Clinical Oncology News - September/October 2009 - Digital Edition

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ALIMTA® is a registered trademark of Eli Lilly and Company. PM58001 0709 PRINTED IN USA © 2009, Lilly USA, LLC. ALL RIGHTS RESERVED.

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 fi 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.

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 drug-related toxicity following administration of ALIMTA alone.

Caution should be used when administering ibuprofen concurrently with ALIMTA to patients with mild to moderate renal insuffi ciency (creatinine clearance from 45 to 79 mL/min). Patients with mild to moderate renal insuffi 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 ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min.

Pregnancy Category D—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 fl uid, such as pleural effusion and ascites, on ALIMTA is unknown. In patients with clinically signifi cant third space fl 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 specifi c information regarding ibuprofen administration.

38355_elonps_maint2p_con10_fa.indd 1 9/24/09 2:51:35 PM


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 Specifi 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 insuffi 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.

Histology Matters with ALIMTA because EXTENDED SURVIVAL MATTERS.



ALIMTA� (pemetrexed for injection)BRIEF SUMMARY. For complete safety, please consult the full Prescribing Information.1 INDICATIONS AND USAGE1.1 Nonsquamous Non-Small Cell Lung Cancer—Combination with Cisplatin

ALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced ormetastatic nonsquamous non-small cell lung cancer.1.2 Nonsquamous Non-Small Cell Lung Cancer—Maintenance

ALIMTA is indicated for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-smallcell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.1.3 Nonsquamous Non-Small Cell Lung Cancer—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 mesotheliomawhose 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 ADMINISTRATION2.1 Combination Use with Cisplatin

Nonsquamous Non-Small Cell Lung Cancer and Malignant Pleural MesotheliomaThe 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 minutesafter 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 CancerThe 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 SupplementationTo 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 precedingthe 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 ofALIMTA 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 commonlyused dose of oral folic acid in clinical trials was 400 mcg [see Warnings and Precautions (5.1)].

CorticosteroidSkin 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 bymouth 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

MonitoringComplete 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 ofeach cycle. Patients should not begin a new cycle of treatment unless the ANC is ≥1500 cells/mm3, the platelet count is≥100,000 cells/ mm3, and creatinine clearance is ≥45 mL/min. Periodic chemistry tests should be performed to evaluate renaland 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-agentor in combination with cisplatin.

If patients develop nonhematologic toxicities (excluding neurotoxicity) ≥Grade 3, treatment should be withheld untilresolution to less than or equal to the patient’s pre-therapy value. Treatment should be resumed according to guidelines in Table 2.

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.

Discontinuation RecommendationALIMTA 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 PatientsIn clinical studies, patients with creatinine clearance ≥45 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 dosagerecommendations 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 sterilesingle-use vials containing 100 mg or 500 mg pemetrexed.4 CONTRAINDICATIONS

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

5 WARNINGS AND PRECAUTIONS5.1 Premedication Regimen

Need for Folate and Vitamin B12 SupplementationPatients 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 infectionwith Grade 3/4 neutropenia were reported when pretreatment with folic acid and vitamin B12 was administered.

Corticosteroid SupplementationSkin 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 arebased on nadir ANC, platelet count, and maximum nonhematologic toxicity seen in the previous cycle [see Dosage andAdministration (2.4)].5.3 Decreased Renal Function

ALIMTA is primarily eliminated unchanged by renal excretion. No dosage adjustment is needed in patients with creatinineclearance ≥45 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 B12died 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 renalinsufficiency (creatinine clearance from 45 to 79 mL/min). Other NSAIDs should also be used with caution [see DrugInteractions (7.1)].5.5 Required Laboratory Monitoring

Patients should not begin a new cycle of treatment unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000cells/mm3, and creatinine clearance is ≥45 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. Pemetrexedadministered intraperitoneally to mice during organogenesis was embryotoxic, fetotoxic and teratogenic in mice at greater than1/833rd the recommended human dose. If ALIMTA is used during pregnancy, or if the patient becomes pregnant while takingthis drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advisedto avoid becoming pregnant. Women should be advised to use effective contraceptive measures to prevent pregnancy duringtreatment 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 clinicallysignificant third space fluid, consideration should be given to draining the effusion prior to ALIMTA administration.6 ADVERSE REACTIONS6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reactions rates cannot be directlycompared 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 ≥20%) during therapy with ALIMTA as a single-agentwere fatigue, nausea, and anorexia. Additional common adverse reactions (incidence ≥20%) during therapy with ALIMTA whenused in combination with cisplatin included vomiting, neutropenia, leukopenia, anemia, stomatitis/pharyngitis, thrombocytopenia,and constipation.

Non-Small Cell Lung Cancer (NSCLC)—Combination with CisplatinTable 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 randomizedto study and received gemcitabine plus cisplatin. All patients received study therapy as initial treatment for locally advanced ormetastatic NSCLC and patients in both treatment groups were fully supplemented with folic acid and vitamin B12.

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 andcisplatin arm.

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

Incidence 1% to 5%Body as a Whole—febrile neutropenia, infection, pyrexiaGeneral Disorders—dehydrationMetabolism and Nutrition—increased AST, increased ALTRenal—creatinine clearance decrease, renal failureSpecial Senses—conjunctivitis

ALIMTA� (pemetrexed for injection) PV 5206 AMP ALIMTA� (pemetrexed for injection) PV 5206 AMP

a These criteria meet the CTC version 2.0 (NCI 1998) definition of ≥CTC Grade 2 bleeding.

Nadir ANC <500/mm3 and nadir platelets ≥50,000/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 bleedinga, regardless of nadir ANC 50% of previous dose(pemetrexed and cisplatin)

Table 1: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin—Hematologic Toxicities

Dose of ALIMTA Dose of Cisplatin(mg/m2) (mg/m2)

Any Grade 3 or 4 toxicities except mucositis 75% of previous dose 75% of previous doseAny diarrhea requiring hospitalization (irrespective of Grade) or Grade 3 or 4 diarrhea 75% of previous dose 75% of previous doseGrade 3 or 4 mucositis 50% of previous dose 100% of previous dose

Table 2: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin—Nonhematologic Toxicitiesa,b

a NCI Common Toxicity Criteria (CTC).b Excluding neurotoxicity (see Table 3).

Dose of ALIMTA Dose of CisplatinCTC Grade (mg/m2) (mg/m2)0-1 100% of previous dose 100% of previous dose2 100% of previous dose 50% of previous dose

Table 3: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin—Neurotoxicity

ALIMTA/cisplatin Gemcitabine/cisplatinReactionb (N=839) (N=830)

All Grades Grade 3-4 All Grades Grade 3-4Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%)

All Adverse Reactions 90 37 91 53LaboratoryHematologic

Anemia 33 6 46 10Neutropenia 29 15 38 27Leukopenia 18 5 21 8Thrombocytopenia 10 4 27 13

RenalCreatinine elevation 10 1 7 1

ClinicalConstitutional Symptoms

Fatigue 43 7 45 5Gastrointestinal

Nausea 56 7 53 4Vomiting 40 6 36 6Anorexia 27 2 24 1Constipation 21 1 20 0Stomatitis/Pharyngitis 14 1 12 0Diarrhea 12 1 13 2Dyspepsia/Heartburn 5 0 6 0

NeurologyNeuropathy-sensory 9 0 12 1Taste disturbance 8 0c 9 0c

Dermatology/SkinAlopecia 12 0c 21 1c

Rash/Desquamation 7 0 8 1

Table 4: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA plus Cisplatin in NSCLCa

a For the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possiblerelationship 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.



Incidence Less than 1%Cardiovascular—arrhythmiaGeneral Disorders—chest painMetabolism and Nutrition—increased GGTNeurology—motor neuropathy

Non-Small Cell Lung Cancer (NSCLC) - MaintenanceTable 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 therapyimmediately following 4 cycles of platinum-based treatment for locally advanced or metastatic NSCLC. Patients in both studyarms were fully supplemented with folic acid and vitamin B12.

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 ≤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 clinicallyrelevant 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) anderythropoiesis stimulating agents (ESAs; erythropoietin and darbepoetin) were higher in the ALIMTA arm compared to theplacebo 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/Skin—alopecia, pruritis/itchingGastrointestinal—constipationGeneral Disorders—edema, fever (in the absence of neutropenia)Hematologic—thrombocytopeniaRenal—decreased creatinine clearance, increased creatinine, decreased glomerular filtration rateSpecial Senses—ocular surface disease (including conjunctivitis), increased lacrimation

Incidence Less than 1%Cardiovascular—supraventricular arrhythmiaDermatology/Skin—erythema multiformeGeneral Disorders—febrile neutropenia, allergic reaction/hypersensitivityNeurology—motor neuropathyRenal—renal failure

Non-Small Cell Lung Cancer (NSCLC)—After Prior ChemotherapyTable 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 toreceive single-agent docetaxel. All patients were diagnosed with locally advanced or metastatic NSCLC and received priorchemotherapy.

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 Whole—abdominal pain, allergic reaction/hypersensitivity, febrile neutropenia, infectionDermatology/Skin—erythema multiformeNeurology—motor neuropathy, sensory neuropathyRenal—increased creatinineIncidence Less than 1%Cardiovascular—supraventricular arrhythmiasMalignant 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 randomlyassigned to receive single-agent cisplatin. In both treatment arms, these chemonaive patients were fully supplemented with folicacid and vitamin B12.

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

Incidence 1% to 5%Body as a Whole—febrile neutropenia, infection, pyrexiaDermatology/Skin—urticariaGeneral Disorders—chest painMetabolism and Nutrition—increased AST, increased ALT, increased GGTRenal—renal failureIncidence Less than 1%Cardiovascular—arrhythmiaNeurology—motor neuropathyEffects of Vitamin SupplementationsTable 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 theincidence in patients who never received vitamin supplementation (never supplemented) during the study in the ALIMTA pluscisplatin arm.

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%).

SubpopulationsNo 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 arereported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establisha causal relationship to drug exposure.

These reactions have occurred with ALIMTA when used as a single-agent and in combination therapies.Gastrointestinal—colitisGeneral Disorders and Administration Site Conditions—edemaInjury, poisoning, and procedural complications—Radiation recall has been reported in patients who have previously

received radiotherapyRespiratory—interstitial pneumonitis


ALIMTA PlaceboReactionb (N=438) (N=218)


All Adverse Reactions 66 16 37 4LaboratoryHematologic

Anemia 15 3 6 1Neutropenia 6 3 0 0Leukopenia 6 2 1 1

HepaticIncreased ALT 10 0 4 0Increased AST 8 0 4 0

ClinicalConstitutional Symptoms

Fatigue 25 5 11 1Gastrointestinal

Nausea 19 1 6 1Anorexia 19 2 5 0Vomiting 9 0 1 0Mucositis/stomatitis 7 1 2 0Diarrhea 5 1 3 0

Infection 5 2 2 0Neurology

Neuropathy-sensory 9 1 4 0Dermatology/Skin

Rash/Desquamation 10 0 3 0

Table 5: Adverse Reactions in Patients Receiving ALIMTA versus Placebo in NSCLCa


b Refer to NCI CTCAE Criteria version 3.0 for each Grade of toxicity.

ALIMTA DocetaxelReactionb (N=265) (N=276)


LaboratoryHematologic

Anemia 19 4 22 4Leukopenia 12 4 34 27Neutropenia 11 5 45 40Thrombocytopenia 8 2 1 0

HepaticIncreased ALT 8 2 1 0Increased AST 7 1 1 0

ClinicalGastrointestinal

Nausea 31 3 17 2Anorexia 22 2 24 3Vomiting 16 2 12 1Stomatitis/Pharyngitis 15 1 17 1Diarrhea 13 0 24 3Constipation 6 0 4 0

Constitutional SymptomsFatigue 34 5 36 5Fever 8 0 8 0

Dermatology/SkinRash/Desquamation 14 0 6 0Pruritis 7 0 2 0Alopecia 6 1c 38 2c

Table 6: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA versus Docetaxel in NSCLCa


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.

ALIMTA/cisplatin CisplatinReactionb (N=168) (N=163)


LaboratoryHematologic

Neutropenia 56 23 13 3Leukopenia 53 15 17 1Anemia 26 4 10 0Thrombocytopenia 23 5 9 0

RenalCreatinine elevation 11 1 10 1Creatinine clearance decreased 16 1 18 2

ClinicalEye Disorder

Conjunctivitis 5 0 1 0Gastrointestinal

Nausea 82 12 77 6Vomiting 57 11 50 4Stomatitis/Pharyngitis 23 3 6 0Anorexia 20 1 14 1Diarrhea 17 4 8 0Constipation 12 1 7 1Dyspepsia 5 1 1 0

Constitutional SymptomsFatigue 48 10 42 9

Metabolism and NutritionDehydration 7 4 1 1

NeurologyNeuropathy-sensory 10 0 10 1Taste Disturbance 8 0c 6 0c

Dermatology/SkinRash 16 1 5 0Alopecia 11 0c 6 0c

Table 7: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA plus Cisplatin in MPMa


b Refer to NCI CTC Criteria version 2.0 for each Grade of toxicity except the term “creatinine clearance decreased” which isderived from the CTC term “renal/genitourinary-other”.

c According to NCI CTC Criteria version 2.0, this adverse event term should only be reported as Grade 1 or 2.

