How reliable is pathological complete response (pCR) as an endpoint in rectal cancer clinical trials

The optimal management of locally advanced rectal cancer continues to evolve with the integration of multimodality treatment strategies. While long-course chemoradiotherapy followed by total mesorectal excision has traditionally been the standard approach, newer strategies such as total neoadjuvant therapy and organ-preservation protocols have significantly increased rates of pathological complete response (pCR). However, improvements in pCR have not consistently translated into meaningful gains in overall survival, raising concerns about its validity as a surrogate endpoint in clinical trials. In parallel, non-operative approaches such as the watch-and-wait strategy have gained acceptance in carefully selected complete responders, further challenging the central role of pCR in treatment decision-making. Emerging biomarkers and response assessment tools, including the neoadjuvant rectal score, MRI-based tumor regression grading, and circulating tumor DNA, offer promising alternatives for predicting long-term outcomes and guiding individualized therapy. This review critically examines the limitations of pCR as a trial endpoint and synthesizes current evidence on novel prognostic markers. Based on available data, we propose a conceptual framework integrating radiological and molecular parameters to refine risk stratification and optimize management in locally advanced rectal cancer.