2. 国家癌症中心,中国医学科学院北京协和医学院肿瘤医院,北京 100021;
3. 武警安徽省总队医院肿瘤科,合肥 230001
2. National Cancer Center, Cancer Hospital of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100021, China;
3. Department of Oncology, Anhui Armed Police Corps Hospital, Hefei 230001, Anhui, China
根据国际癌症研究机构(International Agency for Research on Cancer,IARC)的最新报道[1],2020年中国食管癌发病率和病死率分别居中国主要癌症类型的第6位和第4位,新发病例32.4万例,病死30.1万例。食管癌组织学类型有明显地域差异,中国和日本90%为食管鳞癌(esophageal squamous carcinoma, ESCC),欧美国家80%为食管腺癌(esophageal adenocarcinoma, EAC)。食管癌早期临床症状轻微,大于50%的患者发现时已处中晚期[2]。根治性切除+纵隔淋巴结清扫术仍是该病治疗首选,但单纯手术效果不佳,需要多学科策略来改善生存。本文围绕4个方面的外科手术相关问题进行讨论。
1 局部晚期可切除ESCC的围手术期治疗 1.1 围手术期化疗随着围手术期治疗和免疫治疗的发展,ESCC的治疗已取得巨大进展[3]。术前或术后辅助治疗,包括化疗(chemotherapy,CT)和放化疗(chemoradiotherapy,CRT)对患者的预后至关重要。为预防术后复发,日本最初把术后(顺铂+5-氟尿嘧啶,CF)化疗作为Ⅱ/Ⅲ期ESCC患者的标准治疗方法。但近年的JCOG9907试验[4]显示,术前化疗组和术后化疗组的5年总体生存率(overall survival,OS)为55%和43%,证明化疗最佳时机由术后转向术前,术前新辅助化疗可能使肿瘤降期,进而提高R0切除率,并消灭亚临床远处转移灶;术前化疗可尝试用更大剂量的化疗药物,并观察药物反应,应答不佳的患者则应改变治疗策略。需要注意的是,对于手术后病理提示淋巴结阳性的患者仍需术后辅助化疗[5]。Imai等[6]发现,在术前化疗+R0切除术后有2个或2个以上病理阳性淋巴结的临床Ⅱ/Ⅲ期ESCC患者中,术后辅助化疗与OS改善相关(未达到vs 20.1个月,P=0.0404)。
1.2 新辅助放化疗CROSS试验[7]随机纳入366例食管癌及食管胃交界癌患者,比较新辅助放化疗[neoadjuvant chemoradiotherapy,nCRT;紫杉醇+卡铂(PCB),41.4 Gy/23 Fx]联合手术治疗和单纯手术的临床疗效,治疗后中位生存时间为49.4个月和24个月,5年OS分别为47%和34%,R0切除率为92%和69%;联合治疗后,ESCC组(n=37)和EAC组(n=121)的病理完全缓解率(pathological complete remission,pCR)为49%和23%,提示ESCC对nCRT更敏感。CROSS研究的缺陷是手术组中纳入的鳞癌例数少,单纯手术后5年OS仅约30%,R0切除率存在争议。同期针对ESCC的大样本随机对照试验NEOCRTEC5010[8]中,2007年至2014年入组潜在可切除局部晚期(cT1~4N1M0或T4N0M0)ESCC患者451例,新辅助放化疗组[n=224;长春瑞滨+顺铂(NP),40 Gy/20 Fx]4~8周后手术较直接手术组(n=227)延长了中位生存时间(100.1个月vs 66.5个月)、无病生存时间(disease free survival,DFS;100.1个月vs 41.7个月);新辅助放化疗组pCR率为43.2%,R0切除率为98.4%(P=0.002);两组手术相关并发症和围手术期病死率差异无统计学意义。该研究结果被2019年NCCN指南[9]和2020年CSCO指南[10]引用。在日本,术前新辅助放化疗的优势一直被质疑。日本将新辅助化疗确定为Ⅱ/Ⅲ期ESCC的标准治疗方法,认为预后与患者群体、手术对肿瘤的局部控制等相关[11]。由Nakamura[12]主导的三臂Ⅲ期JCOG1109试验对比了加强化疗(多西他赛+顺铂+5-氟尿嘧啶,DCF)、CF、及nCRT(CF)的术前方案效果,以期获得ESCC的最佳术前策略。中国和日本肿瘤治疗的区别在于,虽然在外科技术方面都有能力达到满意的肿瘤局部控制效果,但中国有较多的局部晚期(包括cT3~4期)患者,这部分患者采用新辅助放化疗的效果可能更佳。西方国家则认为ESCC术前放化疗非常必要[13]。从目前的治疗现状来看,nCRT的循证医学证据更充分,仍是一线选择。
