To our knowledge, the present study is the first to focus on the events of definitive interruption of RT delivery in the neoadjuvant treatment of LARC. We found that one in every ten patients treated with long course chemoradiotherapy presented DTI and that these events were strongly associated with G3 + toxicity. Although these unexpected interruptions did not impact oncologic outcomes (including pathological response, need of definitive ostomy and local control), they indicate that improvements in treatment tolerability are necessary.
Grade 3 diarrhea can be defined as 7 or more stools per day over baseline limiting self-care activities of daily living . In our cohort, these events occurred in less than 10% of the total cases, however it preceded almost 50% of the DTI events. The secondary dehydration and reduction in performance status due to this side effect plays an important role in the decision to suspend treatment. Intriguingly, female patients experienced higher rates of grade 3 + toxicity. Similar association with sex was previously described by a group from the University of Calgary  which hypothesized that the anatomical changes of hysterectomized patients (4 of 11 women in their series) were responsible for such increase in toxicity by exposing more small bowel in the treatment field. In our study, however, no association between absence of uterus at the time of RT and toxicity (p = 0.541) was noted. In addition to that, tumors close to the AV were associated with more toxicity indicating that a better understanding of the dose constraints for organs at risk in the lower pelvis [13, 14] and of the gastro-intestinal physiology [15–16] have the potential to improve tolerability.
Despite having a reduction in the RT dose delivered, cases with DTI did not have worse oncologic outcomes, including pCR and local control. This observation indicates that doses higher than 45 Gy may not be necessary for LCRT. In that respect, researchers from the Toronto (Canada) previously compared the results of three phase II studies that used 40 Gy, 46 Gy and 50 Gy in the neoadjuvant setting . They found a higher pCR rate with increasing the dose (15% vs. 23% vs. 33%, respectively, p = 0.07), but no improvement in 2y-local recurrence-free survival above 46 Gy (72% vs. 90% vs. 89%, p = 0.02). Of note, the high-rate of local recurrences reported may indicate that TME was not performed for all cases and possibly more utilized in the later protocols with high doses, disfavoring the lower dose arm. More recently, some attempts to further escalate the neoadjuvant RT dose with TME were performed. One phase III study from Denmark and Canada  compared two radiation doses (EQD2 49.6 Gy10 vs. 62.1 Gy10) showing same pCR in both arms (18% vs. 18%). Similarly, the RECTAL-BOOST trial conducted in the Netherlands  failed to improve pathological complete response (for operable cases) or 2-year sustained clinical response (for watch-and-wait cases) with an escalated boost delivering an EQD2 of 66.3 Gy10 (compared to EQD2 50 Gy10).
A comparison between the prescription doses of SCRT and LCRT gives another relevant perspective. Applying the normalization by the equivalent dose in 2Gy fractions (EQD2) and assuming α/β = 10, the LCRT regimen of 45 Gy in 5 weeks (25 x 1.8Gy, EQD2 44.2Gy10) delivers 40% more dose when compared with SCRT (5 x 5 Gy, EQD2 31.2 Gy10). This increase raises to 60% when using the fractionation of 50 Gy in five weeks (25 x 2Gy, EQD2 50 Gy10) or adding a 5.4 Gy boost (28 x 1.8 Gy, EQD2 49.6 Gy10). Despite higher doses in LCRT, the local control of both LCRT and SCRT strategies are similar .
Cases with close or positive resection margins after TME had significant worse loco-regional control when compared with patients with negative margins (5-year: 76.2% vs. 100%, p < 0.001). Based on that and the fact the pre-operative boost did not improve local control, it could be hypothesized that omitting the pre-operative boost in order to leave room for additional radiation dose intra-  or post-operatively  could potentially benefit the subgroup of patients that failed to achieve clear margins [23–25] or at the time of a local recurrence . The post-operative indication of boost has an enticing prospect, especially if no further therapy is planned after resection, which is the case in the total neoadjuvant therapy strategy [27–29]. For patients with tumors involving the anatomical anal canal (at or below dentate line) , the risk/benefit ratio is even more unfavorable regarding the pre-operative boost. These patients have a higher risk of grade 3 + toxicity and no benefit of sphincter preservation since they require abdominal perineal resection and colostomy, independently of the theoretical additional downstaging effect of the boost. Importantly, tailoring the indication of boost based on pathological findings could spare unnecessary boost for patients with clear margins (88% in our cohort), automatically reducing the incidence of DTI by about half (55% of cases had interruption during the boost phase).
Limitations of the present study include its retrospective design and relatively modest sample size, which precluded a more robust multivariate analysis of the secondary survival outcomes. In addition, no data on chemotherapy tolerability (dose reduction events and total number of cycles delivered) and patient reported outcomes were available, which could provide more comprehensive insights regarding treatment tolerability. Importantly, the findings of the present study do not apply to the scenario of organ preservation where radiation is potentially the only local treatment.
In summary, we found that one in every ten patients with LARC treated with LCRT presented a DTI event, which was strongly related to grade 3 + toxicity. These treatment interruptions affected the delivery of the boost before surgery, without affecting pCR, definitive ostomy rates, and local control. In addition, patients with positive margins after surgery had worse local control and survival, raising the question of whether the boost should be reserved for those that failed to achieve negative margins and delivered after surgery.