Phase I study of radical thoracic radiation, weekly irinotecan, and cisplatin in locally advanced non-small cell lung carcinoma

BACKGROUND: Irinotecan and cisplatin individually are active in non-small cell lung carcinoma (NSCLC). Each is synergistic with radiation. Dosages of 65 mg/m of irinotecan and 30 mg/m 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 Reserch 7: 68, 2001). A weekly schedule for each agent (versus less frequent doses) limits toxicity and increases the opportunity for radiosensitization. MATERIALS AND METHODS: We initiated a phase I study of weekly irinotecan and cisplatin during radical thoracic radiation (TRT). Cisplatin was fixed at 25 mg/m Q weekly times seven. Irinotecan was dosed initially at 30 mg/m per week for 7 weeks and was increased by 10 mg/m 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; ≤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/m per week; (dose level 1). Seven other patients received irinotecan at a dose of 40 mg/m per week; (dose level 2). The one other patient received irinotecan in doses of 50 mg/m 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/m per week; for dose level 2, it was 31.4 mg/m 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. CONCLUSION: 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/m per week), the maximum-tolerated dose of irinotecan is 30 mg/m per week.