Gemcitabine and carboplatin in combination: an update of phase I and phase II studies in non-small cell lung cancer.

Gemcitabine has demonstrated single-agent activity in advanced, incurable non-small cell lung cancer, yielding response rates of > or =20%. In combination with cisplatin, response rates of 30% to 60% and encouraging survival have been observed. Carboplatin causes much less nonhematologic toxicity than cisplatin. In a phase III Eastern Cooperative Oncology Group trial, initial therapy with carboplatin yielded superior survival in advanced non-small cell lung cancer compared with cisplatin combinations and other cisplatin analogs, despite a lower response rate. Thus, studies designed to identify optimal dose schedules for a combination of gemcitabine plus carboplatin are clearly warranted. Carmichael et al from the United Kingdom have identified a maximum tolerated dose of carboplatin of area under the curve of 5.2 mg/mL/min administered on day I followed by gemcitabine 1,000 mg/m2 on days 1, 8, and 15 of a 28-day cycle. This combination produced a response rate of 31% and a median survival of 10.5 months in 13 evaluable patients. A subsequent phase I evaluation reversing the carboplatin and gemcitabine sequence (gemcitabine preceding carboplatin on day 1) demonstrated no difference in toxicities, pharmacodynamics, or maximum tolerated dose. Other investigators have identified similar promising results with this regimen, although one North American investigator has observed untoward toxicity in a small number of patients using a standard 28-day dose schedule with gemcitabine administered on days, 1, 8, and 15. Day-15 gemcitabine dosing is problematic and may contribute to excessive thrombocytopenia when gemcitabine is combined with carboplatin. The ongoing phase I/II trials reviewed here have focused on a compressed 21-day schedule, with carboplatin administered every 3 weeks and gemcitabine given on days 1 and 8 only.