Downstage migration after neoadjuvant chemoradiotherapy for rectal cancer: The reverse of the Will Rogers phenomenon?

Abstract

Downstaging after neoadjuvant treatment is increasingly used as a prognostic factor and surrogate endpoint in clinical trials. However, in recent trials of neoadjuvant 5‐fluorouracil–based chemoradiotherapy for rectal cancer, downstaging did not translate into a benefit with regard to either disease‐free survival (DFS) or overall survival. By analyzing the 10‐year outcome data of the German CAO/ARO/AIO‐94 phase 3 trial, the authors demonstrated that significantly fewer patients had poor prognostic features (eg, ypT3‐4, ypN1‐2) after preoperative 5‐fluorouracil–based chemoradiotherapy. Nevertheless, these patients with International Union for Cancer Control stage II disease were found to be at a higher risk of developing distant metastases and had poorer DFS compared with patients with corresponding TNM tumor (sub)groups in the postoperative treatment arm, whereas patients with International Union for Cancer Control stage III disease demonstrated a nonsignificant trend toward a worse outcome after preoperative treatment. Overall, DFS remained identical in both treatment arms. Thus, “downstage migration” after neoadjuvant treatment resembles the reverse of the Will Rogers phenomenon and therefore may not be a reliable endpoint for long‐term outcomes. Cancer 2015;121:1724–1727. © 2015 American Cancer Society.

Prognostic influence of histopathological regression patterns in rectal adenocarcinoma receiving neoadjuvant therapy

“…However, this study did not include down-staging in the multivariate analysis. T down-staging has been shown to be a more significant prognostic factor than regression in many reports so both factors should be analysed separately (9,10). In our series we have confirmed that both factors show prognostic influence in the univariate survival analysis but in the multivariate analysis down-staging showed independent prognostic value for DFS and regression for OS.…”

Pathologic stage following preoperative chemoradiotherapy underestimates the risk of developing distant metastasis in rectal cancer: A comparison to staging without preoperative chemoradiotherapy

“…Because any improvement in overall survival may require better control of DM, those studies evaluating 5‐FU based preoperative CRT failed to find improved overall and/or disease‐free survival. In this perspective, Fokas et al recently reported similar results to our study that ypStage II was found to be at a higher risk of developing DM and poorer disease‐free survival than pStage II. A trend toward a worse outcome in ypStage III versus pStage III did not reach statistical significance in the ad hoc analysis of the CAO/AIO/ARO‐94 phase 3 trial of German Rectal Cancer Study Group ; this was surprisingly similar to our analysis in stage III rectal cancer, although they compared disease‐free survival rather than DM.…”

“…In this perspective, Fokas et al recently reported similar results to our study that ypStage II was found to be at a higher risk of developing DM and poorer disease‐free survival than pStage II. A trend toward a worse outcome in ypStage III versus pStage III did not reach statistical significance in the ad hoc analysis of the CAO/AIO/ARO‐94 phase 3 trial of German Rectal Cancer Study Group ; this was surprisingly similar to our analysis in stage III rectal cancer, although they compared disease‐free survival rather than DM. The authors suggested that “downstaging migration” after preoperative CRT resembles the reverse of the Will Rogers phenomenon and is not a reliable endpoint for long‐term outcomes.…”

Prognostic significance of tumour regression grade after neoadjuvant chemoradiotherapy for a cohort of patients with locally advanced rectal cancer: an 8‐year retrospective single‐institutional study

“…Fokas et al . have suggested that ypTNM downstaging might not be a reliable indicator of therapeutic efficacy and prognosis.…”