The pCR rate in our study was 19.8%, which is comparable to local and international clinical trial data. In the German CAO/ARO/AIO-04 trial10, a pCR rate was 17% in the fluorouracil and oxaliplatin arm and 13% in the fluorouracil arm after surgery. The CAO/ARO/AIO-12 trial14 reported that a pCR of the intention-to-treat individuals was achieved in 17% of group A patients who were received three cycles induction chemotherapy of fluorouracil, leucovorin, and oxaliplatin before fluorouracil/oxaliplatin CRT (50.4 Gy) and in 25% of group B patients with consolidation chemotherapy after CRT. Other TNT-related studies19 had similar pCR rates. A Chinese study17 in which we included 24 patients had a pCR rate of up to 30% in the experimental group. It is worth mentioning that 5 (41.7%) out of 12 patients who received CapIriRT, 8 (23.5%) out of 34 in the CapeOXRT arm and 11 (14.7%) out of 75 in the CapRT arm achieved a pCR, respectively, at our institution. According to the UGT1A1 genotype, choosing radiotherapy in combination with irinotecan and capecitabine as neoadjuvant therapy may be an innovative, promising treatment option17. It is worth putting forward that the addition of irinotecan was also associated with increase in the occurrence of grade 3-4 toxicities. Long-term follow-up will determine if the improvement in the pCR is translated into improved survival.
Thirty-four patients were treated with oxaliplatin combined with capecitabine chemotherapy during radiotherapy. Adding oxaliplatin to fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy significantly improved the disease-free survival of patients with staged stage II/III rectal cancer compared with a former fluorouracil-based combined regimen (based on CAO/ARO/AIO-94)1. Seventy-five patients in our study received combinations with concurrent capecitabine chemotherapy during radiotherapy based on clinical studies8,9. Twelve patients received concurrent capecitabine and irinotecan (CapIriRT)17, and the efficacy and safety were demonstrated in previous clinical studies21,22. There were no obviously differences were found in OS and DFS among different concurrent chemotherapy regimens in our study. Some studies have shown that adding additional chemotherapy between the end of nCRT and surgery improved survival outcomes14. After neoadjuvant therapy, there was little tumor regression based on MRI, and we gave the patient more interval consolidation therapy. Three to four cycles of chemotherapy were arranged for 7 patients. Generally, TME surgery was scheduled for 8-12 weeks after the completion of nCRT. We found that 45patients failed to complete all of the chemotherapy cycles. There were also no significant differences in OS and DFS among patients who did and did not complete postoperative chemotherapy at the full dose (yes vs. no) in our study. It is consistent with another study that showed the value of adjuvant chemotherapy might be controversial23. However, Sandra-Petrescu F et al pointed that the complete administration of chemotherapy cycles after surgery were associated with improved the overall and disease-free survival at 5 years in patients with locally advanced rectal cancer24.
Pelvic MRI were required to performed for all our patients to help their staging evaluation before radiation and surgery, similar to other studies15. This allows a better assessment of the efficacy of neoadjuvant therapy and patient staging. In this study, the MRI CRM status was an independent prognostic factor for OS. Preoperative MRI examination can confirm the status of CRM, which can help to make more individualized treatment plans. During follow-up, regular MRI can detect local recurrence and metastasis earlier and help to provide timely intervention treatment.
The 3-year OS was 83.2%, and the 3-year DFS was 74.7% (Fig. 1). After multivariate adjustment, MRI CRM status (X2=7.431, p=.006), and ypTNM stage (X2=8.192, p=.042) remained significant for OS (Fig. 2A1-2). The 3-year OS with PCR, yp stage I, II, III was 94.4%, 81.3%, 92.9%, and 67.6%, respectively. The 3-year OS with or without CRM positivity was 72.1% and 93.8%, respectively. ypTNM stage (X2=14.101, p=.003) was the only independent risk factor for DFS after multivariate Cox regression analysis (Fig. 2B). The 3-year DFS rates with PCR, yp stage I, II, III were 95.7%, 72.7%, 85.1% and 50%, respectively.
One study from Hong Kong15 reported that the 3-year and 5-year OS rates were 77.2% and 63.9%, respectively. The 3-year and 5-year DFS rates were 69.4% and 68.3%, respectively. The survival of patients with positive CRM was significantly reduced compared with those with negative CRM and the 3-year OS for CRM-negative patients was 88.3%. After multivariate adjustment, only suspected CRM and histological grade remained significant for OS. Only suspected CRM and pathological N stage remained significant after multivariate adjustment for DFS. A phase III Germany study8 showed that the 5-year overall survival in the capecitabine arm was not inferior to that in the fluorouracil arm (76% vs 67%; p=0.0004); 3-year disease-free survival was 75% and 67% in the capecitabine group and the fluorouracil group (p=0·07), respectively. The results of FFCD 92033 show that there was no difference for neoadjuvant radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers in the 5-year OS and 5-year PFS in both arms (67.9% v 67.4%; and 55.5% v 59.4%). The total 5-year overall survival rate for all groups was 65.2% in the EORTC Radiotherapy Group Trial 229215. The German CAO/ARO/AIO-04 study published its final results in 2015: the 3-year disease-free survival was 75·9% in the investigational group (infusion fluorouracil and oxaliplatin) and 71.2% in the control group in which patients were underwent chemotherapy with fluorouracil-based combined modality regimen.
Several large trials of TNT14,18,25,26 have reported that TNT had the following therapeutic advantages: it significantly increased the completion of systemic treatment, improved tumor regression, reduced the incidence of tumor-related treatment metastasis and recurrence and increased the CCR ratio and W&W probability. Choosing the watch-and-wait strategy for carefully selected patients who have achieved a clinical complete response with neoadjuvant therapy may be feasible20. As research progresses, individualized treatment plans need to be developed for specific patients.
The main reason for treatment failure in our group was mainly distant metastasis, so ways to implement systemic treatment more effectively is are important. An increasing number of clinical studies have shown that the initial treatment of TNT is satisfactory. At present, we are conducting research on TNT or on choosing a chemotherapy regimen according to the UGT1A1 genotype, aiming to obtain better clinical results and reduce distant failures. Encouraging oncological results were obtained at the 3-year follow-up but needed to be confirmed with longer follow-up. A more detailed analysis of the toxicity and quality of life will be published separately.There are some limitations in our study, such as insufficient sample size and short follow-up time. We will extend the duration of treatment and continue follow-up to overcome the associated deficiencies.