On the basis of the hypothesis that responsiveness of brain metastases (BM) to chemotherapy is primarily determined by the chemosensitivity of primary tumor, rather than the ability of cytotoxic agents to penetrate the blood-brain barrier, we addressed the role of a new combination regimen with Vinorelbine (VNR), Gemcitabine (GEM), and Carboplatin (CBDCA) as a primary treatment modality in non-small-cell lung cancer (NSCLC) patients with BM. Twenty-two consecutive chemotherapy-naïve patients with documented BM from NSCLC and at least 1 evaluable extracerebral lesion were enrolled in this phase II study. Vinorelbine (25 mg/m2) and GEM (1000 mg/m2) were given on day 1, combined with a fixed daily dose of CBDCA at AUC = 5.0 for three consecutive days. The cycle was repeated every three weeks in an outpatient setting. A total of 116 cycles was given (median 4, range 3-9 per patient). Specific evaluation of BM by contrast-enhanced computed tomography (CT) scan showed an overall response rate of 45% in 20 evaluable patients (95% confidence interval, 26-66%), with 3 (15%) complete and 6 (30%) partial remissions; in addition, three minor regressions, five disease stabilizations, and three progressions were found. Patients who responded for the brain also had a response at the extracerebral sites, and a benefit by a remission of symptoms and improvement of performance index was observed in 77% of the whole group. Median time to response was 10 weeks (range 6-12 weeks) and median response duration was 25 weeks (range 12-32 weeks). Median survival time was 33 weeks (range 18-62 + weeks) in the whole group and 48 weeks in responders (range 26-62 + weeks). The adopted schedule was well tolerated and easy to use in the outpatient setting, with good patient compliance. Our results, which are consistent with the study hypothesis, suggest that BM respond to chemotherapy in the same way as systemic disease and primary tumor, and further support the need for reconsideration of the role of chemotherapy in such a clinical setting. Controlled trials comparing chemotherapy with radiotherapy or concomitant sequential chemo-radiotherapy would be appropriate.

Two nitrosourea compounds--1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU)--have been used in the treatment of primary and metastatic brain tumors after operation and/or radiotherapy. Hematological and nonhematological toxicity were recorded in 272 patients treated between May 1973 and June 1978. BCNU was given to 135 patients (80 mg/m2 i.v. daily for 3 days) and CCNU was given to 137 patients (130 mg/m2 orally, single dose) every 8 weeks until progression of the primary disease process or for a total of 12 cycles. Radiation therapy (5500 +/- 500 rads in 6 to 7 weeks) was carried out after the first course of chemotherapy. BCNU and CCNU induced the same hematological and clinical toxicity. The bone marrow toxicity seemed to be dose-related, delayed, and cumulative. One case of acute nonlymphoblastic leukemia arising 2 months after the end of CCNU therapy is reported.

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