Despite extensive clinical research that includes several randomized trials, selection of optimal perioperative treatment for rectal cancer remains a subject of controversies. Recent evidence suggest, however, that short-course preoperative radiotherapy (SCRT- 25 Gy in 5 fractions) combined sequentially with preoperative chemotherapy may offer clinical advantages, compared to other schedules offered in locally advanced disease. The rationale for use of SCRT, as compared to long-course preoperative radio-chemotherapy (LCRT-CT) were established based on results of Polish (Bujko 2006) and Australian (Ngan 2012) phase III trials. They both showed no difference in long-term outcome between SCRT and LCRT-CT. Furthermore, Stockholm III trial (Pettersson 2015) showed therapeutic advantage (improved tumour downstaging, and lower postoperative complications rate) providing surgery was delayed for 4-8 weeks after SCRT, compared to surgery within 1 week after radiotherapy. On the other hand, meta-analyses of randomized trials evaluating the role of adjuvant postoperative chemotherapy for patients with rectal cancer after preoperative radiotherapy/radio-chemotherapy (Breugom 2015, Bujko 2015) indicated that such therapy did not significantly improve overall survival. Based on these results it was hypothesised that SCRT followed by preoperative chemotherapy and surgery may offer the best outcomes in high-risk rectal cancer. Such hypothesis was tested in a randomized trial performed by Polish Colorectal Study Group (Bujko 2016, Cisel 2019) that compared 25 Gy in 5 fractions and three cycles of FOLFOX4, to LCRT (50.5 Gy in 28 fractions) combined with 5-Fu/oxaliplatin-based chemotherapy. Eligibility included cT4 or fixed cT3 cases, R0 resection rate was selected as the main end point. The protocol was amended to postpone use of oxaliplatin. Acute toxicity of SCRT group was lower than in control arm. The long-term outcome of this trial did not, however, demonstrate the superiority of SCRT plus chemotherapy over LCRT-CT. STELLAR (Jin 2021) is a trial of similar design, SCRT was, however, followed by four courses of CAPOX. The outcome presented at ASCO 2021 suggest improvement in overall survival and tumour response rates in SCRT, but long-term outcome is not available. As opposed to Polish and STELLAR trials, RAPIDO trial (Bahadoer 2021) took advantage of exploring more intense neoadjuvant chemotherapy schedule (6 cycles of CAPOX, or 9 of FOLFOX4) that followed SCRT (25 Gy in 5 fractions). Intensification of systemic therapy is important, considering that distant metastases are the most common site cause of treatment failure. LCRT (50-50.4 Gy in 25-28 fractions) was used in control arm. Only high-risk patient were included. The compliance to chemotherapy was better in experimental arm. Also, pathological complete tumour response was more frequent in experimental group (28% vs 14%, OR=2.37) offering, thus, the potential opportunity for organ preservation. This issue is further explored in OPRA trial (Garcia-Aguilar 2020) with encouraging initial results. Disease-free survival in STELLAR was significantly improved in the experimental group (23.7% vs 30.4%, HR=0.75), mostly due to significant reduction in distant metastases rate. There was, however, no significant improvement in overall survival. Similar outcomes were presented in non-randomized studies, including matched-pair analysis of SCRT and FOLFOX chemotherapy, compared to LCRT-CT (Markovina 2017). The meta-analyses of total neoadjuvant therapy (TNT) versus standard neoadjuvant chemoradiotherapy for locally advanced rectal cancer (Liu 2021, Kasi 2020), that included randomized and non-randomized studies, consistently showed improved tumour response rate, disease-free survival, and tendency for improved overall survival in TNT.
An alternative approach to TNT with SCRT may be TNT with intense preoperative chemotherapy followed by LCRT-CT and surgery. Such treatment schedule was explored in PRODIGE 23 trial (Conroy 2021). TNT improved disease-free survival (76% vs 69%, HR=0.69) and complete response rate. An attempt to compare the studies of TNT with SCRT and LCRT-CT was provided in Liu meta-analysis. While such attempt has several limitations the only difference found was higher tumour response rate in SCRT vs LCRT-CT trials. In conclusion, short-course radiotherapy combined with 6 cycles of CAPOX, or 9 of FOLFOX4 may be considered, at present, the best option for perioperative treatment of high-risk rectal cancer. Use of clinical and molecular predictive markers may help, in the future, to optimize such treatment and help to identify subgroups of patients who may benefit from TNT with SCRT with respect to overall survival, as well as those who may need a different treatment schedule.