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. 2022 Nov 4;17(11):e0276599. doi: 10.1371/journal.pone.0276599

Total neoadjuvant therapy versus standard therapy in locally advanced rectal cancer: A systematic review and meta-analysis of 15 trials

Xiping Zhang 1, Shujie Ma 2, Yinyin Guo 3, Yang Luo 4, Laiyuan Li 5,*
Editor: Alessandro Rizzo6
PMCID: PMC9635708  PMID: 36331947

Abstract

Background

Neoadjuvant chemoradiotherapy (nCRT) before total mesorectal excision (TME) and followed systemic chemotherapy is widely accepted as the standard therapy for locally advanced rectal cancer (LARC). This meta-analysis was to evaluate the current evidence regarding nCRT in combination with induction or consolidation chemotherapy for rectal cancer in terms of oncological outcomes.

Methods

A systematic search of medical databases (PubMed, EMBASE and Cochrane Library) was conducted up to the end of July 1, 2021. This meta-analysis was performed to evaluate the efficacy of TNT in terms of pathological complete remission (pCR), nCRT or surgical complications, R0 resection, local recurrence, distant metastasis, disease-free survival (DFS) and overall survival (OS) in LARC.

Results

Eight nRCTs and 7 RCTs, including 3579 patients were included in the meta-analysis. The rate of pCR was significantly higher in the TNT group than in the nCRT group, (OR 1.85, 95% CI 1.39–2.46, p < 0.0001), DFS (HR 0.80, 95% CI 0.69–0.92, p = 0.001), OS (HR 0.75, 95% CI 0.62–0.89, p = 0.002), nCRT complications (OR 1.05, 95% CI 0.77–1.44, p = 0.75), surgical complications (OR 1.02, 95% CI 0.83–1.26, p = 0.83), local recurrence (OR 1.82, 95% CI 0.95–3.49, p = 0.07), distant metastasis (OR 0.77, 95% CI 0.58–1.03, p = 0.08) did not differ significantly between the TNT and nCRT groups.

Conclusion

TNT appears to have advantages over standard therapy for LARC in terms of pCR, R0 resection, DFS, and OS, with comparable nCRT and postoperative complications, and no increase in local recurrence and distant metastasis.

Introduction

Neoadjuvant chemoradiotherapy (nCRT) before total mesorectal excision (TME) and followed systemic chemotherapy is widely accepted as the standard therapy for locally advanced rectal cancer (LARC). Although nCRT and preoperative systemic chemotherapy are the preferred approach for LARC, it does not provide better results in terms of disease-free survival (DFS) and overall survival (OS) compared with surgery and adjuvant chemotherapy [1]. The concept of total neoadjuvant therapy (TNT), in which chemotherapy and chemoradiation are administered before TME, can be administered exclusively for patients with widespread LARC [2, 3]. TNT has also become a platform for studying systemic chemotherapy, new radiation sensitizers and immunotherapy agents for LARC [4, 5]. The NCCN guidelines have approved the use of TNT [6], however, the current evidence is preliminary, we tried to further consolidate the evidence through meta-analysis of related studies.

Methods

Literature search strategy

A systematic search of medical databases (PubMed, EMBASE and Cochrane Library) was conducted up to the end of July 1, 2021. We used the following search MeSH terms: neoadjuvant therapy, neoadjuvant chemoradiotherapy, preoperative chemoradiotherapy, neoadjuvant chemoradiation, chemoradiotherapy, total neoadjuvant therapy, total mesorectal excision, rectal cancer. We also searched bibliographies of identified reports for additional references.

Study inclusion and exclusion criteria

Studies inclusion criteria in the meta-analysis were list as follow: (a) randomized controlled trials (RCTs) or non-randomized controlled trials (nRCTs), (b) TNT versus nCRT in LARC, (c) interest outcomes describing the details of pCR, chemoradiotherapy or surgical complications, R0 resection, local recurrence, distant metastasis, DFS and OS. Review/case reports, no comparable data, repeat publications were excluded.

Data extraction and quality assessment

Two authors performed study selection, evaluation, and data extraction independently, and discrepancies were resolved by consensus including a third author. The primary endpoint was pCR, The secondary endpoints were chemoradiotherapy or surgical complications, R0 resection, local recurrence, distant metastasis, DFS and OS. Study characteristics were extracted independently by two researchers. Corresponding authors were contacted via e-mail for missing data when necessary. The methodological quality of the included studies was assessed using the Jadad Score [total score from 0 (poor) to 5 (excellent)] for RCT or the Newcastle-Ottawa scale (NOS) [total score from 0 (poor) to 9 (excellent)] for nRCTs [7, 8]. A Jadad scale score≥3 points for RCTs and NOS score≥6 points for nRCTs were considered high quality.

Statistical analysis

Continuous variables were analysed using weighted mean differences (WMD) and 95% confidence intervals (CIs). Pooled odds ratios (ORs) and 95% CIs were calculated for dichotomous variables. Statistical heterogeneity between trials was assessed by using the I2 test, a value of 50% or greater suggests moderate to substantial inconsistency among studies. Random effects models were used if high heterogeneity between study existed, Otherwise, fixed-effects models were used. Subgroup analysis and sensitivity analysis was performed to identify potential heterogeneity [9, 10]. Publication bias was investigated using Begg’s and Egger’s tests [11]. All statistical tests were performed using Review Manager Version 5.3 and STATA/SE version 13.1. The significance level was set at p < 0.05.

