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

Abstract

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.

Prognostic significance of neoadjuvant rectal score in locally advanced rectal cancer after neoadjuvant chemoradiotherapy and construction of a prediction model

“…To date, there is no consensus on the benefit or precise indication of adjuvant chemotherapy following nCRT in rectal cancer . Prognostic prediction models might be helpful in the decision‐making whether to spare adjuvant chemotherapy or to recommend it to an individual patient . For better prediction of oncologic outcomes following nCRT for LARC, for the first time, we developed a nomogram based on NAR scores.…”

“…30,31 Prognostic prediction models might be helpful in the decision-making whether to spare adjuvant chemotherapy or to recommend it to an individual patient. 32 For better prediction of oncologic outcomes following nCRT for LARC, for the first time, we developed a nomogram based on NAR scores. The present nomogram with a C-index of 0.701 could be a useful tool of individualized prognostication in LARC.…”

Comparing outcomes following total neoadjuvant therapy and following neoadjuvant chemoradiation therapy in patients with locally advanced rectal cancer

“…One standard of care for locally advanced rectal cancer involves chemoradiation therapy (CRT) delivered in the neoadjuvant setting with preoperative 5-fluorouracil- or capecitabine-based chemotherapy combined with standard fractionated radiotherapy (RT), total mesorectal excision, and adjuvant chemotherapy, henceforth referred to as nCRT [2,3]. However, a significant proportion of patients treated with curative neoadjuvant CRT and surgery do not received their planned adjuvant chemotherapy, with less than 50% of eligible patients receiving the full course adjuvant chemotherapy, due to patient refusal or post-operative complications [2,[4], [5], [6], [7], [8]]. As a result, there has been an interest in the possibility of delivering chemotherapy before the initiation of neoadjuvant CRT, referred to as total neoadjuvant therapy (TNT).…”

Predicting prognosis according to preoperative chemotherapy response in patients with locally advanced lower rectal cancer

“…Although fluorouracil-based adjuvant chemotherapy significantly improves overall survival (OS) and recurrence-free survival (RFS), nearly 30% of eligible patients do not receive adjuvant chemotherapy because of their postoperative status [1,2]. Moreover, in standard treatment, NACRT and surgery delay the start of systemic therapy for approximately 6 months.…”