AbstractBackground and ObjectivesNeoadjuvant chemotherapy (nCT) appears in a few clinical studies as an alternative to neoadjuvant chemoradiation (nCRT) in selected patients with locally advanced rectal cancer (LARC). We aimed to compare the clinical outcomes of nCT with or without nCRT in patients with LARC and to identify patients who may be suitable for nCT alone.Materials and MethodsA total of 155 patients with LARC who received neoadjuvant treatment (NT) were retrospectively analysed from January 2016 to June 2021. The patients were divided into two groups: nCRT (n= 101) and nCT (n= 54). More patients with locally advanced disease (cT4, cN+ and magnetic resonance imaging‐detected mesorectal fascia [mrMRF] positive [+]) were found in the nCRT group. Patients in the nCRT group received a dose of 50 Gy/25 Fx irradiation with concurrent capecitabine, and the median number of nCT cycles was two. In the nCT group, the median number of cycles was four.ResultsThe median follow‐up duration was 30 months. The pathologic complete response (pCR) rate in the nCRT group was significantly higher than that in the nCT group (17.5% vs. 5.6%,p= 0.047). A significant difference was observed in the locoregional recurrence rate (LRR); 6.9% in the nCRT group and 16.7% in the nCT group (p= 0.011). Among patients with initial mrMRF (+) status, the LRR in the nCRT group was significantly lower than that in the nCT group (6.1% vs. 20%,p= 0.007), but not in patients with initial mrMRF negative (−) (10.5% in each group,p= 0.647). Compared with the nCT group, a lower LRR was observed in patients in the nCRT group with initial mrMRF (+) converted to mrMRF (−) after NT (5.3% vs. 23%,p= 0.009). No significant difference was observed between the two groups regarding acute toxicity and overall and progression‐free survivals. Multivariate analysis showed that nCRT and ypN stage were independent prognostic factors for the development of LRR.ConclusionPatients with initial mrMRF (−) may be suitable for nCT alone. However, patients with initial mrMRF (+) converted to mrMRF (−) after nCT are still at high risk of LRR, and radiotherapy is recommended. Prospective studies are required to confirm these findings.