1.3 pCR预测模型和“器官保留”部分患者接受新辅助治疗后可达到临床完全缓解(clinical complete response,cCR),症状消失、辅助检查未发现肿瘤残留。因此有学者[14]认为新辅助治疗后达到cCR且获得pCR的患者可避免食管切除。ESOSTRATE试验、SANO试验(NTR6803)都针对新辅助治疗后cCR患者,比较积极监测与标准手术的差异[15]。谭黎杰等[16]认为,通过临床评估和分子诊断高度考虑pCR为“观察与等待”策略的前提。现阶段运用(PET-CT、MRI、内镜及分子标志物)等检查手段判断肿瘤和淋巴结残留方案仍亟待探究[17],例如影像数据处理、生物学标本采集的标准化、研究成果从实验室向临床应用的转化等。
近年多个预测nCRT后pCR的生物标志物相关研究取得明显进展。Kim等[18]利用液体活检技术对30例食管癌患者nCRT前后的血液样本进行了肿瘤细胞游离DNA(cfDNA)全基因组测序,发现代表全基因组/染色体不稳定性的Ⅰ-score评分和代表cfDNA中短片段比例的FR-score评分越低,提示nCRT反应较好。cfDNA的分子突变负荷(molecular mutational burden,MMB)基因突变特征和拷贝数变异(cfDNA copy number variations,CNVs)标志物同样有重要的新辅助疗效监测价值[19]。而在RNA标志物方面,有研究[20]通过28例ESCC患者的预处理内镜活检样本,构建了3种lncRNAs (SCAT1、PRKAG2-AS1和FLG-AS1)的分类器,能将PCR患者与小于pCR率的患者区分开来,并可与其他RNA标志物互补[20]。无论是传统基因、RNA和蛋白质生物标志物,还是代谢、免疫和肿瘤微环境以及微生物组标志物,都需要结合临床评估和影像学方法建立综合预测模型。但在更大样本量的前瞻性试验验证模型有效性前,nCRT主要目的为提高病理反应率及局部控制率,手术的作用仍不可忽视。
2 初始无法根治切除的ESCC转化手术方案晚期食管癌对邻近器官有高度侵袭性,这类肿瘤首选放化疗,但往往预后不佳。对初始不可切除cT4b期无远处转移食管癌的治疗策略仍存争议[21]。日本一项单中心回顾性研究[22]探讨了这部分患者手术治疗的可能性,对1997年至2016年147例诊断为cT4b的食管癌患者(包括锁骨上淋巴结转移病例)初始接受放化疗(40 Gy+1周期化疗)后通过评估肿瘤外侵情况,在4~6周后进行转化手术(尤其是对边缘可切除的食管癌患者);或因减瘤不足、患者拒绝手术等原因,行根治性放化疗(definitive CRT,dCRT),剂量调整为60 Gy。其中43例在中期评估时接受了根治性切除;104例接受了dCRT,并有21例在后期完成了挽救性手术。dCRT组(不包括挽救性手术)患者的5年疾病特异性生存率和总体生存率分别为22.8%和17.6%,预后差于转化手术组(P=0.01、0.013)。转化策略最初被用于结直肠癌患者。COSMOS试验[23]评估了初始无法切除的局部晚期ESCC患者采用DCF诱导化疗和随后行转化手术的安全性及有效性,其中接受手术者有41.7%,实现R0切除者有39.6%;疾病特异性生存的单因素和多因素分析显示,中期评估结果良好和手术(转化和挽救手术)干预是预后有利因素,而淋巴结转移或远处转移是影响预后的不利因素。手术对于cT4b期患者的重要性甚至高于其对初始可切除ESCC患者。因此,在考虑风险和适当时机后,手术是cT4b期患者的潜在选择[22]。
3 挽救性食管切除术的临床应用根治性放化疗常被用于治疗肿瘤无法切除、不适合手术或拒绝手术的患者。对于dCRT后残留或复发的病例,挽救性手术是推荐治疗方案[24]。Kumagai等[25]发现,与二线放化疗相比,挽救性手术患者可长期生存,但较计划性食管切除患者死亡率高、并发症发生率高、住院周期长,短期预后差[26]。合适的放疗剂量对食管癌患者的生存率和局部控制率有重要影响。改良RTOG方案[27]降低了放射剂量(50.4 Gy),同时行选择性淋巴结放疗者cCR率为70.6%,1年和3年OS分别为88.2%和63.8%,接受挽救性手术后预后更佳。JCOG0909试验[28]验证了接受放化疗联合改良RTOG方案的局部残留或复发Ⅱ/Ⅲ期食管癌患者行挽救性手术后预后改善。Sohda等[29]认为,肿瘤残余是挽救性手术后独立不良预后因素,R0切除是术后长期生存的有利因素,提示患者需要更有效的化疗辅助。刘良忠等[30]发现,应用奥沙利铂联合多西他赛替代CF能获得更高的局部控制率和更长生存期。此外,加强挽救性手术围手术期管理对预后同样重要。
