued after remission. One limitation of topical nitrogen mustard therapy is that it is not widely available and must be prepared by a compounding pharmacy.

Side effects of nitrogen mustard include irritant reactions, and up to 40% of patients develop contact hypersensitivity. Nitrogen mustard is carcinogenic and secondary cutaneous malignancies, such as squamous and basal cell carcinomas, have been attributed to its long-term use.10 Retinoids have demonstrated efficacy in the treatment of MF/SS and have antiproliferative, antiangiogenic, immune-modulating, and cellular effects.11 Bexarotene, a novel RXR-retinoid (rexinoid), has shown biological activity in both a topical formulation, bexarotene gel (Targretin Gel, Eisai) and an oral formulation (Targretin, Eisai; see below) in patients with early and advanced MF/SS. It is very effective in patients with patch-plaque disease. In clinical trials of bexarotene gel, 44% to 64% of patients with stage I MF responded.12 The median time to response was 4.5 months, and the median duration of response was 23 months. The major toxicity of bexarotene gel is cutaneous hypersensitivity and increased redness or itching.

Often, alternating applications of corticosteroids and bexarotene can alleviate these effects.

Phototherapy with psoralen plus ultraviolet A radiation (PUVA) is a skindirected therapy that causes apoptosis of infiltrating tumor cells and mononuclear cells, including Langerhanâ&#x20AC;&#x2122;s cells, which support CTCL survival in the skin microenvironment.13 Retrospective studies of PUVA monotherapy demonstrated response rates from 50% to 63%, with 50% of responders showing sustained remissions, although most of the responders were patients with stage I disease.14,15 Prolonged use of PUVA has been associated with skin erythema and secondary malignancies, including melanoma and squamous and basal cell carcinomas.14 Ultraviolet B radiation (UVB) has a lower penetration into the skin and is selectively absorbed in the epidermis. UVB has been shown to induce CR in 71% of early-stage

20

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MF patients, with a median duration of 22 months; however, fewer durable responses were seen in patients with significantly infiltrated plaque-stage CTCL.16 Narrowband UVB can penetrate deeper in the dermis and is not associated with secondary skin cancers.17-19 The choice of light-directed therapy is based on many factors, including depth of the infiltrate as well as risk for secondary skin changes in the individual patient.

Total skin electron beam therapy (TSEBT) is a therapeutic modality in which electron radiation is administered to the entire skin surface. TSEBT is usually administered over a course of 9 to 12 weeks. Due to the limited penetration by electrons, systemic toxicity is rare. TSEBT, which is often used for patients with extensive skin involvement, can be combined with adjuvant systemic modalities such as retinoids, PUVA, or photopheresis, or with nodal radiation approaches.20-24 The response rate is high for early-stage disease (90%-95%), and the therapy is curative for patients with stage IA disease.25-28 Long-term toxicity includes anhydrosis, telangiectasia, and secondary skin cancers. TSEBT also is effective as palliative therapy in patients with aggressive, extensive disease, including patients with erythroderma. Spot radiation is often employed for palliation in patients with cutaneous tumors, ulcerations, or fissures. Radiation recall may occur when radiation-sensitizing agents such as gemcitabine, adriamycin, or liposomal doxorubicin are administered concurrently with, or within weeks of, TSEBT and should be avoided.

Systemic Therapy Systemic therapies for MF/SS often are employed in patients with stage IIB or higher disease, or in patients with early-stage disease who have become refractory to skin-directed therapies or have developed dose-limiting toxicities to UV or ionizing radiation (Table 3). For these patients, many systemic treatments, including novel agents, are widely acceptable. Often, systemic agents are administered in combination with topical therapies.

EXTRACORPOREAL PHOTOPHERESIS Extracorporeal photopheresis (ECP) is a treatment for MF/SS that involves leukapheresis to isolate mononuclear cells, which are then exposed ex vivo to UVA in the presence of methoxypsoralen and reinfused into the patient.29 Methoxypsoralen incorporates into DNA, and in the presence of ultraviolet light induces strand breaks, and, subsequently, apopotosis.30 Circulating T-cells and SĂŠzary leukemia cells are susceptible to UVA-induced apoptosis. The mechanism of action of ECP is believed to be related to the induction of apoptosis in clonal SĂŠzary T-cells, leading to uptake and processing of tumor antigens by immature dendritic cells generated from the effects of the ECP process on circulating monocytoid dendritic cell precursors.31,32 Edelson et al reported the first results with ECP in 1987, with a response rate of 73% in relapsed MF/SS patients, including those with erythrodermic MF, SS, or nodal involvement.33 Other studies have shown similar responses to ECP monotherapy; however, the best responders seem to be patients with a short duration of disease, an absence of bulky lymphadenopathy, and low SĂŠzary counts, and who have not received immunosuppressive

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Table 2. Treatment Algorithms According to Disease Stage Stage

Initial Therapy

Relapsed/Refractory Disease

IA

Skin-directed therapy

Additional skin-directed therapya OR Skin-directed therapya with biologicb or single-agent therapyc

IB/IIA

Skin-directed therapya and/or biologic therapyb

Skin-directed therapya + biologic therapyb OR Single-agent therapyc

IIB

Skin-directed therapy (PUVA, electron beam radiation therapy) plus biologic therapyb OR Single-agent therapyc

Multimodality combinations: skin-directed therapya plus single-agent chemotherapy or biologic therapyb OR Multiagent therapy OR Allogeneic stem cell transplantation

IIIA/B

ECP Âą skin-directed therapya OR Multimodality combinations with systemic therapy or biologic therapyb

Multimodality combinations with single-agent therapyc or multiagent therapyd OR Allogeneic stem cell transplantation

IVA/B

Single-agent chemotherapyc OR Combination biologic therapyb OR Multiagent therapyd

Salvage chemotherapy OR Allogeneic stem cell transplantation

a

a

Skin-directed therapy: topical steroids (intermediate and high potency); topical nitrogen mustard or bischloroethylnitrosourea ointment or aqueous solution; topical retinoids (bexarotene gel, tazarotene cream and gel); phototherapy (UVB for patch or thin plaque, PUVA for thick plaque); electron beam irradiation (localized for limited disease, total skin for extensive skin involvement).

b

Biologic therapy: interferon-alfa; retinoids (bexarotene, 13-cis retinoic acid, all-trans-retinoic acid); ECP; alemtuzumab.

c

Single-agent therapy: methotrexate (low-dose oral or intravenous); denileukin diftitox; HDAC inhibitor (vorinostat); liposomal doxorubicin; gemcitabine; pentostatin; etoposide; cyclophosphamide; bortezomib; temozolomide.

d

Multiagent combination therapies: biologic combinations (PUVA, UVB, or ECP + retinoids Âą interferon); denileukin diftitox + bexarotene; retinoids + interferon; PUVA, UVB, or ECP with HDAC inhibitor (under investigation); cytotoxic multiagent regimens (gemcitabine, vinorelbine; liposomal doxorubicin; EPOCH; hyper-CVAD; ICE; etoposide, methylprednisolone, cytarabine, cisplatin).

ECP, extracorporeal photopheresis; EPOCH, etoposide, vincristine, doxorubicin, cyclophosphamide, and oral prednisone; HDAC, histone deacetylase; hyper-CVAD, cyclophosphamide, mesna, vincristine, doxorubicin, dexamethasone, filgrastim, methotrexate, leucovorin, cytarabine, methylprednisolone; ICE, ifosfamide, carboplatin, and etoposide; PUVA, psoralen plus ultraviolet A; UVB, ultraviolet B Adapted from reference 7.

chemotherapy.34,35 ECP is well tolerated and often is the first systemic therapy used in patients with erythrodermic CTCL. Maximal response may take as long as 4 to 6 months, and many patients remain on therapy for 1 year or longer. The timing of ECP treatments varies and includes 2 consecutive treatments once per month as well as an escalated schedule of 2 consecutive treatments every other week. Response is measured by reduction in overall skin tumor burden and by a decrease in circulating SĂŠzary cells and restoration of a normal CD4/CD8 ratio. Combinations of ECP with other systemic agents, such as interferon-Îł (INF-Îł) or bexarotene, and other treatment modalities, such as TSEBT or PUVA, have demonstrated efficacy and may reduce the time to response.

CYTOKINE THERAPIES Because the host immune response plays a pivotal role in the immune surveillance and clearing of CTCL cells, biologic agents such as cytokines can be used to augment the immune response. IFN-Îą was first shown to have activity in CTCL in 1984 by Bunn et al.36 Heavily treated patients with advanced disease were treated with IFN-Îą and showed a 45% objective response rate. Subsequent studies confirmed activity in early- and latestage disease patients, with 73% response in stages IA to IIA, and 60% response in stages IIB to IVA, many of them durable.37 The acute toxicities of IFN-Îą, which include fever, chills, arthralgias, myalgias, and malaise, usually dissipate after the first week of treatment. Chronic toxicities such as fatigue, anorexia, weight loss, and mood lability improve over time or with dose modification. In the practical management of early-stage CTCL, IFN-Îą can be used as an adjunct to topical therapy, or after failure of skindirected agents. Combinations of IFN-Îą with ECP,38 and IFN with PUVA, oral retinoids, and cytotoxic chemotherapy39 have also shown encouraging results. The dosing of IFN-Îą and the administration schedule used have varied among clinical studies. In most instances, low doses of 3 million to 10 million units are administered 2 or 3 times per week, and the schedule

and dose are tailored to individual patient response and toxicities.

IFN-Îł also has shown efficacy in patients with early- and advancedstage CTCL when administered with photopheresis. Because SĂŠzary cells are associated with a Th2 cytokine profile, there is a deficit of IFN-Îł in the microenvironment of the malignant cells, and the malignant cells are resistant to its effects.40 Administration of recombinant IFN-Îł to local tumor sites has been studied using TG-1042, a replicationdeficient adenovirus type 5 that carries the IFN-Îł gene, for the potential treatment of CTCL and cutaneous B-cell lymphoma (CBCL).41 A Phase I/II clinical trial in CTCL and CBCL was recently completed and a Phase II clinical trial is under way.

