This study was a single-center retrospective study and the clinical data of 980 patients with mid and low LARC diagnosed and treated in the past 7 years were statistically analyzed. To some extent, it reflects the current situation of diagnosis and treatment of LARC patients in our cancer center. We all know that the MRC CR07 study and CAO/ARO/AIO-94 study established the position of neoadjuvant therapy in mid and low LARC treatment [4, 10], and the National Comprehensive Cancer Network (NCCN) and Chinese Society of Clinical Oncology (CSCO) guidelines recommended preoperative radiotherapy-based neoadjuvant therapy combined with TME as the standard treatment strategy for mid and low LARC. The results of this study showed that the implementation rate of preoperative neoadjuvant therapy gradually increased, while the proportion of surgery as the initial treatment showed a downward trend over time. This shows that the treatment of mid and low LARC by oncologists and surgeons in our center is becoming more and more standardized. In addition, more than 80% of patients were treated with standard neoadjuvant therapy based on radiotherapy. This is evident in the gradual increase in awareness and acceptance of neoadjuvant radiotherapy by physicians and patients.
All patients who underwent surgery were included in two dominant treatments: LCRT combined with neoadjuvant chemotherapy followed by TME and SCRT combined with systemic therapy followed by TME. It can be seen that the neoadjuvant therapy model of patients with mid and low LARC in this retrospective study was consistent with the standard treatment model recommended by the current major clinical practice guidelines [3, 11], which fully reflected that the level of diagnosis and treatment of LARC patients in our center was in line with international standards. While the vast majority of patients undergo neoadjuvant LCRT before 2020, the proportion of patients receiving LCRT declined sharply after 2020, conversely, there was a dramatic increase in patients receiving SCRT. This significant change in treatment mode may be influenced by a phase II clinical study of SCRT sequential 2-cycle CapOX plus immunotherapy conducted by our center. The pCR rate was 48% in this prospective study [8]. This kind of neoadjuvant therapy mode based on SCRT shows an amazing curative effect. In addition, short-course radiotherapy has the advantages of a large single fractionation dose, fewer fractionation times, short radiotherapy cycle, short hospitalization time and low cost, which greatly improves the cognition and acceptance of this treatment model.
In our study, we found that the pCR rate was significantly higher in the SCRT group (Group D) than in the LCRT group (Group C) (38.8% vs. 19.4%, P = 0.001). As we all know, the Polish II study was the first study of SCRT sequential chemotherapy versus LCRT [5], nevertheless, the results showed no significant difference in pCR rates between the two groups (16% vs. 12%, P = 0.17), but a lower rate of acute AEs with SCRT sequential chemotherapy compared with LCRT (75% vs. 83%, P = 0.006). Subsequently, in the RAPIDO trial [6], a total of 920 high-risk LARC patients were enrolled in SCRT combination total neoadjuvant therapy (TNT) versus standard LCRT, and preliminary data found that the pCR rate was significantly higher in SCRT sequential chemotherapy group than in LCRT group (27.7% vs. 13.8%, P < 0.001). The STELLAR trial [12], which used a non-TNT model, was equivalent to the RAPIDO Trial in terms of chemotherapy, and the final reports also suggested that SCRT combined with neoadjuvant chemotherapy had a higher pCR rate (16.6% vs. 11.8%) compared with LCRT. It can be seen that compared with LCRT, the PCR rate of the SCRT group (group C) is higher than that of other previous studies. Further analysis revealed that 62.2% of patients in the short course radiotherapy group received immunotherapy (Group D2) and 37.8% did not (Group D1). The pCR rate in Group D2 was also obviously better than that in Group D1 (49.2% vs. 21.6%, P = 0.007). 82.3% (51/61) of the patients receiving immunotherapy were treated with SCRT sequential 2-cycle CapOX plus Camrelizumab treatment, and the pCR was as high as 52.9%. In addition, immunotherapy did not increase the incidence of Grade 3–4 AEs. We speculate that immunotherapy may play a great role in this neoadjuvant therapy. The mechanisms involved in this high pCR rate will need to be further explored in the future. To this end, we look forward to the innovative phase III clinical trial (NCT04928807) of SCRT sequential chemotherapy plus immunotherapy conducted by our center will bring more benefits to patients with mid and low LARC.
Additionally, the dose of radiotherapy was found to be an important factor in the degree of tumor regression, and increasing the dose of concurrent radiotherapy helped improve the pCR rate with tolerable adverse effects [13, 14]. As we all know, the combination of radiotherapy and immune checkpoint inhibitors has synergistic antitumor effects [15, 16]. Preclinical studies suggest that single-dose > 5 Gy irradiation can effectively activate the immune response, combined with immune checkpoint inhibitors is expected to achieve a 1 + 1 > 2 effect [17]. The conventional 5 × 5 Gy mode was used for SCRT in this study. In the future, it may be possible to consider increasing the dose intensity of SCRT to explore the optimal splitting pattern in conjunction with chemotherapy plus immune checkpoint inhibitors.
There were still some limitations in this study. Firstly, this was a single-center retrospective study, and it was difficult to determine the effect of the sequence, regimen, and the number of cycles of neoadjuvant chemotherapy on outcomes for patients receiving neoadjuvant radiotherapy. Secondly, In the present study, the pCR rates of Group C and Group D1 were comparable, which may be limited by the small sample size. Hence, further expansion of the sample size is needed in the future to validate our conclusions. Despite these limitations, this retrospective study reproduces the current situation of diagnosis and treatment in the real world and has important clinical significance.