Abstract：Advanced esophageal cancer accounts for a large proportion of all esophageal cancer cases, and the treatment modality recommended by the current guidelines is systemic treatment. Radiotherapy is an important treatment option for malignant tumors, which is widely applied in clinical practice. Retrospective analysis and small-sample prospective studies have shown that combination of radiotherapy with chemotherapy, targeted therapy, and immunotherapy has the advantages of improving disease control rate, symptom remission rate and prolonging survival of advanced esophageal cancer patients. Therefore, it is an important clinical topic issue to make better use of the advantages of radiotherapy for esophageal cancer, such as rapid relief of symptoms, durable efficacy, and stimulation of immune neoantigens, etc. To optimize the treatment strategy of advanced esophageal cancer, the radiotherapy strategy for esophageal cancer with oligometastases or multiple metastases, and the screening method for the eligible population for radiotherapy were reviewed, aiming to provide reference for improving the status of radiotherapy in comprehensive treatment of advanced esophageal cancer.
[1] Li C, Wang X, Wang L, et al. Clinical practice and outcome of radiotherapy for advanced esophageal squamous cell carcinoma between2002 and 2018 in China: the multi-center 3JECROG Survey[J]. Acta Oncol, 2021,60(5):627-634. DOI: 10.1080/0284186X.2021.1902564. [2] Shapiro J, van Lanschot J, Hulshof M, et al. Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial[J]. Lancet Oncol, 2015,16(9):1090-1098. DOI: 10.1016/S1470-2045(15)00040-6. [3] Welsh J, Settle SH, Amini A, et al. Failure patterns in patients with esophageal cancer treated with definitive chemoradiation[J]. Cancer, 2012,118(10):2632-2640. DOI: 10.1002/cncr.26586. [4] Verstegen MH, Harker M, van de Water C, et al. Metastatic pattern in esophageal and gastric cancer: influenced by site and histology[J]. World J Gastroenterol, 2020,26(39):6037-6046. DOI: 10.3748/wjg.v26.i39.6037. [5] Allemani C, Matsuda T, Di Carlo V, et al. Global surveillance of trends in cancer survival2000-14 (CONCORD-3): analysis of individual records for 37 513 025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries[J]. Lancet, 2018,391(10125):1023-1075. DOI: 10.1016/S0140-6736(17)33326-3. [6] Jamel S, Tukanova K, Markar S. Detection and management of oligometastatic disease in oesophageal cancer and identification of prognostic factors: a systematic review[J]. World J Gastrointest Oncol, 2019,11(9):741-749. DOI: 10.4251/wjgo.v11.i9.741. [7] Chen YS, Cheng XY, Song HX, et al. Outcomes of concurrent chemoradiotherapy versus chemotherapy alone for esophageal squamous cell cancer patients presenting with oligometastases[J]. J Thorac Dis, 2019,11(4):1536-1545. DOI: 10.21037/jtd.2019.03.10. [8] Liu Q, Zhu ZF, Chen Y, et al. Phase 2 study of stereotactic body radiation therapy for patients with oligometastatic esophageal squamous cell carcinoma[J]. Int J Radiat Oncol Biol Phys, 2020,108(3):707-715. DOI: 10.1016/j.ijrobp.2020.05.003. [9] Schizas D, Mylonas KS, Kapsampelis P, et al. Patients undergoing surgery for oligometastatic oesophageal cancer survive for more than 2 years: bootstrapping systematic review data[J]. Interact Cardiovasc Thorac Surg, 2020,31(3):299-304. DOI: 10.1093/icvts/ivaa116. [10] Kroese TE, van Laarhoven H, Nilsson M, et al. Definition of oligometastatic esophagogastric cancer and impact of local oligometastasis-directed treatment: a systematic review and meta-analysis[J]. Eur J Cancer, 2022,166:254-269. DOI: 10.1016/j.ejca.2022.02.018. [11] Ajani JA, D'Amico TA, Bentrem DJ, et al. Esophageal and esophagogastric junction cancers, version 2.2019, NCCN clinical practice guidelines in oncology[J]. J Natl Compr Canc Netw, 2019,17(7):855-883. DOI: 10.6004/jnccn.2019.0033. [12] Petrasch S, Welt A, Reinacher A, et al. Chemotherapy with cisplatin and paclitaxel in patients with locally advanced, recurrent or metastatic oesophageal cancer[J]. Br J Cancer, 1998,78(4):511-514. DOI: 10.1038/bjc.1998.524. [13] Sun JM, Shen L, Shah MA, et al. