Current and Future Strategies versus Tradeoffs in Maximizing the Treatment Response in Rectal Cancer: A Focus on MSI-H Disease

Abstract Rectal cancer management is rapidly evolving with advances in molecular characterization, systemic therapy, radiotherapy, and immunotherapy. In mismatch repair–deficient (dMMR) or microsatellite instability–high (MSI-H) rectal cancer, PD-1 blockade has produced unprecedented rates of complete clinical response, enabling organ-preserving strategies without chemoradiation or surgery. Circulating tumor DNA (ctDNA) offers additional opportunities to refine surveillance and guide treatment de-escalation. Tradeoffs between oncologic safety, organ preservation, toxicity, and quality of life remain central to treatment decisions. This article reviews current and future strategies, emphasizing the balance between maximizing tumor response and minimizing treatment burden, with distinct considerations for MSI-H rectal cancer.