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stage II/III期で、術前vs術後の5FU+CDDP 2コースを比較し、術前群の生存率が優れる
CROSS trial -- Dutch investigators randomly assigned 363 patients with potentially resectable esophageal or esophagogastric junction (EGJ) cancer (86 SCC, 273 adenocarcinoma, 4 other; majority distal esophageal, 11 percent EGJ) to preoperative chemoradiotherapy using weekly paclitaxel 50 mg/m2 plus carboplatin (area under the curve of concentration X time [AUC] of 2) plus concurrent RT (41.4 Gy over five weeks) or surgery alone . Preoperative chemoradiotherapy was well tolerated, with grade 3 or worse hematologic toxicity in 7 percent, and grade 3 or higher non-hematologic toxicity in <13 percent; there were also no differences in postoperative morbidity or mortality between the two groups. The complete (R0) resection rate was higher with chemoradiotherapy (92 versus 69 percent), and 29 percent of those treated with chemoradiotherapy had a pathologic complete response (pCR). At a median follow-up of 32 months, median overall survival was significantly better with preoperative chemoradiotherapy (hazard ratio [HR] for death 0.657, 95% CI 0.495-0.871, three-year survival rate 58 versus 44 percent).
CALGB 9781 -- CALGB 9781 was originally designed as a randomized Intergroup trial of trimodality therapy versus surgery in 500 patients with stages I-III esophageal or EGJ cancer, staged with esophagogastroduodenoscopy, barium esophagram, and computed tomography (CT). Staging endoscopic ultrasound (EUS) and thoracoscopy/laparoscopy were encouraged. Due to poor accrual, the study was closed prematurely with only 56 patients enrolled (42 adenocarcinomas, 14 SCC). A pCR was achieved in 10 of 25 assessable patients in the trimodality arm (40 percent), and neither perioperative morbidity nor mortality were increased compared with surgery alone . Five-year survival was 39 versus 16 percent in favor of trimodality therapy, although the difference was not statistically significant.
FFCD 9901 -- The benefit of preoperative chemoradiotherapy in smaller resectable tumors was directly addressed in the French FFCD 9901 trial, which randomly assigned 195 patients with stage I or II esophageal or EGJ cancer (T1N0/N+, T2 N0/N+, or T3N0, (table 2)) to preoperative chemoradiotherapy (two courses of infusional 5-fluorouracil [5-FU] 800 mg/m2 daily days 1 to 4 and 29 to 32 plus cisplatin 75 mg/m2 on day 1 or 2 of each course and concurrent RT [45 Gy]) versus surgery alone . At a median follow-up of 94 months, neoadjuvant chemoradiotherapy did not improve three-year overall survival (47.5 versus 53 percent, HR 0.99, 95% CI 0.69-1.40), did not improve the complete (R0) resection rate, and it was associated with a significantly higher rate of perioperative mortality (11.1 versus 3.4 percent). There were no subgroups (eg, node-positive, stage II/IIIA, adenocarcinoma versus squamous cell) for which a survival benefit of initial chemoradiotherapy could be shown. While it is possible that patients with early stage, potentially resectable disease derive minimal to no benefit from trimodality therapy, it is also likely that study was underpowered to show a significant survival benefit, if one was present .
Meta-analyses -- Several meta-analyses have addressed the benefit of trimodality therapy over surgery alone for esophageal cancer. The most recent and largest of these included 12 randomized comparisons of neoadjuvant chemoradiotherapy (either concurrent or sequential) versus surgery alone for esophageal or EGJ cancer, including the FFCD 9901, CALGB 9781, and CROSS trials . The HR for all-cause mortality for neoadjuvant chemoradiotherapy was 0.78 (95% CI 0.70-0.88), and this translated into an absolute survival benefit of 8.7 percent at two years and a number needed to treat to prevent one death of 11. The benefit was similar across histologic subtypes (for SCC, the HR was 0.80, 95% CI 0.68-0.93; for adenocarcinomas, the HR was 0.75, 95% CI 0.59-0.95). The potential benefit of neoadjuvant therapy was not offset by a higher postoperative mortality (in-hospital or 30-day postoperative death).
Sequential chemoradiotherapy -- In contrast to the data on concurrent chemoradiotherapy, at least three trials comparing sequentially administered chemotherapy and RT followed by surgery with surgery alone have failed to show any survival advantage to combined modality therapy [17,28,29].
（これらはUpToDate 記事番号Topic 2478 Version 45.0より引用）