Cisplatin- versus carboplatin-based chemotherapy in first-line treatment of advanced non-small-cell lung cancer: an individual patient data meta-analysis.

BACKGROUND: Because the efficacy of carboplatin and cisplatin in the treatment of advanced non-small-cell lung cancer (NSCLC) has not been proven to be equivalent, an individual patient data meta-analysis comparing the two treatments was performed. METHODS: Randomized trials comparing carboplatin to cisplatin in first-line treatment of advanced NSCLC were identified and their electronic databases obtained. A general variance-based method was used to estimate the summary hazard ratios (HRs), odds ratios (ORs), and their 95% confidence intervals (CIs) for mortality, objective response, and toxicity. Cochran's chi-square test (Q test) was used to test for heterogeneity among trials, and the I2 index, which expresses the proportion of variability of the results due to heterogeneity, was calculated. A random-effects model that takes into account interstudy variation was also applied. All statistical tests were two-sided. RESULTS: Nine trials that included a total of 2968 patients were analyzed; overall median follow-up was 1021 days. The objective response rate was higher for patients treated with cisplatin than for patients treated with carboplatin (30% versus 24%, respectively; OR = 1.37; 95% CI = 1.16 to 1.61; P<.001). Carboplatin treatment was associated with a non-statistically significant increase in the hazard of mortality relative to treatment with cisplatin (HR = 1.07; 95% CI = 0.99 to 1.15; P = .100). In patients with nonsquamous tumors and those treated with third-generation chemotherapy, carboplatin-based chemotherapy was associated with a statistically significant increase in mortality (HR = 1.12; 95% CI = 1.01 to 1.23 and HR = 1.11; 95% CI = 1.01 to 1.21, respectively). Cisplatin-based chemotherapy was associated with more severe nausea and vomiting and nephrotoxicity; severe thrombocytopenia was more frequent during carboplatin-based chemotherapy. CONCLUSIONS: Our individual patient data meta-analysis suggests that cisplatin-based chemotherapy is slightly superior to carboplatin-based chemotherapy in terms of response rate and, in certain subgroups, in prolonging survival without being associated with an increase in severe toxic effects. Therefore, cisplatin-based third-generation regimens should remain the standard reference for the treatment of selected patients with advanced-stage NSCLC and of those with earlier-stage disease.

A phase I study of the trinuclear platinum compound, BBR 3464, in combination with protracted venous infusional 5-fluorouracil in patients with advanced cancer.

PURPOSE: BBR 3464 is a novel trinuclear platinum anticancer agent with a broad spectrum of preclinical antitumour activity. A phase I, open-label dose-escalating study was performed to determine the maximum tolerated dose (MTD) of BBR 3464 administered in combination with protracted venous infusional (PVI) 5-fluorouracil (5-FU) for up to six courses in patients with locally advanced and/or metastatic cancer. METHODS: Dose escalation was based on observation of toxicity at each dose level. BBR 3464 (0.6 mg/m(2) escalated to 0.75 mg/m(2)) was studied in combination with PVI 5-FU (200 mg/m(2) per day). RESULTS: Entered into the study were 14 patients. The most frequent toxicities were nausea, neutropenia, fatigue and diarrhoea. The protocol-defined MTD was not determined as 11/14 patients experienced grade 3 or 4 neutropenia that interrupted the planned administration of PVI 5-FU on day 15 (of 21). Although these events were not dose-limiting, as defined in the protocol, they imposed limitations on the dose of PVI 5-FU administered. Antitumour activity was observed: a partial response in one patient (7%) with invasive breast cancer. Stable disease was confirmed in three patients (21%). These four patients all completed the planned six courses of combined therapy. CONCLUSIONS: In light of the lack of septic events associated with the recorded neutropenia, it may be possible to safely continue PVI 5-FU despite the grade 3 or 4 neutropenia or modify the PVI schedule and administer therapy on days 1-15 of the 21-day cycle, but these modifications were not considered in this study.

Effect of grapefruit juice intake on etoposide bioavailability.

PURPOSE: Oral administration of etoposide is limited by the high degree of unpredictable variation in systemic availability. This pilot study was conducted to evaluate the potential of pretreatment with grapefruit juice for improving the use of oral etoposide. METHODS: In a randomized crossover study, six patients were sequentially treated with 50 mg IV etoposide over 1 h, 50 mg orally, or 50 mg orally post grapefruit juice on day 1, day 4, and day 8. Blood samples were drawn up to 24 h after the end of infusion and oral drug administration. Plasma etoposide concentrations were determined by reversed-phase HPLC with UV detection. A two-compartment model was used for pharmacokinetic parameter estimation. Pharmacokinetic parameters were evaluated using descriptive statistics. RESULTS: Pretreatment with grapefruit juice resulted in an unexpected decrease of 26.2% in the AUC after oral treatment. Median absolute bioavailability with and without pretreatment with grapefruit juice was 52.4% and 73.2%, respectively. Interindividual variability was large in all treatment arms. CONCLUSION: Grapefruit juice seems to reduce rather than increase oral bioavailability of etoposide. Moreover, we did not observe a reduction in interpatient variability of bioavailability.