Another strategy to increase IFN-Îł production in CTCL cells is to administer recombinant human IL-12 (rhIL-12). A clinical study of rhIL-12 in early MF (stages IA-IIA) was conducted in which rhIL-12 was administered biweekly (100 ng/kg for 2 wk, 300 ng/kg thereafter) to 23 MF patients (stage IA, 12 patients; IB, 9; and IIA, 2) who had failed previous therapies.42 Ten of the 23 patients (43%) achieved partial response (PR); 7 (30%) achieved minor response; and 5 (22%) had stable disease. The duration of PRs ranged from 3 to more than 45 weeks. Twelve patients (52%) ultimately progressed, with a mean time to progressive disease of 57 days (range, 28-805). Adverse events included constitutional symptoms of asthenia, headache, chills, fever, injection site reaction, pain, myalgia, arthralgia, as well as elevated aspartate and alanine aminotransferase levels. One patient died from hemolytic anemia.

RETINOID THERAPY In a clinical trial of heavily pretreated patients with refractory CTCL, oral monotherapy with bexarotene resulted in response rates of 54% in early-stage and 45% in advanced-stage disease patients.43 The median response duration was 299 days with continuous dosing of 300 mg/m2 per day, and responses occurred in patients in all groups (57% in stage

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

21

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Table 3. Results of Treatment of CTCL With Systemic Chemotherapy

Treatment

Response Rate, %

Duration of Response, mo

Bortezomib66

67

7-14

Cladribine62-64

13-38

3-4

80

8

19

7.5

70

8

Pegylated liposomal doxorubicin65

88

13

Pentostatin60

71

2-4

67

EPOCH

Fludarabine59 Gemcitabine

57

EPOCH, etoposide, vincristine, doxorubicin, cyclophosphamide, oral prednisone

IIB, 32% in stage III, 44% in stage IVA, and 40% in stage IVB), including those with large cell transformation. Pruritus decreased significantly in the treated patients and led to overall improvement in quality of life.

The major toxicities of bexarotene included elevations in serum lipids and cholesterol and suppression of thyroid function. Elevations in lipids occurred rapidly, within 2 to 4 weeks, and required the use of lipid-lowering agents in the majority of patients. Patients on bexarotene also developed a dose-dependent central hypothyroidism with low levels of thyroid-stimulating hormone and free thyroxin within weeks of starting the medication. Symptoms of hypothyroidism may be subtle because they include fatigue/asthenia, depression, cold intolerance, and constipation. Levothyroxine was found to alleviate these symptoms and improve tolerance of treatment. Oral bexarotene is often started at a low dose (2-4 mg/d) and titrated to achieve therapeutic effect. Laboratory studies should be performed weekly until lipids and thyroid function are stable and then performed monthly during therapy.

Targeted Therapy DENILEUKIN DIFTITOX Denileukin diftitox (Ontak, Eisai) is a fusion protein toxin that targets interleukin-2 (IL-2) receptorâ&#x20AC;&#x201C;bearing cells including CTCL cells. In October 2008, the FDA granted full approval to denileukin diftitox for the treatment of persistent or recurrent CTCL in patients whose malignant cells express the CD25 component of the IL-2 receptor. The previously granted accelerated approval was converted to full approval status based on a priority review of data from a Phase III, randomized, placebo-controlled study (N=144) that verified its clinical benefit. The study by Negro-Vilar et al showed that treatment with denileukin diftitox in either the 9 or 18 mcg/kg per day formulations yielded a significantly increased overall response rate (ORR) compared with placebo (37% and 46% vs 15%; P=0.002 and P=0.03, respectively).44 The 9-mcg/kg per day dose contributed to a 58% reduction in the risk for disease progression and the 18-mcg/kg per day dose resulted in a 73% risk reduction.

Physicians administering this medication should be aware of potentially serious side effects, including serious infusion reactions, capillary leak syndrome, and loss of visual acuity. The FDA boxed warning states that denileukin diftitox should only be administered in a facility equipped and staffed for cardiopulmonary resuscitation and that treatment should be immediately and permanently discontinued if there are serious infusion reactions. The incidence of infusion reactions in 3 clinical studies (N=234) was 70.5%; in 8.1% of patients, the reactions were considered serious. Additionally, because of the risk for potentially fatal capillary leak syndrome, patients should be monitored for weight changes, edema, blood pressure, and serum albumin levels before and during denileukin diftitox therapy. The most common adverse reactions were pyrexia, nausea, fatigue, rigors, vomiting, diarrhea, headache, peripheral edema, cough, dyspnea, and pruritus.

Denileukin diftitox was administered in combination with oral bexarotene in a Phase I trial in patients with relapsed or refractory MF/SS.45 It was demonstrated that oral bexarotene upregulates the expression of the IL-2

22

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receptor and thus may potentiate the effects of denileukin diftitox. The ORR was 70%, and responders included patients who had stable disease or no response on denileukin diftitox alone. The combination was well tolerated, with no overlapping adverse events. The lowest effective dose of bexarotene in the combination trial was 150 mg daily.

MONOCLONAL ANTIBODIES Unmodified monoclonal antibodies have also demonstrated efficacy in the treatment of CTCL. Alemtuzumab (Campath, Bayer) is a humanized monoclonal antibody directed against the CD52 antigen, which is abundantly expressed on all normal and most malignant T lymphocytes. Alemtuzumab has been administered at a dose of 30 mg 3 times a week until maximum response in patients with CTCL and other T-cell malignancies.46,47 Apart from first-dose reactions, which were common, treatment was well tolerated, with the main complications being infection and viral reactivation associated with the prolonged lymphopenia, and cardiac toxicities.

There was a report of large cell transformation of CTCL after treatment with alemtuzumab. In both SS and MF patients, ORRs were high. Zanolimumab (Genmab) is a humanized monoclonal antibody directed against CD4. In a Phase I study, patients with treatment-refractory CD4+ CTCL were treated with escalating doses of zanolimumab (early-stage disease, 280 and 560 mg; advanced-stage disease, 280 and 980 mg). Responses were seen in both MF and SS patients, and the ORR in the high-dose groups was 56%, with a median response of 81 weeks.48 Adverse events included low-grade infections and eczematous dermatitis. Depletion of normal CD4+ cells occurred.

HISTONE DEACETYLASE INHIBITORS Epigenetic modulation has emerged as a novel therapeutic approach for patients with T-cell lymphomas. Histone deacetylase (HDAC) inhibitors prevent the removal of the acetyl modification from lysine residues, leading to a more open chromatin structure and to global alterations in gene expression.49 Vorinostat (Zolinza, Merck), an oral HDAC inhibitor, was approved by the FDA in 2006 for the treatment of the skin manifestations of MF and SS. In a Phase II trial of vorinostat given at different doses and schedules, responses were seen in 30% of the patients; 42% experienced relief of pruritus.50 A multicenter Phase IIB trial using 400 mg vorinostat daily also showed an ORR of 30% with one CR.51 The median time to response was 2 months, and the response duration was 9.8 months or longer. The most common side effects were diarrhea, nausea, fatigue, and anorexia. Asymptomatic QTc prolongation was observed on serial electrocardiograms in 4% of patients but was not clinically significant.

Panobinostat (Novartis) is another orally administered HDAC inhibitor that has shown promising results in CTCL. Preliminary results of a Phase II study of panobinostat in bexarotene-naĂŻve and bexarotenetreated patients have been reported.52 Eleven of 66 evaluable patients (16.7%) who had received bexarotene and were given panobinostat orally at a dose of 20 mg on days 1, 3, and 5, had confirmed responses, including 2 CRs. Of 35 bexarotene-naĂŻve patients, 4 (11.4%) had a confirmed response. Median duration of response ranged from 9.25 to 11 months. Thrombocytopenia and neutropenia were the most common grade 3 or 4 toxicities.

Another HDAC inhibitor, romidepsin (Gloucester Pharmaceuticals), demonstrated activity in CTCL patients in a National Cancer Institute study published in 2001.53 The response rate was 30% and response durations of 8 to 14 months or longer were reported in refractory, heavily pretreated patients.53 More recently, preliminary results of a Phase II, open-label, multiarm, multicenter study of romidepsin in 71 patients with relapsed or refractory CTCL were reported.54 Romidepsin was administered at a dose of 14 mg/m2 as a 4-hour infusion on days 1, 8, and 15 every 28 days. Patients had a median of 2 previous treatments.

For 63 patients who received at least 2 cycles of therapy, the ORR was 40% (CR, 6%; PR, 33%). The median time to response was 1.8 months, and the median duration of response was 11 months or longer. Because earlier studies demonstrated that romidepsin may be associated with electrocardiogram changes, specifically QTc prolongation, extensive electrocardiographic and cardiac monitoring was performed during the study. Independent review of electrocardiograms showed a median increase in QTcF of 6 to 7 ms, which was not clinically significant, and no patient developed symptomatic arrhythmia.54 The FDAâ&#x20AC;&#x2122;s Oncology Drugs Advisory Committee (ODAC) voted on Sept. 2, 2009, to recommend the approval of romidepsin for the treatment of CTCL.

