Outcomes of locally advanced rectal cancer patients treated with total neoadjuvant treatment: a meta-anaysis of randomized controlled trials.

Published:September 17, 2022DOI:


      Background & Aims

      Determining outcomes using the total neoadjuvant therapy (TNT) in patients with local advanced rectal cancer is important for stratifying patients according to expected outcomes in future studies in the era of treatment combination. The present meta-analysis estimated the pathological complete response, disease-free survival, and overall survival probabilities of rectal cancer patients and identified predictors of outcomes.


      Studies reporting pathological complete response rate and time-dependent outcomes (progression or death) after total neoadjuvant treatment of locally advanced rectal cancer (LARC) were identified in MEDLINE through January 2022. Three independent observers extracted data on patient populations and outcomes and combined the data using a distribution-free summary survival curve. The primary outcomes were actuarial probabilities of recurrence and survival.


      Fourteen RCTs, including 18 TNT arms, met the inclusion criteria. The pooled estimate of pathological complete response (pCR) probability was 23.6%, with moderate heterogeneity between studies. The pooled estimates of actuarial disease-free survival rate were 70.6% at three years and 65.4% at five years. The pooled estimates of actuarial survival rates were 93% at three years and 81.6% at five years. In both these outcomes, heterogeneity between studies was highly significant.


      This meta-analysis showed that Total Neoadjuvant Therapy is an optimal approach for LARC patients. The results provide a useful benchmark for future comparisons of the benefits of combinations of other drug families as target therapies or immunotherapies.



      TNT (total neoadjuvant therapy), LARC (locally advanced rectal cancer), 5-FU (5 fluorouracil), RCT (randomized controlled trial), pCR (pathological complete response), DFS (diasese-free survival), OS (overall survival)
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        • Cammà C
        • Giunta M
        • Fiorica F
        • et al.
        Preoperative radiotherapy for resectable rectal cancer: A meta-analysis.
        JAMA. 2000; 284: 1008-1015
        • van Gijn W
        • Marijnen CAM
        • Nagtegaal ID
        • 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: 575-582
        • Kapiteijn E
        • Marijnen CA
        • Nagtegaal ID
        • et al.
        Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer.
        N Engl J Med. 2001; 345: 638-646
        • Tepper JE
        • Wang AZ.
        Improving local control in rectal cancer: radiation sensitizers or radiation dose?.
        J Clin Oncol Off J Am Soc Clin Oncol. 2010; 28: 1623-1624
        • Fiorica F
        • Cartei F
        • Licata A
        • et al.
        Can chemotherapy concomitantly delivered with radiotherapy improve survival of patients with resectable rectal cancer? A meta-analysis of literature data.
        Cancer Treat Rev. 2010; 36: 539-549
        • Glynne-Jones R
        • Wyrwicz L
        • Tiret E
        • et al.
        Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
        Ann Oncol Off J Eur Soc Med Oncol. 2017; 28: 22-40
        • Rödel C
        • Liersch T
        • Becker H
        • et al.
        Preoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: initial results of the German CAO/ARO/AIO-04 randomised phase 3 trial.
        Lancet Oncol. 2012; 13: 679-687
        • Ludmir EB
        • Palta M
        • Willett CG
        • et al.
        Total neoadjuvant therapy for rectal cancer: An emerging option.
        Cancer. 2017; 123: 1497-1506
        • Franke AJ
        • Parekh H
        • Starr JS
        • et al.
        Total Neoadjuvant Therapy: A Shifting Paradigm in Locally Advanced Rectal Cancer Management.
        Clin Colorectal Cancer. 2018; 17: 1-12
        • Tohme S
        • Simmons RL
        • Tsung A.
        Surgery for Cancer: A Trigger for Metastases.
        Cancer Res. 2017; 77: 1548-1552
      1. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation | The BMJ. (accessed 20 Jul 2022).

      2. RoB 2: A revised Cochrane risk-of-bias tool for randomized trials | Cochrane Bias. (accessed 21 Jul 2022).

        • NRG-GI002
        A phase II clinical trial platform using total neoadjuvant therapy (TNT) in locally advanced rectal cancer (LARC)—Pembrolizumab experimental arm (EA) primary results.
        | Journal of Clinical Oncology. 2022; (accessed 12 Feb)
        • George TJ
        • Yothers G
        • Hong TS
        • et al.
        NRG-GI002: A phase II clinical trial platform using total neoadjuvant therapy (TNT) in locally advanced rectal cancer (LARC)—First experimental arm (EA) initial results.
        J Clin Oncol. 2019; 37 (3505): 3505
        • Combescure C
        • Foucher Y
        • Jackson D.
        Meta-analysis of single-arm survival studies: a distribution-free approach for estimating summary survival curves with random effects.
        Stat Med. 2014; 33: 2521-2537
        • Earle CC
        • Pham B
        • Wells GA.
        An assessment of methods to combine published survival curves.
        Med Decis Mak Int J Soc Med Decis Mak. 2000; 20: 104-111
        • DerSimonian R
        • Laird N.
        Meta-analysis in clinical trials.
        Control Clin Trials. 1986; 7: 177-188
        • Cabibbo G
        • Enea M
        • Attanasio M
        • et al.
        A meta-analysis of survival rates of untreated patients in randomized clinical trials of hepatocellular carcinoma.
        Hepatology. 2010; 51: 1274-1283
        • 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: 973-979
      3. 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 Elsevier Enhanced Reader. doi:10.1016/j.ijrobp.2018.04.013

