PURPOSE To ascertain if preoperative short-term radiotherapy followed by chemotherapy is not inferior to a standard schedule of long-term chemoradiotherapy in patients with locally advanced rectal cancer. MATERIALS AND METHODS Patients with distal or middle-third, clinical primary tumor stage 3-4 and/or regional lymph node–positive rectal cancer were randomly assigned (1:1) to short-term radiotherapy (25 Gy in five fractions over 1 week) followed by four cycles of chemotherapy (total neoadjuvant therapy [TNT]) or chemoradiotherapy (50 Gy in 25 fractions over 5 weeks, concurrently with capecitabine [chemoradiotherapy; CRT]). Total mesorectal excision was undertaken 6-8 weeks after preoperative treatment, with two additional cycles of CAPOX (intravenous oxaliplatin [130 mg/m2, once a day] on day 1 and capecitabine [1,000 mg/m2, twice a day] from days 1 to 14) in the TNT group and six cycles of CAPOX in the CRT group. The primary end point was 3-year disease-free survival (DFS). RESULTS Between August 2015 and August 2018, a total of 599 patients were randomly assigned to receive TNT (n = 302) or CRT (n = 297). At a median follow-up of 35.0 months, 3-year DFS was 64.5% and 62.3% in TNT and CRT groups, respectively (hazard ratio, 0.883; one-sided 95% CI, not applicable to 1.11; P < .001 for noninferiority). There was no significant difference in metastasis-free survival or locoregional recurrence, but the TNT group had better 3-year overall survival than the CRT group (86.5% v 75.1%; P = .033). Treatment effects on DFS and overall survival were similar regardless of prognostic factors. The prevalence of acute grade III-V toxicities during preoperative treatment was 26.5% in the TNT group versus 12.6% in the CRT group ( P < .001). CONCLUSION Short-term radiotherapy with preoperative chemotherapy followed by surgery was efficacious with acceptable toxicity and could be used as an alternative to CRT for locally advanced rectal cancer.

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Background. Total neoadjuvant therapy (TNT) is a novel approach for locally advanced rectal cancer (LARC), which attempts to deliver both systemic chemotherapy and neoadjuvant chemoradiotherapy prior to surgery. However, its efficacy and safety remain controversial in randomized controlled trials (RCTs). We conducted this meta-analysis to assess such concerns. Materials and Methods. Head-to-head phase II/III RCTs were searched in Embase, PubMed, Web of Science, and the Cochrane Library, as well as other sources. The primary endpoint was pathologic complete response (pCR). Secondary endpoints were disease-free survival (DFS), overall survival (OS), local recurrence-free survival, distant metastasis-free survival, and the R0 resection rate.Results. Eight phase II/III RCTs involving 2,196 patients with LARC were assessed. The primary analysis demonstrated a statistically significant improvement in the pCR rate for TNT treatment (odds ratio, 1.77; 95% confidence interval [CI], 1.28-2.45; p = .0005). TNT treatment also showed improvements in DFS and OS outcomes compared with standard chemoradiotherapy (hazard ratio [HR], 0.83; 95% CI, 0.72-0.96; p = .03 and HR, 0.88; 95% CI, 0.74-1.05; p = .15). In addition, TNT treatment showed significant efficacy in reducing the risk of distant metastasis (HR, 0.81; 95% CI, 0.68-0.95; p = .012). Conclusion.The overall pCR rate may be improved with TNT compared with standard treatment. The TNT strategy may also improve DFS and OS and reduce the risk of distant metastasis. The Oncologist 2021;26:1-12 Implications for Practice: Locally advanced rectal cancer (LARC) is a relatively common disease, with a poor prognosis because of its high metastatic potential. The role of total neoadjuvant therapy (TNT) has always been controversial. This meta-analysis found that TNT in LARC is associated with a significant improvement in overall pathologic complete response rate, disease-free survival, overall survival, and distant metastasis-free survival compared with standard treatment. TNT is a promising strategy for LARC, especially for patients who have little desire for surgery.