Fully Supplemented Never SupplementedPatients Patients

Adverse Eventa (%) (N=168) (N=32)Neutropenia/granulocytopenia 23 38Thrombocytopenia 5 9Vomiting 11 31Febrile neutropenia 1 9Infection with Grade 3/4 neutropenia 0 6Diarrhea 4 9

Table 8: Selected Grade 3/4 Adverse Events Comparing Fully Supplemented versus Never Supplemented Patients in the ALIMTA plus Cisplatin arm (% incidence)

a Refer to NCI CTC criteria for lab and non-laboratory values for each grade of toxicity (Version 2.0).



7 DRUG INTERACTIONS

7.1 Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)IbuprofenAlthough 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 ≥80 mL/min). Caution should be used when administeringibuprofen 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 NSAIDsPatients 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, especiallymyelosuppression, renal, and gastrointestinal toxicity.

7.2 Nephrotoxic DrugsALIMTA 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 thatare also tubularly secreted (e.g., probenecid) could potentially result in delayed clearance of ALIMTA.

8 USE IN SPECIFIC POPULATIONS

8.1 PregnancyTeratogenic Effects—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 inmice. 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 byincreased embryo-fetal deaths and reduced litter sizes. If ALIMTA is used during pregnancy, or if the patient becomes pregnantwhile taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential shouldbe advised to use effective contraceptive measures to prevent pregnancy during the treatment with ALIMTA.

8.3 Nursing MothersIt 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 bemade to discontinue nursing or discontinue the drug, taking into account the importance of the drug for the mother.

8.4 Pediatric UseThe safety and effectiveness of ALIMTA in pediatric patients have not been established.

8.5 Geriatric UseALIMTA 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 betaken in dose selection. Renal function monitoring is recommended with administration of ALIMTA. No dose reductions otherthan 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 ≥65 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 ≥65 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 ≥65 years and no differenceswere seen in Grade 3/4 adverse reactions as compared to patients <65 years. For patients <65 years, the HR for overall survivalwas 0.74 (95% CI: 0.58, 0.93) and for patients ≥65 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 ≥65 years andGrade 3/4 hypertension was greater as compared to patients <65 years. For patients <65 years, the HR for overall survival was0.95 (95% CI: 0.76, 1.19), and for patients ≥65 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 ≥65 years, and Grade 3/4fatigue, 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 ≥65 years, the HR was 0.85 (95% CI: 0.59, 1.22) in theintent-to-treat population.

8.6 Patients with Hepatic ImpairmentThere 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 andgreater 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 beenstudied in patients with moderate renal impairment.

8.8 GenderIn 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-treatpopulation.

In the maintenance non-small cell lung cancer trial, 73% of patients were males and 27% females. For males the HR foroverall 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-treatpopulation.

In the non-small cell lung cancer trial after prior chemotherapy, 72% of patients were males and 28% females. For malesthe 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-to-treat 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 RaceIn 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 was0.86 (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. ForCaucasians 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 survivalwas 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.

10 OVERDOSAGEThere 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 overdoseoccurs, general supportive measures should be instituted as deemed necessary by the treating physician.

In clinical trials, leucovorin was permitted for CTC Grade 4 leukopenia lasting ≥3 days, CTC Grade 4 neutropenia lasting≥3 days, and immediately for CTC Grade 4 thrombocytopenia, bleeding associated with Grade 3 thrombocytopenia, or Grade 3or 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 TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity studies have been conducted with pemetrexed. Pemetrexed was clastogenic in the in vivo micronucleusassay in mouse bone marrow but was not mutagenic in multiple in vitro tests (Ames assay, CHO cell assay). Pemetrexedadministered 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 INFORMATIONSee 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 reducetreatment-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 theirphysician should any sign of infection develop including fever. Patients should also contact their physician if bleeding orsymptoms of anemia occur.

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

17.4 Concomitant MedicationsPatients 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.

Literature revised July 2, 2009

Eli Lilly and CompanyIndianapolis, IN 46285, USA

Copyright © 2004, 2009, Eli Lilly and Company. All rights reserved.

PV 5206 AMP PRINTED IN USA




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

Everyone agrees that, in the age of budget con-straints, 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 topic—with the task made even more difficult by the ambitious array of therapeutic areas to be tackled under very tight timelines—and that any conclusion favoring one treatment may well lead to other treat-ments being barred.

John I. Allen, MD, clinical associate professor of medicine, University of Minnesota, Minneapolis, not-ed that most people are “on board” with the concept of evidence-based medicine. “But I think skepticism comes from the fact that it’s an extraordinarily com-plicated and costly proposition to arrive at evidence-based 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,” Dr. Allen said. “We’re concerned that this is going to be superficial and not reflect the complexity of real-world patient care. We’re also concerned that compar-ative effectiveness analysis will lead to decisions that might restrict choices for patient care and develop-ment of new technologies and treatments.”

Douglas Blayney, MD, president of the American Society of Clinical Oncology (ASCO), in Alexandria, Va., expressed a similar view. “I think that it is valuable to call attention to the fact that comparative effective-ness research is important for doctors’ and patients’ decision making,” Dr. Blayney said. “But, in general, ASCO also wants to have the decision making remain in the hands of physicians and patients.”

The Top 100

The initiative is part of the rolling out of the Ameri-can Recovery and Reinvestment Act of 2009. The leg-islation, signed into law on Feb. 17 by President Barack Obama, allocated $400 million to the Office of the Sec-retary of the HHS, $400 million to the NIH and $300 million to the AHRQ for CER.

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 council’s report sketched out a framework for arriving at priorities for research, investment of human and sci-entific capital, assembly of data and infrastructure, and dissemination and translation of CER.

Additionally, the American Recovery and

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.

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.

“The report is meant to address the fear that if one treatment comes out ahead, the other treatments will be denied,” remarked Sheldon Greenfield, MD, pro-fessor of medicine at University of California, Irvine, and co-chair of the IOM committee that produced the report. “If one treatment is found to work well, and another treatment works only somewhat better, then both treatments will be available. CER isn’t about denying treatments, it’s about making sure all types of patients are appropriately treated.”

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 suspend-ing the appeals procedure for investigators applying for grants “due to the time sensitivity of the Recovery Act granting process.” 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 Can-cer 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 FDA’s Oncology Drug Advisory Committee, lays out how systematic reviews, prospective clinical tri-als, longitudinal registries, comparative effectiveness simulations and clinical practice guidelines can deliv-er the apparent intent of the Obama initiative, which is to optimally inform clinical decisions.

“But first, we have to carefully define what compar-ative effectiveness research is,” 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 Compre-hensive Cancer Center, in Durham, N.C. “And No. 2, let’s make sure there’s no hidden issues here,” he said. “Let’s make sure there’s no subterfuge for rationing drugs, or for funding your research.”

—Rosemary Frei, MSc

Government-Funded Initiative Meets With SkepticismRecently, 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.

CLINICAL ONCOLOGY NEWS • SEPTEMBER/OCTOBER 2009 A

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 practice–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 surveil-lance, 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, observa-tion or ablative techniques on disease-free and overall survival, tumor recurrence, qual-ity of life and toxicity in patients with liver metastases

Effectiveness of genetic and biomarker test-ing and usual care in preventing and treating breast, colorectal, prostate, lung, and ovarian cancers, and possibly other clinical conditions for which promising biomarkers exist.

PRN

Research

‘[Comparative effectiveness research] isn’t about denying treatments; it’s about making sure all types of patients are appropriately treated.’

—Sheldon Greenfield, MD

‘Let’s make sure there’s no hidden issues here. Let’s make sure there’s no subterfuge for rationing drugs, or for funding your research.’

—Gary Lyman, MD, MPH



http://www.oncologyfellowadvisor.com

CLINICAL ONCOLOGY NEWS • SEPTEMBER/OCTOBER 2009 7

The 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, single-arm, multicenter, international clinical

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 diag-nosis of PTCL was confirmed by inde-pendent 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 pro-gression or unacceptable toxicity. Addi-tionally, patients received 1 mg of vita-min 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 assess-ments 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 docu-mented response to disease progression or death. Response and disease progres-sion were evaluated by independent cen-tral review using the IWC.

The trial revealed that of the 109 eval-uable patients, 29 (27%) responded to

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 thrombocytope-nia (33%), mucositis (21%), neutropenia (20%) and anemia (17%).

The median number of prior system-ic 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 medi-an time to first response was 45 days (range, 37-349 days).

Clinical benefit such as improvement in progression-free survival or over-all 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.

Folotyn Approved for PTCL

Your Letters

Response to Dr. Eng’s EditorialDr. 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 pre-

defined effect on microscopic disease post–primary resection. I know of no other pure adjuvant trials with bevacizumab—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 (comput-ed 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 ther-apy in colon cancer. I’m more interested in the drug’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 “test” whether one should embark on bigger trials and how to do so in a genomically clever fashion.

Regards,

Anthony F. Provenzano, MD

Chief of OncologyLawrence Hospital Center

Bronxville, N.Y.

ADVISORY BOARD

BioethicsJoseph P. DeMarco, PhD

Paul J. Ford, PhD

Community OncologyMichael J. Fisch, MD, MPH

John W. Finnie, MD

Hematologic MalignanciesJennifer R. Brown, MD, PhD

Agnes Y.Y. Lee, MSc, MD

Richard Stone, MD

Oncology Nursing Betty Ferrell, RN, PhD

PharmacyPolly E. Kintzel, PharmD

Melvin E. Liter, MS, PharmD

Policy and ManagementMary Lou Bowers, MBA

Barbara Constable, RN, MBA

Rhonda M. Gold, RN, MSN

Solid Tumors

Bone Metastases

Allan Lipton, MD

Breast Cancer

Andrew Seidman, MD

Gastrointestinal Cancer

Edward Chu, MD

Cathy Eng, MD

Leonard Saltz, MD

Gastrointestinal Cancer and Sarcoma

Ephraim Casper, MD

Genitourinary Cancer

Ronald M. Bukowski, MD

Gynecologic Cancer

Maurie Markman, MD

Lung, and Head and Neck Cancers

Edward S. Kim, MD

Lung Cancer, Emesis

Richard J. Gralla, MD

Infection ControlSusan K. Seo, MD, Director

Symptom Control and Palliative CareWilliam S. Breitbart, MD

Steven D. Passik, PhD

Joseph V. Pergolizzi Jr., MD

Russell K. Portenoy, MD

Charles F. von Gunten, MD

EDITORIAL STAFF

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Copyright © 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.

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FDA NEWS




San Diego—The biggest medical com-pany you’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 offer-ings are focused on improving patient care and safety.

Jim Mazzola, senior vice presi-dent of marketing and communica-tion, explained, “The parent company, Cardinal Health, is primarily a North American distribution business, while CareFusion is primarily a global med-ical device business. We determined that these very different business-es would both be better positioned in their respective markets if they were separate and could therefore invest independently to grow.”

CareFusion’s product lines already are well known and widely used in hos-pitals worldwide. “They run the gamut from surgical instruments, to ventila-tors, to IV infusion pumps,” Mr. Maz-zola explained. One example is Pyxis, “an automated dispensing and patient identification system that secures phar-maceuticals on the nursing floor, cut-ting down the time it takes to deliver drugs to where they are needed—at the patient’s bedside.” The system greatly reduces the possibility of medication errors, an important consideration giv-en the extent of annual adverse drug events among hospitalized patients.

Alaris is CareFusion’s line of infusion pumps. Among its many innovations, “Alaris introduced ‘guardrails safety software,’ which allows hospitals to set parameters for medication infusions. If a nurse accidentally enters a value that is above or below the recommended dosage—for example, 2.0 is entered as 20.0—it will stop the infusion.”

CareFusion also markets AVEA and Pulmonetic Systems, a line of venti-lation 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 safe-ty because it allows the patient to be moved without having to be switched from a bedside ventilator to a trans-port ventilator. Studies have found that changing ventilators increases the risk

for ventilator-associated pneumonia.

Diversified Line of Products

CareFusion, whose internation-al headquarters is located here, also markets the V. Mueller line of surgi-cal instruments; monitoring and diag-nostic products for neurology; prod-ucts for interventional medicine; ChloraPrep, which helps reduce sur-gical site and bloodstream infections;

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

CareFusion has plans to introduce nearly 40 new products in the next 18 months. “Some of our new offerings will connect existing products, such as Pyx-is and MedMined, to further enhance safety and help hospitals measurably

improve the care they deliver.”“We are in business in many parts

of the world,” Mr. Mazzola said. “Although these markets can be very different, many of the challenges hos-pitals face are really the same. Adapta-tion and sensitivity to these local mar-kets come into play, but patient safety and improving patient care are impor-tant everywhere.”