4 食管癌微创外科技术 4.1 淋巴结清扫范围的选择对于局部晚期尤其cT4b期ESCC患者,影响预后的一个重要因素是淋巴结转移或远处转移。日本医生提出三野淋巴结清扫(three-field lymph node dissection,3FD)的概念[31],率先对喉返神经周围淋巴结进行清扫,逐渐进行上纵隔淋巴结清扫,使术后病理分期更准确。之后3FD在全球被逐步推广。国内临床研究[32]显示,3FD与2FD,术后30 d并发症发生率无差异,但3FD后1年和3年生存率均明显高于2FD。因此,日本学者认为手术对于局部控制的作用至关重要。但是锁骨上淋巴结的转移在JES No.11修订版归于(N2),而在AJCC No.8分类归于远处转移(M1)。后者将其定义为不可切除的cT4b期肿瘤,不建议手术治疗。日本则主张在胸中段食管癌手术中应用3FD联合D2根治切除。但这种术式有高创伤性,只有依赖外科技术的进步才能降低并发症风险。
4.2 微创手术方式的发展全胸腔镜、腹腔镜、辅助胸部小切口及开放食管切除术(open esophagectomy, OE)联合腔镜的多种食管癌切除术式被定义为广义微创食管癌切除术(minimally invasive esophagectomy,MIE)。MIRO试验[33]比较了OE和Ivor-Lewis术式(联合手术)术后并发症发生率,OE组为64%、Ivor-Lewis组为36%,3年OS(55% vs 67%)差异不明显。日本国家临床数据库(National Clinical Database,NCD)[34]纳入2011至2016年39 000余例食管癌切除术患者,分阶段对微创手术和开放手术结果对照分析:第一阶段,微创组术后并发症发生率和死亡率高于开放组(44.3% vs 40.8%,P=0.016)[35];第二阶段,微创组手术时长长于开放组[(526±149)min vs (461±156) min,P < 0.01],术后短期并发症发生率低于开放组[36];第三阶段分析了术前治疗和手术方式对短期预后的影响,微创组超过48 h机械通气治疗、计划外气管插管、肺炎等术后并发症发生率及总手术相关死亡率低于或与开放组相似[37]。该研究提示MIE逐步标准化和规范化,而微创、快速康复的理念以及更好的围手术期管理逐渐得到重视。
纵隔镜辅助下食管癌切除术(mediastinoscopy-assisted transhiatal esophagectomy, MATHE)和机器人辅助下MIE (robotic-assisted MIE, RAMIE)术式也被应用于临床,其中MATHE的颈部切口更小,Fujiwara等[38]发现MATHE切除可达到与经胸食管癌切除相似的淋巴结清扫率。而RAMIE因高昂的治疗费用并未被广泛推广。ROBOT试验[39]比较了RAMIE和OE的手术相关总并发症(59% vs 80%,P=0.02),肺部并发症(32% vs 58%,P=0.005),心脏并发症(22% vs 47%,P=0.006),RAMIE术后并发症更少。但RAMIE较传统MIE是否更具备优势,有待进一步探讨。
综上所述,在中国,食管癌的外科综合治疗策略已得到广泛应用。新辅助治疗后再行食管切除术是目前可切除晚期ESCC的标准治疗方法。免疫检查点抑制剂辅助治疗食管癌也取得进展。任何综合治疗策略都应以加强局部控制和提高R0切除率为目的,统一标准、便于普及的nCRT反应准确预测模型以及食管癌的靶向和免疫治疗将成为食管癌治疗研究热点。
利益冲突: 所有作者声明不存在利益冲突。
[1] |
CAO W, CHEN H D, YU Y W, et al. Changing profiles of cancer burden worldwide and in China: a secondary analysis of the global cancer statistics 2020[J]. Chin Med J (Engl), 2021, 134(7): 783-791.
