Classification of Pathologic Response to Neoadjuvant Therapy in Esophageal and Junctional Cancer Assessment of Existing Measures and Proposal of a Novel 3-Point Standard

Objective: To assess existing measures of pathologic response to neoadjuvant therapy in esophageal and junctional cancer, and to recommend an optimum classification. Background: Multimodal therapy is increasingly the standard of care for locally advanced esophageal cancer. Numerous measures of pathologic response have been studied; however, no international standardization exists and no measure is incorporated into the current American Joint Committee on Cancer staging system. Methods: A total of 393 consecutive patients completing multimodal therapy were studied, all with prospectively recorded Mandard tumor regression grades (TRG). Seven other published methods of response were compared, and a novel 3-point TRG [TRG 1 (complete); TRG 2/3 (partial); TRG 4/5 (none/minimal)] was tested. Clinical and pathologic evidence of nodal regression was assessed in a consecutive subset of 200 comprehensively staged patients. Results: All models had similar discriminatory and stratification power, and they predicted survival (P < 0.0001) on univariate analysis. Conversely, only the 3- point TRG (P = 0.042) along with ypN (P < 0.001) and ypT stage (P < 0.001) independently predicted survival. The median survival for TRG1 was 71 months compared with 30 and 17 months for TRG 2/3 and TRG 4/5, respectively (P < 0.0001). Apparent complete nodal response (cN1 to ypN0) was seen in 64% of the TRG 1 group, 30% of the TRG 2/3 group, and 5% of the TRG 4/5 group (P < 0.0001). Conclusions: No existing response measure independently predicts outcome. A complete response (TRG 1) defines a unique cohort after neoadjuvant therapy, associated closely with nodal response, and overall survival. This classification merits consideration for standardization of treatment response, and for inclusion in staging nomenclature.