—Staff

CareFusion’s Focus:

Medical Devices Supporting Patient Care and Safety

PRN

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

Visit www.clinicaloncology.com

Are you looking for more optionsfor your patients? NCI’s Center

for Cancer Research (CCR)conducts more than 150 clinical trialsat the National Institutes of Health(NIH) in Bethesda,Md. In the state-of-the-art NIH Clinical Center, the latestinnovations in medicine are put intopractice every day.

CCR is currently conductingtrials for many types of cancerincluding:

• Prostate Cancer • Lung Cancer• Thymoma• Pediatric Sarcoma• Kidney Cancer• Brain Cancer

To learn whether your patients may be eligible, visit

bethesdatrials.cancer.gov or call

1-888-NCI-1937 (1-888-624-1937)

CCR Clinical Trials at NIH

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A Phase III Study for Patients With Previously Untreated Multiple Myeloma

SWOG S0777 CURRENTLY ENROLLING

Study CoordinatorBrian Durie, MD, Cedars-Sinai Medical Center, Los Angeles, CA

Primary ObjectiveTo compare progression-free survival (PFS) with lenalidomide plus low dose dexamethasone (Ld) ver-sus lenalidomide, bortezomib, and low dose dexamethasone (LBd) in patients with previously untreatedmultiple myeloma without an intent for immediate stem cell transplantation

Secondary Objectives1. To evaluate the role of MRI scan in assessment of stage and response to therapy2. To correlate Gene Expression Profiling and single nucleotide polymorphisms with prognosis and out-comes

Key Eligibility Criteria• Newly diagnosed multiple myeloma with no prior chemotherapy

• Adequate bone marrow function

• Zubrod Performance Status 0-3

• Creatinine clearance >30 mL/min

Study Design

09/09 CELG09152T

Long-term Fol-low-up Phase

Patients followed forsurvival for 6 years

Treatment (Ld)• Lenalidomide 25 mg

po once daily, days 1-21 each cyclea,b

• Dexamethasone 40 mgpo once daily, days 1, 8,15, and 22 each cyclec

• Aspirin 325 mg poonce daily, continuously

28-day cycles; until pro-gression

Note: This study is supported by theNational Cancer Institute Cancer TrialsSupport Unit (CTSU). Institutions notaligned with SWOG will participatethrough the CTSU mechanisms.Funding for this trial provided by Celgene Corporation, Millennium:The Takeda Oncology Company, andthe National Cancer Institute.

aPatients experiencing bortezomib- and/or lenalidomide-related ≥Grade3 non-hematologic or Grade 4 hematologic toxicity will have their doseheld until toxicity has resolved to Grade 1 or better, and then will havetheir dose reduced 1 level from the previous dose received.

bIf serum creatinine is ≥2 mg/dL prior to the first cycle, a reduced doseof lenalidomide of 5 mg/day is recommended.

cInduction dose reduction of dexamethasone is not allowed. In the eventof Grade 3 or Grade 4 gastrointestinal bleeding or severe diabetes,dexamethasone must be discontinued.

Treatment A (Ld)• Lenalidomide 25 mg po once daily, days 1-21

each cyclea,b

• Dexamethasone 40 mg po once weekly, days 1,8, 15, and 22 each cyclec

• Aspirin 325 mg po once daily, continuouslyUp to 6 cycles, 28 days eachb

Treatment B (LBd)• Lenalidomide 25 mg po once daily, days 1-14

each cyclea,b

• Dexamethasone 20 mg po once daily, days 1, 2, 4,5, 8, 9, 11, and 12 each cyclec

• Bortezomib 1.3 mg/m2 intravenously once daily,days 1, 4, 8, and 11 each cyclea

• Aspirin 325 mg po once daily, continuously• HSV prophylaxis per institutional standardUp to 8 cycles, 21 days eachb

N=440

Induction

Maintenance

Enrollment

Funding and editorial support for trial recruitment materials provided by Celgene Corporation.

Patients in both arms considering autologous stem cell transplantation following relapse should undergo stem cell collection after the second cycle of treatment.

For more information contactwww.clinicaltrials.gov (NCT00644228),

www.swog.org,

-OR-

the National Cancer Institute Cancer Trials Support Unit

(888) 823-5923

([email protected])



Newly Diagnosed MyelomaOnce 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 tri-als (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 patient’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 dis-ease 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 ini-tial 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:

effectively controlling disease and minimizing early 1. mortality, thereby providing the maximum possibil-ity of reaching an ASCT; minimizing possible toxicity; 2. administering therapy with the least negative impact 3. on quality of life; minimizing the impact on the ability to collect stem 4. cells; and continuing therapy with minimal modification—giv-5. en the lack of a survival advantage for early ASCT—if a decision is made to delay ASCT.The introduction of newer agents has shifted the

initial approach from the traditional regimens of single-agent dexamethasone or a combination of vincristine, doxorubicin, and dexamethasone (VAD) to 1 of 3 regi-mens: the combination of the thalidomide analogue lenalidomide (Revlimid, Celgene) and low-dose dex-amethasone; thalidomide and dexamethasone (TD); or bortezomib (Velcade, Millennium Pharmaceuticals) and dexamethasone.

Various clinical trials in patients newly diagnosed

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 combina-tion.6,9 The combination also has been compared with the VAD regimen and has been found to have a supe-rior 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 sur-vival rate greater than 90%. In comparison with dex-amethasone 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 lenali-domide and low-dose (weekly) dexamethasone. This study demonstrated improved survival, despite a lower response rate, for patients treated with lower-dose dexamethasone, effectively eliminating high-dose dexamethasone treatment from the setting of newly diagnosed disease.11 Lenalidomide has been studied in combination with alkylators or anthracy-clines, 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 com-bination 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 com-bination can further enhance the up-front treatment of myeloma. The combination of bortezomib, tha-lidomide, and dexamethasone (VTD) was compared with TD in a Phase III trial. VTD resulted in signifi-cantly 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), result-ing 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, dexametha-sOne, and Lenalidomide with or without cyclophos-phamide Using Targeted Innovative ONcology strate-gies in the treatment of front-line multiple myeloma) trial added cyclophosphamide to the VRD combina-tion and reported a 100% response rate with high

INDEPENDENT LY DEVELOPED BY MCMAHON PUBL ISHING2


INDEPENDENTLY DEVELOP ED BY MCMAHON PUBL ISHING 3

Transplant-Ineligible

MPT orMPV x

12 cycles

Continue until maximum response or indefinite based on adverse effects

Option 2

Continue induction therapy

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

Option 1

Autologous stem cell transplant

Transplant-Eligible

Induction Therapya

Lenalidomide-Low-dose Dexamethasone Bortezomib-DexamethasoneThalidomide-Dexamethasone

Collect stem cells after 4 cycles of induction

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.



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 diag-nosed 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 oth-ers have suggested no benefit for ASCT, especially in patients responsive to initial therapy.22-24 In the IFM94 and Myeloma VII trials, previously untreat-ed patients younger than age 65, were randomly assigned to receive either conventional chemother-apy (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 mainte-nance, did not reveal any OS benefit.26 The Spanish cooperative group PETHEMA conducted a random-ized trial comparing ASCT with CCT in patients who responded to initial therapy and demonstrated higher complete response (CR) rates with ASCT but no dif-ferences 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-stimulat-ing factor or granulocyte-macrophage colony-stimu-lating 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

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, with-out any effect on EFS or OS. Ongoing trials are attempting to improve melphalan conditioning by increasing the melphalan dose (alone or in combina-tion 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 contin-ues to evolve in the era of novel agents. The high response rates seen with the new combination regi-mens 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 thera-peutic armamentarium for MM. Ongoing trials are examining the best way to integrate these treatment modalities to provide maximum benefit to patients.

ROLE OF SECOND ASCTThe 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 induc-tion 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 clini-cal trial, patients were randomly assigned to receive single or double ASCTs and then further randomized



Table 1. Response Criteria for MM

Response Subcategory

Response Criteria

CR Negative immunofixation on the serum and urine • and

Disappearance of any soft tissue plasmacytomas • and

<5% plasma cells in bone marrow •

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.

Stringent CR

(CR as above plus)

Normal FLC ratio • and

Absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence •

VGPR Serum and urine M-component detectable by immunofixation but not on electrophoresis • or

≥ • 90% reduction in serum M-component plus urine M-component <100 mg/24 h

PR ≥ • 50% reduction of serum M-protein and reduction in 24-h urinary M-protein by ≥90% or to <200 mg per 24 h

If the serum and urine M-protein are unmeasurable, a • ≥50% decrease in the difference between involved and uninvolved FLC levels is required in place of the M-protein criteria

If serum and urine M-protein are unmeasurable, and serum FLC assay is also •unmeasurable, ≥50% reduction in bone marrow plasma cells is required in place of M-protein, provided baseline percentage was ≥30%

In addition to the above criteria, if present at baseline, • ≥50% reduction in the size of soft tissue plasmacytomas is also required

SD Not meeting criteria for CR, VGPR, PR, or PD •

Relapse from CR

Reappearance of serum or urine M-protein by immunofixation or electrophoresis • or

Development of • ≥5% plasma cells in the bone marrow or

Appearance of any other sign of progression (ie, new plasmacytoma, lytic bone lesion, •or hypercalcemia)

PD Increase of 25% from baseline in:

Serum M-component (absolute increase must be • ≥0.5 g/dL) and/or

Urine M-component (absolute increase must be • ≥200 mg/24 h) and/or

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)

Bone marrow plasma cell percentage (absolute % must be 10%) •

Definite development of new bone lesions or soft tissue plasmacytomas or definite increase •in the size of existing bone lesions or soft tissue plasmacytomas

Development of hypercalcemia (corrected serum calcium >11.5 • mg/dL) that can be attributed solely to the plasma cell proliferative disorder



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 con-siderably 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 ASCTASCT clearly improves response rates in patients

with newly diagnosed MM compared with conven-tional 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 mod-est 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 tan-dem 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 mainte-nance (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 con-trol 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 follow-ing 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 mainte-nance 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 strat-egies, such as dendritic cell vaccines. Long-term

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 graft-versus-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 allo-geneic bone marrow transplant (allo-BMT) were com-pared 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 sur-vival in allo-BMT patients could be attributed mostly to the higher treatment–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 treatment–related mortality by depending more on the anti-tumor effect of the graft than on the ini-tial cytoreduction achieved by the conditioning regi-men. 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 periph-eral blood SCT (median of 2-4 months from ASCT), then mycophenolate mofetil–cyclosporine graft-ver-sus-host disease prophylaxis, and finally a second ASCT.39 At a median follow-up of 3 years, treatment-related mortality was 11% for the alloSCT group ver-sus 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 can-not be generalized.

PATIENTS NOT ELIGIBLE FOR TRANSPLANT

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



65 at diagnosis.40 For decades, melphalan and pred-nisone (MP) have been the mainstays of therapy for patients not eligible for SCT. A meta-analysis of mul-tiple randomized trials failed to demonstrate any ben-efit 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 tha-lidomide 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 deriv-ing 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 remain-ing 64 patients developed thrombosis. A second clini-cal trial, conducted in France (IFM99-06) randomly assigned patients aged 65 to 75 to receive MP (12 cycles at 6-week intervals), MPT (maximum toler-ated 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 mel-phalan 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 correspond-ing 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

regimen and limit the therapy to 12 months. Patients should be given daily aspirin for thromboprophylaxis, and clinicians should limit the use of low–molecular-weight 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 borte-zomib 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 lenalido-mide; Phase II results are promising, and a Phase III trial comparing this regimen with MPT is ongoing.45

Both thalidomide and bortezomib have been com-bined 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 (bort-ezomib 1.3 mg/m2, days 1, 8, 15, and 22; melphalan9 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 administra-tion 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 MMThe 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 cytoge-netic 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



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 recommend-ed 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 decreas-ing response duration, with each relapse reflecting increasingly acquired drug resistance.47

Two of the most promising drugs undergoing clini-cal 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 dexametha-sone 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

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 clini-cal 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) inhibi-tors and the heat-shock protein (Hsp) inhibitors. The HDAC inhibitor vorinostat is in a Phase III trial in com-bination 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 combi-nation 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-RiskFeatures 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

Table 2. Options for Relapsed MM

Bortezomib ± dexamethasone

Lenalidomide ± dexamethasone

Melphalan, prednisone (± thalidomide, lenalidomide, or bortezomib)

Cyclophosphamide, prednisone

Vincristine, adriamycin, dexamethasone

Thalidomide ± dexamethasone

Bortezomib, doxorubicin HCl liposome injection (± dexamethasone)

Bortezomib, thalidomide (or lenalidomide), dexamethasone

Cyclophosphamide, thalidomide (or lenalidomide), dexamethasone

Dexamethasone (pulse dose)

DT-PACE (± bortezomib)

DT-PACE, dexamethasone, thalidomide, cisplatin, adriamycin, cyclophosphamide, etoposide; MM, multiple myeloma



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 heterogene-ity of the disease.56 Selected patients also may be can-didates 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 dura-tion of therapy with bisphosphonates and the frequen-cy 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 zole-dronic 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 thera-py 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 Clinic’s approach is to avoid using erythropoi-etin in patients with MM, unless hemoglobin does not improve with effective therapy. The target for hemo-globin 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.

