Originally published as JCO Early Release 10.1200/JCO.2009.21.9733 on September 21 2009

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Randomized Double-Blind Placebo-Controlled Trial of Thalidomide in Combination With Gemcitabine and Carboplatin in Advanced Non–Small-Cell Lung Cancer

From the University College Hospital, London, Barts and the London Hospital; Cancer Research UK and University College London Cancer Trials Centre, London; Weston Park Hospital, Sheffield; Southampton University Hospitals, Southampton; Addenbrooke's and Papworth Hospitals, Cambridge; and the Edinburgh Cancer Centre, Edinburgh, United Kingdom.

Corresponding author: Siow Ming Lee, MD, PhD, FRCP, Department of Oncology, University College Hospital, 250 Euston Rd, London NW1 2PG, United Kingdom; e-mail: sm.lee{at}uclh.nhs.uk.

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 histology.

Supported by an educational grant from Lilly UK; thalidomide and placebo capsules were provided free of charge by Pharmion Ltd. S.M.L. is supported by University College London Hospital/University College London Comprehensive Biomedical Research Centre, London, United Kingdom.

Presented in oral format at 12th World Conference on Lung Cancer, Seoul, Korea, September 2-6, 2007, and in part at the 44th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 30-June 3, 2008.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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