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PRALATREXATE: A NOVEL TARGETED ANTIFOLATE Pralatrexate (Folotyn, Allos) is a novel targeted antifolate with a high affinity for the reduced folate carrier. Cancer cells overexpress the reduced folate carrier RFC-1, and thus selectively accumulate the drug. Once inside the cells, pralatrexate interferes with the action of dihydrofolate reductase (DHFR), a key enzyme involved in the synthesis of deoxythymidine and the purine DNA nucleotides, which leads to cell death. A recent Phase II trial of pralatrexate (PROPEL) was completed in patients with aggressive PTCL, and the reported response rate in refractory patients was 27%. A multicenter, open-label, Phase I, dose-finding study of pralatrexate is ongoing in patients with CTCL who have failed at least one previous systemic therapy.55 Nine of 17 (53%) evaluable patients achieved a response, including PR in 7 patients and CR in 2 patients. Responding patients had previously received up to 8 treatment regimens. This study is designed as a dose deescalating study, and is ongoing to identify a dose and schedule (2 out of 3 weeks or 3 out of 4 weeks) of pralatrexate that can result in maintained responses with minimal toxicity. The most common toxicities of pralatrexate include mucositis and stomatitis and bone marrow suppression. On September 25, 2009, the FDA granted accelerated approval to pralatrexate for the treatment of relapsed or refractory PTCL based on the results of the PROPEL trial.

FORODESINE: A NOVEL PURINE NUCLEOSIDE PHOSPHORYLASE INHIBITOR Forodesine (BioCryst) is a potent inhibitor of purine nucleoside phosphorylase (PNP) that leads to intracellular accumulation of dGTP, resulting in apoptosis in T lymphocytes. During a Phase I, open-label dose-escalation study of oral forodesine, 9 doses (40-320 mg/m2 daily) were administered to patients with refractory CTCL via IV infusion for 30 minutes (day 1), followed 24 hours later by doses every 12 hours (days 2-5); 3 courses were given at 16-day intervals. Of 13 CTCL patients treated, 9 had an improvement in skin or a decrease in the absolute number of SĂŠzary cells.56 The most frequent adverse events were nausea, fatigue, and reversible lymphopenia. A Phase II study is under way in patients with relapsed or refractory CTCL.

CYTOTOXIC CHEMOTHERAPY If the agents described fail to control indolent disease, or if there is rapidly progressing or aggressive de novo disease, more potent chemotherapy is warranted. Because of the chronic nature of the disease, single-agent chemotherapy that allows the sequential use of these agents is preferred.

Gemcitabine (Gemzar, Lilly) has demonstrated impressive clinical activity in advanced and refractory CTCL, with a 70% response rate and a median response duration of 8 months.57 The incidence of grade 3 neutropenia was 25%. In a study of chemotherapy-naĂŻve patients treated with 1,200 mg/m2, the response rate was 70%, with 5 CRs.57,58 Other purine analogues, including fludarabine, cladribine (Leustatin, Ortho Biotech), and pentostatin, also have demonstrated efficacy.59-64 Pegylated liposomal doxorubicin (Doxil, Centocor Ortho Biotech) was associated with an ORR of 88%, a CR rate of 42%, and a disease-free survival of 13 months.65 With the exception of infusion-related events, liposomal doxorubicin was well tolerated. Responders received up to 18 cycles of pegylated liposomal doxorubicin.

Bortezomib (Velcade, Millennium) administered on a weekly schedule was reported recently to have an impressive response rate of 67% in patients who had recurring MF/SS.66 All responses were durable, lasting from 7 to 14 months or longer. Overall, the drug was well tolerated, with no grade 4 toxicity, and combination therapy studies are under way.

Despite numerous treatment alternatives, many patients who have advanced MF/SS rapidly become refractory to therapy, presumably because of drug resistance. Responses to combination chemotherapy regimens such as cyclophosphamide, doxorubicin, vincristine, and prednisolone are high, but response durations are short. Infusion chemotherapy with etoposide, vincristine, doxorubicin, cyclophosphamide, and oral prednisone (EPOCH) was studied in heavily pretreated CTCL patients and resulted in an ORR of 80%, with a CR rate of 27%.67 The median progression-free survival was 8 months, and SĂŠzary cells were undetectable in 2 of 6 patients who had SS. Other intensive lymphoma salvage regimens likewise have demonstrated responses, albeit with significant toxicity related to immunosuppression.

Hematopoietic Stem Cell Transplantation Hematopoietic stem cell transplantation offers CTCL patients a chance for long-term cure. High-dose chemotherapy and autologous stem cell

transplantation have yielded disappointing results.68 Allogeneic stem cell transplantation provides the advantages of a sustained immune-mediated graft-versus-lymphoma effect and a graft that is uncontaminated with tumor cells but with the risk for peritransplantation morbidity and mortality. Allogeneic transplantation including reduced-intensity conditioning regimens for MF and SS demonstrates a graft-versus-tumor effect and long-term remissions in selected patients.69 The timing of allogeneic stem cell transplantation is also an important factor to consider. In patients who have a large disease burden or who have had multiple previous relapses, allogeneic transplantation should be considered earlier in the disease course if a human leukocyte antigenâ&#x20AC;&#x201C;matched donor is identified.

Conclusion Although several treatments have shown efficacy in the management of CTCL, very few patients are cured of their disease. The overall goals of treatment for most patients are to reduce the disease burden with minimal toxicity from treatment, palliate the symptoms of pruritus and compromised skin integument, and prevent infection and immunosuppression.

As the role of biologic agents is becoming better understood, new combination strategies can be designed and tested.

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27. Quiros PA, Jones GW, Kacinski BM, et al. Total skin electron beam therapy followed by adjuvant psoralen/ultraviolet-A light in the management of patients with T1 and T2 cutaneous T-cell lymphoma (mycosis fungoides). Int J Radiat Oncol Biol Phys.

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52. Duvic M, Becker JC, Dalle S, et al. Phase II trial of oral panobinostat (LBH589) in patients with refractory cutaneous T-cell lymphoma (CTCL). ASH Annual Meeting Abstracts. Blood. 2008;112(11):Abstract 1005.

28. Wilson LD, Quiros PA, Kolenik SA, et al. Additional courses of total skin electron beam therapy in the treatment of patients with recurrent cutaneous T-cell lymphoma. J Am Acad Dermatol. 1996;35(1):69-73, PMID: 8682967.

53. Piekarz RL, Robey R, Sandor V, et al. Inhibitor of histone deacetylation, depsipeptide (FR901228), in the treatment of peripheral and cutaneous T-cell lymphoma: a case report. Blood. 2001;98(9):2865-2868, PMID: 11675364.

29. Knobler RM. Photopheresisâ&#x20AC;&#x201D;extracorporeal irradiation of 8-MOP containing bloodâ&#x20AC;&#x201D;a new therapeutic modality. Blut. 1987;54(4):247-250, PMID: 3493819.

54. Bates S, Piekarz R, Wright J, et al. Final clinical results of a Phase 2 NCI multicenter study of romidepsin in recurrent cutaneous T-cell lymphoma (molecular analyses included). ASH Annual Meeting Abstracts. Blood. 2008;112(11):Abstract 1568.

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31. Edelson RL. Cutaneous T cell lymphoma: the helping hand of dendritic cells. Ann N Y Acad Sci. 2001;941:1-11, PMID: 11594563.

32. Berger CL, Hanlon D, Kanada D, et al. The growth of cutaneous T-cell lymphoma is stimulated by immature dendritic cells. Blood. 2002;99:2929-2939, PMID: 11929784.

33. Edelson R, Berger C, Gasparro F, et al. Treatment of cutaneous T-cell lymphoma by extracorporeal photochemotherapy. Preliminary results. N Engl J Med. 1987;316(6):297303, PMID: 3543674.

34. Zic JA, Miller JL, Stricklin GP, King LE Jr. The North American experience with photopheresis. Ther Apher. 1999;3(1):50-62, PMID: 10079806.

35. Zic J, Arzubiaga C, Salhany KE, et al. Extracorporeal photopheresis for the treatment of cutaneous T-cell lymphoma. J Am Acad Dermatol. 1992;27(5 pt 1):729-736, PMID: 1430395.

36. Bunn PA Jr, Foon KA, Ihde DC, et al. Recombinant leukocyte A interferon: an active agent in advanced cutaneous T-cell lymphomas. Ann Intern Med. 1984;101(4):484-487, PMID: 6332565.

37. Olsen EA, Rosen ST, Vollmer RT, et al. Interferon alfa-2a in the treatment of cutaneous T cell lymphoma. J Am Acad Dermatol. 1989;20(3):395-407, PMID: 2783939.

38. Dippel E, Schrag H, Goerdt S, Orfanos CE. Extracorporeal photopheresis and interferon-alpha in advanced cutaneous T-cell lymphoma. Lancet. 1997;350(9070):32-33, PMID: 9217723.

39. Olsen EA. Interferon in the treatment of cutaneous T-cell lymphoma. Dermatol Ther.

2003;16(4):311-321, PMID: 14686974.

40. Dummer R, Dobbeling U, Geertsen R, Willers J, Burg G, Pavlovic J. Interferon resistance of cutaneous T-cell lymphoma-derived clonal T-helper 2 cells allows selective viral replication. Blood. 2001;97(2):523-527, PMID: 11154232.

41. Urosevic M. Drug evaluation: TG-1042, an adenovirus-mediated IFNgamma gene delivery for the intratumoral therapy of primary cutaneous lymphomas. Curr Opin Investig Drugs. 2007;8(6):493-498, PMID: 17621880.

42. Duvic M, Sherman ML, Wood GS, et al. A phase II open-label study of recombinant human interleukin-12 in patients with stage IA, IB, or IIA mycosis fungoides. J Am Acad Dermatol. 2006;55(5):807-813, PMID: 17052486.

43. Duvic M, Hymes K, Heald P, et al. Bexarotene is effective and safe for treatment of refractory advanced-stage cutaneous T-cell lymphoma: multinational phase II-III trial results. J Clin Oncol. 2001;19(9):2456-2471, PMID: 11331325.

44. Negro-Vilar A, Dziewanowska A, Groves ES, et al. Efficacy and safety of denileukin diftitox (Dd) in a phase III, double-blind, placebo-controlled study of CD25+ patients with cutaneous T-cell lymphoma (CTCL). J Clin Oncol. 2007;25(18 suppl):Abstract 8026.

