Background: Total neoadjuvant therapy (TNT) is a new strategy combining neoadjuvant therapy and chemotherapy to enhance tumor shrinkage and systemic control. Its effectiveness remains debated. Objectives: This study conducts a meta-analysis of randomized controlled trials (RCTs) to assess TNTs impact and provide high-quality evidence for rectal cancer treatment decisions. Method: We searched China National Knowledge Infrastructure, VIP Database, Wanfang Database, China biomedical literature database, PubMed database, Embase database, and The Cochrane Library for RCTs comparing TNT with neoadjuvant chemoradiotherapy (CRT) in locally advanced rectal cancer. The included trials were screened and assessed for quality based on inclusion and exclusion criteria, and meta-analysis was performed using RevMan 5.3 software. Results: A total of 11 RCTs reported in 14 articles, with 1,624 cases in the TNT group and 1,541 cases in the CRT group. The results of the meta-analysis showed that compared with the CRT group, the TNT group had a higher pathological complete response rate (risk ratio [RR] = 1.65, 95% confidence interval [CI]: [1.40, 1.94], p < 0.00001), higher T0 downstaging rate (RR = 1.51, 95% CI: [1.29, 1.77], p < 0.00001), higher 3-year overall survival (hazard ratio [HR] = 0.81, 95% CI: [0.67, 0.98], p = 0.03), and higher 3-year disease-free survival (HR = 0.82, 95% CI: [0.70, 0.95], p = 0.008). However, there was no statistically significant difference between the two groups in terms of R0 resection rate (RR = 1.02, 95% CI: [0.99, 1.05], p = 0.14), sphincter preservation rate (RR = 0.94, 95% CI: [0.88, 1.01], p = 0.12), anastomotic leakage rate (RR = 1.42, 95% CI: [0.85, 2.38], p = 0.18), and grade 3 or higher adverse events (RR = 1.21, 95% CI: [0.95, 1.54], p = 0.13). Conclusions: In the treatment of locally advanced rectal cancer, TNT offers greater survival benefits compared to neoadjuvant CRT and does not significantly increase the incidence of adverse events. However, further data and studies with long-term outcomes are still required.

1.
Leow YC, Henry F, Lee FY. Pelvic exenteration for locally advanced and local recurrent primary rectal cancer: a 5 years Asian retrospective cohort study and lessons to learn. Int Surg J. 2020;7(11):3755–61.
2.
Salerno G, Chandler I, Wotherspoon A, Thomas K, Moran B, Brown G. Sites of surgical wasting in the abdominoperineal specimen. Br J Surg. 2008;95(9):1147–54.
3.
Yang Z, Zhang X, Zhang J, Gao J, Bai Z, Deng W, et al. Rationale and design of a prospective, multicenter, phase II clinical trial of safety and efficacy evaluation of long course neoadjuvant chemoradiotherapy plus tislelizumab followed by total mesorectal excision for locally advanced rectal cancer (NCRT-PD1-LARC trial). BMC Cancer. 2022;22(1):462–10.
4.
Benson AB, Venook AP, Al-Hawary MM, Cederquist L, Chen YJ, Ciombor KK, et al. Rectal cancer, version 2. 2018, NCCN clinical practice guidelines in oncology. Natl Compr Canc Netw. 2018;16(7):874–901.
5.
Wang Y, Shen L, Wan J, Zhang H, Wu R, Wang J, et al. Short-course radiotherapy combined with CAPOX and Toripalimab for the total neoadjuvant therapy of locally advanced rectal cancer: a randomized, prospective, multicentre, double-arm, phase II trial (TORCH). BMC Cancer. 2022;22(1):274–8.
6.
Peeters KC, Marijnen CA, Nagtegaal ID, Kranenbarg EK, Putter H, Wiggers T, et al. The TME trial after a median follow-up of 6 years: increased local control but no survival benefit in irradiated patients with resectable rectal carcinoma. Ann Surg. 2007;246(5):693–701.
7.
van Gijn W, Marijnen CA, Nagtegaal ID, Kranenbarg EMK, Putter H, Wiggers T, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial. Lancet Oncol. 2011;12(6):575–82.
8.
Ludmir EB, Palta M, Willett CG, Czito BG. Total neoadjuvant therapy for rectal cancer. an emerging option. Cancer. 2017;123(9):1497–506.
9.
Goodman KA. Total neoadjuvant therapy for rectal cancer. Cancer Radiother. 2018;22(5):459–65.
10.
Riesco-Martinez MC, Fernandez-Martos C, Gravalos-Castro C, Espinosa-Olarte P, La Salvia A, Robles-Diaz L, et al. Impact of total neoadjuvant therapy vs. standard chemoradiotherapy in locally advanced rectal cancer: a systematic review and meta-analysis of randomized trials. Cancers. 2020;12(12):3655.
