title: Phase I study of radical thoracic radiation, weekly irinotecan, and cisplatin in locally advanced non-small cell lung carcinoma.
abstract: BACKGROUND
  Irinotecan and cisplatin individually are active in non-small cell lung carcinoma (NSCLC). Each is synergistic with radiation. Dosages of 65 mg/m2 of irinotecan and 30 mg/m2 of cisplatin Q weekly times four every 6 weeks yielded a 36% response rate and median survival of 11.6 months in advanced NSCLC (Jagasia et al.; Clinical Cancer Research 7: 68, 2001). A weekly schedule for each agent (versus less frequent doses) limits toxicity and increases the opportunity for radiosensitization.
  
  
  METHODS
  We initiated a phase I study of weekly irinotecan and cisplatin during radical thoracic radiation (TRT). Cisplatin was fixed at 25 mg/m2 Q weekly times seven. Irinotecan was dosed initially at 30 mg/m2 per week for 7 weeks and was increased by 10 mg/m2 per week in three- to six-patient cohorts. TRT was administered in 34 single daily fractions to 63 Gy. Eligibility stipulated locally advanced NSCLC; Eastern Cooperative Oncology Group performance status 0 to 1; < or = 10% unintended weight loss; and adequate physiologic indices.
  
  
  RESULTS
  Fifteen patients were accrued: nine were stage IIIB, five were stage IIIA, and one had isolated mediastinal node recurrence after prior surgery. Median age was 65 years (range, 47-77). Seven patients received irinotecan at a dose of 30 mg/m2 per week; (dose level 1). Seven other patients received irinotecan at a dose of 40 mg/m2 per week; (dose level 2). The one other patient received irinotecan in doses of 50 mg/m2 per week; (dose level 3). Neutropenic fever occurred in one patient each at dose levels 1 and 2. Grade 4 neutropenia occurred in three patients at each dose level. Transient grade 3 diarrhea occurred in one patient at dose level 1. Esophagitis of grade 3 or higher occurred in one patient each at dose levels 2 and 3. There was one late grade 3 pneumonitis at dose level 2. Delivered irinotecan dose intensity for dose level 1 was 27 mg/m2 per week; for dose level 2, it was 31.4 mg/m2 per week. Nine of 13 evaluable patients (69%) responded. At median potential follow-up of 5 years, 14 have progressed, and 11 have died. Projected median survival is 28 months; one patient who was treated for mediastinal node recurrence remains free from progression at 6 years.
  
  
  CONCLUSIONS
  Weekly irinotecan and cisplatin combined with radical TRT (63 Gy) is active and fairly well tolerated in locally advanced NSCLC. In combination with fixed-dose cisplatin (25 mg/m2 per week), the maximum-tolerated dose of irinotecan is 30 mg/m2 per week.
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA 19111, USA. corey.langer@fccc.edu
authors.forename: Corey J
authors.initials: CJ
authors.lastname: Langer
authors.forename: Robert
authors.initials: R
authors.lastname: Somer
authors.forename: Samuel
authors.initials: S
authors.lastname: Litwin
authors.forename: Steven
authors.initials: S
authors.lastname: Feigenberg
authors.forename: Benjamin
authors.initials: B
authors.lastname: Movsas
authors.forename: Christine
authors.initials: C
authors.lastname: Maiale
authors.forename: Eric
authors.initials: E
authors.lastname: Sherman
authors.forename: Michael
authors.initials: M
authors.lastname: Millenson
authors.forename: Nicos
authors.initials: N
authors.lastname: Nicoloau
authors.forename: Chao
authors.initials: C
authors.lastname: Huang
authors.forename: Joseph
authors.initials: J
authors.lastname: Treat
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D002945:Cisplatin / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008175:Lung Neoplasms / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging
chemical_list: D000077146:Irinotecan; D002945:Cisplatin; D002166:Camptothecin