Phase I-II study of high dose epirubicin plus cisplatin in unresectable non-small-cell lung cancer - Searching for the maximal tolerated dose

The purpose of this study was to search for the maximal tolerated dose of c isplatin in the cisplatin plus high-dose epirubicin combination for patient s with non-small-cell lung cancer. The following range of cisplatin dosages were tested in a phase I study: 75, 90, 105, and 120 mg/m(2) in combinatio n with epirubicin 120 mg/m(2) every 3 weeks. Eligibility consisted of previ ously untreated stage IIIb or IV non-small-cell lung cancers, Eastern Coope rative oncology Group Performance Status Less than or equal to 2 age less t han or equal to 70 years, measurable disease, adequate blood counts, chemis try, cardiac function, and no brain metastasis. The maximal tolerated dose was defined as the dose level of cisplatin for which two of three patients or three of six patients developed one or more limiting toxicities during t he first course of therapy. Afterward, the maximal tolerated dose of cispla tin was adopted in a subsequent phase II study. Three centers enrolled 42 p atients: Is in phase I and 24 in phase II. The maximal tolerated dose was a lmost reached at the last dose level (i.e., 120 mg/m2). Taking into account the total duration of the treatment, the real dose intensity for patients treated at the fourth dose level (120 mg/m(2)) did not differ from that of the third dose level (105 mg/m(2)). The latter dosage was therefore conside red as the maximal tolerated one. In the subsequent phase II study, the med ian number of cycles received per patient was three (range: one to eight). Fifty percent required a dose reduction of either epirubicin, cisplatin, or both. The main toxicity was neutropenia, resulting in 10 episodes of febri le grade IV neutropenia requiring readmission. Other toxicities were mild t o moderate. There was no toxic-related death. On intent-to-treat analysis, 10 patients (33%) achieved an objective response. Among them were three com plete responders. Median survival was 8 months. We observed neither detract ion nor improvement of quality of life as assessed using the European organ ization for Research and Treatment of Cancer QLQ-C30-LC13. Given every 3 we eks in combination with epirubicin 120 mg/m(2), the maximal tolerated cispl atin dose is 105 mg/m2. This combination yields activity in non-small-cell lung cancer.