Total Neoadjuvant Therapy in Rectal Cancer: a Network Meta-analysis of Randomized Trials

Overview

Journal Ann Coloproctol

Date 2023 Apr 11

PMID 37038270

Authors

Sergey Sychev

Aleksey Ponomarenko

Stanislav Chernyshov

Mikhail Alekseev

Zaman Mamedli

Dmitriy Kuzmichev

Andrey Polynovskiy

Evgeny Rybakov

Affiliations

Soon will be listed here.

Abstract

Purpose: To assess the efficacy of total neoadjuvant therapy (TNT) for rectal carcinoma in comparison with conventional chemoradiotherapy (CRT).

Methods: A systematic review was performed according to the PRISMA guidelines. A Bayesian network meta-analysis was done using NetMetaXL and WinBUGS. This study was registered in PROSPERO on March 3, 2022 (No. CRD-42022307867).

Results: Outcomes of 2,719 patients from 10 randomized trials between 2010 and 2022 were selected. Of these 1,191 (44%) had conventional long-course CRT (50-54 Gy) and capecitabine, 506 (18%) had induction chemotherapy followed by CRT (50-54 Gy) and capecitabine (iTNT), 230 (9%) had long-course CRT (50-54 Gy) followed by consolidation chemotherapy (cTNT), and 792 (29%) undergone modified short-course radiotherapy (25 Gy) with subsequent chemotherapy (mTNT). Total pathologic complete response (pCR) was 20% in the iTNT group, 21% in the mTNT group, 22% in the cTNT group, and 12% in the CRT group. Statistically significant difference in pCR rates was detected when comparing iTNT with CRT (odds ratio [OR], 1.76; 95% credible interval [CrI], 1.06-2.8), mTNT with CRT (OR, 1.90; 95% CrI, 1.25-2.74), and cTNT with CRT groups (OR, 2.54; 95% CrI, 1.26-5.08). No differences were found in R0 resection rates. No significant difference was found in long-term outcomes.

Conclusion: The early administration of systemic chemotherapy in the TNT regimen has improved short-term outcomes, though long-term results are underreported. Randomized trials with survival as the endpoint are necessary to evaluate the possible advantages of TNT modes.

Citing Articles

Efficacy of Neoadjuvant Hypofractionated Chemoradiotherapy in Elderly Patients with Locally Advanced Rectal Cancer: A Single-Center Retrospective Analysis.

Kim J, Lee J, Park H, Lee S, Kim C, Kim H Cancers (Basel). 2025; 16(24.

PMID: 39766176 PMC: 11674216. DOI: 10.3390/cancers16244280.

Beyond survival: a comprehensive review of quality of life in rectal cancer patients.

Jung W Ann Coloproctol. 2025; 40(6):527-537.

PMID: 39748551 PMC: 11701447. DOI: 10.3393/ac.2024.00745.0106.

A randomized phase 3 trial of total neoadjuvant therapy (induction chemotherapy, neoadjuvant chemoradiation, neoadjuvant chemotherapy, and surgery) vs. standard long-term chemoradiation therapy (neoadjuvant chemoradiation, surgery, and adjuvant....

Foroughi F, Javadinia S, Salek R Front Oncol. 2024; 14:1468279.

PMID: 39711967 PMC: 11660088. DOI: 10.3389/fonc.2024.1468279.

Unveiling the profound advantages of total neoadjuvant therapy in rectal cancer: a trailblazing exploration.

Jung K, Kim H, Kim H, Lee D, Cheong C Ann Surg Treat Res. 2023; 105(6):341-352.

PMID: 38076602 PMC: 10703582. DOI: 10.4174/astr.2023.105.6.341.

References

Marechal R, Vos B, Polus M, Delaunoit T, Peeters M, Demetter P . Short course chemotherapy followed by concomitant chemoradiotherapy and surgery in locally advanced rectal cancer: a randomized multicentric phase II study. Ann Oncol. 2011; 23(6):1525-30. DOI: 10.1093/annonc/mdr473. View

Moher D, Liberati A, Tetzlaff J, Altman D . Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009; 6(7):e1000097. PMC: 2707599. DOI: 10.1371/journal.pmed.1000097. View

Moore J, Price T, Carruthers S, Selva-Nayagam S, Luck A, Thomas M . 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):973-979. DOI: 10.1111/codi.13724. View

Turner R, Davey J, Clarke M, Thompson S, Higgins J . Predicting the extent of heterogeneity in meta-analysis, using empirical data from the Cochrane Database of Systematic Reviews. Int J Epidemiol. 2012; 41(3):818-27. PMC: 3396310. DOI: 10.1093/ije/dys041. View