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study[J]. Lancet, 2021,398(10302):759-771. DOI: 10.1016/S0140-6736(21)01234-4. [14] Luo H, Lu J, Bai Y, et al. Effect of camrelizumab vs placebo added to chemotherapy on survival and progression-free survival in patients with advanced or metastatic esophageal squamous cell carcinoma: the ESCORT-1st randomized clinical trial[J]. JAMA, 2021,326(10):916-925. DOI: 10.1001/jama.2021.12836. [15] Lu ZH, Wang JY, Shu YQ, et al.Sintilimab versus placebo in combination with chemotherapy as first line treatment for locally advanced or metastatic oesophageal squamous cell carcinoma (ORIENT-15): multicentre, randomised, double blind, phase 3 trial[J]. BMJ, 2022,377:e068714. DOI: 10.1136/bmj-2021-068714. [16] Li LQ, Fu QG, Zhao WD, et al.Chemoradiotherapy versus chemotherapy alone for advanced esophageal squamous cell carcinoma: the role of definitive radiotherapy for primary tumor in the metastatic setting[J]. Front Oncol, 2022,12:824206. DOI: 10.3389/fonc.2022.824206. [17] Al-Batran SE, Homann N, Pauligk C, et al. Effect of neoadjuvant chemotherapy followed by surgical resection on survival in patients with limited metastatic gastric or gastroesophageal junction cancer: the AIO-FLOT3 trial[J]. JAMA Oncol, 2017,3(9):1237-1244. DOI: 10.1001/jamaoncol.2017.0515. [18] Hingorani M, Dixit S, Johnson M, et al. Palliative radiotherapy in the presence of well-controlled metastatic disease after initial chemotherapy may prolong survival in patients with metastatic esophageal and gastric cancer[J]. Cancer Res Treat, 2015,47(4):706-717. DOI: 10.4143/crt.2014.174. [19] Muro K, Lordick F, Tsushima T, et al. Pan-Asian adapted ESMO clinical practice guidelines for the management of patients with metastatic oesophageal cancer: a JSMO-ESMO initiative endorsed by CSCO, KSMO, MOS, SSO and TOS[J]. Ann Oncol, 2019,30(1):34-43. DOI: 10.1093/annonc/mdy498. [20] Guttmann DM, Mitra N, Bekelman J, et al. Improved overall survival with aggressive primary tumor radiotherapy for patients with metastatic esophageal cancer[J]. J Thorac Oncol, 2017,12(7):1131-1142. DOI: 10.1016/j.jtho.2017.03.026. [21] Blank S, Lordick F, Dobritz M, et al. A reliable risk score for stage IV esophagogastric cancer[J]. Eur J Surg Oncol, 2013,39(8):823-830. DOI: 10.1016/j.ejso.2013.01.005. [22] Reits EA, Hodge JW, Herberts CA, et al. Radiation modulates the peptide repertoire, enhances MHC class I expression,induces successful antitumor immunotherapy[J]. J Exp Med, 2006,203(5):1259-1271. DOI: 10.1084/jem.20052494. [23] Sharabi AB, Lim M, DeWeese TL, et al. Radiation and checkpoint blockade immunotherapy: radiosensitisation and potential mechanisms of synergy[J]. Lancet Oncol, 2015,16(13):e498-509. DOI: 10.1016/S1470-2045(15)00007-8. [24] Li BT, Wang RQ, Zhang T, et al.Development and validation of a nomogram prognostic model for esophageal cancer patients with oligometastases[J]. Sci Rep, 2020,10(1):11259. DOI: 10.1038/s41598-020-68160-6. [25] Shi ZG, Zhu XJ, Ke SB, et al. Survival impact of concurrent chemoradiotherapy for elderly patients with synchronous oligometastatic esophageal squamous cell carcinoma: a propensity score matching and landmark