45. Foss F, Demierre MF, DiVenuti G. A phase-1 trial of bexarotene and denileukin diftitox in patients with relapsed or refractory cutaneous T-cell lymphoma. Blood.

2005;106(2):454-457, PMID: 15811959.

46. Lundin J, Hagberg H, Repp R, et al. Phase 2 study of alemtuzumab (anti-CD52 monoclonal antibody) in patients with advanced mycosis fungoides/Sezary syndrome.

Blood. 2003;101(11):4267-4272, PMID: 12543862.

24

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

55. Horwitz SM, Duvic M, Kim Y, et al. Pralatrexate (PDX) is active in cutaneous T-cell lymphoma: preliminary results of a multi-center dose-finding trial. ASH Annual Meeting Abstracts. Blood. 2008;112(11):Abstract 1569.

56. Duvic M, Forero-Torres A, Foss F, Olsen E, Pinter-Brown L, Kim Y. Long-term treatment of CTCL with the oral PNP inhibitor, forodesine. J Clin Oncol. 2009;27(suppl 15s):Abstract 8552.

57. Zinzani PL, Baliva G, Magagnoli M, et al. Gemcitabine treatment in pretreated cutaneous T-cell lymphoma: experience in 44 patients. J Clin Oncol. 2000;18(13):2603-2606, PMID: 10893292.

58. Marchi E, Alinari L, Tani M, et al. Gemcitabine as frontline treatment for cutaneous T-cell lymphoma: phase II study of 32 patients. Cancer. 2005;104(11):2437-2441, PMID: 16216001.

59. Von Hoff DD, Dahlberg S, Hartstock RJ, Eyre HJ. Activity of fludarabine monophosphate in patients with advanced mycosis fungoides: a Southwest Oncology Group study. J Natl Cancer Inst. 1990;82(16):1353-1355, PMID: 1696322.

60. Kurzrock R, Pilat S, Duvic M. Pentostatin therapy of T-cell lymphomas with cutaneous manifestations. J Clin Oncol. 1999;17(10):3117-3121, PMID: 10506607.

61. Foss FM, Ihde DC, Breneman DL, et al. Phase II study of pentostatin and intermittent high-dose recombinant interferon alfa-2a in advanced mycosis fungoides/Sezary syndrome. J Clin Oncol. 1992;10(12):1907-1913, PMID: 1453206.

62. Kuzel TM, Hurria A, Samuelson E, et al. Phase II trial of 2-chlorodeoxyadenosine for the treatment of cutaneous T-cell lymphoma. Blood. 1996;87(3):906-911, PMID: 8562961.

63. Saven A, Carrera CJ, Carson DA, Beutler E, Piro LD. 2-Chlorodeoxyadenosine: an active agent in the treatment of cutaneous T-cell lymphoma. Blood. 1992;80(3):587-592, PMID: 1353380.

64. Oâ&#x20AC;&#x2122;Brien S, Kurzrock R, Duvic M, et al. 2-Chlorodeoxyadenosine therapy in patients with T-cell lymphoproliferative disorders. Blood. 1994;84(3):733-738, PMID: 7913841.

65. Wollina U, Dummer R, Brockmeyer NH, et al. Multicenter study of pegylated liposomal doxorubicin in patients with cutaneous T-cell lymphoma. Cancer. 2003;98(5):993-1001, PMID: 12942567.

66. Zinzani PL, Musuraca G, Tani M, et al. Phase II trial of proteasome inhibitor bortezomib in patients with relapsed or refractory cutaneous T-cell lymphoma. J Clin Oncol.

2007;25(27):4293-4297, PMID: 17709797.

67. Akpek G, Koh HK, Bogen S, Oâ&#x20AC;&#x2122;Hara C, Foss FM. Chemotherapy with etoposide, vincristine, doxorubicin, bolus cyclophosphamide, and oral prednisone in patients with refractory cutaneous T-cell lymphoma. Cancer. 1999;86(7):1368-1376, PMID: 10506727.

68. Olavarria E, Child F, Woolford A, et al. T-cell depletion and autologous stem cell transplantation in the management of tumour stage mycosis fungoides with peripheral blood involvement. Br J Haematol. 2001;114(3):624-631, PMID: 11552988.

69. Herbert KE, Spencer A, Grigg A, Ryan G, McCormack C, Prince HM. Graft-versuslymphoma effect in refractory cutaneous T-cell lymphoma after reduced-intensity HLA-matched sibling allogeneic stem cell transplantation. Bone Marrow Transplant.

2004;34(6):521-525, PMID: 15286686.

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26

SOLID TUMORS

CLINICAL ONCOLOGY NEWS SEPTEMBER/OCTOBER 2009

Prostate

Tool Will Help Counsel Patients After Prostatectomy Orlando, Fla.â&#x20AC;&#x201D;Investigators have derived a method for calculating metastasis-free survival using three prognostic factors, based on data collected from almost 9,000 men who underwent radical prostatectomy.

The new tool could be important for counseling patients and planning future clinical trials. By far, the strongest predictor was prostate-specific antigen (PSA) doubling time.

When patients were stratified into four groups by PSA doubling time after surgery (<3, 3-9, 9-15 and >15 months), there were large stepwise increases in the likelihood of remaining metastasis-free as doubling time lengthened. â&#x20AC;&#x153;The median metastasis-free survival was one year among those with a doubling time under three months versus 15 years for those with a doubling time greater than 15 months,â&#x20AC;? said Emmanuel S. Antonarakis, MD, a clinical fellow in the hematology/medical oncology division of the Kimmel Cancer Center, Johns Hopkins University, in Baltimore.

The other two discriminators were a Gleason score of 7 or lower (versus 8 or greater) and PSA relapse of three years or less after surgery (compared with more than three years). Dr. Antonarakis reported the data at the annual meeting of the American Society of Clinical Oncology (ASCO; abstract 5008).

is considered to be an ominous sign of an impending relapse, therapy delivered on this basis alone has not been associated with a change in survival outcomes.

The risk stratifications suggested by this study may help define candidates who will benefit from additional therapy. It could also be used to help design and analyze data from clinical trials.

The study is similar to a natural history analysis conducted by researchers at Johns Hopkins Medical Institutions that was published a decade earlier (JAMA 1999;281:1591-1597, PMID: 10235151). The new analysis was drawn from 8,801 patients who underwent prostatectomy between 1982 and 2008 and did not receive adjuvant or salvage therapy. Of the 8,801 surgeries, 774 (9%) had a PSA recurrence. PSA doubling time was available for 433 of these patients, and this formed the study cohort. Compared with the Johns Hopkins study, which had a median follow-up of 5.3 years in 304 patients (131 with PSA doubling time data), the median follow-up of eight years (range, 1-25 years) in the present study adds considerable power to the observations.

Table. Calculating Metastasis-Free Survival in Patients After Prostatectomy â&#x2030;¤7

Gleason Score

>7

Time to PSA relapse (y)

â&#x2030;¤3

>3

PSA doubling time (mo)

<3

3-9 9-15 >15 <3

3-9

9-15 >15 <3

3-9

9-15 >15 <3

3-9

9-15 >15

Median metastasisfree survival (y)

1

2

2

6

5

9

6

13

7

10

1

â&#x2030;¤3

>11

2

>3

15

1

>14

PSA, prostate-specific antigen NOTE: This table has not been peer-reviewed and should not be used to counsel patients or make any other clinical decisions until it appears in a peer-reviewed journal.

Each of the prognostic factors has independent predictive value, which permitted the investigators to create a table to combine values to calculate metastasis-free survival for an individual patient (Table). Conceivably, the table may permit investigators to address the debate about whether or when to introduce adjuvant or salvage therapy after radical prostatectomy. Although a rise in PSA following prostatectomy

With the PSA doubling time of more than 15 months as an index, the rise in the hazard ratio (HR) for shorter doubling times climbed from 2.4 (95% confidence interval [CI], 1.3-4.4; P=0.004) in a nine- to 15-month period to 6.3 (95% CI, 3.8-10.7; P<0.0001) in a threeto nine-month period and then to 20.6 (95% CI, 11.238.1; P<0.001) for a period of less than three months.

For a Gleason score of 8 or greater, the HR was 2.0

(95% CI, 1.4-3.0; P=0.0002) compared with a lower Gleason score. For time to PSA relapse of more than three years, the HR was 0.3 (95% CI, 0.2-0.4; P<0.0001) compared with less than three years.

There was a surprising lack of discrimination in risk for metastasis based on age, pathologic stage and surgical margin status. One explanation for the margin status finding could have been that many patients with positive surgical margins never achieved a PSA of zero and therefore were excluded from the analysis.

Dr. Antonarakis also said that patients who were administered adjuvant therapies or who received radiation therapy as a salvage intervention were also excluded from the analysis.

The table may permit investigators to address the debate about whether or when to introduce adjuvant or salvage therapy after radical prostatectomy.

Because of the far greater predictive value of PSA doubling time than of Gleason score or time to PSA progression, this variable dominated the prognosis table created by Dr. Antonarakis and his co-investigators. For example, the median time to metastasis for the best set of the three variables (time to PSA relapse of more than three years, Gleason score of 7 or lower and PSA doubling time of more than 15 months) was similar (14 years) compared with that of the longest PSA doubling time alone (15 years). The median metastasis-free survival for the whole patient population was 10 years.