Results

Fig 1 shows the selection of relevant studies for inclusion in the meta-analysis. A total of 8 nRCTs with 1502 and 7 RCTs with 2077 enrolled patients enrolled patients were included for this meta-analysis [12–26] (Fig 1), there were 1812 patients in the TNT group and 1767 patients in the nCRT group. The main characteristics of the included studies are summarized in Table 1.

Fig 1. Flow chart indicating the selection process for this meta-analysis.

Fig 1

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Table 1. Characteristics of the studies included in the meta-analysis.

First author/Year Study design CRTvsTNT TNT regimen CRT regimen Follow-up (months) Study quality
Number of patients Male gender (%) Age (year) (mean ± SD) T4 N2 CRM+ RT Dose (Gys)
Marechal R/2012 RCT 29vs28 75vs55 62.5±8.8vs62 ±14.5 NR NR NR 45vs45 FOLFOX *2→CRT→Sur CRT(5FU)→Sur NR −/3
Fernandez C/2015 RCT 62vs60 70vs65 62±8.3vs60±9.5 3vs2 NR 5vs- NR XELOX * 4→CRT→Sur CRT→Sur→CT 69 −/3
Bujko K/2016 RCT 254vs261 67vs70 NR NR NR NR 50.4vs25 SCRT→FOLFOX *3→Sur CRT→ Sur 35 −/4
Moore J/2017 RCT 24Vs25 75vs73 60.5 ±12.6 vs59.7 ±9.9 163vs165 NR NR NR CRT→5FU * 3→Sur CRT→Sur NR −/4
Kim SY/2018 RCT 55Vs53 84vs68 55± 8 vs56± 10 1vs5 19vs15 14vs16 50.4vs50.4 CRT→XELOX *2→Sur CRT→Sur NR −/4
Conroy T/2020 RCT 230Vs231 NR NR 10vs9 NR NR 50.4vs50.4 FOLFIRINOX*6→CRT→Sur CRT→Sur→ FOLFOX 46.5 −/3
Bahadoer RR/2021 RCT 450vs462 69vs65 62±2.2vs62±2.3 35vs41 NR NR 25vs50.4 CRT→XELOX *6/→Sur CRT→Sur→ CT 54 −/4
Cui J/2020 Re 61vs83 56vs69 56 ±13.5vs54 ±12 20vs15 NR NR NR CRT→XELOX * 2→Sur NR NR 7★/−
Liang HQ/2018 Re 80vs76 NR 64vs75 44vs50 11vs21 NR NR CRT→mFOLFOX *2–4→Sur CRT→Sur 32vs30 6★/−
Cercek A/2018 Re 320vs308 60vs59 NR 57vs62 45vs36 NR NR NR NR 46vs23 7★/−
Bhatti AB /2015 Re 61vs93 69vs68 NR 20vs36 NR 8vs17* 50.4vs50.4 mFOLFOX6 *4→ CRT→Sur CRT→Sur NR 8★/−
Thakur N./2020 Pro 13vs15 -NR NR NR NR NR 25vs25 CRT→mFOLFOX6 *2→Sur CRT→Sur NR 8★/−
van Zoggel D/2018 Pro 71vs58 57Vs79 65±9vs64 ±10 NR NR NR NR FOLFOX *4→ CRT→Sur CRT→Sur NR 7★/−
Garcia-Aguilar J/2015 Pro 60vs65 62vs63 57 ±13.3vs58 ±9.8 NR NR NR NR CRT→mFOLFOX6 *6→Sur CRT→Sur NR 7★/−
Markovina S/2017 Pro 69vs69 67vs71 56.6 ±12.9vs57.2 ±12.6 1vs3 NR NR NR CRT→mFOLFOX6 →Sur NR 54.3 vs49.4 8★/−
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★ number of stars for Nottingham Ottawa scale for each included trial,* Postradiotherapy, NOS = Nottingham-Ottawa scale, CRT = Chemoradiotherapy, CT = chemotherapy, TNT = total neoadjuvant therapy, Pro = prospective, Sur = surgery; Re = retrospective, RCTs = randomized controlled trial, NR = no report.

Primary endpoints

pCR

Overall, including the 15 studies selected, 652 of 3579 patients (18.2%) achieved a pCR after neoadjuvant therapy, 412 of 1812 (22.7%) in the TNT group and 240 of 1767 (13.6%) in the standard group (OR 1.85, 95% CI 1.39–2.46, p < 0.0001), with certain statistical heterogeneity (I2 = 48%, p = 0.02)(Fig 2). A subgroup analysis showed that single-center or multi-center studies, sample size, RCT or nRCT, neoadjuvant therapy were not causes of heterogeneity in view of the dissimilarity between subgroups (Table 2). The sensibility analysis performed showed stability of the pCR when excluding each study at a time (Table 3).

Fig 2. Forest plot for pCR, OR are shown with 95% confidence interval.