analyses[J]. Radiother Oncol, 2021,164:236-244. DOI: 10.1016/j.radonc.2021.09.033. [26] Luke JJ, Lemons JM, Karrison TG, et al. Safety and clinical activity of pembrolizumab and multisite stereotactic body radiotherapy in patients with advanced solid tumors[J]. J Clin Oncol, 2018,36(16):1611-1618. DOI: 10.1200/JCO.2017.76.2229. [27] Chen YS, Zhao WS, Zuo ZG, et al. A prospective clinical trial of camrelizumab in combination with chemoradiotherapy in patients with metastatic esophageal squamous cell carcinoma[J]. J Clin Oncol, 2022,40(4_suppl):326-326. DOI: 10.1200/JCO.2022.40.4_suppl.326. [28] Penniment MG, De Ieso PB, Harvey JA, et al. Palliative chemoradiotherapy versus radiotherapy alone for dysphagia in advanced oesophageal cancer: a multicentre randomised controlled trial (TROG 03.01)[J]. Lancet Gastroenterol Hepatol, 2018,3(2):114-124. DOI: 10.1016/S2468-1253(17)30363-1. [29] Wong RK, Malthaner RA, Zuraw L, et al. Combined modality radiotherapy and chemotherapy in nonsurgical management of localized carcinoma of the esophagus: a practice guideline[J]. Int J Radiat Oncol Biol Phys, 2003,55(4):930-942. DOI: 10.1016/s0360-3016(02)04278-5. [30] Gupta A, Roy S, Majumdar A, et al. A randomized study to compare sequential chemoradiotherapy with concurrent chemoradiotherapy for unresectable locally advanced esophageal cancer[J]. Indian J Med Paediatr Oncol, 2014,35(1):54-59. DOI: 10.4103/0971-5851.133722. [31] Ji YL, Du XH, Zhu WG, et al. Efficacy of concurrent chemoradiotherapy with S-1 vs radiotherapy alone for older patients with esophageal cancer: a multicenter randomized phase 3 clinical trial[J]. JAMA Oncol, 2021,7(10):1459-1466. DOI: 10.1001/jamaoncol.2021.2705. [32] Abdo J, Agrawal DK, Mittal SK."Targeted" chemotherapy for esophageal cancer[J]. Front Oncol, 2017,7:63. DOI: 10.3389/fonc.2017.00063. [33] Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial[J]. Lancet, 2010,376(9742):687-697. DOI: 10.1016/S0140-6736(10)61121-X. [34] Wang J, Wu T, Luo S, et al.Update results of paclitaxel and cisplatin in combination with anlotinib as first-line regimen for patients with advanced ESCC: a multicenter, single-arm, open-label phase II clinical trial[J]. 2022, 40(4_suppl): 315-315.DOI: 10.1200/JCO.2022.40.4_suppl.315. [35] Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy[J]. Science, 2005,307(5706):58-62. DOI: 10.1126/science.1104819. [36] Dings RP, Loren M, Heun H, et al. Scheduling of radiation with angiogenesis inhibitors anginex and avastin improves therapeutic outcome via vessel normalization[J]. Clin Cancer Res, 2007,13(11):3395-3402. DOI: 10.1158/1078-0432.CCR-06-2441. [37] Guo L, Zhang LY, Guan Y, et al. In vitro studies of H520 cell cycle and apoptosis by anlotinib combined with radiotherapy[J]. Thorac Cancer, 2021,12(5):593-602. DOI: 10.1111/1759-7714.13780. [38] Dobosz P, Stępień M, Golke A, et al.Challenges of the immunotherapy: perspectives and limitations of the immune checkpoint inhibitor treatment[J]. Int J Mol Sci, 2022,23(5):2847. DOI: 10.3390/ijms23052847. [39] Dovedi SJ, Adlard AL, Lipowska-Bhalla G, et al. Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade[J]. Cancer Res, 2014,74(19):5458-5468. DOI: 10.1158/0008-5472.CAN-14-1258. [40] Dovedi SJ, Cheadle EJ, Popple AL, et al. Fractionated radiation therapy stimulates antitumor immunity mediated by both resident and infiltrating polyclonal T-cell populations when combined with PD-1 blockade[J]. Clin Cancer Res, 2017,23(18):5514-5526. DOI: 10.1158/1078-0432.CCR-16-1673. [41] Seyedin SN, Parekh KR, Ginader T, et al. The role of definitive radiation and surgery in metastatic esophageal cancer: an NCDB investigation[J]. Ann