Randomized double-blind placebo-controlled trial of thalidomide in combination with gemcitabine and Carboplatin in advanced non-small-cell lung cancer.

Purpose: cancers rely on angiogenesis for their growth and dissemination. We hypothesized that thalidomide, an oral antiangiogenic agent, when combined with chemotherapy, and as maintenance treatment, would improve survival in patients with advanced non–small-cell lung cancer (NSCLC).Patients and Methods: seven hundred twenty-two patients were randomly assigned to receive placebo or thalidomide capsules 100 to 200 mg daily for up to 2 years. All patients received gemcitabine and carboplatin every 3 weeks for up to four cycles. End points were overall survival (OS), progression-free survival (PFS), response rate, grade 3/4 toxicity, and quality of life (QoL).Results: the median OS rates were 8.9 months (placebo) and 8.5 months (thalidomide). The hazard ratio (HR) was 1.13 (95% CI, 0.97 to 1.32; P = .12). The 2-year survival rate was 16% and 12% in the placebo and thalidomide arms, respectively. The PFS results were consistent with those for OS. The risk of having a thrombotic event was increased by 74% in the thalidomide group: HR of 1.74 (95% CI, 1.20 to 2.52; P = .003). There were no differences in hematologic toxicities, but a slight excess of rash and neuropathy in the thalidomide group. QoL scores were similar but thalidomide was associated with less insomnia, and more constipation and peripheral neuropathy. In a retrospective analysis, patients with nonsquamous histology in the thalidomide group had a poorer survival: 2-year risk difference of 10% (95% CI, 4% to 16%; P < .001).Conclusion: in this large trial of patients with NSCLC, thalidomide in combination with chemotherapy did not improve survival overall, but increased the risk of thrombotic events. Unexpectedly, survival was significantly worse in patients with nonsquamous histolog