Phase II Study of Preoperative Chemoradiotherapy with Oxaliplatin, Infusional 5-Fluorouracil, and Cetuximab Followed by Postoperative Docetaxel and Cetuximab in Patients with Adenocarcinoma of the Esophagus: A Trial of the ECOG-ACRIN Cancer Research Group (E2205).

BACKGROUND: A standard approach to treating resectable esophageal adenocarcinoma is chemoradiotherapy (CRT) followed by surgery; however, recurrence is common. To improve this, we designed a single-arm, phase II trial that added an epidermal growth factor receptor (EGFR) inhibitor, cetuximab (C), to CRT, with the hypothesis that EGFR inhibition would improve pathologic complete response (pCR) rate. MATERIALS AND METHODS: We aimed to increase the pCR rate from 25% to 45%. A Simon two-stage design (α and ß of 0.10) required pCR/enrolled 5/18 for stage 1 and 14/40 total. CRT: oxaliplatin 85 mg/m2 days 1, 15, and 29; infusional 5-fluorouracil 180 mg/m2 /24 hours × 35 days; C 400 mg/m2 day 1 then 250 mg/m2 days 8, 15, 22, and 29 and radiation (intensity modulated radiotherapy [IMRT] allowed) 180 cGy/day × 25 fractions (Monday through Friday). Following esophagectomy, adjuvant chemotherapy (CT): weekly docetaxel 35 mg/m2 and C 250 mg/m2 5 out of 6 weeks for two cycles. RESULTS: Of 21 eligible patients enrolled, 17 had surgery; 4 died before operation (due to pulmonary embolism 4 days after CRT, G3 diarrhea, progressive disease during CRT, sepsis/hypoxia during CRT, and acute respiratory distress syndrome [ARDS]). pCR = 7/17. Three postoperative deaths due to ARDS resulted in seven total study-related deaths. Of the 14 remaining patients, 12 started and completed adjuvant CT. Two of seven patients with pCR died, both of ARDS. Out of the 21 eligible subjects in this study, 13 have died and 8 remain alive. The use of IMRT did not correlate with ARDS. CONCLUSION: This regimen demonstrated promising activity. Toxicity was significant, with seven study-related deaths leading to closure after stage 1. All postoperative deaths were due to ARDS. This regimen is not recommended. IMPLICATIONS FOR PRACTICE: Esophageal cancer is a disease with a high death rate. The current treatment involves giving chemotherapy plus radiation followed by surgery, but this cures only a quarter of patients. In order to improve survival, better treatments are needed. This trial evaluated the addition of a novel drug, cetuximab, to chemotherapy plus radiation. Unfortunately, the side effects were too great and the study was stopped early.

Long-term results of a phase II trial of neoadjuvant chemotherapy followed by esophagectomy for locally advanced esophageal neoplasm.

BACKGROUND: Effective systemic therapy is considered essential to improve the outcome for patients with surgically resectable locally advanced esophageal carcinoma. We report the long-term results of our phase II study of neoadjuvant chemotherapy, followed by esophagectomy and adjuvant chemotherapy for potentially resectable esophageal carcinoma. METHODS: Patients were staged with computed tomography scan (n = 70), endoscopic ultrasonography (n = 63), and laparoscopy with or without thoracoscopy (n = 70). The pretreatment stages were T2N0 (n = 1), T2N1 (n = 15), T3N0 (n = 13), and T3N1 (n = 41). Chemotherapy consisted of 2 or 3 cycles of cisplatin, 5-fluorouracil, and paclitaxel followed by esophagectomy and adjuvant chemotherapy. Patients were monitored for recurrence and survival. RESULTS: A total of 70 patients were enrolled (66 adenocarcinoma, 4 squamous cell carcinoma; 64 men and 6 women; median age, 60 years). Esophagectomy was performed in 63 patients. Operative mortality was 0%. The median overall survival of the entire group was 27.4 months. Seventeen patients were alive at a median follow-up of 62.8 months (range, 39.1 to 142). Fourteen patients were alive without recurrence at a median follow-up of 79 months (range, 39 to 138). Nodal status was an important predictor of overall survival. Patients who were downstaged experienced a significantly improved median survival of 63.4 months versus 21.5 months and overall survival (p = 0.005). CONCLUSIONS: This prospective study for esophageal carcinoma demonstrates encouraging long-term results. In particular, downstaging of the tumor with preoperative chemotherapy is predictive of better long-term outcome. Our results support the role for perioperative chemotherapy for locally advanced resectable esophageal cancer.

Combined-modality therapy for esophageal and gastroesophageal junction cancers.

The optimal management of locoregional esophageal cancer is controversial. Preoperative concomitant chemoradiotherapy (two courses of cisplatin and 5-fluorouracil plus 50 Gy of radiation) may provide benefit in survival and local control compared with surgery alone and is a reasonable alternative to surgery alone in stages IIB, III, and possibly stage IVa disease. This benefit is less clear in stages I and IIA, for which surgery alone is thus a reasonable option. Preoperative chemotherapy without radiation also provides a survival benefit compared with surgery alone, but data are insufficient to conclude it is superior to preoperative chemoradiotherapy. Control of distant disease remains a problem with preoperative chemotherapy and preoperative chemoradiotherapy.