[DOI]
|
[2] |
MILLER K D, SIEGEL R L, LIN C C, et al. Cancer treatment and survivorship statistics, 2016[J]. CA Cancer J Clin, 2016, 66(4): 271-289.
[DOI]
|
[3] |
WATANABE M, OTAKE R, KOZUKI R, et al. Recent progress in multidisciplinary treatment for patients with esophageal cancer[J]. Surg Today, 2020, 50(1): 12-20.
[DOI]
|
[4] |
ANDO N, KATO H, IGAKI H, et al. A randomized trial comparing postoperative adjuvant chemotherapy with cisplatin and 5-fluorouracil versus preoperative chemotherapy for localized advanced squamous cell carcinoma of the thoracic esophagus (JCOG9907)[J]. Ann Surg Oncol, 2012, 19(1): 68-74.
[DOI]
|
[5] |
KITAGAWA Y, UNO T, OYAMA T, et al. Esophageal cancer practice guidelines 2017edited by the Japan Esophageal Society: part 1[J]. Esophagus, 2019, 16(1): 1-24.
[DOI]
|
[6] |
IMAI T, TANAKA Y, SATO Y, et al. The role of adjuvant chemotherapy for esophageal squamous cell carcinoma patients with pathological positive lymph nodes after neoadjuvant chemotherapy followed by esophagectomy: a single institute retrospective analysis[J]. Indian J Surg Oncol, 2021, 8(28): 1-9.
|
[7] |
VAN HAGEN P, HULSHOF M C, VAN LANSCHOT J J, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer[J]. N Engl J Med, 2012, 366(22): 2074-2084.
[DOI]
|
[8] |
YANG H, LIU H, CHEN Y, et al. Neoadjuvant chemoradiotherapy followed by surgery versus surgery alone for locally advanced squamous cell carcinoma of the esophagus (NEOCRTEC5010): a phase multicenter, randomized, open label clinical trial[J]. J Clin Oncol, 2018, 36(27): 2796-2803.
[DOI]
|
[9] |
AJANI J A, D'AMICO T A, BENTREM D J, 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] |
中国临床肿瘤学会指南工作委员会. 食管癌诊疗指南(2020版)[M]. 北京: 人民卫生出版社, 2020. Guidelines Working Committee of Chinese Society of Clinical Oncology. Guidelines for diagnosis and treatment of esophageal cancer (Version 2020)[M]. Beijing: People's Medical Publishing House, 2020. |
[11] |
WATANABE M. Recent topics and perspectives on esophageal cancer in Japan[J]. JMA J, 2018, 1(1): 30-39.
[DOI]
|
[12] |
NAKAMURA K, KATO K, IGAKI H, et al. Three-arm phase Ⅲ trial comparing cisplatin plus 5-FU (CF) versus docetaxel, cisplatin plus 5-FU (DCF) versus radiotherapy with CF (CF-RT) as preoperative therapy for locally advanced esophageal cancer (JCOG1109, Next study)[J]. Jpn J Clin Oncol, 2013, 43(7): 752-755.
