Locally advanced rectal cancer: The past, present, and future

From a series of clinical trials in the last several decades, current treatment paradigms for locally advanced rectal cancer include: (1) preoperative long-course radiotherapy (RT) combined with radiosensitizing chemotherapy; (2) preoperative short-course RT alone followed by adjuvant postoperative chemotherapy; and (3) total neoadjuvant therapy with induction chemotherapy followed by chemoradiotherapy. Other strategies under active investigation in both institutional and cooperative trials include neoadjuvant chemotherapy alone without RT in select patients, total neoadjuvant therapy, watchful waiting after a clinical complete response as an alternative to surgical resection, and the use of different chemotherapeutic and targeted agents. The focus of this review is on established and novel therapeutic strategies for locally advanced rectal cancer.