Weekly combination chemotherapy with docetaxel and gemcitabine as first-line treatment for elderly patients and patients with poor performance status who have extensive-stage small cell lung carcinoma: a Minnie Pearl Cancer Research Network phase II trial.

BACKGROUND: The goal of the current study was to evaluate the feasibility, toxicity, and efficacy of a novel combination of weekly docetaxel and gemcitabine for elderly patients and patients with poor performance status who had advanced-stage small cell lung carcinoma (SCLC). METHODS: Previously untreated patients with advanced-stage SCLC were eligible for the current clinical trial. In addition, patients were required to be age > 65 years or to have poor performance status (Eastern Cooperative Oncology Group 2). All patients received 800 mg/m2 gemcitabine and 30 mg/m2 docetaxel intravenously on Days 1, 8, and 15. Courses were repeated at 28-day intervals. RESULTS: Forty patients were enrolled in the current multicenter, community-based trial. Nine patients (23%) had partial responses to treatment. The median survival for the entire group was 4 months. Fourteen percent of patients were alive at 1 year. Myelosuppression was mild to moderate, with no episodes of neutropenia and fever. Grade 3/4 fatigue (25%) was the only common nonhematologic toxicity. CONCLUSIONS: Although relatively well tolerated, the weekly regimen of gemcitabine and docetaxel possessed only modest activity in this group of patients with unfavorable prognosis. The regimen offered no potential advantages over standard treatment approaches and is not recommended for further development.

A randomized phase I and pharmacological trial of sequences of 1,3-bis(2-chloroethyl)-1-nitrosourea and temozolomide in patients with advanced solid neoplasms.

PURPOSE: O(6)-alkylguanine-DNA alkyltransferase (AGAT) is modulated by methylating agents, which, in turn, abrogates nitrosourea resistance in preclinical studies. The feasibility of administering various sequences of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and temozolomide (TEM) in patients with advanced solid neoplasms was evaluated in this Phase I and pharmacological study to assess this premise in the clinical setting. The study also sought to determine the maximum tolerated dose (MTD) levels of BCNU and TEM as a function of Seq, to characterize the pharmacokinetic (PK) behavior of TEM administered both before and after BCNU, assess AGAT fluctuations in peripheral blood mononuclear cells (PBMCs), and seek preliminary evidence of anticancer activity. EXPERIMENTAL DESIGN: Sixty-three patients were randomized to receive treatment with oral TEM daily on days 1-5 and BCNU administered i.v., either on day 1 before TEM [Sequence (Seq) B-->T] or day 5 after TEM (Seq T-->B). Treatment was repeated every 6 weeks. Blood sampling for PK studies was performed on both days 1 and 5 of course one. PBMCs were sampled to evaluate major sequence-dependent effects on AGAT levels. RESULTS: Neutropenia and thrombocytopenia were the principal dose-limiting toxicities of the BCNU/TEM regimen. These effects were more prominent in patients receiving Seq T-->B, resulting in a much lower MTD of 80/100 mg/m(2)/day compared with 150/110 mg/m(2)/day for Seq B-->T. Notable antitumor activity was observed in patients with glioblastoma multiforme, sarcoma, and ovarian carcinoma. No sequence-dependent PK effects were noted to account for sequence-dependent toxicological effects. At the MTD level, AGAT activity in PBMCs decreased 3-fold, on average, and AGAT fluctuations did not appear to be sequence-dependent. CONCLUSIONS: The principal toxicities of the BCNU/TEM regimen were neutropenia and thrombocytopenia, which were consistent and predictable, albeit sequence-dependent. Seq T-->B was substantially more myelosuppressive, resulting in disparate MTDs and dose levels recommended for subsequent disease-directed evaluations (150/110 and 80/100 mg/m(2)/day for Seq B-->T and T-->B, respectively). Sequence-dependent differences in TEM PK do not account for this clinically relevant magnitude of sequence-dependent toxicity. The characteristics of the myelosuppressive effects of BCNU/TEM, the paucity of severe nonhematological toxicities, and antitumor activity at tolerable doses warrant disease-directed evaluations on this schedule.