We found that tumor volume reduction after NAC was associated with a better prognosis in patients with LALRC, even in patients with features that suggest a very high risk of recurrence. Patients with good responses to NAC had better outcomes (5-year RFS, 81.1%; 5-year OS, 94.9%) than patients with poor responses to NAC (5-year RFS, 49.0%; 5-year OS, 80.6%). The best responders had better survival outcomes than the poorest responders. Particularly, all 7 patients with TVRR > 90% experienced cancer-free survival with only 1 patient of resectable lung recurrence. However, of the 7 patients with TVRR < 0%, 6 patients developed unresectable recurrences. Extreme response to NAC could be a useful factor for predicting prognosis and selecting individualized treatment strategies. Additionally, we found that preoperative EMVI was associated with a worse prognosis. In poor responders with ymrEMVI, the 5-year RFS and OS were 21.4 and 50.0%, respectively. However, in good responders without ymrEMVI, the 5-year RFS and OS were 89.0 and 93.8%, respectively. TVRR and EMVI were associated with significantly poorer survival outcomes including local and distant recurrence, even when TME and LPLND were performed after NAC.
Survival outcomes can be predicted from tumor volume reductions after preoperative CRT [13, 16, 17]. MRI-based assessments of response to CRT are associated with survival outcomes, including RFS and OS. Response to preoperative chemotherapy is reportedly associated with tumor regression grade and downstaging; however, associations with prognosis have not been reported . Our study revealed that the TVRR was associated with RFS and OS, and that response to preoperative chemotherapy was predictive of survival, consistent with the findings of prior studies on CRT. Poor response to NAC was associated with worse survival outcomes. There are several potential reasons for this finding, including the biological malignancy of the tumor, sensitivity to the administered drugs, and host immunity. Very good responders may not need NACRT to achieve local disease control. Several randomized controlled trials are currently investigating this topic. Conversely, it may be difficult for very poor responders to obtain good prognosis even when they receive multidisciplinary treatments, such as total neoadjuvant therapy.
EMVI, including mrEMVI and ymrEMVI, was a significant preoperative prognostic factor in this study. EMVI is defined as the presence of tumor cells within blood vessels beyond the extramural area near the primary tumor. The incidence of EMVI in LALRC is approximately 9–61% . Histological EMVI is a poor prognostic factor [20, 21], and mrEMVI is an independent risk factor for poor survival outcomes [5, 22, 23]. Therefore, the European Society for Medical Oncology guidelines suggest that mrEMVI indicates high risk; CRT followed by TME is recommended in such cases . Moreover, several studies have shown that the presence of ymrEMVI, which was evaluated after the neoadjuvant treatment, and not only mrEMVI, had prognostic impact [23, 25,26,27]. Our study revealed that mrEMVI remained after NAC except for 2 patients. EMVI hardly disappears after NAC and may not lead to an improvement in prognosis, even if NAC is performed. EMVI was associated with poor survival outcomes, even in good responders. Indeed, the survival outcomes of good responders with EMVI were similar to those of poor responders. Our results suggest that EMVI is a strong prognostic factor for LALRC. Therefore, the presence of EMVI might require separate treatment strategies.
The local recurrence rate for the whole cohort was high (19%). We selected NAC followed by surgery for patients with high-risk features for distant metastasis, which was regarded as the key factor for survival. In the end, our strategy caused a high rate of local recurrence that might have had a negative effect on patient survival. Further, the results show that NACRT is essential for local control even in patients at high risk of distant recurrence, if the aim is to cure the disease. Good response to NAC without EMVI was strongly associated with good prognosis. Patients who showed very good responses to NAC did not necessarily require NACRT. However, lymph node metastasis, EMVI, and very low location of the tumor were high-risk features for both local and distant recurrences; therefore, not only NAC but also NACRT should be considered for disease control. In our facilities, there has been a tendency to omit radiation therapy and to choose anal-sparing surgery. As the number of patients who undergo NACRT increases, there will be reductions in the rate of anal-sparing surgery, which is strongly affected by CRT in terms of anal function. Although ISR cannot be expected to increase the CRM-positive rate for the surrounding organs and neural tissues, except for the levator ani muscles, the rate of anal-sparing surgery might also affect the rate of local recurrence.
The present study had several limitations. First, it used a retrospective, single-institution study design, and had a small sample size. Several prospective trials of preoperative chemotherapy for LALRC are ongoing, and their results are expected to lead to tailored treatments. Second, the patients received different NAC regimens, such as FOLFOX and CAPOX. However, these regimens were considered to have almost the same therapeutic outcome . Therefore, the differences between these regimens would not have had a substantial effect on the prognosis in each group. Third, the methods of evaluating tumor volume reduction, mrEMVI, and ymrEMVI might not be universally applicable. Moreover, in this study, the size of primary lesions and existence of EMVI were evaluated by two independent experienced colorectal surgeons. Unlike Western radiologists, many Japanese radiologists are unfamiliar with rectal MRI, including EMVI. Therefore, although independent radiologists should have reviewed these factors, two independent experienced colorectal surgeons reviewed the factors, and incongruent results were reviewed and finalized by consensus. However, despite these limitations, our results suggest that these factors after NAC were important prognostic factors for patients with LALRC and might be used to identify patients who will have a good or poor prognosis.