Total Neoadjuvant Therapy: A Shifting Paradigm in Locally Advanced Rectal Cancer Management

Colorectal carcinoma is the second leading cause of cancer-related deaths in the United States, with rectal cancer accounting for approximately one-third of newly diagnosed cases, thus representing a major socioeconomic health burden. Although minimally invasive procedures (ie, transanal excision) may be appropriate for a subset of patients with small, superficially invasive tumors, a more comprehensive trimodality approach with neoadjuvant chemoradiotherapy, total mesorectal excision, and systemic chemotherapy is recommended for medically operable patients with nonmetastatic, locally advanced rectal cancer (LARC). Although such multimodality therapy has markedly reduced local recurrence rates, there remains an estimated 5-year distant relapse rate of 35%, representing the leading cause of death in this population. This review critically assesses the literature regarding neoadjuvant therapy for LARC, as well as the available evidence to support selective exclusion of individual modalities from the contemporary therapeutic paradigm, including controversies of nonoperative management, selective radiation sparing, and neoadjuvant systemic therapy. Through the review of existing data and the anticipated results of ongoing clinical trials, we outline the pragmatic opportunities for future investigation into questions of efficacy, safety, and ultimate improvements to the current status quo.