Wolthuis A, Penninckx F, Haustermans K, De Hertogh G, Fieuws S, Van Cutsem E . 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. DOI: 10.1245/s10434-012-2327-1. View

Fokas E, Allgauer M, Polat B, Klautke G, Grabenbauer G, Fietkau R . Randomized Phase II Trial of Chemoradiotherapy Plus Induction or Consolidation Chemotherapy as Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer: CAO/ARO/AIO-12. J Clin Oncol. 2019; 37(34):3212-3222. DOI: 10.1200/JCO.19.00308. View

Chiorean E, Sanghani S, Schiel M, Yu M, Burns M, Tong Y . Phase II and gene expression analysis trial of neoadjuvant capecitabine plus irinotecan followed by capecitabine-based chemoradiotherapy for locally advanced rectal cancer: Hoosier Oncology Group GI03-53. Cancer Chemother Pharmacol. 2012; 70(1):25-32. DOI: 10.1007/s00280-012-1883-1. View

Kim S, Joo J, Kim T, Hong Y, Kim J, Hwang I . 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):889-899. DOI: 10.1016/j.ijrobp.2018.04.013. View

Kuebler J, Wieand H, OConnell M, Smith R, Colangelo L, Yothers G . Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07. J Clin Oncol. 2007; 25(16):2198-204. DOI: 10.1200/JCO.2006.08.2974. View

10.

Bosset J, Collette L, Calais G, Mineur L, Maingon P, Radosevic-Jelic L . Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med. 2006; 355(11):1114-23. DOI: 10.1056/NEJMoa060829. View

11.

Cumpston M, Li T, Page M, Chandler J, Welch V, Higgins J . Updated guidance for trusted systematic reviews: a new edition of the Cochrane Handbook for Systematic Reviews of Interventions. Cochrane Database Syst Rev. 2019; 10:ED000142. PMC: 10284251. DOI: 10.1002/14651858.ED000142. View

12.

Andre T, Boni C, Navarro M, Tabernero J, Hickish T, Topham C . Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol. 2009; 27(19):3109-16. DOI: 10.1200/JCO.2008.20.6771. View

13.

Cisel B, Pietrzak L, Michalski W, Wyrwicz L, Rutkowski A, Kosakowska E . 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):1298-1303. DOI: 10.1093/annonc/mdz186. View

14.

Zorcolo L, Rosman A, Restivo A, Pisano M, Nigri G, Fancellu A . Complete pathologic response after combined modality treatment for rectal cancer and long-term survival: a meta-analysis. Ann Surg Oncol. 2012; 19(9):2822-32. DOI: 10.1245/s10434-011-2209-y. View

15.

Sauer R, Becker H, Hohenberger W, Rodel C, Wittekind C, Fietkau R . Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004; 351(17):1731-40. DOI: 10.1056/NEJMoa040694. View

16.

Braendengen M, Tveit K, Berglund A, Birkemeyer E, Frykholm G, Pahlman L . Randomized phase III study comparing preoperative radiotherapy with chemoradiotherapy in nonresectable rectal cancer. J Clin Oncol. 2008; 26(22):3687-94. DOI: 10.1200/JCO.2007.15.3858. View

17.

Brown S, Hutton B, Clifford T, Coyle D, Grima D, Wells G . A Microsoft-Excel-based tool for running and critically appraising network meta-analyses--an overview and application of NetMetaXL. Syst Rev. 2014; 3:110. PMC: 4195340. DOI: 10.1186/2046-4053-3-110. View

18.

Tulchinsky H, Shmueli E, Figer A, Klausner J, Rabau M . An interval >7 weeks between neoadjuvant therapy and surgery improves pathologic complete response and disease-free survival in patients with locally advanced rectal cancer. Ann Surg Oncol. 2008; 15(10):2661-7. DOI: 10.1245/s10434-008-9892-3. View

19.

Gollins S, Sebag-Montefiore D . Neoadjuvant Treatment Strategies for Locally Advanced Rectal Cancer. Clin Oncol (R Coll Radiol). 2015; 28(2):146-151. DOI: 10.1016/j.clon.2015.11.003. View

20.

Bosset J, Calais G, Mineur L, Maingon P, Stojanovic-Rundic S, Bensadoun R . Fluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: long-term results of the EORTC 22921 randomised study. Lancet Oncol. 2014; 15(2):184-90. DOI: 10.1016/S1470-2045(13)70599-0. View