The expert invited to comment on the study at the ASCO meeting, Joel B. Nelson, MD, chairman of the Department of Urology, University of Pittsburgh, focused on the PSA doubling time. He called the identification of this factor â&#x20AC;&#x153;important,â&#x20AC;? and suggested that it has immediate clinical relevance given the relatively large size of the study cohort. â&#x20AC;&#x153;We can now tell our patients that â&#x20AC;&#x2DC;if your PSA doubling time is less than three months and we do not treat you, you are going to have metastatic disease within a year,â&#x20AC;&#x2122; â&#x20AC;? Dr. Nelson emphasized. â&#x20AC;&#x153;On the other end of the spectrum, which is PSA doubling time of greater than 15 months, you can tell that patient â&#x20AC;&#x2DC;you have at least a decade before we would expect you to develop a metastasis.â&#x20AC;&#x2122; â&#x20AC;? He indicated that these stratifications may be useful for testing strategies of early intervention when prognostic signs are raising concern. â&#x20AC;&#x201D;Ted Bosworth

Looking for our Clinical Trials section?

O

ur listing of Phase II and III Clinical Trials can be found online at www.clinicaloncology.com.

Click on â&#x20AC;&#x153;departmentsâ&#x20AC;? on the left hand navigation bar and then â&#x20AC;&#x153;clinical trials.â&#x20AC;?

Trials added to the National Cancer Instituteâ&#x20AC;&#x2122;s list of clinical trials in the 30 days prior to September 22, 2009, are listed.

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28

F\b dVYY NY`\ OR Nba\ZNaVPNYYf R[aR_RQ V[a\ N Q_NdV[T a\ dV[ N[ V=\Q a\bPU

SOLID TUMORS

CLINICAL ONCOLOGY NEWS â&#x20AC;˘ SEPTEMBER/OCTOBER 2009

Colorectal

Ed Chu, MD, Highlights Colon Cancer News At the annual meeting of the American Society of Clinical Oncology, several studies on colorectal cancer were presented that can be considered practice-changing.

ADVISORY BOARD EDITORIAL Ed Chu, MD Chief, Section of Medical Oncology Professor of Medicine and Pharmacology Deputy Director of Clinical Research Yale Cancer Center Yale University New Haven, Conn.

In the last print issue of Clinical Oncology News, Cathy Eng, MD, discussed the important results from the NSABP C-08 trial. I discuss other important studies below.

Standard of Care for Rectal Cancer Identified The incorporation of oxaliplatin (Eloxatin, SanofiAventis) into fluoropyrimidine-based chemoradiotherapy regimens for locally advanced rectal cancer cannot be recommended outside the context of a formal clinical trial, according to results from two Phase III trials (abstracts LBA4007 and CRA 4008). These trials

PRIME continued from page 1

Perspective â&#x20AC;&#x153;This study confirms the importance of KRAS as a predictive biomarker in patients with metastatic colorectal cancer treated with an anti-EGFR [epidermal growth factor receptor] monoclonal antibody in combination with chemotherapy,â&#x20AC;? said Jean-Yves Douillard, MD, Centre RenĂŠ Gauducheau, Saint Herblain, Nantes, France, who led the study. â&#x20AC;&#x153;Patients with KRAS mutations should not receive panitumumab.â&#x20AC;? KRAS is a gene primarily involved in regulation of cell division.

Specifically, the study found that patients with wild-type KRAS had a median PFS of 9.6 months if they received FOLFOX4 (oxaliplatin, 5-fluorouracil, leucovorin) plus panitumumab and 8 months if they received FOLFOX4 alone (P=0.02). â&#x20AC;&#x153;This is a well-designed trial with good data confirming the combination of panitumumab and FOLFOX4 in patients with wild-type KRAS leads to increased activity compared to FOLFOX4 alone. The findings are consistent with other data in metastatic colorectal cancer that [show] the benefit of panitumumab is limited to wild-type KRAS patients, and there is a deleterious effect in KRAS-mutant patients,â&#x20AC;? said Eric Van

showed that adding oxaliplatin to fluoropyrimidinebased neoadjuvant chemoradiotherapy significantly increased toxicity with no benefit in terms of tumor downstaging or improvement in the ability of patients to undergo sphincter preservation surgery.

The Prodige 2-ACCORD 12/0405 trial randomized patients with locally advanced (T3-4 N0-2 M0) rectal cancer to preoperative treatment with radiotherapy at a dose of 50 Gy/25F for five weeks, plus capecitabine 800 mg/m2 PO twice daily for five of seven days and oxaliplatin 50 mg/m2 every week for five weeks (Capox 50) or with a dose of 45 Gy/25F for five weeks plus capecitabine 800 mg/m2 PO twice daily for five of seven days every week for five weeks (Cape 45).

Patients underwent total mesorectal excision six weeks after the completion of neoadjuvant chemoradiotherapy. The primary end point of the study was pathologic complete response (pCR), and secondary end points included circumferential resection margin (CRM), toxicity, sphincter preservation, disease-free survival (DFS) and overall survival (OS).

This study showed that the addition of oxaliplatin to the neoadjuvant regimen resulted in significant increases in the incidence of grade 3/4 diarrhea (13% vs. 3%; P<0.0001) and grade 2 peripheral neuropathy (5% vs. <1%; P<0.002). At the same time, there

Cutsem, MD, PhD, professor of internal medicine at the University of Leuven, Belgium. Dr. Van Cutsem was lead author of the CRYSTAL trial that demonstrated that the benefit of cetuximab (Erbitux, Amgen) is confined to KRAS wild-type patients with metastatic colorectal cancer.

Panitumumab and cetuximab are competitive drugs, but there are no head-tohead studies comparing these agents. â&#x20AC;&#x153;Both drugs show improved activity over chemotherapy alone in wild-type patients, but there are minor differences,â&#x20AC;? said Dr. Van Cutsem. â&#x20AC;&#x153;The treatment schedule is more favorable with panitumumab. On the other hand, at this point, we have more robust data for cetuximab [in metastatic colorectal cancer].â&#x20AC;?

Ed Chu, MD, chief of the Section of Medical Oncology and deputy director of clinical research at the Yale Cancer Center, Yale University School of Medicine, New Haven, Conn., said he had been eagerly anticipating the data from the PRIME trial. â&#x20AC;&#x153;In comparing the data from this trial with those from other trials combining cetuximab with either FOLFOX or FOLFIRI chemotherapy, it would seem that both anti-EGFR antibodies confer the same level of clinical benefit to chemotherapy in that group of wild-type KRAS patients. Based on this study, it would now appear that the

Table 1. Comparison of Treatments for Rectal Cancer, the STAR-01 Trial Fluoropyrimidine-Based Neoadjuvant Chemoradiotherapy

Fluoropyrimidine-Based Neoadjuvant Chemoradiotherapy Plus Oxaliplatin

Rate of lower anterior resection for sphincter preservation

72%

73%

Rate of abdomino-perineal resection

19%

18%

Grade 3/4 diarrhea

4%

15%

<1% Grade 2/3 sensory neuropathy

37%

was no additional clinical benefit with the addition of

combination of panitumumab and FOLFOX4 chemotherapy can be viewed as a reasonable treatment option in the frontline therapy of metastatic CRC.â&#x20AC;?

Study Details Panitumumab is approved in the United States for EGFR-expressing metastatic colorectal cancer that has progressed on prior chemotherapy. The Amgensponsored PRIME trial tested the safety and efficacy of panitumumab in the first-line setting. The multicenter, Phase III study randomized 1,183 patients with metastatic adenocarcinoma of the colon or rectum in a 1-1 ratio to receive panitumumab 6 mg/kg every two weeks plus FOLFOX4 or FOLFOX4 alone. Patients who had prior chemotherapy for metastatic disease or received prior oxaliplatin as adjuvant were not included. Randomization was stratified according to performance status (PS) and geographic region. The primary end point was PFS. Both treatment arms were well balanced for demographic characteristics: 63% were male, the median age was 62 years, 95% were PS 0-1, two-thirds had colon cancer as the primary tumor, and 69% had metastases to the liver and other sites. KRAS results were prospectively collected and available in 93%. Sixty percent of the study population had wild-type KRAS, and 40% were KRAS-mutated.

see GROUNDBREAKING, page 34

Median follow-up was 47 to 57 weeks.

In patients with wild-type KRAS, panitumumab added to FOLFOX4 improved PFS compared with FOLFOX4 alone (9.6 vs. 8 months, respectively) as well as response rate (55% and 48%, respectively). Among wild-type patients, most subgroups benefited from panitumumab, with the exception of those with PS 2 and females. Dr. Douillard said that the PRIME investigators plan to analyze the wild-type KRAS female patients further to explain why they did not appear to benefit from panitumumab. In patients with KRAS mutations, PFS was a median of 7.3 months for the panitumumab arm compared with 8.8 months for FOLFOX4 alone.

In an interim analysis of overall survival in those with wild-type KRAS, median survival has not been reached in the panitumumab group versus 18.8 months with FOLFOX4. The difference between the two arms has not reached significance yet, but longer follow-up is needed.

Adverse event rates were comparable for the two arms, except for toxicities known to be associated with antiEGFR inhibitors such as rash, diarrhea and hypomagnesemia. Infusion-related reactions in patients treated with panitumumab occurred in less than 1%. â&#x20AC;&#x201D;Alice Goodman

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ECOG E1A06 CURRENTLY ENROLLING

A New Randomized Phase 3 Intergroup Study of Patients With Newly Diagnosed Multiple Myeloma Study Chair Keith Stewart, MBChB, Mayo Clinic, Scottsdale, AZ

Primary Objective To compare progression-free survival with melphalan, prednisone, and thalidomide (MPT) versus melphalan, prednisone, and lenalidomide (REVLIMIDÂŽ) (MPR) in patients with symptomatic, newly diagnosed multiple myeloma who are not candidates for high-dose therapy.

