Impact of Total Neoadjuvant Therapy vs. Standard Chemoradiotherapy in Locally Advanced Rectal Cancer: A Systematic Review and Meta-Analysis of Randomized Trials

Abstract

Multimodality treatment is a standard of care for LARC, but the optimal sequencing of the treatment modalities remains unclear. Several randomized clinical trials (RCTs) compared total neoadjuvant treatment (TNT) vs. standard neoadjuvant chemoradiotherapy (CRT) with inconsistent results. A systematic review and meta-analysis was performed to evaluate the efficacy of TNT in terms of complete pathological response (pCR) rate, disease-free and overall survival vs. standard CRT in LARC. A systematic search was performed through MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and meeting abstracts up to May 2020. RCTs comparing CRT vs. TNT followed by surgery in LARC were eligible for the study. Study selection and data extraction were done following PRISMA guidelines by two independent reviewers. The Mantel–Haenzel method was used to obtain a fixed-effects model of pooled odds or hazard ratios for the main outcomes. Eight RCTs, including 2301 patients, met the eligibility criteria. TNT significantly improved pCR rate (OR = 1.99, 95% confidence interval (CI) 1.59–2.49; p < 0.001), 3-year disease-free-survival (DFS) (HR = 0.82, 95%CI 0.71–0.95; p = 0.01) and 3-year overall survival (OS) (hazard ratio (HR) = 0.81, p = 0.04). Grade 3–4 adverse events were not significantly different in both strategies (OR = 1.58; p = 0.14). An improved pCR rate was documented regardless of the type of radiotherapy administered (long vs. short fractionation schedules). No significant heterogeneity was found. The results of this meta-analysis show that TNT improves pCR and survival rates vs. standard preoperative CRT in patients with LARC. TNT may become a new standard of care in LARC, although longer follow-up is needed to properly assess its long-term impact on survival.

The Oncologic Efficacy and Long-term Survival Outcomes of Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer: A Systemic Review and Meta-Analysis

“…A series of studies supported the application of TNT due to improved long-term survival outcomes, especially the recently published multicenter RCTs (RAPIDO 21 and PRODIGE 20 trial) further con rmed the survival bene ts of TNT. A recent systemic review and meta-analysis included eight RCTs had a conclusion that TNT could signi cantly improve OS and DFS of locally advanced rectal cancer, compared to NCRT 44 . Similar to this meta-analysis, our study included not only RCTs, but also non-RCTs, the nal results also revealed that TNT had the potential of improving long-term survival outcomes of locally advanced rectal cancer patients, both the RCTs and non-RCTs supported the superiority of TNT.…”

A 41-Gene Pair Signature for Predicting the Pathological Response of Locally Advanced Rectal Cancer to Neoadjuvant Chemoradiation

“…Because the pathological response status has a positive effect on disease-free survival (DFS) ( 24 ), the 41-GPS should be used to predict the survival benefit of 5-FU-based nCRT. First, we used the signature to evaluate the survival benefit of 105 patients with rectal cancer treated with 5-FU-based nCRT in the GSE87211 cohort.…”

Tailored total neoadjuvant therapy for locally advanced rectal cancer: One size may not fit for all!

“…In a review of ERUS/MRI staged patients with mid-and distal rectal clinical T3N0 tumours, detection of mesorectal lymph node positivity in resected specimens was 22% despite neoadjuvant CRT [18]. for DFS, hazard ratio [HR] = 0.82, 95% CI 0.71-0.95, P = 0.01 and OS, HR = 0.81, P = 0.04) without significant increase in serious adverse reactions [19]. However, this meta-analysis did not include the updated long term follow-up data from the Polish II trial which revealed no significant OS advantage with short course RT followed by chemotherapy versus conventional CRTA.…”

“…However, neither the PRODIGE nor RAPIDO trial has demonstrated an overall survival advantage [1–4]. A meta‐analysis including 8 randomized controlled trials and 2301 patients has also indicated an improvement in pCR rates in addition to DFS and OS at 3 years compared to standard neoadjuvant chemoradiotherapy (for pCR, odds ratio [OR] = 1.99, 95% confidence interval [CI] 1.59–2.49, P < 0.001; for DFS, hazard ratio [HR] = 0.82, 95% CI 0.71–0.95, P = 0.01 and OS, HR = 0.81, P = 0.04) without significant increase in serious adverse reactions [19]. However, this meta‐analysis did not include the updated long term follow‐up data from the Polish II trial which revealed no significant OS advantage with short course RT followed by chemotherapy versus conventional CRTA.…”