CHINESE JOURNAL OF MEDICINAL GUIDE >
Research Progress on Neoadjuvant Therapy for Patients with Locally Advanced Rectal Cancer
Received date: 2024-12-20
Revised date: 2025-07-07
Accepted date: 2026-03-18
Online published: 2026-03-19
Objective： This paper focuses on the evolving landscape of neoadjuvant therapy （NAT） for locally advanced rectal cancer （LARC）， systematically summarizing the research progress on neoadjuvant chemoradiotherapy （nCRT）， total neoadjuvant therapy （TNT）， immunotherapy-based combinations， and organ-preserving strategies. Special attention is given to the patient selection， efficacy prediction， and biomarker development for combined immunotherapy. Meanwhile， based on current clinical evidence and frontier researches， this paper further explore feasible approaches to achieve individualized， low-toxicity， and high-response-rate treatment， aiming to provide both theoretical reference and practical guidance for optimizing LARC treatment.Methods： By systematically reviewing the progress of LARC clinical trials and researches at home and abroad in recent years， this paper focuses on reviewing the target populations， therapeutic outcomes， and biomarker predictive value of nCRT， TNT， immunotherapy， and watch-and-wait （W&W） strategies， particularly in the context of mid-to-low rectal cancers.Results： TNT significantly improves both pathological complete response （pCR） and clinical complete response （cCR） rates in patients with LARC， offering increased potential for organ preservation in lower tumors. Immunotherapy demonstrates robust efficacy in patients with deficient mismatch repair （dMMR）/microsatellite instability-high （MSI-H） tumors， while combination strategies show promise in microsatellite stable （MSS） populations. Accurate assessment of cCR and appropriate use of W&W approaches require multidisciplinary support and precise molecular subtyping.Conclusion： NAT strategies aimed at organ preservation are becoming increasingly diverse. Both TNT and immunotherapy offer valuable avenues for functional preservation. Future efforts should focus on individualized molecular classification， response prediction， and standardization of cCR assessment to enable more precise and personalized treatment pathways for patients with LARC.
Key words： ; Locally advanced rectal cancer； ; Neoadjuvant therapy； ; Nonoperative treatment； ; Immunotherapy
涵悦 张
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Research Progress on Neoadjuvant Therapy for
Patients with Locally Advanced Rectal Cancer
［1］ 郑荣寿，陈茹，韩冰峰，等.2022年中国恶性肿瘤流行情况分析［J］.中华肿瘤杂志，2024，46（3）：221-231.
［2］ Benson AB， Venook AP， Bekaii-Saab， et al. Rectal cancer， version 2.2015［J］. J Natl Compr Canc Netw， 2015，13（6）：719-728.
［3］ Glynne-Jones R， Wyrwicz L， Tiret E， et al. Rectal cancer： ESMO clinical practice guidelines for diagnosis， treatment and follow-up［J］.Ann Oncol， 2017， 28（suppl_4）： iv22-iv40.
［4］ 薛珂，宗丹，詹梦娜，等.局部晚期直肠癌新辅助放化疗研究进展［J］.中国肿瘤外科杂志，2022，14（2）：190-194.
［5］ 赵鹏飞，满新贺，赵宏，等.局部晚期直肠癌全程新辅助治疗的系统评价［J］.中国医院用药评价与分析，2023，23（2）：219-225.
［6］ 金旭.直肠癌新辅助治疗后临床完全缓解患者“wait and see”策略的Meta分析及局部复发治疗策略的选择［D］.昆明：昆明医科大学，2016.
［7］ 中华医学会肿瘤学分会，国家卫生健康委员会医政司.中国结直肠癌诊疗规范（2023版）［J］.协和医学杂志，2023，14（4）：706-733.
［8］ Conroy T， Bosset JF， Etienne PL， 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［J］.Lancet Oncol， 2021，22（5）：702-715.
［9］ 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［J］.Lancet Oncol， 2017，18（3）：336-346.
［10］ Erlandsson J， Martling A. Short-course radiotherapy with delayed surgery for rectal cancer - authors' reply［J］.Lancet Oncol， 2017，18（6）：e295.
［11］ Lefevre JH， Mineur L， Kotti S， et al. Effect of interval （7 or 11 weeks） between neoadjuvant radiochemotherapy and surgery on complete pathologic response in rectal cancer： a multicenter， randomized， controlled trial （GRECCAR-6）［J］.J Clin Oncol， 2016，34（31）：3773-3780.