Key Eligibility Criteria â&#x20AC;˘ Newly diagnosed, symptomatic multiple myeloma

â&#x20AC;˘ Treatment naĂŻveâ&#x20AC;&#x201D;no prior therapy except

bisphosphonates, growth factors or MP for less than 4 weeks total or less than 2 weeks if in combination with thalidomide or REVLIMIDÂŽ

â&#x20AC;˘ Declined or ineligible for high-dose therapy

â&#x20AC;˘ Creatinine <2.5 mg/dL â&#x20AC;˘ ECOG performance status â&#x2030;¤2 Induction (Up to twelve 28-day cycles) Discontinue for progressive disease or excessive toxicity

Study Design

Treatment A (MPT) â&#x20AC;˘ Melphalan 9 mg/m 2 po a daily, days 1-4 each cycle b for 12 cycles â&#x20AC;˘ Prednisone 100 mg po daily, days 1-4 each cycle for 12 cycles â&#x20AC;˘ Thalidomide 100 mg po daily, continuously â&#x20AC;&#x201D;Enteric-coated aspirin 325 mg po daily, continuously

Enrollment

Maintenance (Continues until disease progression)

Treatment A â&#x20AC;˘ Thalidomide 100 mg po daily, continuously for 28 days â&#x20AC;&#x201D;Enteric-coated aspirin 325 mg po daily, continuously

QOL assessments performed prior to, during, and following treatment

N=560

Treatment B (MPR) â&#x20AC;˘ Melphalan 5 mg/m 2 po daily, days 1-4 each cycle b for 12 cycles â&#x20AC;˘ Prednisone 100 mg po daily, days 1-4 each cycle for 12 cycles â&#x20AC;˘ Lenalidomide 10 mg po daily, days 1-21 of each cycle, continuously â&#x20AC;&#x201D;Enteric-coated aspirin 325 mg po daily, continuously

Treatment B â&#x20AC;˘ Lenalidomide 10 mg po daily for 21 days every 28 days â&#x20AC;&#x201D;Enteric-coated aspirin 325 mg po daily, continuously

QOL assessments performed prior to, during, and following treatment a

po, orally.

1 cycle = 28 days.

b

For more information, please contact: www.clinicaltrials.gov (NCT00602641) www.ecog.org National Cancer Institute Cancer Trials Support Unit (ctsucontact@westat.com) (888) 823-5923 Supplemental funding for trial recruitment materials provided by Celgene Corporation.

REVLIMIDÂŽ is a registered trademark of Celgene Corporation.

Note: This study is supported by the National Cancer Institute Cancer Trials Support Unit (CTSU). Institutions not aligned with ECOG will participate through the CTSU mechanism.

Supplemental funding for this trial provided by Celgene Corporation.

Investigational use of REVLIMIDÂŽ (lenalidomide).

04/09 CELG09049T

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30

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CLINICAL ONCOLOGY NEWS SEPTEMBER/OCTOBER 2009

Lung

TKIs continued from page 1

for Medical Oncology (ECCO-ESMO; abstract LBA9) showed that gefitinib trumps treatment with carboplatin and paclitaxel in the first-line treatment of patients with advanced NSCLC who have EGFR mutations. The study randomized 200 of these patients to receive either gefitinib (250 mg/day) or carboplatin (AUC 6) plus paclitaxel (200 mg/m2) in 21-day cycles. Patient characteristics were well balanced in the two arms. An interim analysis, conducted in May 2009 on 198 patients, revealed a significantly longer medan progression-free survival (PFS) in patients receiving gefitinib, 10.4 vs. 5.5 months (hazard ratio [HR}, 0.357; P<0.001). Because of this, the independent safety committee recommended terminating accumulation of patients.

The study also revealed a significantly higher response rate in patients receiving gefitinib (74.5% vs.

29.0%; P<0.001). Analysis of preliminary survival data did not reach statistical significance. Grade 4 neutropenia (1% vs. 33%) and grade 3 neuropathy (0% vs. 5%) were more prevalent in patients receiving gefitinib, and grade 3-4 liver dysfunction (25% vs. 1%) was higher in patients receiving the combination therapy (P<0.01). â&#x20AC;&#x153;Gefitinib should be the standard for first-line therapy for advanced NSCLC with sensitive EGFR mutations,â&#x20AC;? said lead author Akira Inoue, MD, Department of Respiratory Oncology and Molecular Medicine, Institute of Development, Aging, and Cancer, Tohuku University, Sendai, Japan.

Further evidence comes from updated findings from the randomized IPASS (IRESSA Pan-ASia Study) presented at the World Conference on Lung Cancer (abstract B9.7). In the original open-label study, presented at the 2008 European Society for Medical Oncology Congress, the HR for PFS among the 1,217 nonsmokers (<10 packs lifetime and no smoking in the last two years) was 0.74 (P<0.0001) in favor of gefitinib over carboplatin/paclitaxel. When stratified by EGFR mutational status in a new post-hoc analysis, the HR for PFS favoring gefitinib fell to 0.377 among subjects with the exon 19 deletion and 0.553 among those with the leucine substitution at amino acid 858 (L858R). Thirty-six percent of patients participating in the study had tumor tissue available for evaluation. â&#x20AC;&#x153;Gefitinib had greater efficacy than carboplatin/ paclitaxel in both of the major EGFR mutation subgroups, although there was a slightly greater relative advantage for those with the exon 19 deletion,â&#x20AC;? said Tony S.K. Mok, MD, a professor in the Department of Clinical Oncology, Chinese University of Hong Kong, in China. In addition to the significant increase in PFS, gefitinib was also associated with a significantly greater improvement in quality of life compared with chemotherapy. There was also a relative advantage for objective response and rates of symptom improvement, but the difference reached significance only for those with the exon 19 deletion. The most common EGFR mutations are exon 19 deletions and L858R point mutations in exon 21. Both are implicated in blocking Akt pathway signaling that promotes apoptosis.

So, does gefitinib have a second life in the United States? Initially approved in 2003, the FDA altered the status of the drug in 2005 after a large randomized study ISEL (Iressa Survival Evaluation in Lung Cancer) showed that the drug failed to significantly improve survival in patients with chemo-refractory NSCLC compared with placebo (Lancet 2005;366:1527-1537, PMID: 16257339). The drugâ&#x20AC;&#x2122;s label was changed to indicate that only cancer patients who had already taken

It is estimated that mutations in the tyrosine kinase domain of EGFR occur in 10% of whites and up to 30% of Asian patients with advanced NSCLC.

treatment with TKIs was similar.

Again, erlotinib led with the longest median PFS of 13.3 months, gefitinib came second with a median PFS of 8.8 months, and chemotherapy resulted in the shortest median PFS at 4.1 months.

Paradigm Shift in Care the medication and whose physicians believed that it was helping could receive the drug. No newly diagnosed lung cancer patients in the United States were given gefitinib after this time, but the drug remained a therapy in other countries. In 2008, the INTEREST study demonstrated that gefitinib had similar activity to chemotherapy with docetaxel in previously treated patients (Lancet 2008;372:1809-1818, PMID: 19027483).

This study also showed an improved response and PFS in EGFR mutation-positive patients. â&#x20AC;&#x153;I do think that gefitinib will have a second life in the U.S. now that the trials related to this agent have been designed to focus on patients with EGFR mutations rather than the broader population of NSCLC patients,â&#x20AC;? said Michael Fisch, MD, medical director of the Clinical Community Oncology Program at M.D. Anderson Cancer Center in Houston. â&#x20AC;&#x153;Just like we have epoetin alfa and darbepoetin, weâ&#x20AC;&#x2122;ll have gefitinib and erlotinibâ&#x20AC;&#x201D; drug duos that serve the same role in patient care.â&#x20AC;?

Philip Bonomi, MD, director of the Division of Hematology-Oncology at Rush University Medical Center, Chicago, agreed. â&#x20AC;&#x153;I believe that reapproval of Iressa should be considered based not only on the IPASS data, but also on the results of the INTEREST study,â&#x20AC;? he said. Richard Gralla, MD, president of the New York Lung Cancer Alliance, said he thought Iressa could have a second life but was not convinced that the drug was better than others currently available.

A spokesperson from AstraZeneca said the company looked forward to a dialogue with the FDA about the new data, but would not provide further details.

Pooled Evidence In a study presented at the recent World Conference on Lung Cancer (abstract B9.7) of the International Association for the Study of Lung Cancer, researchers conducted a pooled analysis that collated data from all NSCLC studies that have evaluated EGFR mutational status. According to the senior author of the study, Luis Paz-Ares, MD, Oncology Service, Hospital Universitario Virgen del RocĂ­o, in Sevilla, Spain, the TKIs erlotinib and gefitinib beat chemotherapy for the end point of PFS, whether they were used first- or secondline. Based on these results, Dr. Paz-Ares characterized EGFR TKIs as â&#x20AC;&#x153;an attractive prospect in patients with EGFR-mutant advanced NSCLC.â&#x20AC;?

The pooled analyses were based on studies that included PFS data, mutational status, and treatment with chemotherapy or either erlotinib or gefitinib. The majority of data came from published Phase II and III studies. There were 413 NSCLC patients treated with gefitinib in 13 studies, 341 patients treated with erlotinib in eight studies and 192 patients who were treated with chemotherapy in six studies. To permit a weighted analysis, the percentage of progression-free survivors at a fixed time point was evaluated using a formula based on assumptions of PFS distribution.

When the treatment strategies were compared in the first-line setting among patients with EGFR mutations, the pooled median PFS was 13.6 months for erlotinib, 9.7 months for gefitinib and 6.4 months for chemotherapy. The distribution of PFS rates for second-line

Until recently, according to Dr. Paz-Ares, it has been â&#x20AC;&#x153;difficult to conduct large-scale investigations of possible associations between EGFR mutations and therapeutic outcomes because of the limited availability of tissue samples.â&#x20AC;? This, however, is likely to change.

The ongoing Phase III EURTAC study, a randomized comparison of erlotinib and chemotherapy, is among a growing number of studies whose protocol requires biopsy and is looking closely at molecular markers, including EGFR mutations, to determine which patients benefit most.