Fig 2

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Table 2. Subgroup analyses of PCR based on the study type, setting, sample size and chemoradiotherapy sequence.
Outcome Subgroup No. of studies No. of patients Study Heterogeneity Model Meta-analysis
TNTvsCRT I 2 (%) P Value OR (95%CI) P Value
pCR Study type RCT 7 1045vs 1032 45 0.09 Fixed 1.75 [1.21, 2.54] 0.003
Prospective 4 207 vs 213 0 0.76 Fixed 2.65 [1.56, 4.50] 0.0003
Retrospective 4 560 vs 522 70 0.02 Random 1.42 [1.03, 1.96] 0.03
Setting Single-center 7 702vs 675 55 0.04 Random 2.01 [1.20, 3.39] 0.009
Multi-center 8 1117vs1095 32 0.20 Fixed 2.19 [1.62, 2.50] < 0.00001
Sample size ≥200 4 1200 vs 1195 81 0.001 Random 1.71 [1.02, 2.84] 0.04
< 200 11 619 vs 565 0 0.50 Fixed 2.24 [1.62, 2.91] < 0.00001
Chemoradiotherapy CT first 4 498 vs 381 31 0.19 Fixed 2.23 [1.61, 3.27] < 0.0001
Radiation first 11 1421 vs 1389 49 0.03 Random 1.81 [1.30, 2.51] 0.0004
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CRT = Chemoradiotherapy, TNT = total neoadjuvant therapy, OR = odds ratio, CI = confidence interval.

Table 3. Sensitivity analysis for pathological complete response.
Study Excluded Random Effect Heterogeneity
OR 95% CI p Value I2 (%) I2- P Value
van Zoggel D/2018 1.79 1.34, 2.38 < 0.00001 48 0.02
Garcia-Aguilar J/2015 1.80 1.33, 2.42 0.0001 50 0.02
Markovina S/2017 1.84 1.36, 2.50 < 0.0001 52 0.01
Thakur N/2020 1.85 1.38, 2.47 < 0.0001 52 0.01
Bhatti AB /2015 1.86 1.37, 2.53 < 0.0001 52 0.01
Cercek A/2018 2.08 1.66, 2.61 < 0.00001 13 0.31
Cui J/2020 1.79 1.34, 2.38 < 0.0001 48 0.02
Liang HQ/2018 1.81 1.33, 2.45 0.0001 50 0.02
Bahadoer RR/2021 1.79 1.30, 2.45 0.0003 46 0.03
Bujko K/2016 1.92 1.40, 2.62 < 0.0001 49 0.02
Conroy T/2020 1.76 1.30, 2.37 0.0002 45 0.03
Fernandez-Martos C/2015 1.91 1.42, 2.56 < 0.0001 50 0.02
Kim SY/2018 1.83 1.36, 2.46 < 0.0001 51 0.01
Marechal R/2012 1.92 1.43, 2.56 < 0.0001 49 0.02
Moore J/2017 1.92 1.45, 2.55 < 0.00001 46 0.03
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OR = odds ratio; CI = confidence interval.

Secondary endpoints

Chemoradiotherapy complications

Overall, including the 11 studies selected, 1000 of 3534 patients (28.3%) occurred G3–4 adverse events after neoadjuvant therapy, 576 of 1996 (28.9%) in the TNT group and 424 of 1538 (27.6%) in the standard group (OR 1.03, 95% CI 0.73–1.43, p = 0.88), with certain statistical heterogeneity (I2 = 66%, p = 0.001) (Fig 3A).

Fig 3. Forest plot for chemoradiotherapy complications and surgical complications, OR are shown with 95% CIs.

Fig 3

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Surgical complications

Overall, including the 10 studies selected, 527 of 2497 patients (21.1%) occurred surgical complications, 267 of 1273 (21.0%) in the TNT group and 260 of 1224 (21.2%) in the standard group (OR 1.02, 95% CI 0.83–1.26, p = 0.83), with no evidence of significant heterogeneity (I2 = 0%, p = 0.92) (Fig 3B).

R0 resection

Overall, including the 11 studies selected, 1894 of 2238 patients (84.6%) achieved R0 resection, 989 of 1143 (86.5%) in the TNT group and 905 of 1095 (82.6%) in the standard group (OR 1.34, 95% CI 1.05–1.71, p = 0.02), with no evidence of significant heterogeneity (I2 = 28%, p = 0.18) (Fig 4A).

Fig 4. Forest plot for R0 resection and distant metastasis, OR are shown with 95% Cis.

Fig 4

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Local recurrence

Overall, including the two studies selected, 42 of 436 patients (9.6%) occurred local recurrence, 25 of 204 (12.2%) in the TNT group and 17 of 232 (7.3%) in the standard group (OR 1.82, 95% CI 0.95–3.49, p = 0.07), with no evidence of significant heterogeneity (I2 = 31%, p = 0.23) (Fig 4B).

Distant metastasis

Overall, including the 7 studies selected, 238 of 1080 patients (22.0%) occurred distant metastasis, 111 of 556 (20.0.5%) in the TNT group and 127 of 524 (24.2%) in the standard group (OR 0.77, 95% CI 0.58–1.03, p = 0.08), with no evidence of significant heterogeneity (I2 = 38%, p = 0.14) (Fig 4C).

