The strategies for treating LARC usually involve a multidisciplinary approach. Radiation therapy might be one of the fundamental modalities in this. However, its role has been challenged in certain circumstances. Conventional LC-CCRT has led to low rates of local recurrence, but the incidence of distant metastases has not decreased as expected [3, 5–7]. Some have attempted to find ways to achieve better results in the treatment of LARC [16–21], especially paying attention to preoperative consolidation or induction chemotherapy with chemoradiation to treat micrometastases early and with increased treatment compliance. Nonetheless, when applied with LC-CCRT, this approach raises a few concerns regarding the exceptionally long period of neoadjuvant treatment with a doubtful response in some patients. Therefore, when considering preoperative chemoradiation and chemotherapy, SCRT seems to be a good alternative because it can be completed within 1 week if equivalent oncologic outcomes are guaranteed compared with conventional LC-CCRT, as already reported by some groups [6, 7]. The waiting time from radiation to surgery could be a valuable period for consolidation chemotherapy to treat distant metastases. Accordingly, we conducted preoperative SCRT followed by three cycles of FOLFOX6 for patients with LARC, and our initial experience shows that it was safe and feasible.
Our indications for using SCRT followed by consolidation chemotherapy are different from those in other studies. The Polish II trial’s eligibility criteria were cT4 or fixed cT3 lesion . The CAO/ARO/AIO-12 trial included patients with cT3 or T4 rectal cancer . During the study period in our study, the indications to adopt SCRT followed by consolidation chemotherapy focused on tumor characteristics suspicious of a high risk of systemic recurrence in preoperative evaluations, such as lymph node positivity or high CEA levels or adverse mrEMVI findings. Elevated CEA was associated with poor prognosis in colorectal cancer patients [22, 23]. Brown et al. reported that mrEMVI was a poor prognostic factor related to distant metastasis in patients with rectal cancer [10, 24]. One of the crucial roles for SCRT and consolidation chemotherapy is efficient control of distant metastases in patients with LARC. Although this study was an initial one with a relatively short follow-up period (median 20.4 months), there has been no recurrence. Long-term follow-ups of our results are needed to clarify the clinical benefit of our strategy.
Our study did not include a totally neoadjuvant treatment scheme. Instead, we adhered to the treatment strategies for locally advanced rectal cancer, which comprise neoadjuvant treatment followed by curative surgery and adjuvant chemotherapy. In the CAO/ARO/AIO-12 trial, adjuvant chemotherapy was not recommended . The experimental arm in the RAPIDO trial comprised full-dose chemotherapy before surgery, after SCRT, and without the adjuvant setting . These trials reported a high rate of pathological complete response (17%–28%) and high compliance with systemic therapy in the group that received totally neoadjuvant treatment [16, 18]. Meanwhile, we chose three cycles of consolidation FOLFOX before surgery to make this similar to the conventional LC-CCRT. To provide personalized treatment, we planned the adjuvant chemotherapy after a MDT meeting that carefully reviewed the intraoperative findings and pathology reports for each patient. We attempt to reduce the need for unnecessary treatment, such as that given to patients who respond poorly to neoadjuvant treatment, and to avoid overadministration of chemotherapy in patients with low-risk disease.
We found a pCR rate of 2/19 (11%), slightly lower than in other trials with pCR rates of ~15% [6, 7, 25]. The reasons for this are unclear because this study was a small case series. However, there are two possible reasons. First, the interval from radiation to surgery might have been insufficient in our cohort, with a median time from initiating radiation to surgery of 10.6 weeks (range 8.6–16.4). In a Polish II trial, the median interval between the initiation of irradiation and surgery in the SCRT group was 12.4 weeks, and the pCR rate was 17% . Second, in this study, we applied three cycles of FOLFOX6 before surgery. In a phase II nonrandomized trial, increasing cycles of FOLFOX6 after chemoradiation and before surgery were associated with a higher rate of pCR with better compliance to chemotherapy and without significant increase in postoperative complications . In the RAPIDO trial, SCRT followed by 18 weeks of chemotherapy and TME achieved a pCR rate of 27.7% . Therefore, here we prepared a prospective randomized trial comparing SCRT with LC-CCRT, considering the SCRT group to comprise four or more cycles of FOLFOX6 and increased the interval from radiation to surgery.
When adopting hypofractionated SCRT followed by consolidation chemotherapy before surgery for patients with LARC, treatment-related toxicities and postoperative complications are of concern compared with fully fractionated LC-CCRT. In terms of radiation- and chemotherapy-related toxicities, our results were similar to those of other studies. The incidence of grade 3 toxicity was 26% in our study. A German trial with LC-CCRT reported a 27% rate of grade 3–4 toxicities . Another study reported that 27.1% of patients experienced grade 3–4 toxicities in the LC-CCRT treatment group . In a recent two randomized trial, the rates of grade 3 or worse adverse events were 23–48 % in a SCRT group and 21–25 % in an LC-CCRT group [7, 18]. The postoperative complication rate was also tolerable at 27%. Grade 3 complication was observed in one patient (5.3%). Other prospective studies with LC-CCRT reported postoperative morbidity rates of 25.0% to 36.0% [5, 25, 28]. In a Polish II trial, the respective postoperative complication and grade 3–4 complication rates were 19% and 8% in a SCRT group, and 21% and 6% in an LC-CCRT group .
MRI assessment of tumor downstaging might provide information on treatment response [11, 29, 30]. In our cohort, a good response (mrTRG 1–3) was seen in 13 of 16 patients (81%). A retrospective study reported that 72.8% of patients showed good responses (mrTRG 1–3) after SCRT alone . Here we conducted consolidation chemotherapy between radiation and surgery that might have influenced our results. However, the prognostic significance of the mrTRG system is controversial, and a prospective trial is ongoing to evaluate it [17, 31]. Further studies are warranted to evaluate the efficacy of mrTRG in the context of SCRT and in real clinical practice.
There were some limitations to our study. First, it was a retrospective study in a single center. Second, we analyzed a small number of patients with a relatively short follow-up period, so late toxicities and long-term oncologic outcomes could not be evaluated. Moreover, discrepancies in the administered consolidation chemotherapy might have influenced our results. We have focused on the short-term outcomes of our strategy in this report. Based on these results, we expect that our proposed prospective multicenter randomized trial will clarify the safety and efficacy of SCRT followed by consolidation chemotherapy before surgery compared with LC-CCRT for patients with LARC.
In conclusion, our initial experience of a short course of radiotherapy followed by oxaliplatin-based consolidation chemotherapy for patients with LARC has shown acceptable toxicity profiles and feasibility. Further large-scale and long-term results of our scheme will help test these conclusions.