Optimal Neoadjuvant Strategies for Locally Advanced Rectal Cancer by Risk Assessment and Tumor Location

Neoadjuvant therapy is standard of care for locally advanced rectal cancer (LARC). Advancements in multimodality therapy options and sequencing of radiation therapy (RT), surgery, and chemotherapy make decision-making challenging. Traditional treatment of patients with LARC involves neoadjuvant chemoradiation followed by total mesorectal excision and consideration of adjuvant chemotherapy. Advancement in RT has led to trials offering both short-course and long-course RT with good long-term clinical outcomes. Intensification of therapy in high-risk patients has led to studies of total neoadjuvant therapy with chemotherapy and chemoradiation, now standard management for most LARC. De-escalation of therapy in patients with favorable prognosis has led to several considerations, including non–total mesorectal excision management or neoadjuvant chemotherapy only. Several considerations of patient and disease factors can help inform the optimal chemotherapy regimens in different sequencing of neoadjuvant strategies. Finally, novel biomarkers, such as microsatellite instability, has led to utilization of novel therapies, including neoadjuvant immunotherapy, with substantial response. This review attempts to frame the rapidly growing data in LARC in context of disease and patient risk factors, to inform optimal, personalized treatment of patients with LARC.