外科理论与实践

外科理论与实践 >

2024 , Vol. 29 >Issue 03: 220 - 229

DOI: https://doi.org/10.16139/j.1007-9610.2024.03.07

专家论坛

局部进展期直肠癌新辅助放化疗联合免疫治疗的回顾和展望

  • 王雅琪 ,
  • 夏凡 ,
  • 章真
展开
  • 复旦大学附属肿瘤医院放射治疗中心，复旦大学上海医学院肿瘤学系，上海市放射肿瘤学重点实验室，上海市放射治疗临床医学研究中心，上海 200032
章真，E-mail：zhen_zhang@fudan.edu.cn

收稿日期: 2024-03-25

  网络出版日期: 2024-09-03

基金资助

北京希思科朝阳肿瘤研究基金(Y-Young2022-0092)

收起

Review and prospect of neoadjuvant chemoradiotherapy combined with immunotherapy in locally advanced rectal cancer

  • WANG Yaqi ,
  • XIA Fan ,
  • ZHANG Zhen
Expand
  • Department of Radiation Oncology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University; Shanghai Key Laboratory of Radiation Oncology; Shanghai Clinical Research Center for Radiation Oncology, Shanghai 200032, China

Received date: 2024-03-25

  Online published: 2024-09-03

Fold

摘要

对于局部进展期直肠癌(LARC)，新辅助放化疗联合全直肠系膜切除术(TME)的标准治疗模式肿瘤退缩和保肛率仍有限，且无法降低远处转移率。放疗可促进机体免疫应答，放疗和免疫治疗联合具有良好的协同作用，有望突破微卫星稳定(MSS)型结肠直肠癌的治疗困境。近年来，新辅助放化疗联合免疫治疗的临床试验逐渐展开，大多获得满意的肿瘤完全缓解率，为MSS型中、低位LARC病人保留器官功能提供新的选择。未来仍需更多大样本随机对照研究进行验证，期待获得更好的保肛和远期生存获益。同时在放疗与免疫治疗模式、疗效准确评估等方面需进一步优化和努力。

关键词： 局部进展期直肠癌; 新辅助放化疗; 免疫治疗; （肿瘤）完全缓解; 器官（功能）保留

本文引用格式

王雅琪 , 夏凡 , 章真 . 局部进展期直肠癌新辅助放化疗联合免疫治疗的回顾和展望[J]. 外科理论与实践, 2024 , 29(03) : 220 -229 . DOI: 10.16139/j.1007-9610.2024.03.07

Abstract

For locally advanced rectal cancer (LARC), the standard treatment of neoadjuvant chemoradiotherapy (nCRT) followed by total mesorectal excision (TME) leaded to limited tumor regression grade and organ preservation rate, and didn’t decrease the rate of distant metastasis. Radiotherapy can promote the immune response and has good synergistic effect with immunotherapy, which is likely to overcome the treatment difficulty of the microsatellite stable(MSS) colorectal cancer. Recently, multiple clinical trials are ongoing in terms of the combination of nCRT and immunotherapy in LARC. Most of them have achieved promising complete response rates, providing new treatment options for preservation of organ functions in mid-low MSS LARC. Large-scale randomized controlled trials are needed in the future to validate these findings and explore the benefit of organ preservation and long-term survival. In addition, studies are still needed on the optimal combination patterns of radiotherapy and immunotherapy and the precise efficacy evaluation, etc.

Key words： Locally advanced rectal cancer(LARC); Neoadjuvant chemoradiotherapy; Immunotherapy; Complete response; Organ preservation

