Total neoadjuvant therapy for locally advanced rectal cancer

Focus on both local and systemic disease control

James Fleck, MD, PhD and Emily Tonin da Costa, MD: Anticancerweb 27 (03), 2022

Currently, data from the International Agency for Research on Cancer (IARC) point to colorectal cancer as the third most incident malignant tumor (ASR = 19.5), assuming the second position in cancer mortality (ASR = 9.0) in the world. A global estimated number of 1,931,590 colorectal cancer was reported in 2020 and more than one-third were rectal cancer (n = 732,210). Although epidemiological data are often analyzed together, these are two completely different diseases. As most cases of rectal cancer are diagnosed as locally advanced disease, the combined treatment approach with curative intent should focus on both local and systemic control. Downstaging has been observed with preoperative chemoradiotherapy, leading to some complete pathological responses and a high resectability index with total mesorectal excision. The benefit of adjuvant chemotherapy has been most clearly established in stage III colon cancer. Fluoropyrimidine-based adjuvant chemotherapy is historically associated to at least 30% reduction in the risk of disease recurrence. An even greater benefit is obtained with the addition of oxaliplatin. The rationale is not the same for rectal cancer. Local control is best achieved with preoperative chemoradiotherapy, which leads to suboptimal compliance to later adjuvant chemotherapy, potentially increasing the risk of progressive metastatic disease. The double challenge imposed by the local and systemic control of advanced rectal cancer has boosted creativity in the design of a therapeutic strategy called total neoadjuvant therapy. Previous clinical trials have identified that total mesorectal excision could be delayed. The use of a short course of radiotherapy created a window of opportunity to administer the entire chemotherapy program preoperatively. Ideally, this strategy would decrease the risk of metastatic disease progression without increasing the risk of locoregional failure, which ultimately would improve overall survival. The approach demonstrated to be feasible in the small Dutch-M1 trial revealing a high neoadjuvant chemotherapy compliance (84%) and primary tumor downstaging (47%), which was associated to 26% of pathologic complete response.

In January 2021, The Lancet Oncology published the results of the RAPIDO Trial, a prospective, randomized, open-label phase III study comparing two different treatment approaches for advanced rectal cancer. The figure below represents the two treatment arms. In the standard of care arm, a traditional course of radiotherapy combined with twice-daily capecitabine is administered preoperatively. The curative intent surgery is a total mesorectal excision, followed by adjuvant chemotherapy. In the experimental arm a short-course of radiotherapy is sequentially combined to neoadjuvant chemotherapy and the total mesorectal excision is delayed until completion of the entire chemoradiotherapy program. Choice of CAPOX or FOLFOX was per physician discretion or according hospital policy.

The primary outcome was 3-year disease-related treatment failure, defined as a locoregional failure, development of distant metastasis , new primary colorectal cancer, or a treatment-related death, all assessed in the intention-to-treat population. After median follow-up of 4.6 years, the cumulative probability of 3-year disease-related treatment failure was 23.7 % in the experimental group versus 30.4 % in the standard of care group ( HR = 0.75, p = 0.019). The 3-year cumulative probability of distant metastases was 20% in the experimental group versus 26.8% in the standard of care group (HR = 0.69, p = 0.0048). Despite the short course of radiotherapy administered in the experimental group, there was no significant difference in the cumulative probability of locoregional failure at three years in the two treatment approaches used (HR = 1.42, p = 0.12). In fact, the probability of pathologic complete response (pCR) achieved after the proposed chemoradiotherapy in the experimental group (28%) was significantly higher than the percentage of pCR  observed in the standard of care group (14%). The difference in overall survival has not yet been observed. A longer follow-up analysis will be needed to address this outcome. However, 3-year disease-related treatment failure is a strong surrogate endpoint, making total neoadjuvant therapy the current best strategy in the treatment of advanced rectal cancer.



1.     Van Dijk TH, Tamas K, Beukema JC, et al: Evaluation of short course radiotherapy followed by neoadjuvant bevacizumab, capecitabine and oxaliplatin, and subsequent radical surgical treatment in primary stage IV rectal cancer, Ann Oncol 24: 1762 – 1769, 2013

2.     Braendengen M, Tveit KM, Berglund A, et al: Randomized phase III study comparing preoperative radiotherapy with chemoradiotherapy in non resectable rectal cancer, J Clin Oncol 26: 3687 – 3694, 2008

3.     Renu Bahadoer, Esmée Dijkstra, Boudewijn van Etten, et al: Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): a randomised, open-label, phase 3 trial, Lancet Oncol 22: 29 – 42, 2021

4.     Photo by Daryan Shamkhali on Unsplash (modified)