        • Maréchal 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: 1525-1530
        • Fernández-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 Cáncer de Recto 3 Study.
        J Clin Oncol. 2010; 28: 859-865
        • Borg C
        • André T
        • Mantion G
        • 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: 2205-2210
        • Fernández-Martos C
        • Pericay C
        • Losa F
        • et al.
        Effect of Aflibercept Plus Modified FOLFOX6 Induction Chemotherapy Before Standard Chemoradiotherapy and Surgery in Patients With High-Risk Rectal Adenocarcinoma: The GEMCAD 1402 Randomized Clinical Trial.
        JAMA Oncol. 2019; 5: 1566
        • Fokas E
        • Schlenska-Lange A
        • Polat B
        • et al.
        Chemoradiotherapy Plus Induction or Consolidation Chemotherapy as Total Neoadjuvant Therapy for Patients With Locally Advanced Rectal Cancer: Long-term Results of the CAO/ARO/AIO-12 Randomized Clinical Trial.
        JAMA Oncol. 2022; 8e215445
        • Conroy T
        • Bosset J-F
        • Etienne P-L
        • 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: 702-715
        • Rahma OE
        • Yothers G
        • Hong TS
        • et al.
        Use of Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer: Initial Results From the Pembrolizumab Arm of a Phase 2 Randomized Clinical Trial.
        JAMA Oncol. 2021; 7: 1225-1230
        • Bujko K
        • Wyrwicz L
        • Rutkowski A
        • 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: 834-842
        • 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: 29-42
        • Jin J
        • Tang Y
        • Hu C
        • et al.
        A multicenter, randomized, phase III trial of short-term radiotherapy plus chemotherapy versus long-term chemoradiotherapy in locally advanced rectal cancer (STELLAR): The final reports.
        J Clin Oncol. 2021; 39 (3510): 3510
        • 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; 26: e1555-e1566
        • Randomized phase II trial of modified (m)
        FOLFOX6 induction chemotherapy with or without aflibercept before standard chemoradiotherapy (CRT) and total mesorectal excision (TME) in patients with high-risk rectal adenocarcinoma (HRRC): Final results of the GEMCAD 1402, and by molecular subtypes.
        Journal of Clinical Oncology. 2022; (accessed 12 Feb)
        • Gagnier JJ
        • Moher D
        • Boon H
        • et al.
        Investigating clinical heterogeneity in systematic reviews: a methodologic review of guidance in the literature.
        BMC Med Res Methodol. 2012; 12: 111
        • Fiorica F
        • Tebano U
        • Gabbani M
        • et al.
        Beyond Abscopal Effect: A Meta-Analysis of Immune Checkpoint Inhibitors and Radiotherapy in Advanced Non-Small Cell Lung Cancer.
        Cancers. 2021; 13: 2352
      4. A phase II study of capecitabine plus concomitant radiation therapy followed by durvalumab (MEDI4736) as preoperative treatment in rectal cancer: PANDORA study first-stage.
        | Journal of Clinical Oncology. 2022; (accessed 16 Feb)
        • Fiorica F
        • Cartei F
        • Carau B
        • et al.
        Adjuvant radiotherapy on older and oldest elderly rectal cancer patients.
        Arch Gerontol Geriatr. 2009; 49: 54-59
        • Berretta M
        • Zanet E
        • Nasti G
        • et al.
        Oxaliplatin-based chemotherapy in the treatment of elderly patients with metastatic colorectal cancer (CRC).
        Arch Gerontol Geriatr. 2012; 55: 271-275
        • Berretta M
        • Aprile G
        • Nasti G
        • et al.
        Oxaliplapin and capecitabine (XELOX) based chemotherapy in the treatment of metastatic colorectal cancer: the right choice in elderly patients.
        Anticancer Agents Med Chem. 2013; 13: 1344-1353
        • Berretta M
        • Cappellani A
        • Fiorica F
        • et al.
        FOLFOX4 in the treatment of metastatic colorectal cancer in elderly patients: a prospective study.
        Arch Gerontol Geriatr. 2011; 52: 89-93
        • Jüni P
        • Witschi A
        • Bloch R
        • et al.
        The hazards of scoring the quality of clinical trials for meta-analysis.
        JAMA. 1999; 282: 1054-1060