DFS

Seven studies reported DFS and the results showed that the TNT group had a significantly longer DFS than the standard group (HR 0.80, 95% CI 0.69–0.92, p = 0.001), with no evidence of significant heterogeneity (I2 = 0%, p = 0.43) (Fig 5A).

Fig 5. Forest plot for DFS and OS, HR are shown with 95% Cis.

Fig 5

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OS

Seven studies reported OS and the results showed that the TNT group had a significantly longer OS than the standard group (HR 0.75, 95% CI 0.62–0.89, p = 0.002), with no evidence of significant heterogeneity (I2 = 36%, p = 0.15) (Fig 5B).

Sensitivity analysis and publication bias

The sensibility analysis performed showed stability of the pooled OR with pCR when excluding each study at a time. There was no significant publication bias in the analyses of pCR (Egger’s test, p = 0.850; Begg’s test, p = 0.729) (Fig 6).

Fig 6. Funnel plot using Begg method for pCR.

Fig 6

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Discussion

In the meta-analysis, we compared the efficacy of TNT with that of standard therapy for LARC. TNT appears to have advantages over standard therapy for LARC in terms of pCR, R0 resection, DFS, and OS, with comparable nCRT and postoperative complications, and no increase in local recurrence and distant metastasis.

In this meta-analysis, we observed that the overall pCR rate of TNT may increase compared with chemoradiotherapy. Our results were consistent with previous reports [27]. However, our meta-analysis included more and newer studies, which further confirmed the advantage of TNT in rectal cancer. In the review of 16 studies involving a total of 3363 patients, patients who experienced pCR had a 75%, lower risk of distant (8.7%) and local (0.7%) recurrence than patients who did not [28]. Compared with patients with incomplete response, patients with pCR after neoadjuvant therapy are less likely to have local recurrence and more likely to have better survival outcomes [29]. pCR is considered to be the key prognostic criterion for the long-term prognosis of LARC [30]. The use of TNT can significantly reduce tumor volume, which may lead to more patients adopting non-surgical observation and waiting strategies in the future. Habr-Gama et al introduced the watch-and-wait strategy [31], they reported that after 10 years of follow-up, patients who gave up surgery after obtaining complete clinical response had an OS rate of 97.7% and a DFS rate of 84%. pCR for rectal cancer is associated with excellent long-term prognosis, independent of treatment strategy. Surgical resection may not improve outcomes while increasing the incidence of temporary or permanent stoma and unnecessary morbidity and mortality. Another potential advantage of simultaneous chemotherapy and radiochemotherapy is that it can avoid or delay surgery when a complete clinical response is observed. The watch-and-wait approach may be considered a better treatment strategy, because surgery may lead to intestinal or bladder incontinence and sexual dysfunction, as well as short-term or permanent stoma [32–35].

Adjuvant chemotherapy is recommended by current guidelines, however, patient compliance is poor and survival benefit is unclear. Although the nCRT approach has made significant improvements in local control, the incidence of distal metastasis has not decreased. In our meta-analysis, the rate of DFS and OS was significantly higher in the TNT group than in the nCRT group, although studies have shown that watch-and-wait approach is associated with higher rectal preservation, which may be at the expense of lower OS rates and increased risk of distant metastasis [36]. In addition, treatment-related toxicity appeared to be acceptable in all patients who completed TNT therapy. Although TNT was associated with an increased incidence of pelvic fibrosis and a longer interval from nCRT to surgery, TNT did not lead to an increase in surgical difficulty or postoperative complications [17]. However, these results should be interpreted with caution, as the lack of standardization of postoperative morbidity reports limits the interpretation of the results. Another disadvantage is the short follow-up period, so the assessment of long-term distant metastases needs to be cautious.

Assessment of quality of life (QOL) was not included in this meta-analysis, in the EXPERT-C trial, intensified neoadjuvant strategy for QoL and bowel function did not appear to be significantly affected [37]. This study was conducted at an appropriate time, because enough data was available to use meta-analytical methods which enabled us to provide the most up-to-date information on this topic.

Our study has the following limitations. First, although the meta-analysis including RCT is ideal, the limited number of RCTs prevents us from drawing clear conclusions. Second, the follow-up included in this meta-analysis is short, and the long-term survival benefit remains to be confirmed. However, this meta-analysis was completed at the appropriate time, and we provide the latest information in this area.

In conclusion, TNT appears to have advantages over standard therapy for LARC in terms of pCR, R0 resection, DFS, and OS, with comparable nCRT and postoperative complications, and no increase in local recurrence and distant metastasis. If these findings can be applied clinically, more patients with LARC will be eligible for organ preservation, which will avoid surgical sequelae and improve quality of life.

Supporting information

S1 Checklist. PRISMA 2009 checklist.

(DOC)

Click here for additional data file. (56.5KB, doc)

Data Availability

All relevant data are within the paper.

Funding Statement

the Natural Science Foundation of Gansu Province (No.20JR10RA371, L.LY), Fundamental Research Funds for the Central Universities (No.lzujbky-2019-kb21 L.L.Y & No.lzujbky-2020-kb22 L.Y), and Institute Scientific Research Fund Project/Youth Project(No. 20GSSY4-8 L.L.Y). The funders (Laiyuan Li and Yang Luo) had a role in study design, data collection, analysis, the decision to publish, and preparation of the manuscript.