11.
Zhang X, Ma S, Guo Y, Luo Y, Li L. Total neoadjuvant therapy versus standard therapy in locally advanced rectal cancer: a systematic review and meta-analysis of 15 trials. PLoS One. 2022;17(11):e0276599.
12.
Liu S, Jiang T, Xiao L, Yang S, Liu Q, Gao Y, et al. Total neoadjuvant therapy (TNT) versus standard neoadjuvant chemoradiotherapy for locally advanced rectal cancer: a systematic review and meta-analysis. Oncologist. 2021;26(9):e1555–66.
13.
Socha J, Bujko K. Does the gain of total neoadjuvant therapy outweigh the harm in rectal cancer? Importance of the ATRESS (neoAdjuvant Therapy-RElated Shortening of Survival) phenomenon: a systematic review. Cancers. 2023;15(4):1016.
14.
Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 2009;151(4): 264–9, W64.
15.
Higgins JPT, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al. The cochrane collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928.
16.
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557–60.
17.
Sedgwick P, Marston L. How to read a funnel plot in a meta-analysis. BMJ. 2015;351:h4718.
18.
Schunemann H, Brozek J, Guyatt G, Oxman A. Handbook for grading the quality of evidence and the strength of recommendations using the GRADE approach; 2013.
19.
Bahadoer RR, Dijkstra EA, van Etten B, Marijnen CAM, Putter H, Kranenbarg EMK, et al. Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22(1):29–42.
20.
Borg C, André T, Mantion G, Boudghène F, Mornex F, Maingon P, et al. Pathological response and safety of two neoadjuvant strategies with bevacizumab in MRI-defined locally advanced T3 resectable rectal cancer: a randomized, noncomparative phase II study. Ann Oncol. 2014;25(11):2205–10.
21.
Bujko K, Wyrwicz L, Rutkowski A, Malinowska M, Pietrzak L, Kryński J, et al. Long-course oxaliplatin-based preoperative chemoradiation versus 5 × 5 Gy and consolidation chemotherapy for cT4 or fixed cT3 rectal cancer: results of a randomized phase III study. Ann Oncol. 2016;27(5):834–42.
22.
Ciseł B, Pietrzak L, Michalski W, Wyrwicz L, Rutkowski A, Kosakowska E, et al. Long-course preoperative chemoradiation versus 5 × 5 Gy and consolidation chemotherapy for clinical T4 and fixed clinical T3 rectal cancer: long-term results of the randomized Polish II study. Ann Oncol. 2019;30(8):1298–303.
23.
Conroy T, Bosset JF, Etienne PL, Rio E, François É, Mesgouez-Nebout N, et al. Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer (UNICANCER-PRODIGE 23): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22(5):702–15.
24.
Fernández-Martos C, Pericay C, Aparicio J, Salud A, Safont MJ, Massuti B, et al. Phase II, randomized study of concomitant chemoradiotherapy followed by surgery and adjuvant capecitabine plus oxaliplatin (CAPOX) compared with induction CAPOX followed by concomitant chemoradiotherapy and surgery in magnetic resonance imaging–defined, locally advanced rectal cancer: grupo cáncer de recto 3 study. J Clin Oncol. 2010;28(5):859–65.
25.
Fernandez-Martos C, Garcia-Albeniz X, Pericay C, Maurel J, Aparicio J, Montagut C, et al. Chemoradiation, surgery and adjuvant chemotherapy versus induction chemotherapy followed by chemoradiation and surgery: long-term results of the Spanish GCR-3 phase II randomized trial. Ann Oncol. 2015;26(8):1722–8.
26.
Garant A, Kavan P, Martin AG, Azoulay L, Vendrely V, Lavoie C, et al. Optimizing treatment sequencing of chemotherapy for patients with rectal cancer: the KIR randomized phase II trial. Radiother Oncol. 2021;155:237–45.
27.
Jin J, Tang Y, Hu C, Jiang L, Jiang J, Li N, et al. Multicenter, randomized, phase III trial of short-term radiotherapy plus chemotherapy versus long-term chemoradiotherapy in locally advanced rectal cancer (STELLAR). J Clin Oncol. 2022;40(15):1681–92.
28.
Kim SY, Joo J, Kim TW, Hong YS, Kim JE, Hwang IG, et al. A randomized phase 2 trial of consolidation chemotherapy after preoperative chemoradiation therapy versus chemoradiation therapy alone for locally advanced rectal cancer: kcsg CO 14-03. Int J Radiat Oncol Biol Phys. 2018;101(4):889–99.
29.
Li L, Wang W, Dong H, Wang G, Luo Y, Hu Y, et al. Prospective phase: study of neoadjuvant chemoradiotherapy followed by chemotherapy in locally advanced rectal cancer. Chin J Radiological Med Prot. 2017;37(2):107–13.
