Journal of the National Cancer Institute Advance Access originally published online on July 16, 2009
JNCI Journal of the National Cancer Institute 2009 101(15):1049-1057; doi:10.1093/jnci/djp200
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© The Author 2009. Published by Oxford University Press.
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Anti-angiogenic Therapy Using Thalidomide Combined With Chemotherapy in Small Cell Lung Cancer: A Randomized, Double-Blind, Placebo-Controlled Trial
Affiliations of authors: Department of Oncology (SML) and Department of Thoracic Medicine (SS), University College Hospital, London, UK; Cancer Research UK & University College London Cancer Trials Centre, London, UK (SML, LJ, KA, MJ, AH); Academic Unit of Clinical Oncology, Weston Park Hospital, University of Sheffield, Sheffield, UK (PJW); Department of Oncology, St Bartholomew's Hospital, London, UK (RR); Institute of Cancer Studies, University of Birmingham, Birmingham, UK (DF); Lung Unit, Royal Marsden Hospital, Sutton, UK (MO); Department of Oncology, Royal Surrey County Hospital, Guildford, UK (GM)
Correspondence to: Siow Ming Lee, MD, Department of Oncology, University College Hospital, 250 Euston Rd, London NW1 2PG, UK (e-mail: sm.lee{at}uclh.nhs.uk).
Background: Cancer cells rely on angiogenesis for growth and dissemination, and small cell lung cancer (SCLC) is a highly angiogenic tumor. We evaluated thalidomide, an anti-angiogenic agent, when combined with chemotherapy and as maintenance treatment.
Methods: A total of 724 patients (51% with limited and 49% with extensive disease) were randomly assigned to receive placebo or thalidomide capsules, 100–200 mg daily for up to 2 years. All patients received etoposide and carboplatin every 3 weeks for up to six cycles. Endpoints were overall survival, progression-free survival, tumor response rate, toxicity, and quality of life (QoL). Hazard ratios (HRs) for comparing thalidomide against placebo were estimated using Cox regression modeling. Statistical tests were two-sided.
Results: The median overall survival was 10.5 months (placebo) and 10.1 months (thalidomide) (HR for death = 1.09, 95% confidence interval [CI] = 0.93 to 1.27; P = .28). Among patients with limited-stage disease, there was no evidence of a survival difference (HR for death = 0.91, 95% CI = 0.73 to 1.15), but among patients with extensive disease, survival was worse in the thalidomide group (HR for death = 1.36, 95% CI = 1.10 to 1.68). Progression-free survival rates were also similar in the two groups (HR = 1.07, 95% CI = 0.92 to 1.24). Thalidomide was associated with an increased risk of having a thrombotic event, mainly pulmonary embolus and deep vein thrombosis (19% thalidomide vs 10% placebo; HR = 2.13, 95% CI = 1.41 to 3.20; P < .001). There were no statistically significant differences between treatments in hematological and nonhematological toxic effects, except more patients in the thalidomide group had rash, constipation, or neuropathy. Overall, QoL scores were similar in the two treatment groups, but thalidomide was associated with less insomnia and diarrhea and more constipation and peripheral neuropathy.
Conclusions: In this large randomized trial, thalidomide in combination with chemotherapy did not improve survival of patients with SCLC but was associated with an increased risk of thrombotic events.
| CONTEXT AND CAVEATS Prior knowledge Small cell lung cancer is very angiogenic, and thalidomide is an anti-angiogenic agent that has been used in combination with chemotherapy. Study design Randomized controlled trial of thalidomide vs placebo in 724 patients with small cell lung cancer who were undergoing chemotherapy. Overall survival and toxic effects were compared overall and among patients with extensive vs limited disease. Contribution Median overall survival was similar in the two groups; in analysis by disease extent, patients with extensive disease who were treated with thalidomide had worse overall survival than those treated with placebo. Patients treated with thalidomide had higher risk of thrombotic events than patients treated with placebo. Implications Overall, among patients with small cell lung cancer in this study, treatment with thalidomide did not improve overall survival but increased the risk of having a thrombotic event. Limitations The dose of thalidomide given in this study was lower than that given in some previous studies. Because bone or brain scans are not routinely performed in the United Kingdom, results of analysis by disease extent may not be generalizable to other populations with more stringent criteria.
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Manuscript received October 27, 2008; revised April 30, 2009; accepted June 5, 2009.
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