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, includ-ing cast nephropathy, hypercalcemia, hyperuricemia, dehydration, hyperviscosity, medications such as non-

steroidal anti-inflammatory drugs and, rarely, coexis-tent amyloidosis or light chain deposition disease. Renal insufficiency in MM should be managed aggres-sively 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 impor-tant to prevent further deterioration of, and possibly ensure improvement of, renal function. Patients with advanced renal failure will require dialysis support.

VERTEBRAL COMPRESSION FRACTURES Vertebral compression fractures contribute to sig-

nificant morbidity in patients with MM, and verte-broplasty 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.

Table 3. Novel Drugs Undergoing Clinical Trials in Myeloma

IMiD—pomalidomide (Celgene)

New proteasome inhibitor—carfilzomib (Proteolix)

Histone deacetylase inhibitors—vorinostat (Zolinza, Merck); panabinostat (Novartis)

Monoclonal antibodies—neural cell adhesion molecule (CD56), interleukin-6

Hsp-90 inhibitors—tanespimycin (Kosan); retaspimycin (Infinity Pharmaceuticals)

PI3k/Akt pathway inhibitor—perifosine (Keryx Biopharmaceuticals)

Farnesytransferase inhibitor—tipifarnib (Zarnestra, Johnson & Johnson)

Bcl2 inhibitors—ABT737, obatoclax

Anti-VEGF agents—sorafenib (Nexavar, Bayer); sunitinib (Sutent, Pfizer)

mTOR inhibitors—everolimus (Afinitor, Novartis); temsirolimus (Toricel, Wyeth)



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Barlogie B, Smith L, Alexanian R. Effective treatment of advanced 4. multiple myeloma refractory to alkylating agents. N Engl J Med. 1984;310(21):1353-1356, PMID: 6546971.

Kumar S, Lacy MQ, Dispenzieri A, et al. Single agent dexametha-5. sone for pre-stem cell transplant induction therapy for multiple myeloma. Bone Marrow Transplant. 2004;34(6):485-490, PMID: 15286691.

Rajkumar SV, Blood E, Vesole D, Fonseca R, Greipp PR; Eastern 6. Cooperative Oncology Group. Phase III clinical trial of thalido-mide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordi-nated by the Eastern Cooperative Oncology Group. J Clin Oncol. 2006;24(3):431-436, PMID: 16365178.

Rajkumar SV, Hayman SR, Lacy MQ, et al. Combination therapy 7. with lenalidomide plus dexamethasone (Rev/Dex) for newly diag-nosed myeloma. Blood. 2005;106(13):4050-4053, PMID: 16118317.

Kumar S, Lacy MQ, Dispenzieri A, et al. High-dose therapy and 8. autologous stem cell transplantation for multiple myeloma poorly responsive to initial therapy. Bone Marrow Transplant. 2004;34(2):161-167, PMID: 15133489.

Rajkumar SV, Rosinol L, Hussein M, et al. Multicenter, randomized, 9. double-blind, placebo-controlled study of thalidomide plus dex-amethasone compared with dexamethasone as initial therapy for newly diagnosed multiple myeloma. J Clin Oncol. 26(13):2171-2177, PMID: 18362366.

Cavo M, Zamagni E, Tosi P, et al. Superiority of thalidomide 10. and dexamethasone over vincristine-doxorubicin-dexamethasone (VAD) as primary therapy in preparation for autologous transplantation for multiple myeloma. Blood. 2005;106:35-39, PMID: 15761019.

Rajkumar SV, Jacobus S, Callander N, et al. Phase III trial of 11. lenalidomide plus high-dose dexamethasone versus lenali-domide plus low-dose dexamethasone in newly diagnosed multiple myeloma (E4A03): a trial coordinated by the Eastern Cooperative Oncology Group. ASH Annual Meeting Abstracts. Blood. 2007;110:74.

Kumar S, Hayman S, Buadi F, et al. Phase II trial of lenalidomide 12. (Revlimid™) with cyclophosphamide and dexamethasone (RCd) for newly diagnosed myeloma. ASH Annual Meeting Abstracts. Blood. 2008;112:91.

Baz R, Hussein MA, Sullivan D, et al. Phase II study of pegylated 13. liposomal doxorubicin (PLD), low-dose dexamethasone (DEX), and lenalidomide (LEN) in patients with newly diagnosed (ND) multiple myeloma (MM). J Clin Oncol. 2009;27:(15 suppl):Abstract 8518.

Spencer A, Taylor K, Lonial S, et al. Panobinostat plus lenalido-14. mide and dexamethasone phase I trial in multiple myeloma (MM). J Clin Oncol. 2009;27:(15 suppl):Abstract 8542.

Siegel DS, Weber DM, Mitsiades CS, et al. Vorinostat in combi-15. nation with lenalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma: A phase I study. J Clin Oncol. 2009;27:(15 suppl):Abstract 8586.

Jagannath S, Durie BG, Wolf J, et al. Bortezomib therapy alone 16. and in combination with dexamethasone for previously untreated symptomatic multiple myeloma. Br J Haematol. 2005;129(6):776-783, PMID: 15953004.

Harousseau JL, Mathiot C, Attal M, et al. Bortezomib/dexametha-17. sone versus VAD as induction prior to autologous stem cell transplantation (ASCT) in previously untreated multiple myeloma (MM): updated data from IFM 2005/01 Trial. J Clin Oncol. 2008;26(suppl):Abstract 8505.

Cavo M, Tacchetti P, Patriarca F, et al. Superior complete response 18. rate and progression-free survival after autologous transplanta-tion with up-front Velcade-thalidomide-dexamethasone compared with thalidomide-dexamethasone in newly diagnosed multiple myeloma. ASH Annual Meeting Abstracts. Blood. 2008;112:158.

Richardson PG, Lonial S, Jakubowiak A, et al. Safety and efficacy 19. of lenalidomide (Len), bortezomib (Bz), and dexamethasone (Dex) in patients (pts) with newly diagnosed multiple myeloma (MM): a phase I/II study. J Clin Oncol. 2008;26(suppl):Abstract 852.

Kumar S, Flinn IW, Noga SJ, et al. Safety and efficacy of 20. novel combination therapy with bortezomib, dexamethasone,



cyclophosphamide, and lenalidomide in newly diagnosed mul-tiple myeloma: initial results from the Phase I/II multicenter EVOLUTION trial. ASH Annual Meeting Abstracts. Blood. 2008;112:93.

Jakubowiak AJ, Hofmeister CC, Campagnaro EL, et al. 21. Lenalidomide, bortezomib, pegylated liposomal doxorubicin hydrochloride, and dexamethasone in newly diagnosed multiple myeloma: Initial results of phase I/II MMRC trial. J Clin Oncol. 2009;27:(15 suppl):Abstract 8517.

Attal M, Harousseau JL, Stoppa AM, et al. A prospective, ran-22. domized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med. 1996;335(2):91-97, PMID: 8649495.

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

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

Fermand JP, Katsahian S, Divine M, et al. High-dose therapy and 25. autologous blood stem-cell transplantation compared with con-ventional 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.

Barlogie B, Kyle RA, Anderson KC, et al. Standard chemotherapy 26. 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.

Fermand JP, Ravaud P, Chevret S, et al. High-dose therapy and 27. 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.

Moreau P, Facon T, Attal M, et al. Comparison of 200 mg/m28. 2 mel-phalan and 8 Gy total body irradiation plus 140 mg/m2 melphalan as conditioning regimens for peripheral blood stem cell transplan-tation in patients with newly diagnosed multiple myeloma: final analysis of the Intergroupe Francophone du Myelome 9502 ran-domized trial. Blood. 2002;99(3):731-735, PMID: 11806971.

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

Cavo M, Tosi P, Zamagni E, et al. Prospective, randomized study 30. of single compared with double autologous stem-cell transplanta-tion for multiple myeloma: Bologna 96 Clinical Study. J Clin Oncol. 2007;25(17):2434-2441, PMID: 17485707.

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

Cunningham D, Powles R, Malpas J, et al. A randomized trial of 32. maintenance interferon following high-dose chemotherapy in multiple myeloma: long-term follow-up results. Br J Haematol. 1998;102(2):495-502, PMID: 9695964.

Attal M, Harousseau JL, Leyvraz S, et al. Maintenance therapy with 33. thalidomide improves survival in patients with multiple myeloma. Blood. 2006;108(10):3289-3294, PMID: 16873668.

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

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

Tricot G, Vesole DH, Jagannath S, Hilton J, Munshi N, Barlogie 36. B. Graft-versus-myeloma effect: proof of principle. Blood. 1996;87(3):1196-1198, PMID: 8562947.

Bjorkstrand BB, Ljungman P, Svensson H, et al. Allogeneic bone 37. marrow transplantation versus autologous stem cell transplanta-tion 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.

Garban F, Attal M, Michallet M, et al. Prospective comparison of 38. autologous stem cell transplantation followed by dose-reduced allograft (IFM99-03 trial) with tandem autologous stem cell trans-plantation (IFM99-04 trial) in high-risk de novo multiple myeloma. Blood. 2006;107(9):3474-3480, PMID: 16397129.


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

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

Palumbo A, Bringhen S, Caravita T, et al. Oral melphalan and 41. 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.

Facon T, Mary JY, Hulin C, et al. Melphalan and prednisone 42. 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.

Hulin C, Facon T, Rodon P, et al. Efficacy of melphalan and pred-43. nisone 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.

San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus mel-44. phalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008;359(9):906-917, PMID: 18753647.

Palumbo A, Falco P, Corradini P, et al. Melphalan, prednisone, and 45. 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.

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

Kumar SK, Therneau TM, Gertz MA, et al. Clinical course of 47. patients with relapsed multiple myeloma. Mayo Clin Proc. 2004;79(7):867-874, PMID: 15244382.

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

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

patients with relapsed and refractory multiple myeloma (MM). ASH Annual Meeting Abstracts. Blood. 2008;112(11):864.

Richardson PG, Chanan-Khan A, Lonial S, et al. Tanespimycin 50. plus bortezomib in patients with relapsed and refractory mul-tiple myeloma: final results of a phase I/II study. J Clin Oncol. 2009;27(15 suppl):Abstract 8503.

Gertz MA, Lacy MQ, Dispenzieri A, et al. Clinical implications 51. 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.

Jagannath S, Richardson PG, Sonneveld P, et al. Bortezomib 52. 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.

San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus mel-53. phalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008;359(9):906-917, PMID: 18753647.

Kapoor P, Kumar S, Fonseca R, et al. Impact of risk stratification 54. on outcome among patients with multiple myeloma receiving initial therapy with lenalidomide and dexamethasone. Blood. 2009;114(3):518-521, PMID: 19324902.

Reece D, Song KW, Fu T, et al. Influence of cytogenetics in 55. 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.

Moreau P, Attal M, Garban F, et al. Heterogeneity of t(4;14) in 56. multiple myeloma. Long-term follow-up of 100 cases treat-ed with tandem transplantation in IFM99 trials. Leukemia. 2007;21(9):2020-2024, PMID: 17625611.

Kyle RA, Yee GC, Somerfield MR, et al. American Society of 57. 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.

Lacy MQ, Dispenzieri A, Gertz MA, et al. Mayo Clinic consensus 58. statement for the use of bisphosphonates in multiple myeloma. Mayo Clinic Proc. 2006;81(8):1047-1053, PMID: 16901028.




The FDA’s approval of the pain drug Onsolis, however, is replete with back-story and the potential for ongoing contro-versy, as the agent is the first in the opioid drug class to come with a Risk Evaluation and Mitigation Strategy (REMS), an FDA-mandated plan for minimizing risks asso-ciated with taking a drug.

The Onsolis REMS—and most likely the risk plans for all opioids for which they will be required—will include a restricted distribution program under which pre-scribers, pharmacies and patients would have to register in order to prescribe, dis-pense and receive Onsolis, respectively. The drug will be delivered directly to the patient’s home and is restricted in phy-sician 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 regard-ing REMS during its development pro-cess 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 long-acting and extended-release opioids to develop such risk management plans for their products. Each of these agents is for-mulated with one of the following active ingredients: fentanyl, hydromorphone, methadone, morphine, oxycodone and oxymorphone.

Onsolis (fentanyl buccal soluble film, Meda AB, BioDelivery Sciences) is indi-cated for the management of break-through pain in adult patients with cancer (aged ≥18 years) already taking and tolerant of opioids for their chron-ic cancer pain. The focus of a clinical trial program involving more than 300 patients and 90,000 administered dos-es, 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 fenta-nyl products. An opioid analgesic, fenta-nyl 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 differ-ences between the pharmacokinetic pro-file of Onsolis and other fentanyl products that affect the degree of drug absorption,

Onsolis should not be substituted by or for any other fentanyl products.