[DOI]
|
[13] |
郭旭峰, 冷雪峰, 戴亮. 食管癌外科热点问题—日本专家访谈[J]. 中华胸部外科电子杂志, 2019, 6(4): 207-211. GUO X F, LENG X F, DAI L. The interview with famous esophageal surgeons in Japan on hot topics of esophageal cancer surgery[J]. Chin J Thorac Surg(Electronic Edition), 2019, 6(4): 207-211. [CNKI] |
[14] |
TING Y C, HSU P K, CHEN H S, et al. Surgery or surveillance for esophageal squamous cell carcinoma with clinical complete response after neoadjuvant chemoradiotherapy[J]. Semin Thorac Cardiovasc Surg, 2022, S1043-0679(22)00074-0.
|
[15] |
NOORDMAN B J, WIJNHOVEN B P L, LAGARDE S M, et al. Neoadjuvant chemoradiotherapy plus surgery versus active surveillance for oesophageal cancer: a stepped wedge cluster randomised trial[J]. BMC Cancer, 2018, 18(1): 142.
[DOI]
|
[16] |
谭黎杰, 林栋. 食管癌新辅助治疗时代关于病理反应预测与食管保留策略的思考[J]. 中华消化外科杂志, 2019, 18(6): 528-531. TAN L J, LIN D. Thoughts on prediction of pathological response and strategies of esophageal preservation in the era of neoadjuvant therapy for esophageal cancer[J]. Chinese Journal of Digestive Surgery, 2019, 18(6): 528-531. |
[17] |
傅剑华, 谭子辉. 食管鳞癌新辅助放化疗后完全缓解是否仍需手术[J]. 中华胃肠外科杂志, 2018, 21(9): 983-986. FU J H, TAN Z H. Is esophagectomy necessary for esophageal cancer patients with complete response after neoadjuvant chemoradiotherapy[J]. Chin J Gastrointest Surg, 2018, 21(9): 983-986. |
[18] |
KIM E J, IM H S, LEE J, et al. Genome-wide and size-based cell-free DNA indices as predictive biomarkers for locally advanced esophageal squamous cell carcinoma treated with preoperative or definitive chemoradiotherapy[J]. Curr Probl Cancer, 2021, 45(3): 100685.
[DOI]
|
[19] |
ZHANG R X, HU Y, ZHOU T, et al. The mutation profiles of cell-free DNA in patients with oesophageal squamous cell carcinoma who were responsive and non-responsive to neoadjuvant chemotherapy[J]. J Thorac Dis, 2020, 12(8): 4274-4283.
[DOI]
|
[20] |
ZHANG C, ZHANG Z, ZHANG G, et al. A three-lncRNA signature of pretreatment biopsies predicts pathological response and outcome in esophageal squamous cell carcinoma with neoadjuvant chemoradiotherapy[J]. Clin Transl Med, 2020, 10(4): 156-171.
|
[21] |
SAEKI H, SOHDA M, SAKAI M, et al. Role of surgery in multidisciplinary treatment strategies for locally advanced esophageal squamous cell carcinoma[J]. Ann Gastroenterol Surg, 2020, 4(5): 490-497.
[DOI]
|
[22] |
SOHDA M, MIYAZAKI T, SAKAI M, et al. Multidisciplinary therapy for locally advanced oesophageal cancer with special reference to surgical conversion and salvage[J]. Anticancer Res, 2019, 39(6): 3167-3175.
[DOI]
|
[23] |
YOKOTA T, KATO K, HAMAMOTO Y, et al. Phase Ⅱ study of chemoselection with docetaxel plus cisplatin and 5-fuorouracil induction chemotherapy and subsequent conversion surgery for locally advanced unresectable oesophageal cancer[J]. Br J Cancer, 2016, 115(11): 1328-1334.
[DOI]
|
[24] |
SOHDA M, KUWANO H. Current status and future prospects for esophageal cancer treatment[J]. Ann Thorac Cardiovasc Surg, 2017, 23(1): 1-11.
[DOI]
|
[25] |
KUMAGAI K, MARIOSA D, TSAI J A, et al. Systematic review and meta-analysis on the significance of salvage esophagectomy for persistent or recurrent esophageal squamous cell carcinoma after definitive chemoradiotherapy[J]. Dis Esophagus, 2016, 29(7): 734-739.
