Clinical and Translational Research
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Feb 15, 2021; 13(2): 119-130
Published online Feb 15, 2021. doi: 10.4251/wjgo.v13.i2.119
Total neoadjuvant therapy vs standard therapy of locally advanced rectal cancer with high-risk factors for failure
Mojca Tuta, Nina Boc, Erik Brecelj, Monika Peternel, Vaneja Velenik
Mojca Tuta, Nina Boc, Division of Radiology, Institute of Oncology, Ljubljana 1000, Slovenia
Mojca Tuta, Vaneja Velenik, Faculty of Medicine, University of Ljubljana, Ljubljana 1000, Slovenia
Erik Brecelj, Division of Surgery, Institute of Oncology, Ljubljana 1000, Slovenia
Monika Peternel, Vaneja Velenik, Division of Radiotherapy, Institute of Oncology, Ljubljana 1000, Slovenia
Author contributions: Tuta M designed and performed the research, and wrote the paper; Velenik V designed and performed the research, and supervised the report; Boc N and Peternel M designed the research and contributed to the analysis; Brecelj E designed the research and provided clinical advice.
Institutional review board statement: The study was reviewed and approved by the institutional review boards and the National Medical Ethics Committee of Slovenia (No. 0120-298/2019/5).
Clinical trial registration statement: This study is registered at The registration identification number is NCT04679597.
Informed consent statement: Patients were not required to give informed consent to the study because the analysis used anonymised clinical data that were obtained after each patient agreed to treatment by written consent.
Conflict-of-interest statement: The authors declare that they have no financial relationships to disclose.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Vaneja Velenik, MD, PhD, Associate Professor, Division of Radiotherapy, Institute of Oncology, Zaloška cesta 2, Ljubljana 1000, Slovenia.
Received: September 27, 2020
Peer-review started: September 27, 2020
First decision: December 12, 2020
Revised: December 22, 2020
Accepted: January 7, 2021
Article in press: January 7, 2021
Published online: February 15, 2021

For locally advanced rectal cancer (LARC), standard therapy [consisting of neoadjuvant chemoradiotherapy (CRT), surgery, and adjuvant chemotherapy (ChT)] achieves excellent local control. Unfortunately, survival is still poor due to distant metastases, which remains the leading cause of death among these patients. In recent years, the concept of total neoadjuvant treatment (TNT) has been developed, whereby all systemic ChT-mainly affecting micrometastases-is applied prior to surgery.


To compare standard therapy and total neoadjuvant therapy for LARC patients with high-risk factors for failure.


In a retrospective study, we compared LARC patients with high-risk factors for failure who were treated with standard therapy or with TNT. High-risk for failure was defined according to the presence of at least one of the following factors: T4 stage; N2 stage; positive mesorectal fascia; extramural vascular invasion; positive lateral lymph node. TNT consisted of 12 wk of induction ChT with capecitabine and oxaliplatin or folinic acid, fluorouracil and oxaliplatin, CRT with capecitabine, and 6-8 wk of consolidation ChT with capecitabine and oxaliplatin or folinic acid, fluorouracil and oxaliplatin prior to surgery. The primary endpoint was pathological complete response (pCR). In total, 72 patients treated with standard therapy and 89 patients treated with TNT were included in the analysis.


Compared to standard therapy, TNT showed a higher proportion of pCR (23% vs 7%; P = 0.01), a lower neoadjuvant rectal score (median: 8.43 vs 14.98; P < 0.05), higher T-and N-downstaging (70% and 94% vs 51% and 86%), equivalent R0 resection (95% vs 93%), shorter time to stoma closure (mean: 20 vs 33 wk; P < 0.05), higher compliance during systemic ChT (completed all cycles 87% vs 76%; P < 0.05), lower proportion of acute toxicity grade ≥ 3 during ChT (3% vs 14%, P < 0.05), and equivalent acute toxicity and compliance during CRT and in the postoperative period. The pCR rate in patients treated with TNT was significantly higher in patients irradiated with intensity-modulated radiotherapy/volumetric-modulated arc radiotherapy than with 3D conformal radiotherapy (32% vs 9%; P < 0.05).


Compared to standard therapy, TNT provides better outcome for LARC patients with high-risk factors for failure, in terms of pCR and neoadjuvant rectal score.

Keywords: Locally advanced rectal cancer, Total neoadjuvant therapy, Pathological complete response, Neoadjuvant rectal cancer score

Core Tip: Our data suggest that treatment of locally advanced rectal cancer (LARC) with high-risk factors for failure using total neoadjuvant therapy (TNT) is more effective than standard therapy, achieving a higher rate of pathological complete response, more favourable survival prognosis, higher proportion of T-and N-downstaging, shorter time to temporary stoma closure, better compliance, and lower toxicity grade 3-5 during systemic chemotherapy. The outcomes of TNT in patients with the most aggressive form of LARC are completely comparable to TNT in all patients with LARC.