“Onsolis can provide strong pain relief to patients who are opioid tolerant. But for patients who are not opioid toler-ant, it can lead to overdose, sudden seri-ous breathing difficulties and death,” said Bob Rappaport, MD, director, Division of Anesthesia, Analgesia and Rheuma-tology Products in the FDA’s Center for Drug Evaluation and Research (CDER). “For this reason, Onsolis should be pre-scribed only under the safeguards pro-vided by the FDA-required REMS and by health care professionals knowledgeable about Onsolis and the use of potent opi-oid medications.”

FOCUS

The Onsolis Full Ongoing Commit-ment 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 distri-bution program.

“There is a restricted distribution pro-gram that the FDA has required but we don’t see that being in any way an obsta-cle to the proper patients receiving the product,” said Andrew Finn, MD, exec-utive vice president of product devel-opment for BioDelivery Sciences, in a July 17 teleconference. “The product will be delivered to a courier service, and that’s the way it will be delivered to the patient directly. We think that’s a positive.”

“We don’t see it [the REMS] affect-ing the long-term sales of this product,” agreed BioDelivery Sciences CEO Mark Sirgo in the same teleconference. “We actually think this educational process will drive usage, and do it in an appro-priate way by making sure the product gets to appropriate patients.”

The FDA was quick to point out that the REMS for Onsolis was not a “one-size-

fits-all” plan for all opioids, given that the product is a short-acting medication.

“The REMS for Onsolis was specif-ically tailored to that drug and should not be viewed as a model REMS for long-acting and extended-release opi-oid products,” said Douglas Throck-morton, MD, deputy director of CDER. “Developing the comprehensive REMS for these other products is a complex undertaking. We will take the time nec-essary to review all of the public com-ments and will proceed in a deliber-ate manner toward the mutual goals of patient access and patient protection.”

“The chief concern for oral membrane fentanyl products is the fact that patients need to be opioid tolerant,” said Dr. Finn. “That’s not the concern for long-acting products. There are different safety con-cerns for the two products so they have to be different kinds of REMS.”

APS Frustration

“The FDA has held a series of meet-ings with stakeholders, including a large public meeting, and also has solic-ited written public comments to hear more about how to develop this REMS,” said the FDA in a statement announcing the Onsolis approval. In a July 24 letter from APS president Charles E. Intur-risi, PhD, to Dr. Rappaport, the APS

acknowledged the opportunity to pres-ent its recommendations to the agen-cy, but added that it was “surprised and disappointed” that the Onsolis REMS was “in stark contrast to many of the stakeholder suggestions made.”

“We [the APS] are concerned with the well-documented issues of misuse, abuse and overdose deaths—particularly in [young people]—but we advocate for a rational approach that will minimize secondary, unintended consequenc-es such as restriction of access to prop-er pain care,” said Edward Michna, MD, APS Public Policy Committee co-leader. “Of concern, in particular, are the already underserved communities.”

One of the concerns of the APS is that REMS will not be required for all opioids.

“We do want to emphasize again our belief that opiate-induced dangers and

the REMS to address them share many features across the opiate drug class—regardless of their route of administra-tion, onset of action and potency,” the APS president wrote in the letter.

If the REMS do not cover all opioids, “you will probably drive prescribing to the uncovered class,” said Dr. Michna.

The following issues were among those described in the APS letter regarding the “stringent and compli-cated” Onsolis REMS.

Registry requirements. “The attempt-ed reassurance in the announcement that after patient, prescriber and dis-penser 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,” wrote the APS, “particular-ly if the patient happens to be located in a place where distribution is restricted like a hospital.”

Restricted distribution. “Not allow-ing hospital and institutional phar-macies to stock these medications for immediate use … denies patients and prescribers access to medications that may for these clinical situations be the best alternative,” according to the APS.

Patient education. Although medi-cation guides are “worthwhile educa-tional efforts,” they are not an adequate replacement for a knowledgeable phar-macist or clinician, according to the APS. “Many patients suffering from cancer- related pain are cognitively impaired, particularly at the end of life, which makes counseling and education of a patient, let alone a counseling call, diffi-cult or impossible.”

The APS urged the FDA to once again be open to stakeholder input, especial-ly from pain and palliative care groups, to ensure the “unintended consequenc-es” of implementing REMS are reduced.

“It would indeed be tragic if the very patients that these products were devel-oped and approved for were denied access to their specific therapeutic qual-ities,” 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.

“I have spoken to many physicians about this and no one is going to be cer-tified for this med,” he said.

Actiq (transmucosal fentanyl citrate, Cephalon) and Fentora (fentanyl buc-cal tablet, Cephalon), two other fentanyl-based products, will also include REMS, both of which are purported to be similar in nature to the Onsolis risk plan.

—Donald M. Pizzi

Onsolis Comes With First Opioid REMS—and Some RancorThe 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.

SUPPORTIVE CARE

Pain Management


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No monoclonal antibody is immune to immune reactionsFour important molecular features of therapeutic monoclonal antibodies may contribute

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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.

©2009 Amgen. All rights reserved. 7-09 44246




compliance than I am about potential audits, surveys or ‘out-right’ government intrusion into practices … I don’t think many private practices have spent a lot of time other than concern, but I might be wrong on this issue.”

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 FTC’s Identity Theft Red Flags Rule program is the agency’s assertion that physicians, by accepting credit cards and deferring payments, are “creditors” or “financial institutions,” and therefore are covered under bank-ing regulations regarding consumer pri-vacy. The program mandates that med-ical practices must create and institute programs that are appropriate to their size and operation, with the goal of iden-tifying and detecting patterns, practices and activities that indicate the possible breach of privacy of patient data. The FTC calls such breaches “red flags.”

Identity thieves are increasing-ly focused on stealing medical records, which contain not only Social Security and credit card numbers, billing address-es and dates of birth, but also insur-ance 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 victim’s name, ultimately corrupting the victim’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 vic-tims 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 physicians’ 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:

Physicians should not be considered • creditors because they submit claims to health insurance carriers, who

should be considered the creditors;Physicians already have devoted sub-• stantial resources to complying with privacy and security requirements of HIPAA; andThe mandate could have unintended • consequences, such as physicians de manding payment up front or aban-doning 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, HIPAA’s data security requirements.

Nor should the measure impose significant burdens on providers, especially those “in a low-risk environment,” because it is designed to be flexible and “tailored,” said Eileen Harrington, acting director of the FTC’s Bureau of Consumer Protection.

Ms. Harrington noted that many simple protections already are in place in physicians’ 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 wasn’t necessarily hard to do. “The rule is more of nuisance,” Dr. Kovach said. “I would like clear direction from the government as to what they would like us to do and we are not getting it.”

Legal Viewpoint

Mark F. Weiss, an attorney with the

POLICY & MANAGEMENT

Health Care

RED FLAGScontinued from page 1 �

see RED FLAGS, page 16 �


16 CLINICAL ONCOLOGY NEWS • SEPTEMBER/OCTOBER 2009

Advisory Law Group, a California firm with offices in Los Angeles and Santa Barbara, said clinicians need to understand that compliance goes hand-in-hand with fidelity to HIPAA. “HIPAA and other patient confidentiality rules exist to protect the secrecy of patients’ health care information; compliance with the red flags rule will help prevent an individual’s health care records from becoming polluted with an imposter’s data,” 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 billing service, Mr. Weiss said. “However, as the group is responsible for compliance, the process cannot simply be outsourced to the billing service and then forgotten.”

According to Mr. Weiss, “security breaches” 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? “The penalty can be as high as $2,500 for each ‘knowing violation,’ ” he said. “A group’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.”

Advice From an ID Theft Specialist

In the minds of specialists who deal with solutions to identity theft, busi-nesses—including medical practices—can hardly go far enough to protect cus-tomers, clients and in this case, patients.

Harry Perret, a certified identity theft risk management spe cialist and executive director of the con sulting 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. “The liabilities follow the data, and leave the doctors at risk,” 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. “Medical identity theft is the fastest growing type,” he said, “with both financial and potentially life-threatening results.”

—Audrey Andrews

POLICY & MANAGEMENT

Health Care

RED FLAGScontinued from page 15 �

The Nov. 1 deadline is the third extension of the Red

Flags Rule program given to medical practices, as fewseem to have established

programs and many appear to be unaware

of the mandate.

Breakthrough cancer pain

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 conversationIdentifying 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 patient’s description of various breakthrough cancer pain episodes—often described as “burning, aching, sharp, searing, throbbing, excruciating, relentless, or intolerable”1,2—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 effects—such as mental confusion and analgesic addiction—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

Closing the Gap by Opening the Dialogue


©2009 MEDA Pharmaceuticals Inc. All rights reserved. Printed in the USA. 08/09 BEM9033

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

Starting the right conversationThere 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 instance—

If your patients seem afraid to complain, say:

not have to suffer in pain from cancer

pain aren’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 “unbearable” 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

exactly as prescribed

Patient dialogue tools can facilitate discussion 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, “What is your average pain?” and, “What is your worst pain?” to help determine if the pain is breakthrough cancer pain. Also ask, “How often

things you want or need to do?” to help understand how breakthrough cancer pain impacts their quality of life.

Discussion leads to actionable informationBreakthrough 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: “Knowing Your Options Can Help Keep It Under Control”

References:1. Cleeland CS. The impact of pain on the patient with cancer. Cancer. 1984;54(11 suppl):2635-2641. 2.

3.opioids among patients with metastatic cancer during the last year of life. J Pain Symptom Manage 4.

Cancer5.in the comprehensive management of pain. Pain Practitioner


Cancer Center in New York. “Furthermore, medical isotope providers are telling us to expect continued shortages of technetium-99m.”

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 identi-fy obstructions in the kidneys, visualize gastric emp-tying, 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 chemother-apy. A small amount of Tc-99m also is used as a tracer in sentinel lymph node procedures.

“It is in many respects an ideal radioisotope,” said Michael M. Graham, MD, PhD, president of the Soci-ety of Nuclear Medicine, and professor of radiolo-gy and director of nuclear medicine at the Universi-ty 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 molybde-num-99 (Mo-99). Molybdenum is created by placing uranium-235 into the core of a nuclear reactor. The fis-sion of the uranium-235 atom breaks it into two frag-ments, one of which, Dr. Graham explained, is Mo-99.

“As you can imagine, the fuel element is extraordi-narily radioactive. So, this has to be done in a remote processing facility, and there are a fairly limited num-ber of these facilities around,” he said.

Historically, about 80% of the United States’ molyb-denum came from two reactors, the Chalk River reac-tor 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 con-cerns. 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 world’s supply, said Dr. Graham.

The Impact

David Mankoff, MD, PhD, professor of radiology, med-icine and bioengineering at the University of Washing-ton in Seattle, is seeing an impact of the shortage.

“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 neces-sary, triaging studies when this happens, so that the

most urgent tests get done,” he said.Patients seeking elective tests, including some can-

cer patients, sometimes have short delays in their stud-ies. “Technetium-99m is fairly heavily used in oncolo-gy, but [only] in a few specific indications, for example bone scans, and most of them tend not to be emergen-cies. Fortunately, so far, the delays have been short; nevertheless, delays in diagnostic scans can cause delays in treatment and should be avoided whenev-er possible.”

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 reac-tor, he said.

Dr. Macapinlac has worked with his supplier to get advance warning of shortages, which can help with plan-ning. 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. “In the past, the average cost at our uni-versity 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.”

For patients needing tests, there are some alterna-tives but they can have drawbacks. For example, a full-body 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 differ-

ent radioactive tracer, in patients who need myocardi-al perfusion imaging.

“We might not be able to do the scan as optimal-ly as we’d like, and we certainly do not like to switch techniques, but we need to deal with this on a daily or weekly basis,” he said.

Waiting for a Solution

Dr. Graham said the Tc-99m shortage was not unex-pected. About a decade ago, Canada announced it would build two new reactors to supply the world’s need for medical isotopes while replacing the produc-tion of the aging reactors.

“That was supposed to be the solution for the whole world. Everybody was sort of standing back and saying, ‘let’s let Canada do it.’ But those reactors have a criti-cal design flaw that makes it essentially impossible, or financially unfeasible, for them to fix,” Dr. Graham said.

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

On July 21, Rep. Edward J. Markey (D-Mass.) intro-duced 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. Maca-pinlac called the bill “our best hope to have a lasting solution to this [shortage].”

On Sept. 9, several experts, including Dr. Larson, tes-tified on behalf of the bill to the House Committee on Energy and Commerce. “The recent shutdown of NRU reactor at Chalk River in Canada has disrupted supplies of this important isotope to our clinic and to other hos-pitals in the northeastern United States,” Dr. Larson said. “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 coun-tries whose operational life expectancy is unpredictable. The development of a reliable domestic supply of tech-netium-99m is good public policy.”

