Phase 2 Study of Adjuvant Chemoradiation Therapy Using Docetaxel/Cisplatin/5-Fluorouracil Before and After Intensity-Modulated Radiation Therapy With Concurrent Docetaxel in Patients With Completely (R0) Resected Gastric Carcinoma

Abstract

Complete surgical R0 resection has traditionally been considered the only curative treatment in localized gastric cancer (GC). The INT 0116 study has demonstrated a significant survival benefit for completely resected (R0) GC patients treated with a fluorouracil/leucovorin chemo-radiotherapy regimen. However, this regimen is also toxic and less effective in terms of distant disease control. Therefore, a more efficacious and safer regimen is urgently needed. The eligibility criteria included histologically confirmed adenocarcinoma of the stomach or gastroesophageal junction, complete resection of the tumor defined as surgical resection performed with curative intent and resulting in negative resection margins, disease stage IB through IV (M0). Patients received up to two 21-day cycles of post-operative adjuvant pre- and post-radiation DCF chemotherapy (docetaxel 37.5 mg/m2 on days 1 and 8, cisplatin 25 mg/m2 on days 1-3, and a continuous infusion of fluorouracil 750 mg/m2 on days 1-5), respectively. Chemo-radiotherapy between pre- and post-radiation chemotherapy was initiated on day 43 and consisted of intensity-modulated radiotherapy (45 Gy) plus concurrent docetaxel 20 mg/m2 weekly for 5 weeks. The clinical tumor volume (CTV) included the tumor bed, anastomoses, and stumps, regional draining lymph nodes. The planning target volume (PTV) consisted of the CTV plus a 0.5-cm margin in all directions to account for daily patient set-up variation. The primary end point was PFS. This single-stage phase II trial was designed to have 93% power to detect a 20% improvement in the 20-month PFS rate from 50 to 70% with a two-sided significance level of exactly 0.05. The accrual goal was 55 patients. A total of 55 patients were evaluated and 76% (42) of patients completed the prescribed therapy. The median age was 59 years (range, 28–75 years). The majority of patients had locally advanced disease (stage T3 or T4, 71%; N1–3, 93%). With a median follow-up of 61 months, the 20-month PFS rate was 75% (95% confidence interval [CI] = 64–86%). The 3- and 5- year progression-free survival rates were 67% (95% CI: 54%-80%) and 59% (95% CI: 46%-72%), respectively; and the 3- and 5-year overall survival rates were 72% (95% CI: 60%-84%) and 61% (95% CI: 48%-74%), respectively. Of 21 documented sites of first treatment failure, local-regional relapse occurred in 5 patients, distant relapse including peritoneal carcinomatosis was observed in 13 patients, and 3 patients had both local-regional and distant recurrences. The most common grade 3 or greater toxicity, during the chemotherapy phase, was neutropenia (24%). Common grade 3/4 toxicities during concurrent chemo-radiotherapy were nausea (32%), vomiting (26%), fatigue (15%), and anorexia (19%). These results demonstrate that this adjuvant regimen is active with an acceptable toxicity profile. A randomized phase 3 trial comparing the INT-0116 chemo-radiotherapy regimen with this regimen is underway.