The ability of TKIs to provide a far more profound effect on cancer growth than traditional cytotoxic agents suggests a paradigm shift away from nonspecific cytotoxic agents to drugs targeted at vulnerable molecular processes. While Dr. Paz-Ares speculated that EGFRmutant NSCLC â&#x20AC;&#x153;may be considered as a distinct disease within the broader spectrum of NSCLC,â&#x20AC;? the same may be said for other forms of NSCLC that can be categorized by a molecular or genetic profile. Recently, there has been surging interest in identifying molecular profiles that can help predict treatment response in a broad variety of cancers, not just NSCLC. For example, several guidelines now recommend that patients with colorectal cancer who are candidates for cetuximab (Erbitux, ImClone) should first undergo tissue sampling to confirm the K-ras mutation, a criterion for suitability. The new data from Dr. Paz-Ares, if confirmed, will have a similar implication. For clinicians, this means that tissue biopsies or another form of tissue sampling must be incorporated into routine patient care. â&#x20AC;&#x153;I believe we are now rapidly moving to a primarily molecular-based therapy from a primarily empiricbased therapy in lung cancer,â&#x20AC;? said David R. Gandara, MD, director of the Thoracic Oncology Program at the University of California, Davis Cancer Center, in Sacramento, Calif. Echoing an often-repeated theme regarding the coming importance of tissue sampling and molecular profiling in routine care, Dr. Gandara, who was a co-chair of the World Conference on Lung Cancer, indicated that the shift is already under way.

For many, it has already taken place. Philip Bonomi, MD, director of the Division of Hematology and Oncology, Rush University Medical Center, in Chicago, said that he is already ordering EGFR mutational profiles in all nonsmokers before initiating therapy. In those patients who do have the mutations, clinicians administer a TKI first-line. Although studies have shown that this treatment decision may only improve PFS, he considers this a â&#x20AC;&#x153;reasonableâ&#x20AC;? approach based on current science.

It is estimated that mutations in the tyrosine kinase domain of EGFR occur in 10% of whites and up to 30% of Asian patients with advanced NSCLC. The mutations are most common in female nonsmokers, but clinical characteristics provide poor sensitivity and specificity for the presence or absence of the mutations. Although level 1 evidence does not yet support the use of routine biopsies of advanced NSCLC to test for EGFR mutations, there is a growing conviction among clinicians that these data are forthcoming. â&#x20AC;&#x201D;Ted Bosworth

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FIRSTâ&#x20AC;&#x201C;Frontline Investigation of REVLIMIDÂŽ/dex vs Standard Thal

CURRENTLY ENROLLING

A Randomized Phase III Study of Patients With Previously Untreated Multiple Myeloma (CC-5013-MM-020/IFM 07-01) Primary Objective To compare progression-free survival with lenalidomide (REVLIMID) plus low-dose dexamethasone (Rd) given until disease progression or for 18 four-week cycles versus combination of melphalan, prednisone, and thalidomide (MPT) given for 12 six-week cycles.

Key Eligibility Criteria â&#x20AC;˘ Previously untreated, symptomatic multiple myeloma â&#x20AC;˘ Not a candidate for or have declined stem cell transplantation â&#x20AC;˘ ECOG PS â&#x2030;¤2

Study Design Treatment Aa (Rd) â&#x20AC;˘ Lenalidomide po once daily, days 1-21 each cycle â&#x20AC;˘ Dexamethasone po once weekly, days 1, 8, 15, and 22 each cycle Treatment (28-day cycles) continues until disease progression

Treatment Ba (Rd) N=1590

â&#x20AC;˘ Lenalidomide po once daily, days 1-21 each cycle â&#x20AC;˘ Dexamethasone po once weekly, days 1, 8, 15, and 22 each cycle 18 cycles, 28 days each

Treatment Cb (MPT)

Progressionfree Survival Follow-up Phase Patients will be followed until disease progression

Long-term Follow-up Phase Patients followed for survival and subsequent antimyeloma therapies

â&#x20AC;˘ Melphalan po once daily, days 1-4 each cycle â&#x20AC;˘ Prednisone po once daily, days 1-4 each cycle â&#x20AC;˘ Thalidomide po once daily, continuously 12 cycles, 42 days each Dosage varies based on age and renal function.

Dosage varies by age and baseline neutrophil and platelet counts.

a

b

For more information or to participate, please contact: www.clinicaltrials.gov (NCT00689936) Elvira Klissourska, PhD (eklissourska@celgene.com) Celgene Corporation www.celgene.com

REVLIMIDŽ is a registered trademark of Celgene Corporation. Investigational use of REVLIMIDŽ (lenalidomide). Š 2008 Celgene Corporation 06/08

CELG08050T

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CLINICAL ONCOLOGY NEWS â&#x20AC;˘ SEPTEMBER/OCTOBER 2009

Table 2. Comparison of Regimens for Metastatic Colorectal Cancer

Colorectal

GROUNDBREAKING

XELIRI + Bev

continued from page 28

oxaliplatinâ&#x20AC;&#x201D;surgery was performed at a similar rate in each treatment arm with a similar incidence of lower anterior resections (LAR) for sphincter preservation in patients who received Capox 50 or Cape 45 (76% vs. 73%; P=NS). With regard to tumor downstaging and pathologic efficacy, the pCR rates were similar in patients who received Capox 50 compared with those who received Cape 45 (19% vs. 14%; P=0.11). In addition, the CRM at â&#x2030;¤1 mm was not significantly reduced in the Capox 50 arm compared with the Cape 45 arm (7% vs.

12%; P=0.21).

Also presented at the meeting were interim results from the STAR-01 trial, which randomized patients with locally advanced rectal cancer defined as T3-4 and/or N+, and M0 to preoperative treatment with radiotherapy at a dose of 50.4 Gy, plus 5-fluorouracil (5-FU) 225 mg/m2 per day or to the same regimen plus oxaliplatin 60 mg/m2 every week for six weeks. Total mesorectal excision surgery was conducted six to eight weeks after the completion of neoadjuvant chemoradiotherapy. The primary end point of the trial was OS. Secondary end points included pCR, DFS and safety.

In terms of safety profile, significant increases in grade 3/4 diarrhea (15% vs. 4%; P<0.0001) and grade 2/3 sensory neuropathy (37% vs. <1%; P<0.0001) were reported in patients receiving oxaliplatin. Similar rates of LAR (73% vs. 72%) and abdominoperineal resection (18% vs. 19%) were reported for patients treated with standard chemoradiotherapy with or without oxaliplatin, respectively (Table 1). The pCR (pT0N0) was 16%

FOLFIRI + Bev

Overall 42% response rate

46%

Progressionfree survival

9 mo

9 mo

Overall survival

23 mo

23 mo

Bev, bevacizumab; FOLFIRI, folinic acid, fluorouracil and irinotecan; XELIRI, capecitabine plus irinotecan

in each arm (P=0.94), and the local tumor response was similar with both neoadjuvant regimens.

Clinicians must await results of the NSABP R-04 Phase III trial, which is evaluating the efficacy of neoadjuvant chemoradiotherapy with intravenous infusional 5-FU compared with chemoradiotherapy with oral capecitabine along with the role of oxaliplatin in patients with locally advanced rectal cancer.

XELIRI Plus Bev Standard Option in Front-Line mCRC The combination of XELIRI (capecitabine plus irinotecan) and bevacizumab (Avastin, Genentech) is a safe and effective regimen that can be considered a standard option in the front-line treatment of metastatic colorectal cancer (mCRC), according to results from the MEXICO trial. This Phase II study investigated the efficacy and safety of bevacizumab (Bev) in combination with FOLFIRI or XELIRI chemotherapy in patients with mCRC (abstract 4086).

Notably, in the XELIRI regimen, the dose of

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oin a well-established and very reputable group of three boardcertified hem/onc physicians in a thriving practice. Outpatient chemotherapy visits total 16,000 per year and daily inpatient census averages from 15-30. Employed by Allegiance Health, a 411-bed community hospital with a 19-bed inpatient oncology unit.

The patient population is diverse and is drawn from more than 250,000 people. Participate in both industry and cooperative clinical trials with SWOG, CCOP, HOG and NSABP. University of Michigan Cancer Center Network affiliate further extends access to Universitybased clinical trials. Allegiance Healthâ&#x20AC;&#x2122;s radiation oncology center is a joint venture with the University of Michigan Medical Center and utilizes two linear accelerators using 3D conformational treatment planning.

Competitive salary and benefits package with excellent recruitment incentives including $50k student loan forgiveness, $10k moving expenses, signing bonus, $30k relocation incentive and more.

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irinotecan used was 200 mg/m2, which was 20% lower than the dose previously used in the BICC-C and EORTC 4015 studies, in which significant toxicities with XELIRI were observed.

In general, both combination regimens were well tolerated with manageable safety profiles. In particular, the incidence of grade 3/4 toxicities was comparable between the two arms of the study, and the combination of XELIRI plus bevacizumab resulted in a respective 15% and 11% incidence of grade 3/4 neutropenia and diarrhea. The clinical activities of XELIRI plus bevacizumab and FOLFIRI plus bevacizumab were equivalent with regard to overall response rates (42% and 46%), PFS (nine months for each) and OS (23 months for each) (Table 2).

CaMg Effective Neuroprotective Agent In Adjuvant Setting The NO4C7 study provides further evidence that CaMg can be recommended as an effective neuroprotective agent in the adjuvant setting. In this Phase III trial, patients who were receiving adjuvant mFOLFOX6 chemotherapy were randomized to receive 1 g calcium gluconateâ&#x20AC;&#x201C;1 g magnesium sulfate (CaMg) infusions immediately before and after oxaliplatin versus placebo (abstract 4025).