—David Jakubiak

18 CLINICAL ONCOLOGY NEWS • SEPTEMBER/OCTOBER 2009SUPPORTIVE CARE

Bone Metastases

RADIOACTIVE DRUGcontinued from page 1 �

‘The shortage will sometimes limit the number of studies that can be done in a particular day.’

—David Mankoff, MD, PhD

CareFusion 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 com-

bines its proven technologies with informa-

tion to help measurably improve the delivery of

patient care. The Jazz Festival Series compris-

es some of the largest and oldest jazz festivals

in the world, attracting both big-name and up-

and-coming artists.

“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,” said David

Schlotterbeck, CEO of CareFusion. “Both jazz

and the practice of medicine embrace innova-

tion, performance and change. Jazz is also

used to teach listening skills to medical stu-

dents and resonates with our customers.” (The

connection between jazz and medicine is also

made at mcmahonjazzmedicine.com, a sister

publication of this newsmagazine, which cele-

brates the improvisational nature of creative

art and the practice of medicine.)

The CareFusion Jazz Festival Series schedule

includes:

George Wein’s CareFusion Jazz Festival 55 (Newport, R.I.), Aug. 7–9, 2009, completedChicago Jazz Festival presented by CareFusion, Sept. 4–6, 2009, completedCareFusion Presents Dizzy’s Den at the Monterey Jazz Festival, Sept. 18–20, 2009, completedCareFusion Manly Jazz Festival (Australia), Oct. 3–5, 2009, completedCareFusion Jazz Festival Paris, Oct. 16–24, 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 adminis-

trators from hospitals across the United States,

Europe and Australia will also be invited to spe-

cial VIP events at the festivals to raise funds and

awareness for a new health care safety cam-

paign named “Rhythm of Care,” which brings

together organizations and people from health

care to promote best practices.

CareFusion Launches Jazz Festival Series

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.


Management ofCutaneous T-Cell Lymphoma

FREDERICK LANSIGAN, MDAssistant Professor of MedicineHematology and OncologyNorris Cotton Cancer CenterDartmouth-Hitchcock Medical CenterLebanon, New Hampshire

FRANCINE M. FOSS, MDProfessor of MedicineHematological MalignanciesMedical OncologyYale Cancer CenterNew Haven, Connecticut

Cutaneous 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-Hodgkin’s lymphomas in the United States.

The classification of cutaneous lymphomas describes several subtypes of CTCL: mycosis fungoides (MF), its variants, and the Sézary syndrome (SS), which comprise 44% of cases; the CD30+ lymphomas, such as ana-plastic large cell lymphoma of the skin and lymphomatoid papulosis; and aggressive forms of peripheral T-cell lymphoma (PTCL), including PTCL-unspecified, 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 indo-lent 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 vis-ceral 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 Pautrier’s microabscess. In early-stage 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.

Clinical Staging and Prognosis of MF and SSStaging of patients with MF and SS is essential both for its prognostic

value and for decisions in management. The most commonly used stag-ing 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 patch-plaque 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 medi-an 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 immu-nosuppressive effects of systemic therapies.

TreatmentDecisions 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 dis-ease, approaches often include skin-directed as well as systemic thera-pies, 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 fre-quently depends on the experience of the treating physicians and institu-tion, as well as patient preference. Treatment algorithms for MF/SS include combined or sequential therapies with multiple skin-directed and system-ic agents (Table 2).7

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

19INDEPENDENTLY DEVELOP ED BY M C M AH ON P U BL ISHIN G CL IN ICA L ON COLOGY NEWS • SEPTEMBER/OCTOBER 2009

PRINTER-FRIENDLY VERSION AT CLINICALONCOLOGY.COM


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 clin-ical 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 approximate-ly 15% of patients treated, and can cause cutaneous atrophy. Oral corti-costeroids 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 avail-able in an ointment-based preparation and can be very effective in palli-ating 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 carcino-genic 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 dis-ease. 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 bexar-otene gel is cutaneous hypersensitivity and increased redness or itching. Often, alternating applications of corticosteroids and bexarotene can alle-viate these effects.

Phototherapy with psoralen plus ultraviolet A radiation (PUVA) is a skin-directed therapy that causes apoptosis of infiltrating tumor cells and mono-nuclear cells, including Langerhan’s cells, which support CTCL survival in the skin microenvironment.13 Retrospective studies of PUVA monothera-py demonstrated response rates from 50% to 63%, with 50% of respond-ers showing sustained remissions, although most of the responders were patients with stage I disease.14,15 Prolonged use of PUVA has been asso-ciated with skin erythema and secondary malignancies, including mela-noma 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

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 limit-ed penetration by electrons, systemic toxicity is rare. TSEBT, which is often used for patients with extensive skin involvement, can be com-bined with adjuvant systemic modalities such as retinoids, PUVA, or pho-topheresis, 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 anhydro-sis, 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 pallia-tion 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 TherapySystemic 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-limit-ing 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 Cir-culating T-cells and Sézary 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 Sézary 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 respons-es to ECP monotherapy; however, the best responders seem to be patients with a short duration of disease, an absence of bulky lymphadenopathy, and low Sézary counts, and who have not received immunosuppressive

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

N MT1: Limited Patch/Plaque (<10% BSA)

T2: Generalized Patch/Plaque (≥10% BSA) T3 Tumor T4 Erythroderma

N0: Nodes clinically uninvolved M0 IA IB IIB IIIA

N1: Nodes enlarged, histologically uninvolved M0 IIA IIIB

N2–3: Nodes clinically normal (N2) or enlarged (N3), histologically involved

M0 IVA

N0–3: Visceral involvement M1 IVB

B: Classification not incorporated in the clinical stage

B0: Absence of significant peripheral blood Sézary cells

B1: Presence of significant peripheral blood Sézary cells

BSA, body surface area

Adapted from reference 3.

20 INDEPENDENTLY DEVELOP ED BY M C M AH ON P UBL ISHIN G


chemotherapy.34,35 ECP is well tolerated and often is the first systemic ther-apy 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 consec-utive treatments every other week. Response is measured by reduction in overall skin tumor burden and by a decrease in circulating Sézary cells and restoration of a normal CD4/CD8 ratio. Combinations of ECP with other systemic agents, such as interferon-γ (INF-γ) or bexarotene, and other treatment modalities, such as TSEBT or PUVA, have demonstrated effica-cy 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-α 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-α and showed a 45% objective response rate. Subsequent studies confirmed activity in early- and late-stage 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 toxici-ties of IFN-α, 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-α can be used as an adjunct to topical therapy, or after failure of skin-directed agents. Combinations of IFN-α with ECP,38 and IFN with PUVA, oral retinoids, and cytotoxic chemotherapy39 have also shown encourag-ing results. The dosing of IFN-α 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-γ also has shown efficacy in patients with early- and advanced-

stage CTCL when administered with photopheresis. Because Sézary cells are associated with a Th2 cytokine profile, there is a deficit of IFN-γ in the microenvironment of the malignant cells, and the malig-nant cells are resistant to its effects.40 Administration of recombinant IFN-γ to local tumor sites has been studied using TG-1042, a replication-deficient adenovirus type 5 that carries the IFN-γ 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-γ production in CTCL cells is to admin-ister 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%) ultimate-ly 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

Table 2. Treatment Algorithms According to Disease Stage

Stage Initial Therapy Relapsed/Refractory Disease

IA Skin-directed therapya Additional skin-directed therapya

ORSkin-directed therapya with biologicb or single-agent therapyc

IB/IIA Skin-directed therapya and/or biologic therapyb Skin-directed therapya + biologic therapyb

ORSingle-agent therapyc

IIB Skin-directed therapy (PUVA, electron beam radiation therapy) plus biologic therapyb

ORSingle-agent therapyc

Multimodality combinations: skin-directed therapya plus single-agent chemotherapy or biologic therapyb

ORMultiagent therapyORAllogeneic stem cell transplantation

IIIA/B ECP ± skin-directed therapya

ORMultimodality combinations with systemic therapy or biologic therapyb

Multimodality combinations with single-agent therapyc or multiagent therapyd

ORAllogeneic stem cell transplantation

IVA/B Single-agent chemotherapyc

ORCombination biologic therapyb

ORMultiagent therapyd

Salvage chemotherapyORAllogeneic stem cell transplantation

a Skin-directed therapy: topical steroids (intermediate and high potency); topical nitrogen mustard or bischloroethylnitrosourea ointment or aqueous solution; topical retinoids (bexar-otene 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 exten-sive 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 ± 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, methylpredniso-lone, 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.

21IN D E PE N D E NTLY DEVELOPED BY MCMAHON PUBL ISHING


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-stim-ulating hormone and free thyroxin within weeks of starting the medica-tion. Symptoms of hypothyroidism may be subtle because they include fatigue/asthenia, depression, cold intolerance, and constipation. Levothy-roxine 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 per-formed weekly until lipids and thyroid function are stable and then per-formed monthly during therapy.

Targeted TherapyDENILEUKIN DIFTITOX

Denileukin diftitox (Ontak, Eisai) is a fusion protein toxin that targets interleukin-2 (IL-2) receptor–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 acceler-ated 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% reduc-tion 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 poten-tially serious side effects, including serious infusion reactions, capil-lary 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 treat-ment should be immediately and permanently discontinued if there are serious infusion reactions. The incidence of infusion reactions in 3 clin-ical 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 chang-es, 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, peripher-al edema, cough, dyspnea, and pruritus.

Denileukin diftitox was administered in combination with oral bexaro-tene 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

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 tol-erated, 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 abun-dantly expressed on all normal and most malignant T lymphocytes. Alem-tuzumab 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 reactiva-tion 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. Zanoli-mumab (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). Respons-es 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) inhibi-tors 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, respons-es 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. Asymptomat-ic QTc prolongation was observed on serial electrocardiograms in 4% of patients but was not clinically significant.

Panobinostat (Novartis) is another orally administered HDAC inhibi-tor that has shown promising results in CTCL. Preliminary results of a Phase II study of panobinostat in bexarotene-naïve and bexarotene-treated patients have been reported.52 Eleven of 66 evaluable patients (16.7%) who had received bexarotene and were given panobinostat oral-ly at a dose of 20 mg on days 1, 3, and 5, had confirmed responses, including 2 CRs. Of 35 bexarotene-naïve patients, 4 (11.4%) had a con-firmed 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, heav-ily 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 FDA’s Oncology Drugs Advisory Committee (ODAC) voted on Sept. 2, 2009, to recom-mend the approval of romidepsin for the treatment of CTCL.

Table 3. Results of Treatment of CTCL With Systemic Chemotherapy

TreatmentResponse Rate, %

Duration of Response, mo

Bortezomib66 67 7-14

Cladribine62-64 13-38 3-4

EPOCH67 80 8

Fludarabine59 19 7.5

Gemcitabine57 70 8

Pegylatedliposomal doxorubicin65

88 13

Pentostatin60 71 2-4

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



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 multi-center, open-label, Phase I, dose-finding study of pralatrexate is ongoing in patients with CTCL who have failed at least one previous systemic ther-apy.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 de-escalating 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 pralatrex-ate include mucositis and stomatitis and bone marrow suppression. On September 25, 2009, the FDA granted accelerated approval to pralatrex-ate 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 phos-phorylase (PNP) that leads to intracellular accumulation of dGTP, resulting in apoptosis in T lymphocytes. During a Phase I, open-label dose-escala-tion study of oral forodesine, 9 doses (40-320 mg/m2 daily) were adminis-tered 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 improve-ment in skin or a decrease in the absolute number of Sézary cells.56 The most frequent adverse events were nausea, fatigue, and reversible lym-phopenia. A Phase II study is under way in patients with relapsed or refrac-tory CTCL.

CYTOTOXIC CHEMOTHERAPY

If the agents described fail to control indolent disease, or if there is rap-idly progressing or aggressive de novo disease, more potent chemothera-py 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 medi-an response duration of 8 months.57 The incidence of grade 3 neutrope-nia was 25%. In a study of chemotherapy-naïve 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 pentosta-tin, 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 sur-vival of 13 months.65 With the exception of infusion-related events, lipo-somal doxorubicin was well tolerated. Responders received up to 18 cycles of pegylated liposomal doxorubicin.

Bortezomib (Velcade, Millennium) administered on a weekly sched-ule 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 pred-nisolone are high, but response durations are short. Infusion chemother-apy 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 progres-sion-free survival was 8 months, and Sézary cells were undetectable in 2 of 6 patients who had SS. Other intensive lymphoma salvage regimens like-wise have demonstrated responses, albeit with significant toxicity related to immunosuppression.

Hematopoietic Stem Cell TransplantationHematopoietic 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-mediat-ed graft-versus-lymphoma effect and a graft that is uncontaminated with tumor cells but with the risk for peritransplantation morbidity and mor-tality. 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 relaps-es, allogeneic transplantation should be considered earlier in the disease course if a human leukocyte antigen–matched donor is identified.

ConclusionAlthough 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 mini-mal toxicity from treatment, palliate the symptoms of pruritus and com-promised skin integument, and prevent infection and immunosuppression. As the role of biologic agents is becoming better understood, new combi-nation strategies can be designed and tested.