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3510 Background: It’s presented the results of a phase III trial of short-term radiotherapy (SCRT) combined with chemotherapy versus long-term chemoradiotherapy (LCRT) in patients with locally advanced rectal cancer (LARC). Methods: Patients with distal or middle third, T3-T4 and/or N+ rectal adenocarcinomas diagnosed by MRI, were randomly assigned to experimental group or control group. In experimental group, patients received SCRT (25 Gy / 5 fractions / 5 days), followed by four courses of CAPOX. In control group, patients received LCRT (50 Gy / 25 fractions / 35 days with concurrent capecitabine). Surgery was recommended in both groups and performed 6-8 weeks after preoperative treatment. Two or six courses of CAPOX was prescribed as the postoperative chemotherapy in experimental group and control group, respectively. This trial was a multicenter, open-label, randomized, noninferior, phase III study, and all the patients were from 16 hospitals of China. The primary endpoint for this study was 3-year disease-free survival (DFS). Results: From Aug 30, 2015 to Aug 27, 2018, 599 patients were enrolled and entered random. Finally, 591 intention-to-treat (ITT) populations were included in the analysis, 298 patients assigned to SCRT followed by chemotherapy and 293 to CRT. For the experimental group and control group, cT3 and cT4 accounted for 82.3% vs. 84.6% and 15.4% vs. 12.3%, respectively, and approximately 85% were mrN positive (85.6% vs. 84.0%). As a whole, the completion and full-dose completion rates of preoperative treatment were 82.6% vs. 95.2% (p＜0.001) and 74.8% vs 93.2% (p＜0.001) in the experimental and control groups, respectively. Among the 465 patients who received surgery, 16.6% and 11.8% of them achieved pCR (p=0.134), respectively. Accounting for cCR after preoperative treatment, the total rate of pCR+cCR in experimental group was 22.5% and significantly higher than control group (12.6%, p=0.001). With median follow-up 35.0 months, the HR between experimental and control of DFS was 0.883, with 1-sided noninferiority p-value <0.001, so the noninferiority hypothesis was confirmed. The probability of DFS and OS at 3 years was 64.5% and 86.5% in the experimental group compared with 62.3% and 75.1% in control group. It’s observed the OS rate of the experimental group was significantly higher than that of the control group (p=0.036) and no significant difference in metastasis-free survival or loco-regional recurrence was observed. Conclusions: For LARC with high risk factors, SCRT combined with sequential chemotherapy was noninferior to CRT and could be used as an alternative to LCRT. Meanwhile, SCRT combined with chemotherapy presented a higher cCR+pCR and 3-year overall survival rates as compared with CRT. However, the long term results need to be further followed up. (ClinicalTrails No.: NCT02533271 ). Clinical trial information: NCT00833131.

BackgroundThe prognosis of locally unresectable colon cancer (CC) is poor. This prospective observational study aimed to further evaluate the feasibility and efficacy of neoadjuvant chemoradiotherapy (NACRT) followed by surgery in these patients.Patients and methodsWe consecutively enrolled patients who were diagnosed with locally unresectable CC from November 2010 to March 2017, and received NACRT followed by surgery. The data of all the patients were collected prospectively. The R0 resection, down-stage and pathologic complete response (pCR) rates were calculated to evaluate the short-term treatment effects. The overall survival (OS) was used to evaluate the long-term outcome. The incidence of NACRT-related acute toxicities and postsurgical complications were used to assess the safety.ResultsA total of 60 patients were eligible for analysis, including 57 (95.0%) patients who attained resectability after NACRT. Among patients managed with surgery, 49 cases (86.0%) achieved R0 resection, and 15 cases (26.3%) achieved pCR. Down T stage was seen in 47 cases (82.5%), and down N stage was seen in 53 cases (93.0%). After a median follow-up time of 26 months, the OS appeared as 76.7%. The most common grade 3/4 NACRT-related toxicity was myelosuppression (incidence, 20.0%). The incidence of grade 3/4 surgery-related complication was 7.0%.ConclusionNACRT might be a safe and effective choice for patients with locally unresectable CC to improve treatment effects, long-term survival and life quality, though further validation is needed.

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