The introduction of radiotherapy, chemoradiotherapy, and total mesorectal excision has significantly changed the treatment landscape of locally advanced rectal cancer (LARC) in the last two decades. A number of large randomized controlled trials have established preoperative chemoradiotherapy followed by total mesorectal excision as the standard of care treatment. The addition of oxaliplatin, irinotecan, bevacizumab, or anti-EGFR therapies to 5-fluorouracil or capecitabine and radiation therapy has failed to improve outcomes at an acceptable toxicity. With excellent control of local recurrences (5-10%), the focus has shifted to reducing distant metastases and improving pathological complete response. Despite no proven benefit, adjuvant chemotherapy remains the standard of care in the United States based on extrapolation from colon cancer trials. Defining the best chemotherapy combination has remained a challenge. Trials are ongoing to address the best sequence of the most efficacious combination chemotherapy to be given either before or after preoperative chemoradiotherapy. In this review, we have summarized the literature of LARC and addressed the role and sequence of different chemotherapy combinations with respect to surgery and radiotherapy in the multimodality treatment. Lastly, we discuss important questions that need to be addressed for future clinical trials.
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