The primary end point was the incidence of grade 2+ sensory neurotoxicity (sNT), and neurotoxicity was assessed using the NCI-CTC v3.0 scale, an oxaliplatinspecific scale, and patient-reported quality-of-life outcome questionnaires. Acute neurotoxicity was evaluated on day 2 of cycle 1, and CaMg was effective at reducing the chronic cumulative neurotoxic symptoms of numbness, tingling and muscle cramps, but not symptoms

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CLINICAL ONCOLOGY NEWS â&#x20AC;˘ SEPTEMBER/OCTOBER 2009

Colorectal

relating to cold sensitivity, swallowing difficulty and throat discomfort.

This study is important as it provides further evidence that CaMg can be recommended as an effective neuroprotective agent in the adjuvant setting. However, one issue that has yet to be addressed is whether CaMg might reduce the clinical activity of adjuvant FOLFOX chemotherapy. While it is unlikely based on the potential mechanism of CaMg neuroprotection that has been identified to date, clinicians must be aware of this issue and use CaMg with caution in the adjuvant setting.

Can a Multigene Assay Identify Recurrent Colon Cancer?

A multigene assay (Oncotype DX colon cancer test, Genomic Health) can identify patients with stage II colon cancer who have a high risk for recurrence (abstract 4000), according to David Kerr, MD, DSc, professor of cancer medicine at the University of Oxford, in London.

In the first multigene RT-PCR assay, a total of 761 genes were assessed in formalin-fixed, paraffin-embedded tumor samples from 1,851 patients. These patients had stage II colon cancer and had been enrolled in four randomized trials evaluating 5-FU-based adjuvant therapy compared with surgery alone. Forty-eight genes associated with recurrence risk and 66 genes predictive of benefit from 5-FU/ LV (leucovorin) were identified through the combined analysis of these four development studies. Additional modeling and refinement was used to further narrow the gene set, yielding a multigene assay with algorithms for a continuous recurrence score (RS) based on seven genes significantly associated with disease recurrence and a separate continuous treatment score based on six genes significantly associated with 5-FU/LV therapy benefit.

For the validation phase of this study, the final multigene assay was assessed using tumor blocks from 1,436 evaluable patients with stage II colon cancer who had been enrolled in the QUASAR (Quick and Simple and Reliable) trial. Conducted in the United Kingdom, this trial is important as it showed that adjuvant chemotherapy with 5-FU and LV resulted in a small improvement in DFS and OS in patients with stage II colon cancer. A significant relationship between the risk for recurrence at three years and the RS as a continuous variable was observed, such that the RS was predictive of disease recurrence at three years following surgery in patients with stage II colon cancer (P=0.004).

In a prespecified risk group analysis, patients with an RS greater than 40 had a significantly higher risk for recurrence at three years than patients with a score less than 30 (hazard ratio [HR], 1.47; P=0.046).

A multivariate analysis revealed that the RS and other clinicopathologic factors including mismatch repair (MMR) status, T stage, tumor grade and the number

of examined lymph nodes were all significantly and independently associated with disease recurrence. Of note, MMR, RS and T stage were the most significant factors that correlated with disease recurrence. In addition, RS was prognostic for DFS (HR, 1.42; 95% confidence interval [CI], 1.09-1.84; P=0.010) and OS (HR, 1.33; 95% CI, 1.01-1.76; P=0.041).

In contrast to predicting the risk for recurrence, the multigene treatment score was not predictive of differential 5-FU/LV benefit for relapse-free interval (P=0.19), DFS (P=0.12) or OS (P=0.15) in patients with stage II colon cancer. Similarly, RS was unable to predict benefit

from 5-FU/LV adjuvant chemotherapy (P=0.69) in this patient population.

This is the first study to show that a prospectively defined gene expression assay can independently predict disease recurrence following surgery in patients with stage II colon cancer. This assay may help improve patient selection for adjuvant therapy to optimize outcomes, and may be most useful in patients for whom conventional risk assessment parameters, such as T stage or microsatellite instability, are uninformative.

These results are similar to findings reported with gene expression assays for early-stage estrogen receptorâ&#x20AC;&#x201C;positive

breast cancer. However, in contrast to the 21-gene RS in breast cancer, the seven-gene RS in colon cancer is unable to precisely discriminate between low, intermediate and high risks for disease recurrence. Moreover, the RS in colon cancer is unable to predict which patients would benefit most from adjuvant chemotherapy. Further studies are required to more precisely refine the RS as both a prognostic marker for stage II colon cancer and, perhaps more importantly, as a predictive marker for identifying chemotherapy benefit in this disease. â&#x20AC;&#x201D;Ed Chu, MD

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Based on independent review of disease progression, a statistically significant prolongation in PFS was observed in patients receiving VectibixÂŽ plus BSC vs those patients receiving BSC alone1,2 100% 90%

Kaplan-Meier Plot of PFS Time as Determined by the Independent Review Committee1,2

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70%

Treatment Group VectibixÂŽ + BSC (n=231) BSC Alone (n=232)

P < 0.0001

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Safety data are available from 15 clinical trials in which 1467 patients received VectibixÂŽ; of these, 1293 received VectibixÂŽ monotherapy and 174 received VectibixÂŽ in combination with chemotherapy.

WARNING: DERMATOLOGIC TOXICITY and INFUSION REACTIONS Dermatologic Toxicity: Dermatologic toxicities occurred in 89% of patients and were severe (NCI-CTC grade 3 and higher) in 12% of patients receiving VectibixÂŽ monotherapy. Withhold VectibixÂŽ for dermatologic toxicities that are grade 3 or higher or are considered intolerable. If toxicity does not improve to â&#x2030;¤ grade 2 within 1 month, permanently discontinue VectibixÂŽ. The clinical manifestations included, but were not limited to, dermatitis acneiform, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, and abscesses requiring incisions and drainage were reported.

Infusion Reactions: Severe infusion reactions occurred in approximately 1% of patients. Severe infusion reactions included anaphylactic reactions, bronchospasm, and hypotension. Although not reported with VectibixÂŽ, fatal infusion reactions have occurred with other monoclonal antibody products. Stop infusion if a severe infusion reaction occurs. Depending on the severity and/or persistence of the reaction, permanently discontinue VectibixÂŽ.

VectibixÂŽ is not indicated for use in combination with chemotherapy. In an interim analysis of a randomized (1:1) clinical trial of patients with previously untreated metastatic colorectal cancer, the addition of VectibixÂŽ to the combination of bevacizumab and chemotherapy resulted in decreased overall survival and increased incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions.

In a single-arm study of 19 patients receiving VectibixÂŽ in combination with IFL, the incidence of NCI-CTC grade 3-4 diarrhea was 58%; in addition, grade 5 diarrhea occurred in 1 patient. In a single-arm study of 24 patients receiving VectibixÂŽ plus FOLFIRI, the incidence of NCI-CTC grade 3 diarrhea was 25%.

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Important Safety Information including Boxed WARNINGS:

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INDICATION: VectibixÂŽ is indicated as a single agent for the treatment of EGFR-expressing, metastatic colorectal carcinoma (mCRC) with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens.

The effectiveness of VectibixÂŽ as a single agent for the treatment of EGFR-expressing mCRC is based on progression-free survival.

Currently, no data demonstrate an improvement in disease-related symptoms or increased survival with VectibixÂŽ.

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*Correlation with safety and efficacy is unknown

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Weeks Subjects at risk: VectibixÂŽ + BSC BSC Alone

Statistically significant prolongation in PFS time vs BSC alone1,2 The recommended dose of VectibixÂŽ is 6 mg/kg administered over 60 minutes (for doses over 1000 mg infuse over 90 minutes) as an intravenous infusion every 14 days1 The use of premedication was not standardized in clinical trials (the utility of premedication in preventing infusional toxicity is unknown)1 ~1% incidence of severe infusion reactions reported1 - See Important Safety Information including Boxed WARNINGS for infusion reactions

Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of VectibixÂŽ. Following the initial fatality, patients with a history of interstitial pneumonitis, pulmonary fibrosis, evidence of interstitial pneumonitis, or pulmonary fibrosis were excluded from clinical studies. Therefore, the estimated risk in such patients is uncertain. Permanently discontinue VectibixÂŽ therapy in patients developing interstitial lung disease, pneumonitis, or lung infiltrates.

In the randomized, controlled clinical trial, median magnesium levels decreased by 0.1 mmol/L in the VectibixÂŽ arm. Additionally, hypomagnesemia (NCI-CTC grade 3 or 4) requiring electrolyte repletion occurred in 2% of patients 6 weeks or longer after the initiation of VectibixÂŽ. In some patients, both hypomagnesemia and hypocalcemia occurred. Patientsâ&#x20AC;&#x2122; electrolytes should be periodically monitored during and for 8 weeks after the completion of VectibixÂŽ therapy, and appropriate treatment instituted, as needed.

Exposure to sunlight can exacerbate dermatologic toxicity. It is recommended that patients wear sunscreen and hats and limit sun exposure while receiving VectibixÂŽ.

Dermatologic, mucosal, and ocular toxicities were also reported.

Adequate contraception in both males and females must be used while receiving VectibixÂŽ and for 6 months after the last dose of VectibixÂŽ therapy.

The most common adverse events of VectibixÂŽ are skin rash with variable presentations, hypomagnesemia, paronychia, fatigue, abdominal pain, nausea, and diarrhea, including diarrhea resulting in dehydration. The most serious adverse events of VectibixÂŽ are pulmonary fibrosis, severe dermatologic toxicity complicated by infectious sequelae and septic death, infusion reactions, abdominal pain, hypomagnesemia, nausea, vomiting, and constipation.

Please see brief summary of Prescribing Information on next page.

References: 1. VectibixÂŽ (panitumumab) prescribing information, Amgen.

2. Van Cutsem E, Peeters M, Siena S, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol.

2007;13:1658-1664.

Š2009 Amgen. All rights reserved.

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