References

  • 1.Bosset JF, Collette L, Calais G, et al. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med 2006; 355(11): 1114–23. doi: 10.1056/NEJMoa060829 [DOI] [PubMed] [Google Scholar]
  • 2.Chau I, Brown G, Cunningham D, et al. Neoadjuvant capecitabine and oxaliplatin followed by synchronous chemoradiation and total mesorectal excision in magnetic resonance imaging-defined poor-risk rectal cancer. J Clin Oncol 2006; 24(4): 668–74. doi: 10.1200/JCO.2005.04.4875 [DOI] [PubMed] [Google Scholar]
  • 3.Cercek A, Roxburgh CSD, Strombom P, et al. Adoption of Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer. JAMA Oncol 2018; 4(6): e180071. doi: 10.1001/jamaoncol.2018.0071 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Goodman KA. Total neoadjuvant therapy for rectal cancer. Cancer Radiother 2018; 22(5): 459–65. doi: 10.1016/j.canrad.2018.01.004 [DOI] [PubMed] [Google Scholar]
  • 5.Franke AJ, Parekh H, Starr JS, Tan SA, Iqbal A, George TJ Jr. Total Neoadjuvant Therapy: A Shifting Paradigm in Locally Advanced Rectal Cancer Management. Clin Colorectal Cancer 2018; 17(1): 1–12. doi: 10.1016/j.clcc.2017.06.008 [DOI] [PubMed] [Google Scholar]
  • 6.National Comprehensive Cancer Network. NCCN guidelines: rectal cancer. https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1461. Accessed Version 1.2021.
  • 7.Clark HD, Wells GA, Huet C, et al. Assessing the quality of randomized trials: reliability of the Jadad scale. Control Clin Trials 1999; 20(5): 448–52. doi: 10.1016/s0197-2456(99)00026-4 [DOI] [PubMed] [Google Scholar]
  • 8.Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 2010; 25(9): 603–5. doi: 10.1007/s10654-010-9491-z [DOI] [PubMed] [Google Scholar]
  • 9.Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959; 22(4): 719–48. [PubMed] [Google Scholar]
  • 10.DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986; 7(3): 177–88. doi: 10.1016/0197-2456(86)90046-2 [DOI] [PubMed] [Google Scholar]
  • 11.Egger M, Smith GD, Phillips AN. Meta-analysis: principles and procedures. BMJ 1997; 315(7121): 1533–7. doi: 10.1136/bmj.315.7121.1533 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Conroy T., Lamfichekh N., Etienne P., E, et al. Total neoadjuvant chemotherapy with mFOLFIRINOX versus preoperative chemo-radiation in patients with locally advanced rectal cancer: Final results of the PRODIGE 23 phase III trial, a UNICANCER GI trial. J. Clin. Oncol. 2020, 38, 4007. 2020. [Google Scholar]
  • 13.Bahadoer RR, Dijkstra EA, van Etten B, 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. doi: 10.1016/S1470-2045(20)30555-6 [DOI] [PubMed] [Google Scholar]
  • 14.Bhatti AB, Waheed A, Hafeez A, et al. Can induction chemotherapy before concurrent chemoradiation impact circumferential resection margin positivity and survival in low rectal cancers? Asian Pac J Cancer Prev 2015; 16(7): 2993–8. doi: 10.7314/apjcp.2015.16.7.2993 [DOI] [PubMed] [Google Scholar]
  • 15.Bujko K, Wyrwicz L, Rutkowski A, et al. Long-course oxaliplatin-based preoperative chemoradiation versus 5 x 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. [DOI] [PubMed] [Google Scholar]
  • 16.Fernandez-Martos C, Garcia-Albeniz X, Pericay 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 trialdagger. Ann Oncol 2015; 26(8): 1722–8. [DOI] [PubMed] [Google Scholar]
  • 17.Garcia-Aguilar J, Chow OS, Smith DD, et al. Effect of adding mFOLFOX6 after neoadjuvant chemoradiation in locally advanced rectal cancer: a multicentre, phase 2 trial. Lancet Oncol 2015; 16(8): 957–66. doi: 10.1016/S1470-2045(15)00004-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Kim SY, Joo J, Kim TW, 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. doi: 10.1016/j.ijrobp.2018.04.013 [DOI] [PubMed] [Google Scholar]
  • 19.Liang HQ, Dong ZY, Liu ZJ, et al. Efficacy and safety of consolidation chemotherapy during the resting period in patients with local advanced rectal cancer. Oncol Lett 2019; 17(2): 1655–63. doi: 10.3892/ol.2018.9804 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Marechal R, Vos B, Polus M, 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. doi: 10.1093/annonc/mdr473 [DOI] [PubMed] [Google Scholar]
  • 21.Markovina S, Youssef F, Roy A, et al. Improved Metastasis- and Disease-Free Survival With Preoperative Sequential Short-Course Radiation Therapy and FOLFOX Chemotherapy for Rectal Cancer Compared With Neoadjuvant Long-Course Chemoradiotherapy: Results of a Matched Pair Analysis. Int J Radiat Oncol Biol Phys 2017; 99(2): 417–26. doi: 10.1016/j.ijrobp.2017.05.048 [DOI] [PubMed] [Google Scholar]