30.
Maréchal R, Vos B, Polus M, Delaunoit T, Peeters M, Demetter P, et al. Short course chemotherapy followed by concomitant chemoradiotherapy and surgery in locally advanced rectal cancer: a randomized multicentric phase II study. Ann Oncol. 2012;23(6):1525–30.
31.
Moore J, Price T, Carruthers S, Selva-Nayagam S, Luck A, Thomas M, et al. Prospective randomized trial of neoadjuvant chemotherapy during the “wait period”following preoperative chemoradiotherapy for rectal cancer: results of the WAIT trial. Colorectal Dis. 2017;19(11):973–9.
32.
van der Valk MJM, Marijnen CAM, van Etten B, Dijkstra EA, Hilling DE, Kranenbarg EM, et al. Compliance and tolerability of short-course radiotherapy followed by preoperative chemotherapy and surgery for high-risk rectal cancer–Results of the international randomized RAPIDO-trial. Radiother Oncol. 2020;147:75–83.
33.
MacFarlane JK, Ryall RDH, Heald RJ. Mesorectal excision for rectal cancer. Lancet. 1993;341(8843):457–60.
34.
Bosset JF, Collette L, Calais G, Mineur L, Maingon P, Radosevic-Jelic L, et al. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med. 2006;355(11):1114–23.
35.
Ceelen W, Fierens K, Van Nieuwenhove Y, Pattyn P. Preoperative chemoradiation versus radiation alone for stage II and III resectable rectal cancer: a systematic review and meta-analysis. Int J Cancer. 2009;124(12):2966–72.
36.
Hong TS, Ryan DP. Adjuvant chemotherapy for locally advanced rectal cancer: is it a given. J Clin Oncol. 2015;33(17):1878–80.
37.
Maas M, Nelemans PJ, Valentini V, Das P, Rödel C, Kuo L, et al. Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data. Lancet Oncol. 2010;11(9):835–44.
38.
Valentini V, Van Stiphout RGPM, Lammering G, Gambacorta M, Barba M, Bebenek M, et al. Selection of appropriate end-points (pCR vs 2yDFS) for tailoring treatments with prediction models in locally advanced rectal cancer. Radiother Oncol. 2015;114(3):302–9.
39.
García-Aguilar J, Hernandez de Anda E, Sirivongs P, Lee S, Madoff R, Rothenberger D. A pathologic complete response to preoperative chemoradiation is associated with lower local recurrence and improved survival in rectal cancer patients treated by mesorectal excision. Dis Colon Rectum. 2003;46(3):298–304.
40.
Kasi A, Abbasi S, Handa S, Al-Rajabi R, Saeed A, Baranda J, et al. Total neoadjuvant therapy vs standard therapy in locally advanced rectal cancer: a systematic review and meta-analysis. JAMA Netw Open. 2020;3(12):e2030097.
41.
de Campos-Lobato LF, Geisler DP, da Luz Moreira A, Stocchi L, Dietz D, Kalady M. Neoadjuvant therapy for rectalcancer: the impact of longer interval between chemoradiation and surgery. J Gastrointest Surg. 2011;15(3):444–50.
42.
Wolthuis AM, Penninckx F, Haustermans K, De Hertogh G, Fieuws S, Van Cutsem E, et al. Impact of interval between neoadjuvant chemoradiotherapy and TME for locally advanced rectal cancer on pathologic response and oncologic outcome. Ann Surg Oncol. 2012;19(9):2833–41.
43.
Sun Z, Adam MA, Kim J, Shenoi M, Migaly J, Mantyh CR. Optimal timing to surgery after neoadjuvant chemoradiotherapy for locally advanced rectal cancer. J Am Coll Surg. 2016;222(4):367–74.
44.
Mei SW, Liu Z, Wei FZ, Chen JN, Wang ZJ, Shen HY, et al. Impact of interval between neoadjuvant chemoradiotherapy and surgery in rectal cancer patients. World J Gastroenterol. 2020;26(31):4624–38.
45.
van der Valk M, Hilling DE, Bastiaannet E, Meershoek-Klein Kranenbarg E, Beets G, Figueiredo N, et al. Long-term outcomes of clinical complete responders after neoadjuvant treatment for rectal cancer in the International Watch &amp; Wait Database (IWWD): an international multicentre registry study. Lancet. 2018;391(10139):2537–45.
46.
Jiang W, Wang H, Zheng J, Zhao Y, Xu S, Zhuo S, et al. Post-operative anastomotic leakage and collagen changes in patients with rectal cancer undergoing neoadjuvant chemotherapy vs chemoradiotherapy. Gastroenterol Rep. 2022;10:goac058.
You do not currently have access to this content.