Phase I/II study of carboplatin and oral etoposide with granulocyte-colony stimulating factor in advanced nonsmall cell lung cancer.

Abstract

A combination of carboplatin (CBDCA) and oral etoposide is better tolerated than, and as effective as, more aggressive chemotherapy regimens in patients with advanced nonsmall cell lung cancer (NSCLC). A Phase I/II study was conducted to determine whether the addition of the granulocyte-colony stimulating factor (G-CSF) allows the administration of higher doses of CBCDA. The starting dose of CBDCA was 300 mg/m2 on day 1 every 28 days, in combination with a fixed dose of oral etoposide 50 mg/m2/day days 1-21, G-CSF (5 micrograms/ kg/day subcutaneously) was administered from day 7 until postnadir neutrophil count of more than 10,000/mm3, and from day 25 through day 28. From March 1991 to November 1993, 39 previously untreated patients with NSCLC (18 Stage IIIb and 21 Stage IV) entered this trial. Overall eight patients experienced dose-limiting toxicity in the first two courses. Five of them were older than 70 years. Age, CBDCA dose, CBDCA area under the curve (AUC), and performance status were correlated with severe neutropenia and thrombocytopenia, but carboplatin AUC was the only independent variable predictive of severity of both at multiple regression analysis. Thrombocytopenia was the major dose-limiting toxicity in this study. The maximum tolerated CBDCA dose and AUC were 600 mg/m2 and 8 respectively. No treatment-related death occurred. There was 1 (2.5%) complete response and 14 (36%) partial responses (overall response rate of 38.5%). AUC was more predictive of response achievement than carboplatin dose. Higher carboplatin dose and AUC were also associated with longer survival by univariate analysis, but by Cox regression analysis age was the only parameter independently predictive of survival. The administration of G-CSF permits safe escalation of CBDCA dose and AUC up to 600 mg/m2 and 8 respectively, in combination with a fixed dose of oral etoposide. Age older than 70 years represents a major obstacle to dose escalation. The increase of the body exposure to carboplatin seems to be associated with a better outcome. The determination of CBDCA AUC permits a better prediction of myelotoxicity and response rate.