  • 22.Moore J, Price T, Carruthers S, 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. doi: 10.1111/codi.13724 [DOI] [PubMed] [Google Scholar]
  • 23.van Zoggel D, Bosman SJ, Kusters M, et al. Preliminary results of a cohort study of induction chemotherapy-based treatment for locally recurrent rectal cancer. Br J Surg 2018; 105(4): 447–52. doi: 10.1002/bjs.10694 [DOI] [PubMed] [Google Scholar]
  • 24.Fernandez-Martos C, Pericay C, Aparicio J, 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 cancer de recto 3 study. J Clin Oncol 2010; 28(5): 859–65. doi: 10.1200/JCO.2009.25.8541 [DOI] [PubMed] [Google Scholar]
  • 25.Cui J, Dou X, Sun Y, Yue J. Consolidation chemotherapy may improve pathological complete response for locally advanced rectal cancer after neoadjuvant chemoradiotherapy: a retrospective study. PeerJ 2020; 8: e9513. doi: 10.7717/peerj.9513 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Thakur N, Seam RK, Gupta MK, et al. A Prospective Observational Study Comparing Long-Course Conventional Neoadjuvant Chemoradiotherapy with Short-Course Radiotherapy Followed by Consolidation Chemotherapy with Delayed Surgery in Locally Advanced Rectal Cancer. South Asian J Cancer 2020; 9(2): 80–5. doi: 10.1055/s-0040-1721220 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Liu S, Jiang T, Xiao L, 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–e66. doi: 10.1002/onco.13824 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Martin ST, Heneghan HM, Winter DC. Systematic review and meta-analysis of outcomes following pathological complete response to neoadjuvant chemoradiotherapy for rectal cancer. Br J Surg 2012; 99(7): 918–28. doi: 10.1002/bjs.8702 [DOI] [PubMed] [Google Scholar]
  • 29.Garcia-Aguilar J, Hernandez de Anda E, Sirivongs P, Lee SH, Madoff RD, Rothenberger DA. 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. doi: 10.1007/s10350-004-6545-x [DOI] [PubMed] [Google Scholar]
  • 30.Omejc M, Potisek M. Prognostic Significance of Tumor Regression in Locally Advanced Rectal Cancer after Preoperative Radiochemotherapy. Radiol Oncol 2018; 52(1): 30–5. doi: 10.1515/raon-2017-0059 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Habr-Gama A, Perez RO, Nadalin W, et al. Operative versus nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: long-term results. Ann Surg 2004; 240(4): 711–7; discussion 7–8. doi: 10.1097/01.sla.0000141194.27992.32 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Sun V, Grant M, Wendel CS, et al. Sexual Function and Health-Related Quality of Life in Long-Term Rectal Cancer Survivors. J Sex Med 2016; 13(7): 1071–9. doi: 10.1016/j.jsxm.2016.05.005 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Thyo A, Emmertsen KJ, Laurberg S. The Rectal Cancer Female Sexuality Score: Development and Validation of a Scoring System for Female Sexual Function After Rectal Cancer Surgery. Dis Colon Rectum 2018; 61(6): 656–66. doi: 10.1097/DCR.0000000000001064 [DOI] [PubMed] [Google Scholar]
  • 34.Lewis OA, McCallum IJ, Dixon S, Katory M. Longterm -ostomy as a quality marker: Comparison of outcomes from a six year series of laparoscopic surgery in MRI defined low rectal cancer. Int J Surg 2015; 23(Pt A): 108–14. doi: 10.1016/j.ijsu.2015.09.054 [DOI] [PubMed] [Google Scholar]
  • 35.Wu X, Lin G, Qiu H, Xiao Y, Wu B, Zhong M. Loop ostomy following laparoscopic low anterior resection for rectal cancer after neoadjuvant chemoradiotherapy. Eur J Med Res 2018; 23(1): 24. doi: 10.1186/s40001-018-0325-x [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Smith JJ, Strombom P, Chow OS, et al. Assessment of a Watch-and-Wait Strategy for Rectal Cancer in Patients With a Complete Response After Neoadjuvant Therapy. JAMA Oncol 2019; 5(4): e185896. doi: 10.1001/jamaoncol.2018.5896 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Sclafani F, Peckitt C, Cunningham D, et al. Short- and Long-Term Quality of Life and Bowel Function in Patients With MRI-Defined, High-Risk, Locally Advanced Rectal Cancer Treated With an Intensified Neoadjuvant Strategy in the Randomized Phase 2 EXPERT-C Trial. Int J Radiat Oncol Biol Phys 2015; 93(2): 303–12. doi: 10.1016/j.ijrobp.2015.03.038 [DOI] [PubMed] [Google Scholar]

