食管癌放疗相关多原发恶性肿瘤的研究进展
Research Progress of Multiple Primary Malignancies Related to Radiotherapy for Esophageal Cancer
DOI: 10.12677/acm.2025.152310, PDF, HTML, XML,   
作者: 巫海涓*:重庆医科大学第二临床学院,重庆;高 建#:重庆医科大学附属第二医院消化内科,重庆
关键词: 食管癌放射治疗多原发恶性肿瘤Esophageal Cancer Radiotherapy Multiple Primary Malignancies
摘要: 食管癌是全球范围内常见的恶性肿瘤之一,包括鳞状细胞癌和腺癌,其特点是预后差。随着诊疗技术的发展,食管癌患者生存率略有提高,多原发恶性肿瘤也越来越普遍。放射治疗是食管癌治疗基石,也是多原发恶性肿瘤的病因之一。本研究旨在综述目前食管癌多原发恶性肿瘤的临床特征及放疗相关多原发恶性肿瘤的研究现状。
Abstract: Esophageal cancer is among the most common malignant tumors globally, encompassing both squamous cell carcinoma and adenocarcinoma, and is characterized by a poor prognosis. With advancements in diagnostic and therapeutic technologies, the survival rate of patients with esophageal cancer has seen a slight improvement; concurrently, the incidence of multiple primary malignancies is becoming increasingly prevalent. Radiation therapy serves as the cornerstone of esophageal cancer treatment and is also a contributing factor to the emergence of multiple primary malignancies. This study aims to review the current clinical characteristics of multiple primary malignancies associated with esophageal cancer, as well as the existing research on the relationship between radiotherapy and these tumors.
文章引用:巫海涓, 高建. 食管癌放疗相关多原发恶性肿瘤的研究进展[J]. 临床医学进展, 2025, 15(2): 22-27. https://doi.org/10.12677/acm.2025.152310

1. 引言

食管癌(esophageal cancer, EC)是全球范围内常见的恶性肿瘤之一,而中国是食管癌高发地区,虽然中国食管癌的发病率及死亡率均呈下降趋势,但依旧是威胁我国居民健康的主要恶性肿瘤[1] [2]。食管癌的两种最主要的组织学亚型是食管鳞状细胞癌(esophageal squamous cell carcinoma, ESCC)和食管腺癌(esophageal adenocarcinoma, EAC) [3]。尽管手术、化疗、放疗和免疫疗法等治疗方式取得了进展,但食管癌仍然是一种具有挑战性的疾病,预后差。在大多数国家,5年生存率在10%~30%之间[4],这主要是由于许多患者被诊断为晚期。

基于多学科团队(multi-disciplinary team, MDT)的规范诊疗是食管癌综合治疗的基础,放射治疗已成为食管癌治疗基石,并在疾病的各个阶段都发挥着关键作用,包括新辅助放疗、根治性放疗、术后辅助放疗等[5] [6]

随着诊断技术和治疗方式的稳步发展,近年来食管癌患者的生存率略有提高,而生存率的提高使得治疗的长期风险变得更加重要。其中放射治疗虽然可以增强局部控制并可能提高生存率,但也会带来潜在的长期副作用和多原发恶性肿瘤(multiple primary malignancies, MPMs)的风险。放射治疗相关的多原发恶性肿瘤是一种值得注意的癌症治疗晚期并发症[7]。现对食管癌放疗相关多原发恶性肿瘤进行综述,以期为食管癌患者放疗后远期监测提供建议。

2. 定义

早期发现和适当的管理使得癌症患者的生存率在全球范围内不断提高,有癌症病史的患者可能在一生中患上几种癌症[8]。当患者被诊断患有一种以上的癌症时,可能会报告多原发恶性肿瘤。临床上多原发恶性肿瘤被误诊为转移癌或癌症复发的情况并不少见[9] [10]。多原发恶性肿瘤,又称多发性癌,是指同一患者1个或多个器官和组织中2个及以上的原发恶性肿瘤同时或先后发生[1]。多原发恶性肿瘤的临床诊断标准倾向于Warren和Gates提出的标准,即:(1) 所有原发恶性肿瘤必须经病理证实;(2) 所有原发恶性肿瘤的病理形态不同;(3) 必须排除癌症复发或转移的可能性[11]。根据两个原发恶性肿瘤之间的时间间隔,Meortel将多原发恶性肿瘤分为同时性多原发恶性肿瘤(诊断间隔 ≤ 6个月)和异时性多原发恶性肿瘤(诊断间隔 > 6个月) [12]。异时性多原发恶性肿瘤不仅反映了与初始癌症共有的病因因素的影响,如烟酒、饮食、免疫功能、环境因素,而且还反映了癌症治疗的后期效应[13]。本综述提到的放疗相关多原发恶性肿瘤即为异时性多原发恶性肿瘤。

3. 食管癌多原发恶性肿瘤

多原发恶性肿瘤在食管癌患者中并不少见,既往研究报告,约0.6%~14.5%的食管癌患者在随访期间发生多原发恶性肿瘤[14]-[17]。食管癌患者发生多原发恶性肿瘤与年龄、性别、基因(包括家族史)、病理诊断、疾病分期、烟酒史等有关[18]-[20]。此外,食管癌新疗法的引入,包括手术、化疗、放疗或这些方式的组合,不仅提高了患者的生存率,而且还可能增加异时性多原发恶性肿瘤的风险[20]。文献报道的与食管癌相关的多原发恶性肿瘤部位各不相同,但多数集中在头颈部、胃、结直肠和肺[20]-[22],原因可能包括以下几个方面:(1) 胃、结直肠、肺是恶性肿瘤最常见的部位;(2) 不良饮食、吸烟、饮酒等因素刺激食管癌,也容易诱发邻近区域(喉咽、贲门等)癌变;(3) 食管癌的放射治疗也可能诱发邻近器官的肿瘤,如肺、甲状腺等[1]。有趣的是,一项基于美国国家癌症中心的监测、流行病学和结果数据库(The Surveillance, Epidemiology, and End Results, SEER)的观察性研究发现,食管癌人群中前列腺癌作为第二原发恶性肿瘤的发生风险降低,目前还没有明确的临床或生物学机制来解释这个发现,仍需进一步研究[20]