Thorac Surg, 2021,112(2):459-466. DOI: 10.1016/j.athoracsur.2020.08.034. [42] Boustani J, Grapin M, Laurent PA, et al.The 6th R of radiobiology: reactivation of anti-tumor immune response[J]. Cancers (Basel), 2019,11(6):860. DOI: 10.3390/cancers 11060860. [43] Tanaka H, Arakawa H, Yamaguchi T, et al. A ribonucleotide reductase gene involved in a p53-dependent cell-cycle checkpoint for DNA damage[J]. Nature, 2000,404(6773):42-49. DOI: 10.1038/35003506. [44] Okumura H, Natsugoe S, Yokomakura N, et al. Expression of p53R2 is related to prognosis in patients with esophageal squamous cell carcinoma[J]. Clin Cancer Res, 2006,12(12):3740-3745. DOI: 10.1158/1078-0432.CCR-05-2416. [45] Kim MK, Cho KJ, Kwon GY, et al. Patients with ERCC1-negative locally advanced esophageal cancers may benefit from preoperative chemoradiotherapy[J]. Clin Cancer Res, 2008,14(13):4225-4231. DOI: 10.1158/1078-0432.CCR-07-4848. [46] Noda M, Okumura H, Uchikado Y, et al. Correlation between biomarker candidate proteins with the effect of neoadjuvant chemoradiation therapy on esophageal squamous cell carcinoma[J]. Ann Surg Oncol, 2018,25(2):449-455. DOI: 10.1245/s10434-017-6271-y. [47] Coussens LM, Werb Z. Inflammation and cancer[J]. Nature, 2002,420(6917):860-867. DOI: 10.1038/nature01322. [48] Al Lawati Y, Cools-Lartigue J, Ramirez-GarciaLuna JL, et al. Dynamic alteration of neutrophil-to-lymphocyte ratio over treatment trajectory is associated with survival in esophageal adenocarcinoma[J]. Ann Surg Oncol, 2020,27(11):4413-4419. DOI: 10.1245/s10434-020-08521-7. [49] Kanda M, Koike M, Tanaka C, et al. Modified systemic inflammation score is useful for risk stratification after radical resection of squamous cell carcinoma of the esophagus[J]. Ann Surg Oncol, 2019,26(13):4773-4781. DOI: 10.1245/s10434-019-07914-7. [50] Messager M, Neofytou K, Chaudry MA, et al. Prognostic impact of preoperative platelets to lymphocytes ratio (PLR) on survival for oesophageal and junctional carcinoma treated with neoadjuvant chemotherapy: a retrospective monocentric study on 153 patients[J]. Eur J Surg Oncol, 2015,41(10):1316-1323. DOI: 10.1016/j.ejso.2015.06.007. [51] van Sandick JW, Boermeester MA, Gisbertz SS, et al. Lymphocyte subsets and T(h)1/T(h)2 immune responses in patients with adenocarcinoma of the oesophagus or oesophagogastric junction: relation to pTNM stage and clinical outcome[J]. Cancer Immunol Immunother, 2003,52(10):617-624. DOI: 10.1007/s00262-003-0406-7. [52] Gao XC, Pan YN, Han WL, et al. Association of systemic inflammation and body mass index with survival in patients with resectable gastric or gastroesophageal junction adenocarcinomas[J]. Cancer Biol Med, 2021,18(1):283-297. DOI: 10.20892/j.issn.2095-3941.2020. 0246. [53] Liang S, Li CM, Gao ZH, et al.A nomogram to predict short-term outcome of radiotherapy or chemoradiotherapy based on pre/post-treatment inflammatory biomarkers and their dynamic changes in esophageal squamous cell carcinoma[J]. Int Immunopharmacol, 2021,90:107178. DOI: 10.1016/j.intimp.2020.107178. [54] Ueda M, Iguchi T, Masuda T, et al. Somatic mutations in plasma cell-free DNA are diagnostic markers for esophageal squamous cell carcinoma recurrence[J]. Oncotarget, 2016,7(38):62280-62291. DOI: 10.18632/oncotarget.11409. [55] Poulet G, Massias J, Taly V. Liquid biopsy: general concepts[J]. Acta Cytol, 2019,63(6):449-455. DOI: 10.1159/000499337. [56] Azad TD, Chaudhuri AA, Fang P, et al. Circulating tumor DNA analysis for detection of minimal residual disease after chemoradiotherapy for localized esophageal cancer[J]. Gastroenterology, 2020,158(3):494-505.e6. DOI: 10.1053/j.gastro.2019.10.039.
2023, Vol. 32 