Decision Letter 0

Norikatsu Miyoshi

16 Jun 2022

PONE-D-22-09905Total Neoadjuvant Therapy versus Standard Therapy in Locally Advanced Rectal Cancer:A Systematic Review and Meta-Analysis of 16 TrialsPLOS ONE

Dear Dr. Li,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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Academic Editor

PLOS ONE

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Reviewer #1: Yes

Reviewer #2: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

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Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

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Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: These findings come from a meta-analysis of 16 research, eight of which were non-randomized and eight of which were randomized controlled trials comparing TNT to regular CRT.

However, there are a few aspects that need to be clarified:

1. Before therapy, the characteristics of tumors in both groups should be evaluated and the results given (T stage N stage, whether they threaten CRM).

2. Both groups' post-radiotherapy waiting periods must be compared.

3. Distant metastases were investigated, but not local recurrence rates. Local recurrence rates, which are a crucial predictor of preoperative neoadjuvant therapy success, should not be overlooked.

4. Minor correction: Disease-free survival should be shortened to DFS.

Reviewer #2: The authors meta-analysis answered a significant research question in the field of surgical oncological treatment for locally advanced rectal cancer . However, the following issues needed to be addressed before this piece of work could be published

1. There are spelling mistakes "PFS wrongly used for DFS"

2. The authors didn't give a based argument on the subject of TNT and standard care (CRT). In line 5, under discussion, the authors were silent /did not discuss the controversies surrounding the result from Habr -Gama et al, there are other excellent centres in the world who have not been able to reproduce the same result following TNT

3. The sentence in 15 is unclear to me "In this meta-analysis, the DFS and distant metastasis of TNT were significantly superior to nCRT alone, despite studies have shown that the watch-and-wait approach is associated with higher preserved rectum, which may be at the cost of reducing the rate of OS and increasing the risk of distant metastasis"

4. There is a similar publication on this subject by Liu S, Jiang T, Xiao L, Yang S et .at in cancer 2021. Why would you repeat a similar meta-analysis within a year part. I would have expected the authors to make reference to this study and show us a clear benefit of there's over the 2021 publication- this have not been done.

5. I would have expected the authors to buttress the positive findings from TNT by citing other authors report and perhaps proffer suggestion why there is no significant difference as regards surgical complication , R0 resection rate and distant metastasis .

6. I am not sure if the authors were meant to use the term superiority when referencing to the overall benefit of TNT over standard CRT. The superiority and inferiority test mostly applies to original research where is a null or alternative hypothesis to prove or disprove , hence to my understanding it does not apply to this meta-analysis.

7. There are other limitations to this study that was not discussed.

8. Would have expected the authors to make reference to QOL in TNT vs CRT even though , this might have not been discussed in the other main articles.

**********

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Reviewer #1: Yes: Cihangir Akyol,MD.

Reviewer #2: No

**********

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PLoS One. 2022 Nov 4;17(11):e0276599. doi: 10.1371/journal.pone.0276599.r002

Author response to Decision Letter 0

21 Jul 2022

Dear Editors and Reviewers:

Thank you for your letter and for the reviewers’ comments concerning our manuscript entitled “Total Neoadjuvant Therapy versus Standard Therapy in Locally Advanced Rectal Cancer:A Systematic Review and Meta-Analysis of 15 Trials” (ID: PONE-D-22-09905).Those comments are all valuable and very helpful for revising and improving our paper, as well as the important guiding significance to our researches. We have studied comments carefully and have made correction which we hope meet with approval. Revised portion are marked in red in the paper. The main corrections in the paper and the responds to the reviewer’s comments are as flowing:

We appreciate for Editors/Reviewers’ warm work earnestly, and hope that the correction will meet with approval.

Once again, thank you very much for your comments and suggestions.

Laiyuan Li

Review Comments to the Author

Reviewer #1: These findings come from a meta-analysis of 16 research, eight of which were non-randomized and eight of which were randomized controlled trials comparing TNT to regular CRT.

However, there are a few aspects that need to be clarified:

1.Before therapy, the characteristics of tumors in both groups should be evaluated and the results given (T stage N stage, whether they threaten CRM).

Response –We are very sorry for our negligence of characteristics of tumors, We have added CRM+ in Table 1, due to space constraints, only the stage of T4 N2 was added.

2.Both groups' post-radiotherapy waiting periods must be compared.

Response –We have added in table 1.

3.Distant metastases were investigated, but not local recurrence rates. Local recurrence rates, which are a crucial predictor of preoperative neoadjuvant therapy success, should not be overlooked.

Response –We have added it in methods and results section.

4. Minor correction: Disease-free survival should be shortened to DFS.

Response –Yes, we have revised it.Special thanks to you for your careful revision. 

Reviewer #2: The authors meta-analysis answered a significant research question in the field of surgical oncological treatment for locally advanced rectal cancer . However, the following issues needed to be addressed before this piece of work could be published

1.There are spelling mistakes "PFS wrongly used for DFS"

Response –We are very sorry for our incorrect writing, we have revised it.

2.The authors didn't give a based argument on the subject of TNT and standard care (CRT). In line 5, under discussion, the authors were silent /did not discuss the controversies surrounding the result from Habr -Gama et al, there are other excellent centres in the world who have not been able to reproduce the same result following TNT

Response –We have made correction according to the comments.We made the following comments about the study: pCR for rectal cancer is associated with excellent long-term prognosis, independent of treatment strategy. Surgical resection may not improve outcomes while increasing the incidence of temporary or permanent stoma and unnecessary morbidity and mortality.Please find it on page 6, line 15.

