Improved staging, introduction of multidisciplinary decision-making, refined surgery and appropriate use of preoperative radiotherapy, together with quality assessment by pathology and registries have all contributed to substantially lowering rates of local recurrence in rectal cancer from historical figures of above 30% to below 10% in many cohorts. Although there are certain subgroups who still suffer a high risk of not having R0 surgery or a local failure, the problem of local control can be seen as solved for a majority of rectal cancer patients. However, the improvements regarding local control achieved over the past decades are not matched by same-size improvements with respect to survival. Without compromising local therapy, it may therefore be justified to shift focus from local control to systemic control and survival when designing trials aiming at further development of rectal cancer treatment.
The primary aim of adjuvant systemic chemotherapy is to treat occult disease dissemination that may later occur as distant metastases. Current standard for locally advanced rectal cancer includes preoperative chemoradiation but, because of the risk of toxicity, dosage of chemotherapeutic agents must be reduced which may negatively affect the systemic efficacy. In many centres additional chemotherapy is administered postoperatively. However, since rectal cancer surgery is afflicted with high rates of postoperative complications, a substantial number of eligible patients are not fit to receive chemotherapy postoperatively [21, 22, 44]. In addition, when preoperative chemoradiation is administered (5 weeks) followed by surgery after 6–8 weeks and patients having to recover after surgery for 5–6 weeks, postoperative chemotherapy for suspected occult metastases cannot be delivered until after 4–5 months. On the other hand, neo-adjuvant chemotherapy yields favourable outcomes in oesophageal and gastric cancer [26, 27], in colorectal hepatic metastases  and is currently investigated in primary colon cancer . In contrast to these trials, in which chemotherapy is delivered pre- and postoperatively, all chemotherapy is given preoperatively in the experimental arm of the RAPIDO-trial. This was also the regimen in the Dutch “M1”-trial . In this trial 50 patients with metastatic rectal cancer received short-course radiation followed by 6 cycles of full-dose capecitabine/oxaliplatin and bevacizumab preoperatively. The completion rate for all 6 cycles of chemotherapy was 85% and more than 90% received 4 cycles or more, and toxicity reported was mostly mild. Thus, the assumption that preoperatively administered chemotherapy is more likely to be accepted in full-dose than concomitant or postoperative appears to be valid.
Two randomized trials have compared short-course preoperative radiotherapy to preoperative chemoradiation in patients with resectable rectal cancer [45, 46]. No evidence that chemoradiation was superior concerning local control or survival was provided in these studies. Furthermore, there were no indications of differences in late toxicity between the two regimens and short-course radiation resulted in less acute toxicity . In these studies, in which patients underwent surgery the immediate week following short-course radiotherapy down-staging occurred to a much greater extent in patients who had received chemoradiation with delayed surgery. However, in an interim analysis of the on-going Stockholm III trial, also in resectable (intermediate stage) rectal cancer, the rate of pCR after short-course radiotherapy with delayed surgery was 12.5% . Additionally, there are also other randomized data  and observational data [36–38] indicating a down-staging effect of short-course radiotherapy, given that surgery is after a delay. Among patients who underwent resection of the primary tumour in the “M1”-trial (approximately 75% with T3/T4N+ tumours), 91% had a R0 resection and pCR was found in 27% . None of the included patients was considered inoperable because of primary tumour progression and only one patient suffered local symptoms which occurred due to massive tumour response with tumour necrosis and an abscess. The observational data from Stockholm also indicate that the risk of tumour progression during the “waiting time” is low even if chemotherapy is not administered in this period [38, 47]. With this background, a rationale to test short-course radiation also for the locally advanced tumours appears to exist.
The RAPIDO-trial is designed with the aim of improving survival without compromising local control in patients with locally advanced rectal cancer. The aforementioned support in the literature for down-staging following short-course radiation with delayed surgery and the rationale for neo-adjuvant chemotherapy opens a window to test the combination of these two concepts, and to compare results with current standard being preoperative chemoradiotherapy with or without adjuvant chemotherapy. Although it is reasonable to assume that neo-adjuvant chemotherapy not only has systemic effects but also acts on the primary tumour it would be difficult to gain acceptance for a trial in which surgery is postponed after a prolonged chemotherapy period. Even if chemotherapy with the addition of biologics has improved substantially during the past decade , the medical therapy has limited cell kill effect and is the weakest component in the treatment armamentarium. The initial 5 Gy x 5 will prevent local progression during the prolonged chemotherapy aimed at killing all potential subclincal cancer cells, without postponing the start of the systemic therapy more than marginally. Most adjuvant schedules in colorectal cancer consist of 8 cycles (24 weeks) of chemotherapy but in the “M1”-trial only 6 cycles were given preoperatively , an approach that reduces the “waiting time” between short-course radiation and surgery. Bevacizumab was included in that trial but there is no evidence supporting an effect of either bevacizumab or cetuximab against sub-clinical disease [49, 50] which renders it superfluous in the RAPIDO setting.
In the RAPIDO-trial, the logistically simple approach with initial local therapy with short-course radiotherapy followed by systemic adjuvant full-dose up-front chemotherapy in 6 cycles, before local treatment is finalized with surgery according to TME-principles, is being explored. If this concept in the RAPIDO trial yields improved survival with maintained results regarding local control, the established management of locally advanced rectal cancer with preoperative chemoradiation is challenged.