DISCUSSION
tumor, Toxicity
TUMOR, STD, SECONDARY, RECURRENT DISEASE
The results from the RAPIDO trial demonstrated that the EXP treatment is associated with a decreased incidence of DM and an increased rate of pathological complete response (pCR), and comparable LRF rates to the STD treatment at 3 years of follow-up.eLRF are rarely seen but occur at similar rates in the EXP and the STD groups of the RAPIDO trial. Most patients with eLRF, both among EXP and STD, also developed DM before or in conjunction with the eLRF. Patients with eLRF seem to represent a subset of patients who have an extremely poor prognosis irrespective of the treatment approach. We demonstrated that the vast majority of eLRF patients had cN2 and mesorectal fascia involvement. Hopefully, future research may result in the identification of these patients pretherapeutically (eg, via biomarkers) and offer more personalized approaches. The rareness of eLRF constitutes an obstacle to meaningful statistical analyses of risk factors.Of the patients in the RAPIDO trial, the overall LRR rate is 7.8% which is comparable to literature considering the locally advanced stages included.The radiation technique was the only statistically significant different baseline/initial treatment characteristic when comparing the 2 groups of LRF patients. Patients from the EXP group received more often 3D-CRT, whereas the STD group received IMRT/VMAT to a higher degree. During the time of RAPIDO inclusion (2011-2016), IMRT/VMAT, a relatively new radiation technique at the time, had become standard-of-care more commonly in patients treated with long-course CRT compared with scRT, although this difference did not reach statistical significance. There is no obvious explanation why patients treated with 3D-CRT more often had an LRR in the EXP group (12%) than in the STD group (6%), whereas no such difference was seen in patients treated with IMRT/VMAT (6% vs. 5%, respectively). Irradiated volumes concerning tumor coverage should not differ between the techniques and are therefore unlikely to be associated with an LRR. In addition, the excess risk of LRR in the EXP group was predominantly seen in the anastomotic region usually located centrally in the target volume. Whereas IMRT/VMAT always requires individual target volume delineation, this may not always be performed for 3D-CRT. Therefore, geographical misses may have occurred more often in the EXP than in the STD group, but more in-depth analyses are required to confirm this. Toxicity, on the other hand, may differ between the 2 RT techniques but this was not examined in this report.An important difference between the EXP and STD groups concerns overall treatment time before surgery, which is ~40 weeks in the EXP group versus ~25 weeks in the STD group. Judging from MRI, a larger proportion of good responders were observed in the EXP group at restaging [80.1% vs. 70.1% (ELLN, a known predictive factor for locally recurrent disease,We classified the localization of LRR according to Kusters et al.Although based on a large randomized trial, this report has several limitations. First, the RAPIDO trial was not powered for the secondary endpoint reported here. Second, a central review of MRIs, RT target volumes, dose volume histograms, delivered RT, and histopathology specimens have not yet been performed, and information was mostly retrieved by CRFs. However, MRIs and histopathological specimens are currently being revised. Third, restaging MRI was performed in most patients, but not in all. In addition, there may be unrecorded tumor characteristics, and perioperative or intraoperative variables not accounted for.The outcomes previously reported from the RAPIDO trial showed important gains from a TNT approach including a significant decrease in DrTF at 3 years and a doubled rate of pCR.