［12］ Guzmán Y， Ríos J， Paredes J， et al. Time interval between the end of neoadjuvant therapy and elective resection of locally advanced rectal cancer in the CRONOS study［J］.JAMA Surg， 2023，158（9）：910-919.
［13］ Ngan SY， Burmeister B， Fisher RJ， et al. Randomized trial of short-course radiotherapy versus long-course chemoradiation comparing rates of local recurrence in patients with T3 rectal cancer： Trans-Tasman Radiation Oncology Group trial 01.04［J］.J Clin Oncol， 2012，30（31）：3827-3833.
［14］ 梁玉汶，杜小波.局部晚期直肠癌新辅助治疗反应评估及预测研究进展［J］.华西医学，2024，39（5）：825-832.
［15］ Díaz Beveridge R， Akhoundova D， Bruixola G， et al. Controversies in the multimodality management of locally advanced rectal cancer［J］.Med Oncol， 2017，34（6）：102.
［16］ Baxter NN， Habermann EB， Tepper JE， et al. Risk of pelvic fractures in older women following pelvic irradiation［J］.JAMA， 2005，294（20）：2587-2593.
［17］ Mei WJ， Wang XZ， Li YF， et al. Neoadjuvant chemotherapy with CAPOX versus chemoradiation for locally advanced rectal cancer with uninvolved mesorectal fascia （CONVERT）： initial results of a phase Ⅲ trial［J］.Ann Surg， 2023，277（4）：557-564.
［18］ He F， Yu L， Ding Y， et al. Effects of neoadjuvant chemotherapy with or without intensity-modulated radiotherapy for patients with rectal cancer［J］.Cancer Sci， 2020，111（11）：4205-4217.
［19］ Sauer R， Becker H， Hohenberger W， et al. Preoperative treatment of locally advanced rectal cancer［J］.N Engl J Med， 2023，389（4）：322-334.
［20］ Basch E， Dueck AC， Mitchell SA， et al. Patient-reported outcomes during and after treatment for locally advanced rectal cancer in the PROSPECT Trial （Alliance N1048）［J］.J Clin Oncol， 2023，41（21）：3724-3734.
［21］ 完全新辅助疗法治疗局部晚期直肠癌［J］.实用肿瘤学杂志，2018，32（3）：240.
［22］ 胡方杰，崔滨滨.直肠癌经新辅助治疗后达到临床完全缓解的评估策略及观察和等待策略［J］.现代肿瘤医学，2018，26（14）：2309-2314.
［23］ 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［J］.Lancet Oncol， 2021，22（1）：29-42.
［24］ Dijkstra EA， Hospers GAP， Kranenbarg EM， et al. Quality of life and late toxicity after short-course radiotherapy followed by chemotherapy or chemoradiotherapy for locally advanced rectal cancer - the RAPIDO trial［J］.Radiother Oncol， 2022，171：69-76.
［25］ Bahadoer RR， Hospers GAP， Marijnen CAMet al. Risk and location of distant metastases in patients with locally advanced rectal cancer after total neoadjuvant treatment or chemoradiotherapy in the RAPIDO trial［J］.Eur J Cancer， 2023，185：139-149.
［26］ Dijkstra EA， Nilsson PJ， Hospers GAP， et al. Locoregional failure during and after short-course radiotherapy followed by chemotherapy and surgery compared with long-course chemoradiotherapy and surgery： a 5-year follow-up of the RAPIDO rrial［J］.Ann Surg， 2023，278（4）：e766-e772.
［27］ Jin J， Tang Y， Hu C， et al. Multicenter， randomized， phase Ⅲ trial of short-term radiotherapy plus chemotherapy versus long-term chemoradiotherapy in locally advanced rectal cancer （STELLAR）［J］.J Clin Oncol， 2022，40（15）：1681-1692.
［28］ Bascoul-Mollevi C， Gourgou S， Borg C， et al. Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer （UNICANCER PRODIGE 23）： health-related quality of life longitudinal analysis［J］.Eur J Cancer， 2023，186：151-165.
［29］ Conroy T， Castan F， Etienne PL， et al. Total neoadjuvant therapy with mFOLFIRINOX versus preoperative chemoradiotherapy in patients with locally advanced rectal cancer： long-term results of the UNICANCER-PRODIGE 23 trial［J］.Ann Oncol， 2024，35（10）：873-881.
［30］ Fokas E， Allgäuer M， Polat B， et al. 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］.J Clin Oncol， 2019，37（34）：3212-3222.
［31］ 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［J］.JAMA Oncol， 2022，8（1）：e215445.
