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Phase III Trial of Paclitaxel Plus Carboplatin With or Without Tirapazamine in Advanced Non–Small-Cell Lung Cancer: Southwest Oncology Group Trial S0003

From the University of Kansas Medical Center, Kansas City, KS; Southwest Oncology Group Statistical Center, Seattle, WA; University of California, Davis, Sacramento, CA; Wake Forest University School of Medicine, Winston-Salem, NC; and Louisiana State University, Shreveport, LA.

Address reprint requests to Bonnie Granados, Southwest Oncology Group (SWOG-S0003), Operations Office, 14980 Omicron Dr, San Antonio, TX 78245-3217; e-mail: bgranados{at}swog.org

PURPOSE: Tumor hypoxia confers chemotherapy resistance. Tirapazamine is a cytotoxin that selectively targets hypoxic cells. We conducted a phase III clinical trial to determine whether the addition of tirapazamine to paclitaxel and carboplatin offered a survival advantage when used in the treatment of patients with advanced non–small-cell lung cancer (NSCLC).

PATIENTS AND METHODS: Of 396 patients registered, 367 eligible patients were randomly assigned to either arm 1 (n = 181), which consisted of treatment every 21 days with paclitaxel 225 mg/m²/3 h, carboplatin (area under the curve = 6), and tirapazamine 260 mg/m² in cycle 1 (which was escalated, if tolerable, to 330 mg/m² in cycle 2), or arm 2 (n = 186), which consisted of paclitaxel and carboplatin as in arm 1 with no tirapazamine.

RESULTS: Patient characteristics were similar between the two arms. There were no statistically significant differences in response rates, progression-free survival, or overall survival. Patients on arm 1 had significantly (P < .05) more abdominal cramps, fatigue, transient hearing loss, febrile neutropenia, hypotension, myalgias, and skin rash and were removed from treatment more often as a result of toxicity than patients in arm 2 (26% v 13%, respectively; P = .003). More than 40% of patients did not have the tirapazamine dose escalated, primarily because of toxicity. The trial was closed early after an interim analysis demonstrated that the projected 37.5% improvement in survival (8 v 11 months median survival) in arm 1 was unachievable (P = .003).

CONCLUSION: The addition of tirapazamine to paclitaxel and carboplatin does not result in improved survival in advanced NSCLC compared with paclitaxel and carboplatin alone but substantially increases toxicity.

Supported by the following Public Health Service Cooperative Agreement Grant Nos. awarded by the National Cancer Institute, Department of Health and Human Services: CA38926, CA32102, CA46441, CA58416, CA46282, CA35261, CA58658, CA35431, CA45807, CA58882, CA35119, CA67663, CA76447, CA12644, CA63844, CA45808, CA35128, CA20319, CA42777, CA16385, CA45377, CA52654, CA67575, CA35192, CA22433, CA46113, CA37981, CA35176, CA11083, CA74647, CA74811, CA14028, CA27057, CA58861, CA45461, CA35090, and CA58686; also supported in part by Sanofi-Synthelabo.

Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003; and the 10th World Conference on Lung Cancer, Vancouver, British Columbia, Canada, August 10-14, 2003.

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

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