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68. Olavarria E, Child F, Woolford A, et al. T-cell depletion and autologous stem cell trans-plantation 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-versus-lymphoma 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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41780ALT_Tab_v1 1 4/15/08 3:43:55 PM


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 step-wise increases in the likelihood of remaining metastasis-free as dou-bling time lengthened. “The medi-an metastasis-free survival was one year among those with a dou-bling time under three months ver-sus 15 years for those with a dou-bling time greater than 15 months,” said Emmanuel S. Antonarakis, MD, a clinical fellow in the hema-tology/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).

Each of the prognostic factors has independent pre-dictive value, which permitted the investigators to create a table to combine values to calculate metasta-sis-free survival for an individual patient (Table). Con-ceivably, the table may permit investigators to address the debate about whether or when to introduce adju-vant or salvage therapy after radical prostatecto-my. Although a rise in PSA following prostatectomy

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 addi-tional therapy. It could also be used to help design and

analyze data from clinical trials.The study is similar to a natural his-

tory analysis conducted by research-ers at Johns Hopkins Medical Insti-tutions 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.

With the PSA doubling time of more than 15 months as an index, the rise in the hazard ratio (HR) for short-er 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 three- to nine-month period and then to 20.6 (95% CI, 11.2-38.1; 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 mar-gin 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.

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-investiga-tors. 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 low-er and PSA doubling time of more than 15 months) was similar (14 years) compared with that of the lon-gest PSA doubling time alone (15 years). The median metastasis-free survival for the whole patient popula-tion 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 iden-tification of this factor “important,” and suggested that it has immediate clinical relevance given the relatively large size of the study cohort.

“We can now tell our patients that ‘if your PSA dou-bling time is less than three months and we do not treat you, you are going to have metastatic disease within a year,’ ” Dr. Nelson emphasized. “On the other end of the spectrum, which is PSA doubling time of greater than 15 months, you can tell that patient ‘you have at least a decade before we would expect you to develop a metastasis.’ ” He indicated that these stratifications may be useful for testing strategies of early interven-tion when prognostic signs are raising concern.

—Ted Bosworth

Tool Will Help Counsel Patients After ProstatectomyOrlando, Fla.—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.

Table. Calculating Metastasis-Free Survival in Patients After Prostatectomy

Gleason Score >7 ≤7

Time to PSA relapse (y) ≤3 >3 ≤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 metastasis-free survival (y) 1 2 7 10 1 2 6 >11 2 5 9 15 1 6 13 >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.

26 CLINICAL ONCOLOGY NEWS SEPTEMBER/OCTOBER 2009SOLID TUMORS

Prostate

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

Looking for our Clinical Trials section?

Our listing of Phase II and III Clinical Trials can be found online at www.clinicaloncology.com. Click on “departments” on the left hand navigation bar and then “clinical trials.”

Trials added to the National Cancer Institute’s list of clinical trials in the 30 days prior to September 22, 2009, are listed.



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 stud-ies below.

Standard of Care for Rectal Cancer Identified

The incorporation of oxaliplatin (Eloxatin, Sanofi-Aventis) into fluoropyrimidine-based chemoradiother-apy regimens for locally advanced rectal cancer cannot be recommended outside the context of a formal clin-ical trial, according to results from two Phase III tri-als (abstracts LBA4007 and CRA 4008). These trials

showed that adding oxaliplatin to fluoropyrimidine-based neoadjuvant chemoradiotherapy significant-ly 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) rec-tal cancer to preoperative treatment with radiothera-py at a dose of 50 Gy/25F for five weeks, plus capecit-abine 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 chemora-diotherapy. 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 oxalipla-tin to the neoadjuvant regimen resulted in signifi-cant increases in the incidence of grade 3/4 diarrhea (13% vs. 3%; P<0.0001) and grade 2 peripheral neu-ropathy (5% vs. <1%; P<0.002). At the same time, there

was no additional clinical benefit with the addition of

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

Perspective“This study confirms the importance

of KRAS as a predictive biomarker in patients with metastatic colorectal can-cer treated with an anti-EGFR [epidermal growth factor receptor] monoclonal anti-body in combination with chemothera-py,” said Jean-Yves Douillard, MD, Centre René Gauducheau, Saint Herblain, Nant-es, France, who led the study. “Patients with KRAS mutations should not receive panitumumab.” 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-fluo-rouracil, leucovorin) plus panitumumab and 8 months if they received FOLFOX4 alone (P=0.02). “This is a well-designed trial with good data confirming the com-bination of panitumumab and FOLFOX4 in patients with wild-type KRAS leads to increased activity compared to FOL-FOX4 alone. The findings are consistent with other data in metastatic colorectal cancer that [show] the benefit of pani-tumumab is limited to wild-type KRAS patients, and there is a deleterious effect in KRAS-mutant patients,” said Eric Van

Cutsem, MD, PhD, professor of inter-nal medicine at the University of Leu-ven, Belgium. Dr. Van Cutsem was lead author of the CRYSTAL trial that dem-onstrated that the benefit of cetuximab (Erbitux, Amgen) is confined to KRAS wild-type patients with metastatic col-orectal cancer.

Panitumumab and cetuximab are com-petitive drugs, but there are no head-to-head studies comparing these agents. “Both drugs show improved activity over chemotherapy alone in wild-type patients, but there are minor differenc-es,” said Dr. Van Cutsem. “The treatment schedule is more favorable with panitu-mumab. On the other hand, at this point, we have more robust data for cetuximab [in metastatic colorectal cancer].”

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 Med-icine, New Haven, Conn., said he had been eagerly anticipating the data from the PRIME trial. “In comparing the data from this trial with those from other tri-als combining cetuximab with either FOLFOX or FOLFIRI chemotherapy, it would seem that both anti-EGFR anti-bodies 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

combination of panitumumab and FOL-FOX4 chemotherapy can be viewed as a reasonable treatment option in the front-line therapy of metastatic CRC.”

Study Details

Panitumumab is approved in the Unit-ed States for EGFR-expressing metastat-ic colorectal cancer that has progressed on prior chemotherapy. The Amgen-sponsored PRIME trial tested the safe-ty 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 panitu-mumab 6 mg/kg every two weeks plus FOLFOX4 or FOLFOX4 alone. Patients who had prior chemotherapy for met-astatic disease or received prior oxali-platin as adjuvant were not included. Ran-domization was stratified according to performance status (PS) and geographic region. The primary end point was PFS.

Both treatment arms were well bal-anced 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 oth-er sites. KRAS results were prospectively collected and available in 93%. Sixty per-cent of the study population had wild-type KRAS, and 40% were KRAS-mutated.

Median follow-up was 47 to 57 weeks. In patients with wild-type KRAS, pani-tumumab added to FOLFOX4 improved PFS compared with FOLFOX4 alone (9.6 vs. 8 months, respectively) as well as response rate (55% and 48%, respec-tively). Among wild-type patients, most subgroups benefited from pani-tumumab, 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 panitu-mumab. In patients with KRAS muta-tions, 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 surviv-al in those with wild-type KRAS, medi-an 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 compara-ble for the two arms, except for toxic-ities known to be associated with anti-EGFR inhibitors such as rash, diarrhea and hypomagnesemia. Infusion-related reactions in patients treated with pani-tumumab occurred in less than 1%.

—Alice Goodman

Table 1. Comparison of Treatments for Rectal Cancer, the STAR-01 Trial

Fluoropy-rimidine-Based Neoadjuvant Chemoradio-therapy

Fluoropy-rimidine-Based Neoadjuvant Chemoradio-therapy Plus Oxaliplatin

Rate of lower anterior resection for sphincter preserva-tion

72% 73%

Rate of abdomi-no-perineal resection

19% 18%

Grade 3/4 diarrhea

4% 15%

Grade 2/3 sensory neuropathy

<1% 37%

28 CLINICAL ONCOLOGY NEWS • SEPTEMBER/OCTOBER 2009SOLID TUMORS

Colorectal

Ed Chu, MD

Chief, Section of Medical OncologyProfessor of Medicine and PharmacologyDeputy Director of Clinical ResearchYale Cancer CenterYale UniversityNew Haven, Conn.

ADVISORY BOARD EDITORIAL

see GROUNDBREAKING, page 34 �

PRIMEcontinued from page 1 �


A New Randomized Phase 3 Intergroup Study of Patients With Newly Diagnosed Multiple Myeloma

Study ChairKeith Stewart, MBChB, Mayo Clinic, Scottsdale, AZ

Primary ObjectiveTo compare progression-free survival with melphalan, prednisone, and thalidomide (MPT) versus

melphalan, prednisone, and lenalidomide (REVLIMID®) (MPR) in patients with symptomatic, newly

diagnosed multiple myeloma who are not candidates for high-dose therapy.

Key Eligibility Criteria• Newly diagnosed, symptomatic

multiple myeloma

• Declined or ineligible for

high-dose therapy

Study Design

• Treatment naïve—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 REVLIMID®

• Creatinine <2.5 mg/dL

• ECOG performance status ≤2

ECOG E1A06 CURRENTLY ENROLLING

Maintenance(Continues until disease progression)

Enrollment

For more information, please contact:www.clinicaltrials.gov (NCT00602641)

www.ecog.org

National Cancer Institute Cancer Trials Support Unit

([email protected])

(888) 823-5923

Note: This study is supported by the National Cancer Institute CancerTrials Support Unit (CTSU). Institutionsnot aligned with ECOG will participatethrough the CTSU mechanism. Supplemental funding for this trialprovided by Celgene Corporation.

Supplemental funding for trial recruitment materials provided by Celgene Corporation. Investigational use of REVLIMID® (lenalidomide).

REVLIMID® is a registered trademark of Celgene Corporation. 04/09 CELG09049T

apo, orally.b1 cycle = 28 days.

Treatment A (MPT)• Melphalan 9 mg/m2 poa daily, days 1-4 each cycleb

for 12 cycles• Prednisone 100 mg po daily, days 1-4 each cycle

for 12 cycles• Thalidomide 100 mg po daily, continuously

—Enteric-coated aspirin 325 mg po daily, continuously

QOL assessments performed prior to, during, and following treatment

Induction (Up to twelve 28-day cycles) Discontinue for progressive disease or excessive toxicity

Treatment B (MPR)• Melphalan 5 mg/m2 po daily, days 1-4 each cycleb

for 12 cycles• Prednisone 100 mg po daily, days 1-4 each cycle

for 12 cycles• Lenalidomide 10 mg po daily, days 1-21 of each

cycle, continuously—Enteric-coated aspirin 325 mg po daily, continuously

QOL assessments performed prior to, during, and following treatment

N=560

Treatment A• Thalidomide 100 mg po daily,

continuously for 28 days—Enteric-coated aspirin

325 mg po daily, continuously

Treatment B• Lenalidomide 10 mg po daily

for 21 days every 28 days—Enteric-coated aspirin

325 mg po daily, continuously


for Medical Oncology (ECCO-ESMO; abstract LBA9) showed that gefitinib trumps treatment with carbo-platin 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 pacli-taxel (200 mg/m2) in 21-day cycles. Patient characteris-tics were well balanced in the two arms. An interim anal-ysis, 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 terminat-ing 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 neutro-penia (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).

“Gefitinib should be the standard for first-line ther-apy for advanced NSCLC with sensitive EGFR muta-tions,” said lead author Akira Inoue, MD, Department of Respiratory Oncology and Molecular Medicine, Insti-tute of Development, Aging, and Cancer, Tohuku Uni-versity, Sendai, Japan.

Further evidence comes from updated findings from the randomized IPASS (IRESSA Pan-ASia Study) pre-sented at the World Conference on Lung Cancer (abstract B9.7). In the original open-label study, present-ed 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 carbopla-tin/paclitaxel. When stratified by EGFR mutational sta-tus 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 substi-tution at amino acid 858 (L858R). Thirty-six percent of patients participating in the study had tumor tissue available for evaluation.

“Gefitinib had greater efficacy than carboplatin/paclitaxel in both of the major EGFR mutation sub-groups, although there was a slightly greater relative advantage for those with the exon 19 deletion,” 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 chemo-therapy. There was also a relative advantage for objec-tive response and rates of symptom improvement, but the difference reached significance only for those with the exon 19 deletion. The most common EGFR muta-tions 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 Unit-ed 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 drug’s label was changed to indi-cate that only cancer patients who had already taken

the medication and whose physicians believed that it was helping could receive the drug. No newly diag-nosed 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.

“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,” said Michael Fisch, MD, medical director of the Clini-cal Community Oncology Program at M.D. Anderson Cancer Center in Houston. “Just like we have epoetin alfa and darbepoetin, we’ll have gefitinib and erlotinib—drug duos that serve the same role in patient care.”