［32］ Thompson HM， Omer DM， Lin S，， et al. Organ preservation and survival by clinical response grade in patients with rectal cancer treated with total neoadjuvant therapy： a secondary analysis of the OPRA randomized clinical trial［J］.JAMA Netw Open， 2024，7（1）：e2350903.
［33］ Verheij FS， Omer DM， Lin ST， et al. Compliance and toxicity of total neoadjuvant therapy for rectal cancer： a secondary analysis of the OPRA trial［J］.Int J Radiat Oncol Biol Phys， 2024，118（1）：115-123.
［34］ Verheij FS， Omer DM， Williams H， et al. Long-term results of organ preservation in patients with rectal adenocarcinoma treated with total neoadjuvant therapy： the randomized phase Ⅱ OPRA Trial［J］.J Clin Oncol， 2024，42（5）：500-506.
［35］ Basile D， Garattini SK， Bonotto M， et al. Immunotherapy for colorectal cancer： where are we heading？［J］.Expert Opin Biol Ther， 2017，17（6）：709-721.
［36］ Cercek A， Lumish M， Sinopoli J， et al. PD-1 blockade in mismatch repair-deficient， locally advanced rectal cancer［J］.N Engl J Med， 2022，386（25）：2363-2376.
［37］ Chen G， Jin Y， Guan WL， et al. Neoadjuvant PD-1 blockade with sintilimab in mismatch-repair deficient， locally advanced rectal cancer： an open-label， single-centre phase 2 study［J］.Lancet Gastroenterol Hepatol， 2023，8（5）：422-431.
［38］ Le DT， Durham JN， Smith KN， et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade［J］.Science， 2017，357（6349）：409-413.
［39］ Xiao WW， Chen G， Gao YH， et al. Effect of neoadjuvant chemoradiotherapy with or without PD-1 antibody sintilimab in pMMR locally advanced rectal cancer： a randomized clinical trial［J］.Cancer Cell， 2024，42（9）：1570-1581.
［40］ Yang Z， Gao J， Zheng J， et al. Efficacy and safety of PD-1 blockade plus long-course chemoradiotherapy in locally advanced rectal cancer （NECTAR）： a multi-center phase 2 study［J］.Signal Transduct Target Ther， 2024，9（1）：56.
［41］ Lin ZY， Zhang P， Chi P， et al. Neoadjuvant short-course radiotherapy followed by camrelizumab and chemotherapy in locally advanced rectal cancer （UNION）： early outcomes of a multicenter randomized phase Ⅲ trial［J］.Ann Oncol， 2024，35（10）：882-891.
［42］ Yamazaki T， Gunderson AJ， Gilchrist M， et al. Galunisertib plus neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer： a single-arm， phase 2 trial［J］.Lancet Oncol， 2022，23（9）：1189-1200.
［43］ 金敏.直肠癌免疫亚型鉴定及其在新辅助放化疗后免疫治疗疗效的预测作用［D］.重庆：中国人民解放军陆军军医大学，2024.
［44］ Riedesser JE， Ebert MP， Betge J. Precision medicine for metastatic colorectal cancer in clinical practice［J］.Ther Adv Med Oncol， 2022，14：17588359211072703.
［45］ Karapetis CS， Khambata-Ford S， Jonker DJ， et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer［J］.N Engl J Med， 2008，359（17）：1757-1765.
［46］ Wu C， Williams TM， Robb R， et al. Phase I trial of trametinib with neoadjuvant chemoradiation in patients with locally advanced rectal cancer［J］.Clin Cancer Res， 2020，26（13）：3117-3125.
［47］ Alexandrakis G， Brown EB， Tong RT， et al. Two-photon fluorescence correlation microscopy reveals the two-phase nature of transport in tumors［J］.Nat Med， 2004，10（2）：203-207.
［48］ Jain RK. Normalizing tumor vasculature with anti-angiogenic therapy： a new paradigm for combination therapy［J］.Nat Med， 2001，7（9）：987-989.
［49］ Papadopoulos N， Martin J， Ruan Q， et al. Binding and neutralization of vascular endothelial growth factor （VEGF） and related ligands by VEGF Trap， ranibizumab and bevacizumab［J］.Angiogenesis， 2012，15（2）：171-185.
［50］ 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［J］.JAMA Oncol， 2019，5（11）：1566-1573.
［51］ Pesántez D， Ten Hoorn S， Machado I， et al. Total neoadjuvant therapy with or without aflibercept in rectal cancer： 3-year results of GEMCAD-1402［J］.J Natl Cancer Inst， 2023，115（12）：1497-1505.
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