Review Article| Volume 2, ISSUE 1, P227-236, May 2022

Total Neoadjuvant Strategies for Locally Advanced Rectal Cancer

  • Dustin A. Deming
    1111 Highland Avenue WIMR 2, Rm 6507, Madison, WI 53705.
    Department of Medicine, University of Wisconsin School of Medicine and Public Health, 1111 Highland Avenue 6507, Madison, WI 53705, USA

    Department of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, 1111 Highland Avenue 6507, Madison, WI 53705, USA

    Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA
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        • American Cancer Society
        Cancer facts & figures 2021.
        American Cancer Society, Atlanta2021
        • Benson A.B.
        • Venook A.P.
        • Al-Hawary M.M.
        • et al.
        NCCN guidelines insights: rectal cancer, version 6.2020.
        J Natl Compr Canc Netw. 2020; 18: 806-815
        • Loannidis A.
        • Konstantinidis M.
        • Apostolakis S.
        • et al.
        Impact of multidisciplinary tumor boards on patients with rectal cancer.
        Mol Clin Oncol. 2018; 9: 135-137
        • Eng C.
        • Jácome A.A.
        • Agarwal R.
        • et al.
        A comprehensive framework for early-onset colorectal cancer research.
        Lancet Oncol. 2022; 23: e116-e128
        • Gollub M.J.
        • Arya S.
        • Beets-Tan R.G.
        Use of magnetic resonance imaging in rectal cancer patients: society of abdominal radiology (SAR) rectal cancer disease-focused panel (DFP) recommendations 2017.
        Abdom Radiol (NY). 2018; 43 (MRI guidelines): 2893-2902
        • Nougaret S.
        • Jhaveri K.
        • Kassam Z.
        • et al.
        Rectal cancer MR staging: pearls and pitfalls at baseline examination.
        Abdom Radiol (NY). 2019; 44: 3536-3548
        • MERCURY Study Group
        Diagnostic accuracy of preoperative magnetic resonance imaging in predicting curative resection of rectal cancer: prospective observational study.
        BMJ. 2006; 333: 779
        • Battersby N.J.
        • How P.
        • Moran B.
        • et al.
        MERCURY II study group. prospective validation of a low rectal cancer magnetic resonance imaging staging system and development of a local recurrence risk stratification model: The MERCURY II study.
        Ann Surg. 2016; 263: 751-760
        • Fritzmann J.
        • Contin P.
        • Reissfelder C.
        • et al.
        Comparison of three classifications for lymph node evaluation in patients undergoing total mesorectal excision for rectal cancer.
        Langenbecks Arch Surg. 2018; 403: 451-462
        • Gröne J.
        • Loch F.N.
        • Taupitz M.
        • et al.
        Accuracy of various lymph node staging criteria in rectal cancer with magnetic resonance imaging.
        J Gastrointest Surg. 2018; 22: 146-153
        • Sauer R.
        • Becker H.
        • Hohenberger W.
        • et al.
        • German Rectal Cancer Study Group
        Preoperative versus postoperative chemoradiotherapy for rectal cancer.
        N Engl J Med. 2004; 351: 1731-1740
        • 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: 668-674
        • 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: 859-865
        • 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 trial.
        Ann Oncol. 2015; 26: 1722-1728
        • Nogué M.
        • Salud A.
        • Vicente P.
        • et al.
        Addition of bevacizumab to XELOX induction therapy plus concomitant capecitabine-based chemoradiotherapy in magnetic resonance imaging-defined poor-prognosis locally advanced rectal cancer: the AVACROSS study.
        Oncologist. 2011; 16: 614-620
        • 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: 1525-1530
        • Cercek A.
        • Goodman K.A.
        • Hajj C.
        • et al.
        Neoadjuvant chemotherapy first, followed by chemoradiation and then surgery, in the management of locally advanced rectal cancer.
        J Natl Compr Canc Netw. 2014; 12: 513-519
        • Perez K.
        • Safran H.
        • Sikov W.
        • et al.
        Complete neoadjuvant treatment of rectal cancer: the Brown University Oncology Group CONTRE study.
        Am J Clin Oncol. 2017; 40: 283-287
        • Cercek A.
