The current NCCN guidelines fail to clearly describe that the adjuvant treatment and prognosis of rectal cancer after surgery are based on pre-radiotherapy cTNM stage or ypTNM stage. In this study, we found that ypTNM stage was a more accurate factor to reflect the prognosis of rectal cancer patients who underwent nCRT. In the pCR group, cN stage was the most important independent prognostic factor. In the non-pCR group, however, ypTNM stage was a more important prognostic factor than cTNM stage. Many studies have also reported the importance of the neoadjuvant pathological stage in the prognosis of patients. Sun et al.(Sun et al. 2016b) investigated 317 rectal cancer patients who underwent radical surgical resection following nCRT and observed that ypTNM stage was the only independent risk factor in these patients. Similarly, Kim et al.(Kim et al. 2016) reported that ypTNM stage was an important prognostic factor in the prediction of local recurrence and distant metastasis in rectal cancer patients. Jang et al.(Jang et al. 2012) studied 830 patients with rectal cancer who underwent nCRT and reported that the residual tumor cells in local lymph nodes were risk factors for distant metastasis. Moreover, Kim et al.(Kim et al. 2008) reported that ypN + stage and lateral lymph node size were risk factors for recurrence in the lateral pelvis. Therefore, we concluded that ypTNM stage might better reflect the prognosis of patients than cTNM stage. Furthermore, we speculated that the patients who were sensitive to nCRT might have a better prognosis.
Rectal cancer is often reduced to different degrees after nCRT, although some patients achieve pCR, which brings much controversy to the use of adjuvant chemotherapy. Sun et al.(Zhifei et al. 2017) retrospectively studied 12696 patients in the National Cancer Database and observed that adjuvant chemotherapy among patients with rectal cancer who underwent nCRT conferred a survival benefit. On the contrary, Baird et al.(Baird et al. 2017) found no significant difference in survival or disease recurrence between patients who received adjuvant chemotherapy and patients who did not. We believe that the opposite conclusions might be due to differences in the composition of patients between the two studies. In the following studies, patients were stratified according to stage. Hu et al.(Xiang et al. 2019) reported that patients with ypTis-2N0 rectal cancer did not benefit from adjuvant chemotherapy after nCRT, while Maas et al.(Maas et al. 2015) systematically analyzed 13 databases of neoadjuvant radiotherapy for rectal cancer and concluded that postoperative adjuvant chemotherapy did not benefit patients with pCR. However, some contrary studies showed that adjuvant chemotherapy is effective for early-stage cancer patients who underwent nCRT(Sven et al. 2017; Turner Megan et al. 2019). Although there are different conclusions, most studies believe that adjuvant chemotherapy is still necessary for patients with advanced- stage disease, which is similar to our result. A multicenter randomized controlled clinical study conducted in Asia confirmed that oxaliplatin + 5-FU combination chemotherapy can significantly improve the 3-year disease-free survival of patients with ypTNM stage III rectal cancer compared with 5-FU chemotherapy alone, but it has no effect on the prognosis of patients with ypTNM stage II rectal cancer(Hong et al. 2014). You et al.(You et al. 2014) performed a retrospective study of 160 rectal cancer patients and observed that adjuvant chemotherapy might not improve the survival of ypT0-2N0 patients but might be meaningful for ypT3-4N0 patients in terms of the 5-year OS.
In our analysis, we concluded that adjuvant chemotherapy had no significant effect on the prognosis of patients who had descending stage-to-pCR and ypTNM stage I rectal cancer, regardless of the stage before treatment. Therefore, we believe that adjuvant chemotherapy is unnecessary for patients in pCR, as well as for those with ypTNM stage I rectal cancer. Liao et al.(Liao et al. 2021) also reported that adjuvant chemotherapy is not required for patients with ypT0-2N0 rectal cancer down-staged by nCRT, which was consistent with our findings. In the analysis of adjuvant chemotherapy in patients with ypTNM stage II rectal cancer, we found that the prognosis of patients who received mFolfox6 was significantly better than that of patients who received no chemotherapy. However, the prognosis of patients who received capecitabine was similar to those who received mFolfox6. This finding shows that mFolfox6 adjuvant chemotherapy is the best choice for patients with ypTNM stage II rectal cancer, but capecitabine might also be an option. Moreover, in the analysis of patients with ypTNM stage III rectal cancer, we found that the prognosis of patients who received mFolfox6 was significantly better than that of patients who received capecitabine or no chemotherapy. However, the prognosis of patients who received capecitabine was similar to those who received no chemotherapy. This finding shows that mFolfox6 adjuvant chemotherapy is the best choice for patients with ypTNM stage III rectal cancer, rather than capecitabine and no chemotherapy. This conclusion was similar to that of Hong and colleagues(Hong et al. 2014). In summary, adjuvant chemotherapy might not be necessary in early-stage rectal cancer patients with pCR and ypTNM stage I who achieved good effects in nCRT. For patients with advanced-stage disease, the intensity of the adjuvant chemotherapy might need to be strengthened with the increase of ypTNM stage.
The main strength of our study is that all patients were stratified according to ypTNM stage. Therefore, we could systematically analyze the clinical significance of the adjuvant therapy regimen in different stages, while avoiding the impact of the different stages on survival. However, there are several limitations in the current study. First, the sample size was relatively small, especially when stratified by ypTNM stage, which contributed to the low statistical power of the prognostic comparisons. Second, because of the nature of retrospective studies, selectivity bias was inevitable. Therefore, further studies should be carried out to confirm our results.
In conclusion, our study offers two important conclusions. First, it concluded that ypTNM stage was better than cTNM stage in predicting the prognosis of patients, which is not clearly pointed out in the current NCCN guidelines. Second, due to the importance of ypTNM stage in the prognosis of patients with nCRT, we stratified patients according to this parameter and analyzed the impact of adjuvant chemotherapy on the prognosis of patients. Adjuvant chemotherapy might not be necessary for patients with pCR and ypTNM stage I who achieved good effects in nCRT, and for patients with advanced-stage disease, the intensity of adjuvant chemotherapy might need to be strengthened with the increase of ypTNM stage. This study provides evidence for the implementation of more accurate adjuvant therapy after nCRT. To further the findings of this study, we are currently conducting a large multicenter retrospective study.