参考文献

[1] VAN DER VALK M J M, HILLING D E, BASTIAANNET E, et al. Long-term outcomes of clinical complete responders after neoadjuvant treatment for rectal cancer in the International Watch & Wait Database (IWWD): an international multicentre registry study[J]. Lancet, 2018, 391(10139):2537-2545.
[2] GARCIA-AGUILAR J, CHOW O S, SMITH D D, et al. Effect of adding mFOLFOX6 after neoadjuvant chemoradiation in locally advanced rectal cancer: a multicentre, phase 2 trial[J]. Lancet Oncol, 2015, 16(8):957-966.
[3] 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 cancer de recto 3 study[J]. J Clin Oncol, 2010, 28(5):859-865.
[4] CERCEK A, ROXBURGH C S D, STROMBOM P, et al. Adoption of total neoadjuvant therapy for locally advanced rectal cancer[J]. JAMA Oncol, 2018, 4(6):e180071.
[5] BAHADOER R R, DIJKSTRA E A, 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.
[6] 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[J]. Lancet Oncol, 2021, 22(5):702-715.
[7] COHEN R, COLLE R, PUDLARZ T, et al. Immune checkpoint inhibition in metastatic colorectal cancer harboring microsatellite instability or mismatch repair deficiency[J]. Cancers (Basel), 2021, 13(5):1149.
[8] ANDRé T, SHIU K K, KIM T W, et al. Pembrolizumab in microsatellite-instability-high advanced colorectal cancer[J]. N Engl J Med, 2020, 383(23):2207-2218.
[9] 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.
[10] CHEN G, JIN Y, GUAN W L, 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.
[11] KAMRAVA M, BERNSTEIN M B, CAMPHAUSEN K, et al. Combining radiation, immunotherapy, and antiangiogenesis agents in the management of cancer: the Three Musketeers or just another quixotic combination?[J]. Mol Biosyst, 2009, 5(11):1262-1270.
[12] LUGADE A A, MORAN J P, GERBER S A, et al. Local radiation therapy of B16 melanoma tumors increases the generation of tumor antigen-specific effector cells that traffic to the tumor[J]. J Immunol, 2005, 174(12):7516-7523.
[13] TWYMAN-SAINT VICTOR C, RECH A J, MAITY A, et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer[J]. Nature, 2015, 520(7547):373-377.
[14] BERNSTEIN M B, KRISHNAN S, HODGE J W, et al. Immunotherapy and stereotactic ablative radiotherapy (ISABR): a curative approach?[J]. Nat Rev Clin Oncol, 2016, 13(8):516-524.
[15] KO E C, RABEN D, FORMENTI S C. The integration of radiotherapy with immunotherapy for the treatment of non-small cell lung cancer[J]. Clin Cancer Res, 2018, 24(23):5792-5806.
[16] POSTOW M A, CALLAHAN M K, BARKER C A, et al. Immunologic correlates of the abscopal effect in a patient with melanoma[J]. N Engl J Med, 2012, 366(10):925-931.
[17] BRIX N, TIEFENTHALLER A, ANDERS H, et al. Abscopal, immunological effects of radiotherapy: narrowing the gap between clinical and preclinical experiences[J]. Immunol Rev, 2017, 280(1):249-279.
[18] BANDO H, TSUKADA Y, INAMORI K, et al. Preoperative chemoradiotherapy plus nivolumab before surgery in patients with microsatellite stable and microsatellite instability-high locally advanced rectal cancer[J]. Clin Cancer Res, 2022, 28(6):1136-1146.
[19] THOMAS J. G, GREG Y, SAMUEL A. J, et al. Phase Ⅱ study of durvalumab following neoadjuvant chemoRT in operable rectal cancer: NSABP FR-2[J]. J Clin Oncol, 2022, 40(4 suppl):99.
[20] STEFANO T, ELISA G, CHIARA Z, et al. A phase Ⅱ study of capecitabine plus concomitant radiation therapy followed by durvalumab (MEDI4736) as preoperative treatment in rectal cancer: PANDORA study final results[J]. J Clin Oncol, 2022, 40(17 suppl):LBA3513.
[21] LISA S, MARIA B, SALVATORE C, et al. Phase Ⅱ study of preoperative (PREOP) chemoradiotherapy (CTRT) plus avelumab (AVE) in patients (PTS) with locally advanced rectal cancer (LARC): the AVANA study[J]. J Clin Oncol, 2021, 39(15 suppl):3511.