[DOI]
|
[26] |
MARKAR S R, KARTHIKESALINGAM A, PENNA M, et al. Assessment of short-term clinical outcomes following salvage esophagectomy for the treatment of esophageal malignancy: systematic review and pooled analysis[J]. Ann Surg Oncol, 2014, 21(3): 922-931.
[DOI]
|
[27] |
KATO K, NAKAJIMA T E, ITO Y, et al. Phase Ⅱ study of concurrent chemoradiotherapy at the dose of 50.4 Gy with elective nodal irradiation for Stage Ⅱ-Ⅲ esophageal carcinoma[J]. J Clin Oncol, 2013, 43(6): 608-615.
|
[28] |
TAKEUCHI H, ITO Y, MACHIDA R, et al. A single-arm confirmatory study of definitive chemoradiotherapy including salvage treatment for clinical stage Ⅱ/Ⅲ esophageal squamous cell carcinoma (JCOG0909 study)[J]. Int J Radiat Oncol Biol Phys, 2022, S0360-3016(22)00726-X.
|
[29] |
SOHDA M, KUMAKURA Y, SAITO H, et al. Clinical significance of salvage esophagectomy for patients with esophageal cancer and factors of influencing long-term survival[J]. Anticancer Res, 2017, 37(9): 5045-5051.
|
[30] |
刘良忠, 李小红, 彭科瑜, 等. 调强放疗同步多西他赛联合奥沙利铂化疗治Ⅲ/Ⅳ期食管癌的临床研究[J]. 实用医学杂志, 2019, 35(24): 3808-3812. LIU L Z, LI X H, PENG K Y, et al. Clinical study of intensity modulated radiotherapy combined with Docetaxel and Oxaliplatin chemotherapy in the management of stage Ⅲ/Ⅳ esophageal cancer[J]. J Pract Med, 2019, 35(24): 3808-3812. [CNKI] |
[31] |
FUJITA H. History of lymphadenectomy for esophageal cancer and the future prospects for esophageal cancer surgery[J]. Surg Today, 2015, 45(2): 140-149.
[DOI]
|
[32] |
张智光, 韩泳涛. 胸中上段食管鳞癌三野与二野淋巴结清扫疗效比较[J]. 实用医学杂志, 2019, 35(20): 3193-3198. ZHAN Z G, HAN Y T. Retrospective study on the efficacy of three-field and two-field lymph node dissection in esophageal squa-mous cell carcinoma[J]. J Pract Med, 2019, 35(20): 3193-3198. [CNKI] |
[33] |
MARIETTE C, MARKAR S R, DABAKUYO-YONLI T S, et al. Hybrid minimally invasive esophagectomy for esophageal cancer[J]. N Engl J Med, 2019, 380(2): 152-162.
|
[34] |
BABA H. National Clinical Database(NCD)in Japan: clinical and social signifcance[J]. Ann Gastroenterol Surg, 2019, 3(5): 462-463.
|
[35] |
TAKEUCHI H, MIYATA H, GOTOH M, et al. A risk model for esophagectomy using data of 5354 patients included in a Japanese nationwide web-based database[J]. Ann Surg, 2014, 260(2): 259-266.
|
[36] |
TAKEUCHI H, MIYATA H, OZAWA S, et al. Comparison of short-term outcomes between open and minimally invasive esophagectomy for esophageal cancer using a nationwide database in Japan[J]. Ann Surg Oncol, 2017, 24(7): 1821-1827.
|
[37] |
YOSHIDA N, YAMAMOTO H, BABA H, et al. Can minimally invasive esophagectomy replace open esophagectomy for esophageal cancer? Latest analysis of 24, 233 esophagectomies from the Japanese National Clinical Database[J]. Ann Surg, 2020, 272(1): 118-124.
|
[38] |
FUJIWARA H, SHIOZAKI A, KONISHI H, et al. Perioperative outcomes of single-port mediastinoscope-assisted transhiatal esophagectomy for thoracic esophageal cancer[J]. Dis Esophagus, 2017, 30(10): 1-8.
|
[39] |
VAN DER SLUIS P C, VAN DER HORST S, MAY A M, et al. Robot-assisted minimally invasive thoracolaparoscopic esophagectomy versus open transthoracic esophagectomy for resectable esophageal cancer: a randomized controlled trial[J]. Ann Surg, 2019, 269(4): 621-630.
|