The therapeutic approach of LACR primarily aims to improve the disease-free survival, local or distant recurrence rates. Recently, TNT is attracting more and more interests [11–16]. In these studies, the authors discovered the following advantage: moving systemic therapy earlier than CRT to address possible microscopic metastatic disease, increased treatment compliance, assessed the sensitivity of chemotherapy in vivo, avoided the discomfort of patents undergoing chemotherapy with a stoma. Currently, there are more studies on the model of induction chemotherapy followed by CRT than the model of consolidation chemotherapy. However, which is the most reasonable TNT model are still unknown. There have been series of published studies suggesting that a critical decrease in tumor metabolism from CRT completion is associated with improved rates of CR and overall outcomes [24–26]. So, we chose the consolidation chemotherapy regiment in our study and compared it with CRT in safety and efficacy.
In our study, we show that total neoadjuvant treatment that consists of 5 cycles of neoadjuvant CAPOX (concurrent 2 cycles followed by 3 cycles) and radiotherapy of 50.0 Gy in 25 fractions, is effective and safe for patients with locally advanced rectal cancer. Lengthening the neoadjuvant treatment time by delivering CAPOX before operation did not increase the risk of disease progression. The rates of distant metastasis diagnosed during neoadjuvant treatment were equivalent between the two groups. No grade 4 or serious adverse events were observed in our study. Although TNT group had higher grade 3 toxicity rate than CRT group, there was no statistically significant difference between them. Our results were consistent with previously published evidence [12, 27]. In a phase 2 trial performed by Fernandez-Martos [12], the addition of induced chemotherapy did not increase the incidence of grade 3–4 adverse events in the neoadjuvant treatment. In another study [27], a similar conclusion was reached that consolidation chemotherapy did not increase the incidence of complications after chemoradiotherapy.
As to the safety of surgery, our data showed that the mean operative time and blood loss was longer and more in TNT group(195.1 ± 11.3minutes vs 180.5 ± 12.3minutes, P = 0.132; 122.1 ± 20.2 milliliters vs 102.1 ± 15.2 milliliters, P = 0.343), which may be related to more APR patients in TNT group (31.6% vs 13%, P < 0.05). The other specific complications, such as pelvic infection, anastomotic leakage, bowel obstruction, wound infection and pulmonary infection did not differ between study groups. Garcia-Aguilar et al conducted a multicenter study [28] and they found that delivering systemic chemotherapy after chemoradiation did not increase the risk of surgical complication.
We showed in our study that our 32.7% pCR rate in TNT was significantly higher than the 12.8% rate in CRT (P = 0.002). These results were comparable with those of previously published studies about induction chemotherapy [11, 13–14]. In a recnet study published by Cercek et al [13], which examined 308 patients received TNT (introduction fluorouracil-and oxaliplatin-based chemotherapy followed by chemoRT), the pCR rate was 35.7% in the TNT cohort compared with 21.3% in the chemoRT with planned adjuvant chemotherapy cohort. However, in a large phase Ⅲ Polish trail, patients with consolidation chemotherapy only had 16% pCR rate [16]. In this trail, patients were randomly assigned to two treatment groups: one with short-course radiotherapy (5 × 5 Gy) followed by 3 cycles of chemotherapy with fluorouracil and oxaliplatin and the other with standard CRT. In fact, a recent systematic review of factors affecting tumor response to neoadjuvant therapy in over 4,700 patients undergoing Phase II and Phase III trials has shown that a dose of ༞45Gy was significantly associated with increased rates of complete tumor response [29]. In our study, all patients underwent IMRT received a total dose of 50.0 Gy in the two groups, which may be one of the factors leading to a higher rate of pCR after neoadjuvant therapy in rectal cancer. TNT includes different strategies, the most reasonable sequence of the induction chemotherapy, concurrent CRT and consolidation chemotherapy are still unknown. The pathologic complete response following neoadjuvant chemoradiotherapy and interval proctectomy, in patients with rectal cancer, was associated with excellent long-term survival and low rates of local recurrence and distant disease [30]. Park et al reported that tumor response (complete v intermediate v poor) to neoadjuvant chemoradiotherapy among patients with locally advanced rectal cancer undergoing radical resection was associated with 5-year RFS(Recurrence-free survival ) (90.5% vs 78.7% vs 58.5%; P༜0.001), 5-year DM(distant metastasis) rates (7.0% vs 10.1% vs 26.5%; P༜0.001), and 5-year LR(local recurrence) rates (0% vs 1.4% vs 4.4%; P = 0.002) [31].
The chemoradiation-to-surgery interval was prolonged in the TNT group. Although the optimal interval between completion of neoadjuvant chemoradiotherapy and surgery in rectal cancer is controversial [32–34], more and more evidences showed that operating 12 weeks after radiotherapy is safe with improved treatment response [35–36]. In our study, the interval between radiotherapy and surgery in TNT group was 12 weeks, which did not increase the surgical complications. Habr-Gama et al found that patients undergoing surgery 12 weeks or more from CRT completion was safe and did not negatively affect survival [35]. Time from completing neoadjuvant therapy to surgery was almost at 12 weeks in Cercek et al.’ s study [13].
We did not routinely evaluate cCR to neoadjuvant therapy in two groups. Six patients (2 patients in CRT group, 4 patients in TNT group) refused operation because of cCR and underwent observational management. In 2004, Habr-Gama et al. published that the overall survival (OS) and disease-free survival (DFS) at 5 years ended up being higher in the observation group than resection group [37]. OnCoRe et al. from the UK performed a prospectively study supporting watch-and-wait approach [38]. They demonstrated that there was no statistical difference between watch and wait and surgical resection in 3-year DFS and OS. In addition, the colostomy-free survival was significantly better in the observational group (47% vs 74%, P༜0.001). Evaluation of clinic complete response according to current adopted criteria has low sensitivity [39], so how to identify the patients with a cCR who may potentially benefit from the nonoperative management is still a problem.
Several limitations of our trail deserve mention. First, this study was a retrospective study, which might have selection bias. Although our findings lend support to the TNT mode (consolidation chemotherapy), they should still be regards as exploratory and in need of confirmation in a prospective randomized trial. Second, our study used pCR rate as the primary endpoint, and it was revealed that TNT strategy used in this study achieved a pCR rate of 32.7%. Although pCR is associated with improved the long-term outcomes [30–31], further investigation with mature follow-up and survival data are warranted. Third, we did not routinely assess cCR to neoadjuvant therapy in all patients. The watch-and-wait approach to the management of cCR in rectal cancer is often the first concern of a patient and we as clinicians are obliged to discuss these options with our patients.