        • Roxburgh C.S.D.
        • Strombom P.
        • et al.
        Adoption of Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer.
        JAMA Oncol. 2018; 4: e180071
        • Rahma O.E.
        • Yothers G.
        • Hong T.S.
        • 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
        • Garcia-Aguilar J.
        • Patil S.
        • Kim J.K.
        • et al.
        • on behalf of the OPRA Consortium
        Preliminary results of the organ preservation of rectal adenocarcinoma (OPRA) trial.
        J Clin Oncol. 2020; 38 (abstr 4008))
        • Bahadoer R.R.
        • Dijkstra E.A.
        • van Etten B.
        • et al.
        RAPIDO collaborative investigators. 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
        • Conroy T.
        • Bosset J.F.
        • Etienne P.L.
        • et al.
        • Unicancer Gastrointestinal Group and Partenariat de Recherche en Oncologie Digestive (PRODIGE) Group
        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
        • Pectasides D.
        • Karavasilis V.
        • Papaxoinis G.
        • et al.
        Randomized phase III clinical trial comparing the combination of capecitabine and oxaliplatin (CAPOX) with the combination of 5-fluorouracil, leucovorin and oxaliplatin (modified FOLFOX6) as adjuvant therapy in patients with operated high-risk stage II or stage III colorectal cancer.
        BMC Cancer. 2015; 15: 384
        • de Gramont A.
        • Van Cutsem E.
        • Schmoll H.J.
        • et al.
        Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): a phase 3 randomised controlled trial.
        Lancet Oncol. 2012; 13: 1225-1233
        • Schmoll H.J.
        • Twelves C.
        • Sun W.
        • et al.
        Effect of adjuvant capecitabine or fluorouracil, with or without oxaliplatin, on survival outcomes in stage III colon cancer and the effect of oxaliplatin on post-relapse survival: a pooled analysis of individual patient data from four randomised controlled trials.
        Lancet Oncol. 2014; 15: 1481-1492
        • Allegra C.J.
        • Yothers G.
        • O'Connell M.J.
        • et al.
        Neoadjuvant 5-FU or capecitabine plus radiation with or without oxaliplatin in rectal cancer patients: a phase iii randomized clinical trial.
        J Natl Cancer Inst. 2015; 107: djv248
        • Andre T.
        • Boni C.
        • Navarro M.
        • et al.
        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: 3109-3116
        • André T.
        • Meyerhardt J.
        • Iveson T.
        • et al.
        Effect of duration of adjuvant chemotherapy for patients with stage III colon cancer (IDEA collaboration): final results from a prospective, pooled analysis of six randomised, phase 3 trials.
        Lancet Oncol. 2020; 21: 1620-1629
        • Shi Q.
        • Sobrero A.F.
        • Shields A.F.
        • et al.
        Timothy Iveson. Prospective pooled analysis of six phase III trials investigating duration of adjuvant (adjuv) oxaliplatin-based therapy (3 vs 6 months) for patients (pts) with stage III colon cancer (CC): The IDEA (International Duration Evaluation of Adjuvant chemotherapy) collaboration.
        J Clin Oncol. 2017; 35 (abstr LBA1))
        • Sobrero A.F.
        • Andre T.
        • Meyerhardt J.A.
        • et al.
        Overall survival (OS) and long-term disease-free survival (DFS) of three versus six months of adjuvant (adj) oxaliplatin and fluoropyrimidine-based therapy for patients (pts) with stage III colon cancer (CC): Final results from the IDEA (International Duration Evaluation of Adj chemotherapy) collaboration.
        J Clin Oncol. 2020; 38 (abstr 4004))
        • Ding M.
        • Zhang J.
        • Hu H.
        • et al.
        mFOLFOXIRI versus mFOLFOX6 as neoadjuvant chemotherapy in locally advanced rectal cancer: a propensity score matching analysis.
        Clin Colorectal Cancer. 2021; (S1533-0028(21)00125-130)
        • De Felice F.
        • D'Ambrosio G.
        • Iafrate F.
        • Gelibter A.
        • et al.
        Intensified total neoadjuvant therapy in patients with locally advanced rectal cancer: a phase II trial.