Philip Bonomi, MD, director of the Division of Hema-tology-Oncology at Rush University Medical Cen-ter, Chicago, agreed. “I believe that reapproval of Ires-sa should be considered based not only on the IPASS data, but also on the results of the INTEREST study,” 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 mutation-al status. According to the senior author of the study, Luis Paz-Ares, MD, Oncology Service, Hospital Uni-versitario Virgen del Rocío, in Sevilla, Spain, the TKIs erlotinib and gefitinib beat chemotherapy for the end point of PFS, whether they were used first- or second-line. Based on these results, Dr. Paz-Ares character-ized EGFR TKIs as “an attractive prospect in patients with EGFR-mutant advanced NSCLC.”

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 chemo-therapy. The distribution of PFS rates for second-line

treatment with TKIs was similar. Again, erlotinib led with the lon-gest median PFS of 13.3 months, gefitinib came second with a medi-an PFS of 8.8 months, and chemotherapy resulted in the shortest median PFS at 4.1 months.

Paradigm Shift in Care

Until recently, according to Dr. Paz-Ares, it has been “difficult to conduct large-scale investigations of pos-sible associations between EGFR mutations and ther-apeutic outcomes because of the limited availability of tissue samples.” This, however, is likely to change. The ongoing Phase III EURTAC study, a random-ized 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 cyto-toxic agents to drugs targeted at vulnerable molecular processes. While Dr. Paz-Ares speculated that EGFR-mutant NSCLC “may be considered as a distinct disease within the broader spectrum of NSCLC,” the same may be said for other forms of NSCLC that can be catego-rized by a molecular or genetic profile. Recently, there has been surging interest in identifying molecular pro-files that can help predict treatment response in a broad variety of cancers, not just NSCLC. For example, several guidelines now recommend that patients with colorec-tal cancer who are candidates for cetuximab (Erbitux, ImClone) should first undergo tissue sampling to con-firm 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 tis-sue biopsies or another form of tissue sampling must be incorporated into routine patient care.

“I believe we are now rapidly moving to a primari-ly molecular-based therapy from a primarily empiric-based therapy in lung cancer,” said David R. Gandara, MD, director of the Thoracic Oncology Program at the University of California, Davis Cancer Center, in Sacra-mento, Calif. Echoing an often-repeated theme regard-ing 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 Can-cer, indicated that the shift is already under way.

For many, it has already taken place. Philip Bono-mi, MD, director of the Division of Hematology and Oncology, Rush University Medical Center, in Chica-go, said that he is already ordering EGFR mutation-al profiles in all nonsmokers before initiating ther-apy. In those patients who do have the mutations, clinicians administer a TKI first-line. Although stud-ies have shown that this treatment decision may only improve PFS, he considers this a “reasonable” 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 muta-tions, there is a growing conviction among clinicians that these data are forthcoming.

—Ted Bosworth

30 CLINICAL ONCOLOGY NEWS SEPTEMBER/OCTOBER 2009SOLID TUMORS

Lung

TKIscontinued from page 1 �

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.


A Randomized Phase III Study of PatientsWith Previously Untreated MultipleMyeloma (CC-5013-MM-020/IFM 07-01)

Primary ObjectiveTo 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• Previously untreated, symptomatic multiple myeloma

• Not a candidate for or have declined stem cell transplantation

• ECOG PS ≤2

Study Design

For more information or to participate, please contact: www.clinicaltrials.gov (NCT00689936)

Elvira Klissourska, PhD ([email protected])

Celgene Corporation

www.celgene.com

Long-termFollow-up

Phase

Patients followed for survival andsubsequent antimyelomatherapies

Progression-free Survival

Follow-upPhase

Patients will befollowed untildisease progression

Treatment Aa (Rd)• Lenalidomide po once daily, days 1-21 each cycle• Dexamethasone po once weekly, days 1, 8, 15, and 22

each cycleTreatment (28-day cycles) continues until disease progression

Treatment Ba (Rd)• Lenalidomide po once daily, days 1-21 each cycle• Dexamethasone po once weekly, days 1, 8, 15, and 22

each cycle

18 cycles, 28 days each

Treatment Cb (MPT)• Melphalan po once daily, days 1-4 each cycle• Prednisone po once daily, days 1-4 each cycle• Thalidomide po once daily, continuously 12 cycles, 42 days each

N=1590

aDosage varies based on age and renal function.bDosage varies by age and baseline neutrophil and platelet counts.

REVLIMID® is a registered trademark of Celgene Corporation. Investigational use of REVLIMID® (lenalidomide).

©2008 Celgene Corporation 06/08 CELG08050T

FIRST–Frontline Investigation of REVLIMID®/dex vs Standard Thal CURRENTLYENROLLING



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For Doctors Only: A Guide to Working Less & Building MoreChristopher R. Jarvis, MBA; David B. Mandell, JD, MBA;

Jason M. O’Dell, CWP; Claudio A. DeVellis, JD, CPAFor Doctors Only teaches doctors how to perform efficiently so they can get more outof a medical practice. More specifically, For Doctors Only will help doctors protecttheir personal and practice assets from lawsuits, taxes and bad investments whileshowing them the secrets to building wealth through the leverage of people, assetsand effort.

Integrative OncologyLorenzo Cohen, PhD; Maurie Markman, MD

Integrative medicine strives to integrate the best of complementary and con-ventional modalities using a multidisciplinary approach through integrativeservices. This book outlines integrative medicine programs at five leadingNational Cancer Institute Comprehensive Cancer Centers. The focus is onhow these centers started their programs, what they are currently doing andrecommendations for starting integrative medicine clinics.

Pancreatic CancerAndrew M. Lowy; Steven D. Leach; Philip A. Philip

Since the previous M.D. Anderson Solid Tumor Oncology Series publicationon pancreatic cancer, there have been major advances in our understandingof molecular events which underlie pancreatic cancer development, both inthe sporadic and inherited forms.

Principles of Cancer Reconstructive SurgeryCharles E. Butler; Neil A. Fine

Principles of Cancer Reconstructive Surgery is a reference text for medicaland surgical oncologists, radiation oncologists, family practice physiciansand dermatologists, providing an overview for reconstructive procedures.Interested residents, medical students and health care professionals mayfind this to be a resource for information on reconstructive plastic surgery.

Targeted Cancer TherapyRazelle Kurzrock, MD; Maurie Markman, MD

Emerging technologies in target identification, drug discovery, molecularmarkers and imaging are rapidly changing the face of cancer. Targeted CancerTherapy provides a foundation of knowledge in targeted cancer therapeutics.

The Merck Manual of Health & AgingMark H. Beers; Thomas V. Jones; Michael Berkwits

From one of the most trusted names in medical references comes anaccessible, all-inclusive guide for older adults that shares what measures totake to optimize the aging process, prevent disease, and improve youroverall health.

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oxaliplatin—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 ≤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 chemora-diotherapy. 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 oxalipla-tin, respectively (Table 1). The pCR (pT0N0) was 16%

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 chemoradiothera-py with oral capecitabine along with the role of oxali-platin in patients with locally advanced rectal cancer.

XELIRI Plus Bev Standard Option in Front-Line mCRC

The combination of XELIRI (capecitabine plus iri-notecan) and bevacizumab (Avastin, Genentech) is a safe and effective regimen that can be considered a standard option in the front-line treatment of meta-static colorectal cancer (mCRC), according to results from the MEXICO trial. This Phase II study investi-gated the efficacy and safety of bevacizumab (Bev) in combination with FOLFIRI or XELIRI chemothera-py in patients with mCRC (abstract 4086).

Notably, in the XELIRI regimen, the dose of

irinotecan used was 200 mg/m2, which was 20% low-er 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 partic-ular, the incidence of grade 3/4 toxicities was compa-rable between the two arms of the study, and the com-bination of XELIRI plus bevacizumab resulted in a respective 15% and 11% incidence of grade 3/4 neutro-penia 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 neuropro-tective agent in the adjuvant setting. In this Phase III trial, patients who were receiving adjuvant mFOL-FOX6 chemotherapy were randomized to receive 1 g calcium gluconate–1 g magnesium sulfate (CaMg) infusions immediately before and after oxaliplatin ver-sus 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 oxaliplatin-specific scale, and patient-reported quality-of-life out-come questionnaires. Acute neurotoxicity was evaluated on day 2 of cycle 1, and CaMg was effective at reducing the chronic cumulative neurotoxic symptoms of numb-ness, tingling and muscle cramps, but not symptoms

Table 2. Comparison of Regimens for Metastatic Colorectal Cancer

XELIRI + Bev FOLFIRI + Bev

Overall response rate

42% 46%

Progression-free survival

9 mo 9 mo

Overall survival

23 mo 23 mo

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

34 CLINICAL ONCOLOGY NEWS • SEPTEMBER/OCTOBER 2009SOLID TUMORS

Colorectal

GROUNDBREAKINGcontinued from page 28 �

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relating to cold sensitivity, swallowing dif-ficulty and throat discomfort.

This study is important as it provides further evidence that CaMg can be rec-ommended as an effective neuroprotec-tive agent in the adjuvant setting. Howev-er, one issue that has yet to be addressed is whether CaMg might reduce the clinical activity of adjuvant FOLFOX chemothera-py. While it is unlikely based on the poten-tial 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 iden-tify patients with stage II colon can-cer 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 forma-lin-fixed, paraffin-embedded tumor sam-ples from 1,851 patients. These patients had stage II colon cancer and had been enrolled in four randomized trials evalu-ating 5-FU-based adjuvant therapy com-pared 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 devel-opment 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 signifi-cantly 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 evalu-able patients with stage II colon can-cer who had been enrolled in the QUA-SAR (Quick and Simple and Reliable) trial. Conducted in the United King-dom, 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 vari-able 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) sta-tus, T stage, tumor grade and the number

of examined lymph nodes were all sig-nificantly and independently associated with disease recurrence. Of note, MMR, RS and T stage were the most significant factors that correlated with disease recur-rence. 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. Sim-ilarly, 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 microsat-ellite instability, are uninformative.

These results are similar to findings reported with gene expression assays for early-stage estrogen receptor–positive

breast cancer. However, in contrast to the 21-gene RS in breast cancer, the sev-en-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 che-motherapy. 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.

—Ed Chu, MD

SOLID TUMORS

Colorectal


INDICATION: Vectibix® 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 Vectibix® 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 Vectibix®.

Important Safety Information including Boxed WARNINGS:Safety data are available from 15 clinical trials in which 1467 patients received Vectibix®; of these, 1293 received Vectibix® monotherapy and 174 received Vectibix®

in combination with chemotherapy.

WARNING: DERMATOLOGIC TOXICITY and INFUSION REACTIONSDermatologic Toxicity: Dermatologic toxicities occurred in 89% of patients and were severe (NCI-CTC grade 3 and higher) in 12% of patients receiving Vectibix® monotherapy. Withhold Vectibix® for dermatologic toxicities that are grade 3 or higher or are considered intolerable. If toxicity does not improve to ≤ grade 2 within1 month, permanently discontinue Vectibix®. 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 Vectibix®, 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 Vectibix®.

Vectibix® 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 Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased overall survival and increasedincidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions.

In a single-arm study of 19 patients receiving Vectibix® 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 Vectibix® plus FOLFIRI, the incidence of NCI-CTC grade 3 diarrhea was 25%.

Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. 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 Vectibix® 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 Vectibix® 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 Vectibix®. In some patients, both hypomagnesemia and hypocalcemia occurred. Patients’ electrolytes should be periodically monitored during and for 8 weeks after the completion of Vectibix® 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 Vectibix®.

Dermatologic, mucosal, and ocular toxicities were also reported.

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

The most common adverse events of Vectibix® 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 Vectibix® 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. Vectibix® (panitumumab) prescribing information, Amgen. 2. Van Cutsem E, Peeters M, Siena S, et al. Open-label phase III trial of panitumumabplus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007;13:1658-1664.

©2009 Amgen. All rights reserved. 4-09 45904

*Correlation with safety and efficacy is unknown

The first fully human*

anti-EGFR monoclonalantibody

Based on independent review of disease progression, a statistically

significant prolongation in PFS was observed in patients receiving

Vectibix® plus BSC vs those patients receiving BSC alone1,2

Weeks

Prop

orti

on E

vent

Fre

e

0%

10%

20%

30%

60%

70%

100%

90%

80%

50%

40%

0 4 10 12 14 16 40 42 44 46 4832 34 36 388 186 20 302 50 5222 24 26 28

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

Treatment Group

Vectibix® + BSC (n=231)

BSC Alone (n=232)

P < 0.0001

Subjects at risk:

Vectibix® + BSCBSC Alone

231 217 209 197 118 85 76 65 49 41 40 40 31 22 19 19 13 8 8 8 5 2 2 1 1 1

232 209 175 149 75 41 31 20 17 11 7 7 7 4 4 3 3 3 2 1 1 1 1 1 1 0

Statistically significant prolongation in PFS time vs BSC alone1,2

The recommended dose of Vectibix® is 6 mg/kgadministered over 60 minutes (for doses over1000 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 includingBoxed WARNINGS for infusion reactions

Infusionreactions

Q2Wdosing

ProlongedPFS


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