title: Pemetrexed in relapsed small-cell lung cancer and the impact of shortened vitamin supplementation lead-in time: results of a phase II trial.
abstract: BACKGROUND
  We undertook a phase II trial to assess the efficacy and safety of single-agent pemetrexed (P) in relapsed small-cell lung cancer (SCLC) patients.
  
  
  METHODS
  Patients had limited- or extensive-stage SCLC, performance status 0 to 2, and one prior chemotherapy regimen. Initial P dose was 500 mg/m every 21 days. Planned sample sizes were 36 sensitive (S) patients in a two-stage sequential fashion with early stopping rule, and 25 refractory (R) patients in a single-stage design without stopping rule. Patients received folic acid and Vitamin B12 prior to P, and B12 could be given up until P treatment. Primary outcome measure was response rate.
  
  
  RESULTS
  Enrollment occurred from July 2004 to March 2006. The stopping rule was invoked when <3 of 14 S patients responded. The protocol was amended to evaluate P 900 mg/m in cohorts of 40 S and 40 R patients. Overall, 121 patients were enrolled, with 116 patients treated. S (n = 53) and R (n = 63) patients were analyzed separately at both dose levels. Across the 4 treatment groups (S500, S900, R500, R900), 1 patient (2.63%) in the S900 group had a partial response. Overall, 18 patients (16%) had stable disease. Eighty-seven patients (75%) had progressive disease. Responses were not evaluable in 10 patients (8.6%). Overall response rate was 0.9%. Across treatment groups, disease control rates (partial response + stable disease) were 20%, 15.8%, 21.7%, and 12.5%, respectively. Median time to progression ranged from 1.2 to 1.5 months, median survival times ranged from 2.5 to 6.1 months, and 1-year survival rates ranged from 5.6 to 25.8%. Common grade 3/4 hematologic toxicities (at 500 and 900 mg/m) were neutropenia (16%; 9%) and leukopenia (11%; 8%), and nonhematologic toxicities were dyspnea (11%; 10%) and fatigue (16%; 9%). Retrospective analysis of cycle 1 events by timing of B12 administration showed no trend toward more frequent serious toxicities when B12 was given <7 days prior to P.
  
  
  CONCLUSIONS
  Single-agent P 500 mg/m shows minimal activity in relapsed SCLC patients. P can be given at 900 mg/m without significant increase in serious toxicities, but does not seem to increase efficacy. B12 given <7 days before P does not seem to be associated with increased serious toxicities.
authors.affiliation: University of North Carolina, Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina 27599-7305, USA. socinski@med.unc.edu
authors.forename: Mark A
authors.initials: MA
authors.lastname: Socinski
authors.forename: Robert N
authors.initials: RN
authors.lastname: Raju
authors.forename: Marcus
authors.initials: M
authors.lastname: Neubauer
authors.forename: David A
authors.initials: DA
authors.lastname: Smith
authors.forename: Donald A
authors.initials: DA
authors.lastname: Richards
authors.forename: Michael
authors.initials: M
authors.lastname: Savin
authors.forename: Robert L
authors.initials: RL
authors.lastname: Ruxer
authors.forename: Craig H
authors.initials: CH
authors.lastname: Reynolds
authors.forename: Feng
authors.initials: F
authors.lastname: Zhan
authors.forename: Jane L
authors.initials: JL
authors.lastname: Bromund
authors.forename: Ruqin
authors.initials: R
authors.lastname: Chen
authors.forename: Coleman
authors.initials: C
authors.lastname: Obasaju
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015331:Cohort Studies; D019587:Dietary Supplements; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage*; D005971:Glutamates / Q000627:therapeutic use*; D006147:Guanine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology; D009367:Neoplasm Staging; D000068437:Pemetrexed; D011379:Prognosis; D016879:Salvage Therapy; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy* / Q000473:pathology; D015996:Survival Rate; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors; D014803:Vitamin B Complex / Q000008:administration & dosage*
chemical_list: D000970:Antineoplastic Agents; D005971:Glutamates; D000068437:Pemetrexed; D014803:Vitamin B Complex; D006147:Guanine; D005492:Folic Acid; D013940:Thymidylate Synthase