ORIGINAL ARTICLE Phase II Trial of Gemcitabine Plus Irinotecan In Patients With Esophageal Cancer A Southwest Oncology Group (SWOG) Trial Stephen K. Williamson, MD,* Sheryl A. McCoy, MS,† David R. Gandara, MD,‡ Shaker R. Dakhil, MD,§ Kathleen J. Yost, MD,¶ Jorge C. Paradelo, MD, James N. Atkins, MD,** Charles D. Blanke, MD,†† and James L. Abbruzzese, MD‡‡ Objectives: Metastatic esophageal carcinoma is an incurable dis- ease with median survival duration of 6 to 8 months. Based on preclinical data suggesting a dose-dependent synergy between gem- citabine and irinotecan we have conducted a phase II trial in patients with advanced or metastatic esophageal carcinoma. Methods: Patient eligibility included a diagnosis of squamous cell or adenocarcinoma of the esophagus/gastroesophageal (GE) junction, metastatic or recurrent disease, no CNS metastasis, no prior chemother- apy, prior adjuvant/neoadjuvant chemotherapy was allowed, no prior gemcitabine or irinotecan, performance status of 0 to 2 and adequate organ function. Patients received gemcitabine 1000 mg/m 2 and irino- tecan 100 mg/m 2 given day 1 and day 8, every 3 weeks. The primary end point was the 6-month survival rate. The secondary end point was to assess qualitative and quantitative toxicities. Results: Fifty-seven eligible patients were accrued. There were 4 treatment-related deaths. The primary grade 3 to 4 toxic events were diarrhea, dehydration, neutropenia, thrombocytopenia, anemia, and anorexia; and 4 episodes of grade 3 to 5 febrile neutropenia, 1 fatal. The study was designed to detect a difference between the null hypothesis of 30% 6-month survival and the alternative hypothesis of 50% 6-month survival. The Kaplan-Meier estimate of 6-month survival is 56% (95% CI: 43– 69%), with a median of 6.3 months. The median time to progression was 3.7 months. The 6-month progression-free survival estimate is 25% (95% CI: 13–36%). Conclusions: The length of survival suggests that this combination has benefit similar to platinum containing regimens, however, the toxicity is substantial and is unlikely to prove superior to platinum containing regimens. Key Words: gemcitabine, irinotecan, esophageal carcinoma, phase 2 (Am J Clin Oncol 2006;29: 116 –122) I t is estimated that in 2004 there will be 14,250 new cases of esophageal cancer diagnosed in the United States. 1 More than 90% of patients die of their disease, accounting for 2% of American cancer deaths. About half of all patients diag- nosed, present with metastatic disease and chemotherapy is commonly employed for palliation. 2 Metastatic esophageal carcinoma is an incurable disease with median survival du- ration of 4 to 8 months. 3 Two previous SWOG trials obtained a median survival of 3 months in evaluating the phase II agent topotecan 4 and 7 months in a phase II evaluation of gemcit- abine and cisplatinum. 5 Responses to chemotherapy are gen- erally short-lived, and toxicity of cisplatin-based chemotherapy is often substantial. More effective and less toxic treatment regimens are needed. Because cisplatin is associated with substantial toxicity, there is enthusiasm for evaluating the effectiveness of nonplatinum containing regimens. Gemcitabine is a nucleoside analogue that exhibits anti- tumor activity. It is S-phase specific, primarily killing cells undergoing DNA synthesis. It also blocks the progression of cells through the G1/S2 phase boundary. It is metabolized intracellularly by deoxycytidine kinase into active diphosphate and triphosphate nucleosides (dFdCDP and dFdCTP, respec- tively). The cytotoxic effects of gemcitabine are secondary to DNA synthesis inhibition by the active nucleosides. Gemcit- abine diphosphate (dFdCDP) inhibits ribonucleotide reduc- tase. This results in the absence of deoxynucleoside triphos- phates needed for DNA synthesis and also causes a reduction of intracellular deoxynucleotides, including deoxycytidine triphosphate (dCTP). Gemcitabine triphosphate (dFdCTP) From the *University of Kansas Medical Center, Kansas City, KS; †South- west Oncology Group Statistical Center, Seattle, WA; ‡University of California, Davis, Sacramento, CA; §Wichita Community Clinical On- cology Program, Wichita, KS; ¶Grand Rapids Community Clinical Oncology Program, Grand Rapids, MI; Kansas City Community Clini- cal Oncology Program, Kansas City, MO; **Southeast Cancer Control Consortium, Community Clinical Oncology Program, Goldsboro, NC; ††Oregon Health Sciences University, Portland, OR; ‡‡University of Texas M.D. Anderson Cancer Center, Houston, TX. Supported in part by the following PHS Cooperative Agreement grant numbers awarded by the National Cancer Institute, DHHS: CA38926, CA32102, CA12644, CA46441, CA35431, CA35178, CA35176, CA45808, CA45461, CA42777, CA27057, CA86780, CA11083, CA45807, CA45377, CA35261, CA35119, CA58861, CA76447, CA46368, CA04919, CA35090, CA52654, CA58416, CA67575, CA45560, CA63850, CA35192, CA35262. Reprints: Stephen K. Williamson, MD, Professor, Division Director, Divi- sion of Hematology/Oncology, University of Kansas Medical Center, Mail Stop 1044, 3901 Rainbow Blvd., Kansas City, KS 66160. E-mail: swilliam@kumc.edu. Copyright © 2006 by Lippincott Williams & Wilkins ISSN: 0277-3732/06/2902-0116 DOI: 10.1097/01.coc.0000199883.10685.2b American Journal of Clinical Oncology • Volume 29, Number 2, April 2006 116