3.The sentence in 15 is unclear to me "In this meta-analysis, the DFS and distant metastasis of TNT were significantly superior to nCRT alone, despite studies have shown that the watch-and-wait approach is associated with higher preserved rectum, which may be at the cost of reducing the rate of OS and increasing the risk of distant metastasis"

Response –Considering the your suggestion,we have revised it as follow: In our meta-analysis, the rates of DFS and OS was significantly higher in the TNT group than in the nCRT group, although studies have shown that watch-and-wait approach is associated with higher rectal preservation, which may be at the expense of lower OS rates and increased risk of distant metastasis.Please find it on page 6, line 27.

4.There is a similar publication on this subject by Liu S, Jiang T, Xiao L, Yang S et .at in cancer 2021. Why would you repeat a similar meta-analysis within a year part. I would have expected the authors to make reference to this study and show us a clear benefit of there's over the 2021 publication- this have not been done.

Response –Our comments are follow: Our results were consistent with previous reports.(PMID 33987952), however, our meta-analysis included more and newer studies, which further confirmed the advantage of TNT in rectal cancer. This study was conducted at an appropriate time, because enough data was available to use meta-analytical methods which enabled us to provide the most up-to-date information on this topic.Please find it on page 6, line 3.

Liu S, Jiang T, Xiao L, et al. Total Neoadjuvant Therapy (TNT) versus Standard Neoadjuvant Chemoradiotherapy for Locally Advanced Rectal Cancer: A Systematic Review and Meta-Analysis. The oncologist 2021.

5.I would have expected the authors to buttress the positive findings from TNT by citing other authors report and perhaps proffer suggestion why there is no significant difference as regards surgical complication , R0 resection rate and distant metastasis.

Response –Special thanks to you for your good comments.We have added relevant discussion as follow: However, these results should be interpreted with caution, as the lack of standardization of postoperative morbidity reports limits the interpretation of the results.Another disadvantage is the short follow-up period, so the assessment of long-term distant metastases needs to be cautious. Please find it on page 7, line 4.

6.I am not sure if the authors were meant to use the term superiority when referencing to the overall benefit of TNT over standard CRT. The superiority and inferiority test mostly applies to original research where is a null or alternative hypothesis to prove or disprove , hence to my understanding it does not apply to this meta-analysis.

Response –We have re-written this sentence according to your suggestion:The rates of pCR was significantly higher in the TNT group than in the nCRT group.Please find it on page 1, line 25.

7.There are other limitations to this study that was not discussed.

Response –Considering the Reviewer’s suggestion, we have added discussion as follow: However, these results should be interpreted with caution, as the lack of standardization of postoperative morbidity reports limits the interpretation of the results.Another disadvantage is the short follow-up period, so the assessment of long-term distant metastases needs to be cautious.Please find it on page 6, line 4.

8.Would have expected the authors to make reference to QOL in TNT vs CRT even though , this might have not been discussed in the other main articles.

Response –We are very sorry for our incorrect writing, we have added it: Assessment of QoL was not included in this study, in a recent analysis of the EXPERT-C trial, intensified neoadjuvant strategy for QoL and bowel function did not appear to be significantly affected (PMID:26031368). Nevertheless, the absence of a control group of standard CRT limits the general applicability of our results and a definitive conclusion on the role of TNT in high-risk LARC can only be provided by randomised phase III trials.Please find it on page 7, line 9.

Sclafani F, Peckitt C, Cunningham D, et al. Short- and Long-Term Quality of Life and Bowel Function in Patients With MRI-Defined, High-Risk, Locally Advanced Rectal Cancer Treated With an Intensified Neoadjuvant Strategy in the Randomized Phase 2 EXPERT-C Trial. Int J Radiat Oncol Biol Phys 2015; 93(2): 303-12.

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Response –I agree with including full peer review and any attached files.Special thanks to you for your good comments.

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Submitted filename: Reviewer response.docx

Click here for additional data file. (16.8KB, docx)

Decision Letter 1

Alessandro Rizzo

11 Oct 2022

Total Neoadjuvant Therapy versus Standard Therapy in Locally Advanced Rectal Cancer:A Systematic Review and Meta-Analysis of 15 Trials

PONE-D-22-09905R1

Dear Dr. Li,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Alessandro Rizzo

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

**********

6. Review Comments to the Author

Reviewer #1: I would want to express my gratitude to the authors for all of the revisions. I believe that this study will be published in the form of a meta-analysis in the scientific literature. This meta-analysis will be an important cornerstone in the multidisciplinary treatment of rectal cancer, which is updated every day.

I would also like to thank them for detecting the duplicate article that both reviewers overlooked and removed it from the study after they realized there was a problem.

My opinion is that the version of the paper that is now being worked on is ready for publication.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Cihangir Akyol

**********

Acceptance letter

Alessandro Rizzo

13 Oct 2022

PONE-D-22-09905R1

Total Neoadjuvant Therapy versus Standard Therapy in Locally Advanced Rectal Cancer:A Systematic Review and Meta-Analysis of 15 Trials

Dear Dr. Li:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Alessandro Rizzo

Academic Editor

PLOS ONE

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