Neoadjuvant Therapy for Locally Advanced Esophageal Cancer Should Be Targeted to Tumor Histology

Background: Controversy exists over the optimal neoadjuvant therapy in patients with locally advanced esophageal cancer (EC). Although most groups favor neoadjuvant chemoradiation (nCRT), some prefer preoperative chemotherapy (nCT) without radiation. The objective of this study was to compare outcomes in EC patients undergoing either regimen, followed by surgery.

Methods: We reviewed a prospectively collected database of EC patients undergoing esophagectomy after nCT or nCRT from 1989 to 2016. Choice of therapy was at the discretion of the multidisciplinary team. Disease-free survival (DFS) and cancer-specific survival (CSS) were compared by the Kaplan-Meier log-rank test. Independent predictors of CSS were estimated by Cox regression analysis.

Results: Among 700 EC patients 338 patients were treated with nCRT (n = 112) or nCT (n = 226) followed by surgery. Patients were well matched for age, gender, and clinical stage, although patients with squamous cell carcinoma were more likely to receive nCRT (49% vs 26%, p < 0.001). At surgery 90% and 91% of nCRT and nCT patients, respectively, underwent transthoracic esophagectomy. nCRT, in comparison with nCT, was associated with similar rates of Calvien-Dindo grade III/IV complications (34% vs 33%, p = 0.423) but with a trend toward higher perioperative mortality (5% vs 1%, p = 0.064). Among adenocarcinoma patients (n = 239) the use of nCRT was associated with higher rates of complete clinical response (18% vs 7.4%), pathologically negative lymph nodes (52% vs 30%, p = 0.001), and complete pathologic response (21% vs 5.1%, p < 0.001). However, there was no difference between nCRT and nCT for 5-year DFS (28% vs 31%, p = 0.636) or CSS (51% vs 52%, p = 0.824) among adenocarcinoma patients. For patients with squamous cell carcinoma (n = 98), nCRT and nCT had similar rates of complete clinical response (31% vs 26%, p = 0.205), but the rates of negative nodes (65% vs 46%, p = 0.064) and of complete pathologic response (42% vs 12%, p < 0.05) were higher with nCRT. For these patients nCRT was associated with no statistical difference in 5-year DFS (57% vs 40%, p = 0.595) but with improved 5-year CSS (87% vs 68%, p = 0.019) compared with nCT. On multivariable analysis for CSS, nCRT predicted improved survival for patients with squamous cell carcinoma (hazard ratio, 0.242; 95% confidence interval, 0.071-0.830) but not for those with adenocarcinoma (univariate hazard ratio, 0.940; 95% confidence interval, 0.544-1.623).

Conclusions: For adenocarcinoma patients undergoing surgery for EC, nCRT leads to increased local tumor response compared with nCT alone but with no difference in survival. For squamous carcinoma patients nCRT appears to improve CSS compared with nCT. For patients with locally advanced EC targeted neoadjuvant regimens should be used depending on tumor histology.