Neoadjuvant Treatment for Locally Advanced Rectal Cancer: New Concepts in Clinical Trial Design

Treatment for locally advanced rectal cancer has evolved from surgery alone to surgery plus adjuvant therapy. Preoperative 5-fluorouracil- or capecitabine-based chemoradiation with standard fractionated radiation, surgery utilizing total mesorectal excision, and further chemotherapy has become the standard of care in the USA. Preoperative adjuvant chemoradiation treatment sequencing has allowed for decreased toxicity, more sphincter-sparing surgery, and improved local control rates as compared to delivering the chemoradiation postoperatively. Yet, given the heterogeneity of locally advanced disease, some patients may be over-treated with this approach, leading to unnecessary toxicity and costs, while others may have a propensity to develop distant metastases and may benefit from intensified therapy. Therefore, the trend in modern clinical trial design has been to individualize therapy. As such, current studies are examining shortening the duration of radiation, omitting preoperative chemoradiation in patients who have a robust response to induction chemotherapy alone, omitting or delaying surgery in patients who have a clinical complete response to preoperative chemoradiation, and completing all of the adjuvant treatment prior to surgery.