Doses Determined for Phase II Study of Irinotecan/Cisplatin with Concurrent Radiation

NAGASAKI, Japan—The combination of irinotecan (Camptosar) 40 mg/m² and cisplatin (Platinol) 60 mg/m² with concurrent thoracic radiotherapy should be tested for its potential role in treating patients with limited-stage small-cell lung cancer (SCLC).The recommendation was made at the conclusion of a phase I trial that evaluated the combination of irinotecan and cisplatin in three dose schedules in patients with histologically or cytologically proven limited-stage SCLC who had not undergone prior therapy for their disease.

Results of the study were presented by Masaaki Fukuda, MD, of the Japanese Red Cross Nagasaki Atomic Bomb Hospital in Nagasaki.

The initial dose was irinotecan 40 mg/m² and cisplatin 60 mg/m² (level 1), which was escalated to irinotecan 50 mg/m² with cisplatin 60 mg/m² (level 2), and then irinotecan 60 mg/m² with cisplatin 60 mg/m² (level 3). Irinotecan was administered intravenously on days 1, 8, and 15, and cisplatin was administered intravenously on day 1. The regimen was repeated for four cycles at a 28-day interval. Standard thoracic radiotherapy of 2 Gy daily was started on the second day of each chemotherapy cycle, and 20 Gy were given with the first three chemotherapy cycles, for a total of 60 Gy.

Escalating Doses

Three patients were included at each dose level, with escalation to the next higher dose level if no acute dose-limiting toxicity (DLT) was observed. The dose escalation was performed on the basis of the toxicity data of cycles 1 to 3 because split-course concurrent thoracic radiotherapy was used. If DLT was observed in one of three patients, three additional patients were entered at the same dose level. The maximum tolerated dose (MTD) was determined when greater than one third of patients experienced DLT at a given dose. Several additional patients were entered into a dose level below the level where DLT had been observed.

The median age of the study population was 65 years. Four patients had a performance status of 0, 11 had a performance status of 1, and 1 had a performance status of 2. One patient had stage IIB disease. Six patients had stage IIIA and nine patients had stage IIIB disease.

Sixteen of 17 patients entered in the trial were eligible for evaluation, Dr. Fukuda, said. Two of four patients at level 3 refused to continue with therapy because of severe general fatigue, and this dosing regimen was considered as the MTD. Two additional patients subsequently entered at level 2 received only half the scheduled irinotecan because of leukocytopenia and fatigue, and this dosing regimen was also considered as the MTD. The dose-limiting toxicities in this study were fatigue (defined as a fall in performance status) and leukocytopenia.

Response Rates

There were 4 (25%) complete responses and 11 (69%) partial responses, resulting in an overall response rate of 94%. The median survival time was 23.1 months. The 1-year survival rate was 81.3%, the 2-year survival rate was 50.0%, and the 3-year survival rate was 12.5%.

The present study was prompted by earlier research showing that combined modality with thoracic irradiation and chemotherapy demonstrated benefit in limited SCLC, Dr. Fukuda said. The combination of irinotecan and cisplatin is very active against SCLC.

Several studies have shown that early administration of radiation compared with delayed irradiation may improve outcome in limited-stage SCLC, he continued. In a study of irinotecan and cisplatin plus concurrent continuous thoracic radiotherapy, toxicity was shown to be unacceptable. For this reason, the present study combined irinotecan/cisplatin with split-course concurrent thoracic radiotherapy.