[22] CARRASCO J, SCHR?DER D, SINAPI I, et al. R-IMMUNE interim analysis:a phase Ⅰb/Ⅱ study to evaluate safety and efficacy of atezolizumab combined with radio-chemotherapy in a preoperative setting for patients with localized rectal cancer[J]. Ann Oncol, 2021, 32(suppl 5):S537.
[23] 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.
[24] 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[J]. JAMA Oncol, 2021, 7(8):1225-1230.
[25] ZHOU L Q, YU G Y, SHEN Y X, et al. The clinical efficacy and safety of neoadjuvant chemoradiation therapy with immunotherapy for the organ preservation of ultra low rectal cancer: a single arm and open label exploratory study[J]. J Clin Oncol, 2022, 40(16 suppl):e15603.
[26] WU A W, Li Y J, Ji D B, et al. PKUCH 04 trial: total neoadjuvant chemoradiation combined with neoadjuvant PD-1 blockade for pMMR/MSS locally advanced middle to low rectal cancer[J]. J Clin Oncol, 2022, 40(16 suppl):3609.
[27] CAPDEVILA C J, ALONSO V, MACIAS D I, et al. The DUREC trial: durvalumab plus total neoadjuvant therapy in locally advanced rectal cancer - a multicenter, single-arm, phase Ⅱ study (GEMCAD-1703)[J]. Ann Oncol, 2023, 34(suppl 2):S430-S431.
[28] LIU X, HE L, TONG W, et al. Safety and effectiveness analysis of neoadjuvant chemoradiation plus consolidative chemotherapy with concurrent anti-PD-1 therapy in mid-low locally advanced rectal cancer[J]. Ann Oncol, 2023, 34(suppl 1):S159.
[29] CROCENZI T, COTTAM B, NEWELL P, et al. A hypofractionated radiation regimen avoids the lymphopenia associated with neoadjuvant chemoradiation therapy of borderline resectable and locally advanced pancreatic adenocarcinoma[J]. J Immunother Cancer, 2016, 4:45.
[30] LAN J, LI R, YIN L M, et al. Targeting myeloid-derived suppressor cells and programmed death ligand 1 confers therapeutic advantage of ablative hypofractionated radiation therapy compared with conventional fractionated radiation therapy[J]. Int J Radiat Oncol Biol Phys, 2018, 101(1):74-87.
[31] SHAMSEDDINE A, ZEIDAN Y H, EL HUSSEINI Z, et al. Efficacy and safety-in analysis of short-course radiation followed by mFOLFOX-6 plus avelumab for locally advanced rectal adenocarcinoma[J]. Radiat Oncol, 2020, 15(1):233.
[32] LIN Z, CAI M, ZHANG P, et al. Phase Ⅱ, single-arm trial of preoperative short-course radiotherapy followed by chemotherapy and camrelizumab in locally advanced rectal cancer[J]. J Immunother Cancer, 2021, 9(11):e003554.
[33] ZHANG T, TAO K, LIN Z, et al. LBA25 Neoadjuvant short-course radiotherapy followed by camrelizumab plus chemotherapy versus long-course chemoradiotherapy followed by chemotherapy in locally advanced rectal cancer: a randomized phase Ⅲ trial (UNION)[J]. Ann Oncol, 2023, 34(suppl 2):S1266-S1267.
[34] XIA F, WANG Y, WANG H, et al. Randomized phase Ⅱ trial of immunotherapy-based total neoadjuvant therapy for proficient mismatch repair or microsatellite stable locally advanced rectal cancer (TORCH)[J]. J Clin Oncol, 2024,JCO2302261.
[35] DAI S, WANG F, SHEN Y B, et al. Efficacy and safety of neoadjuvant preoperative short-course radiation followed by envafolimab plus CAPEOX in microsatellite stable (MSS)/mismatch repair proficient (pMMR) locally advanced rectal cancer[J]. J Clin Oncol, 2023, 41(4 suppl):134.
[36] DARRAGH L B, GADWA J, PHAM T T, et al. Elective nodal irradiation mitigates local and systemic immunity generated by combination radiation and immunotherapy in head and neck tumors[J]. Nat Commun, 2022, 13(1):7015.
[37] MARCISCANO A E, GHASEMZADEH A, NIRSCHL T R, et al. Elective nodal irradiation attenuates the combinatorial efficacy of stereotactic radiation therapy and immunotherapy[J]. Clin Cancer Res, 2018, 24(20):5058-5071.
Options
文章导航

/

〈 〉