Major Pathologic Response in Esophageal Adenocarcinoma: should we adopt a new paradigm in defining response to treatments?

Abstract Background Incidence of adenocarcinoma (ADC) of the esophagus is arising in Western countries and it is still burdened by a significant mortality. A complete primary tumor regression after neoadjuvant treatment is associated with improved long-term survival, however this favorable response is rarely achieved. The primary endpoint of this study was to determine whether the survival benefit associated with a complete tumor regression could be achieved also with a major, albeit subtotal, tumor response. Methods We evaluated all consecutive patients who underwent esophagectomy for cancer at 2 high-volume centers. Inclusion criteria were histologically confirmed ADC involving the thoracic esophagus or Siewert I and II cancers, treated by neoadjuvant chemotherapy (CT) or chemoradiotherapy (CRT) and surgery. Pathological tumor response was quantified using the Mandard score. Kaplan-Maier plots were used to estimate overall survival (OS) according to the TRG. Results Overall, 424 patients were recruited in the study period, 236 received CT and 188 CRT. The median follow-up time was 55 months. TRG 1 and 2 showed comparable OS curves both in the CT group (p = 0.76) and in the CRT group (p = 0.82) (Figure 1). TRG 1–2 were associated with a significantly improved OS compared to TRG 3–5 after CT (p = 0.004) and CRT (p = 0.0003). The trend was confirmed in the whole cohort, with TRG 1 and 2 patients showing comparable 5-years OS proportions (70% vs. 65%, p = 0.52) and a significantly improved survival compared to TRG 3–5 (p < 0.0001). Conclusion Tumor regression after neoadjuvant treatment is significantly associated with long term survival irrespective of the adopted regimen. The long-term survival was comparable between TRG 1 and TRG 2 patients after CT and CRT and in the overall population. This finding allowed us to define the criterion of major tumor response, which includes both TRG 1 and 2 patients, potentially creating a homogeneous and larger subgroup of subjects to be evaluated in future clinical trials.