Cetuximab plus cisplatin, irinotecan, and thoracic radiotherapy as definitive treatment for locally advanced, unresectable esophageal cancer: a phase-II study of the SWOG (S0414).
The specific aims of the study were to evaluate the 2-year overall survival (OS) and progression-free survival (PFS), toxicity profile, and best objective response rate in patients with locally advanced, clinically unresectable esophageal cancer receiving cetuximab, cisplatin, irinotecan, and thoracic radiotherapy (TRT) within a multi-institutional cooperative-group setting.Eligible patients (cT4 M0 or medically unresectable, biopsy proven, and noncervical esophageal cancer) were to receive four 21-day cycles of cetuximab 400 mg/m (day 1, cycle 1), cetuximab 250 mg/m (day 8, 15, cycle 1; then days 1, 8, and 15 for subsequent cycles), cisplatin 30 mg/m (days 1 and 8, all cycles), and irinotecan 65 mg/m (days 1 and 8, all cycles). TRT was administered at 1.8 Gy in 28 daily fractions to a total dose of 50.4 Gy, to begin with on day 1 of cycle 3. The primary endpoint was 2-year OS, with an accrual goal of 75 patients with adenocarcinoma.The study was closed because of slow accrual, with 21 eligible patients (11 squamous, 10 adenocarcinoma) enrolled from May 2005 to September 2007. Two-year OS and PFS (95% confidence interval [CI]) were 33.3% (14.6-57.0%) and 23.8% (8.2-47.2%), respectively. Kaplan-Meier estimates of median (95% CI) OS and PFS were 11.2 (6.4-43.6) and 6.4 (3.7-12.0) months, respectively. The overall response rate (95% CI) among 17 evaluable patients was 17.6% (3.8-43.4%), including 6% confirmed complete responders and 12% unconfirmed partial responders. Two deaths resulted from protocol treatment (sudden death and gastrointestinal necrosis). Ten (47.6%) and 6 (28.6%) patients had grade-3 or -4 toxicity, respectively: 52.4% were hematologic, 23.8% had fatigue, 19.0% had nausea, 19.0% had dehydration, and 19.0% had anorexia.Concomitant cetuximab, cisplatin, irinotecan, and TRT were poorly tolerated in the first North American cooperative group trial testing this regimen for locally advanced esophageal cancer as treatment-related mortality approached 10%. Single-institution phase-II cetuximab-based combined modality trials have yielded encouraging results in preliminary analyses. The SWOG GI Committee endorses enrollment to open clinical trials to clarify the therapeutic ratio of cetuximab-based combined modality approaches for esophageal cancer.
Tomblyn, MB; Goldman, BH; Thomas, CR; Benedetti, JK; Lenz, H-J; Mehta, V; Beeker, T; Gold, PJ; Abbruzzese, JL; Blanke, CD; SWOG GI Committee,
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