        Clin Oncol (R Coll Radiol). 2021; 33: 788-794
        • Hofheinz R.D.
        • Wenz F.
        • Post S.
        • et al.
        Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial.
        Lancet Oncol. 2012; 13: 579-588
        • Yuval J.B.
        • Garcia-Aguilar J.
        Watch-and-wait management for rectal cancer after clinical complete response to neoadjuvant therapy.
        Adv Surg. 2021; 55: 89-107
        • Bujko K.
        • Nowacki M.P.
        • Kepka L.
        • et al.
        • Polish Colorectal Study Group
        Postoperative complications in patients irradiated pre-operatively for rectal cancer: report of a randomised trial comparing short-term radiotherapy vs chemoradiation.
        Colorectal Dis. 2005; 7: 410-416
        • Erlandsson J.
        • Holm T.
        • Pettersson D.
        • et al.
        Optimal fractionation of preoperative radiotherapy and timing to surgery for rectal cancer (Stockholm III): a multicentre, randomised, non-blinded, phase 3, non-inferiority trial.
        Lancet Oncol. 2017; 18: 336-346
        • Kapiteijn E.
        • Marijnen C.A.
        • Nagtegaal I.D.
        • et al.
        • Dutch Colorectal Cancer Group
        Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer.
        N Engl J Med. 2001; 345: 638-646
        • Yeo S.G.
        • Kim D.Y.
        • Kim T.H.
        • et al.
        Pathologic complete response of primary tumor following preoperative chemoradiotherapy for locally advanced rectal cancer: long-term outcomes and prognostic significance of pathologic nodal status (KROG 09-01).
        Ann Surg. 2010; 252: 998-1004
        • Fernandez L.M.
        • São Julião G.P.
        • Figueiredo N.L.
        • et al.
        • International Watch & Wait Database Consortium
        Conditional recurrence-free survival of clinical complete responders managed by watch and wait after neoadjuvant chemoradiotherapy for rectal cancer in the International Watch & Wait Database: a retrospective, international, multicentre registry study.
        Lancet Oncol. 2021; 22: 43-50
        • Smith J.J.
        • Strombom P.
        • Chow O.S.
        • 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: e185896
        • Le D.T.
        • Uram J.N.
        • Wang H.
        • et al.
        PD-1 Blockade in Tumors with Mismatch-Repair Deficiency.
        N Engl J Med. 2015; 372: 2509-2520
        • Cercek A.
        • Dos Santos Fernandes G.
        • Roxburgh C.S.
        • et al.
        Mismatch repair-deficient rectal cancer and resistance to neoadjuvant chemotherapy.
        Clin Cancer Res. 2020; 26: 3271-3279
        • Henriksen T.V.
        • Tarazona N.
        • Frydendahl A.
        • et al.
        Circulating tumor DNA in stage III colorectal cancer, beyond minimal residual disease detection, toward assessment of adjuvant therapy efficacy and clinical behavior of recurrences.
        Clin Cancer Res. 2022; 28: 507-517
        • Tie J.
        • Cohen J.D.
        • Wang Y.
        • et al.
        Serial circulating tumour DNA analysis during multimodality treatment of locally advanced rectal cancer: a prospective biomarker study.
        Gut. 2019; 68: 663-671
        • Murahashi S.
        • Akiyoshi T.
        • Sano T.
        • et al.
        Serial circulating tumour DNA analysis for locally advanced rectal cancer treated with preoperative therapy: prediction of pathological response and postoperative recurrence.
        Br J Cancer. 2020; 123: 803-810
        • Ganesh K.
        • Wu C.
        • O'Rourke K.P.
        • et al.
        A rectal cancer organoid platform to study individual responses to chemoradiation.
        Nat Med. 2019; 25: 1607-1614
        • Pasch C.A.
        • Favreau P.F.
        • Yueh A.E.
        • et al.
        Patient-derived cancer organoid cultures to predict sensitivity to chemotherapy and radiation.
        Clin Cancer Res. 2019; 25: 5376-5387
        • Kratz J.D.
        • Rehman S.
        • Johnson K.A.
        • et al.
        Integrating Subclonal Response Heterogeneity to Define Cancer Organoid Therapeutic Sensitivity.
        bioRxiv. 2021;