4. 食管癌放疗相关多原发恶性肿瘤

4.1. 放疗诱发MPMs的机制及危险因素

放射治疗是一种利用高能量的电离辐射(如X射线、伽马射线)来杀死或损伤肿瘤细胞的治疗方法[23]。DNA双链断裂很难修复,因此具有极大的细胞毒性,特别是对快速增殖的细胞。因此,产生双链断裂的暴露因素,如电离辐射,可以成为非常有效的抗癌剂[13]。电离辐射的杀伤机制包括直接损伤和间接损伤:直接损伤是指电离辐射可以直接破坏生物分子,例如蛋白质和脂质,特别是DNA,导致DNA双链断裂和其他类型的DNA损伤[24];间接损伤是指通过自由基破坏生物分子,主要是通过活性氧(reactive oxygen species, ROS)破坏癌细胞的完整性并诱导DNA损伤,随后导致细胞死亡[25]

可是放射治疗杀死肿瘤组织的同时,不可避免地辐射癌灶周围正常组织,这可能会造成一些短期毒性和长期效应。短期毒性(如粘膜炎)通常在几周到几个月内愈合;长期效应,如纤维化,通常被认为是不可逆的,并且随着时间的推移而进展[23] [26]

在放射治疗的长期效应中,辐射诱导的第二原发恶性肿瘤是不可忽视的,这可能改变患者的生存结局。放射治疗引起正常组织的DNA损伤,当损伤的DNA双链断裂被修复时,它们有可能被错误地修复,导致存在基因改变的初始克隆细胞的形成,从而导致治疗性致癌[1] [13]。一项研究发现接受治疗的霍奇金淋巴瘤患者肺部放射治疗剂量与随后发展为肺癌的风险之间的关系近似线性,这说明了放疗诱导双链断裂的致癌潜力[27]。另一方面,电离辐射还可能继续作用于食管癌周围的基因改变区域,进一步加速肿瘤前细胞向肿瘤细胞的转化[1]。因此,放疗虽然可以治疗肿瘤,但也会诱发附近器官的多原发恶性肿瘤[28] [29]

与放疗诱发MPMs相关的因素包括年龄、生存时间、放射治疗剂量、危险器官的功能状态、遗传危险因素等[23] [30]-[33]。一般来说,年龄越小,生存时间越长,放射剂量越大,发生MPMs风险越大。另外,我们将辐射敏感器官(如肺、结肠、乳腺、甲状腺)、与食管有相似致癌因素的器官以及与食管相邻的器官称为危险器官,如果这些器官本身健康状况差,就更易被辐射诱导致癌。此外,一些遗传危险因素,如携带ATM基因突变也会显著增加放疗后发生MPMs的风险[32]

4.2. 食管癌放疗相关MPMs的预防

放射治疗中使用的剂量远高于辐射防护领域通常关注的剂量[34],要想预防放射治疗相关的多原发恶性肿瘤,一个显而易见的方法是减少影响正常组织的辐射剂量。这种剂量的减少可以通过两种方式实现:一方面可以减少总剂量,这通常通过与化疗联合使用来实现;另一方面,可以减少接受辐射的器官和正常组织的体积,在这方面,3D适形放疗和调强放疗技术已做出重大贡献[23]。近年来,放射治疗技术的重点是通过图像引导、提高光束传输精度和粒子治疗来减少对正常组织的辐射剂量[31]。探索干预策略和治疗方案对预防食管癌放疗相关MPMs至关重要,旨在实现个性化治疗,平衡放射治疗益处与长期风险。

4.3. 食管癌放疗相关MPMs研究现状

据我们所知,目前关于放疗相关的食管癌多原发恶性肿瘤研究有限。一项使用SEER数据库分析食管癌患者治疗后发生第二种癌症风险的研究报道,食管癌患者的放射治疗可能与某些部位发生第二种癌症的风险增加有关,包括喉癌,肺癌和甲状腺癌[20]。另一项研究同样从SEER数据库获取数据,统计分析结果指出食管癌幸存者的放疗可能会增加第二原发肺癌风险,而不会影响总体死亡率;强调了对食管癌幸存者进行治疗后密切监测的重要性,以加强第二原发肺癌的早期发现和治疗,从而可能改善患者的预后[35]。仅有的几项研究面临着局限性,如回顾性研究存在着潜在的不可测量的混杂因素,以及有限的治疗细节,如辐射剂量。此外,SEER数据库的人口统计范围和不断发展的癌症治疗方式可能会影响研究结果的普遍性。因此,未来的研究对于更深入地了解放疗后多原发恶性肿瘤的风险至关重要,强调考虑全面的治疗细节和生活方式因素以准确评估这种风险。未来的研究应该深入前瞻性验证食管癌放疗后的多原发恶性肿瘤的机制,以及降低食管癌幸存者多原发恶性肿瘤风险的放疗技术。因此,需要更大规模、高质量的研究来进一步探讨放疗和食管癌相关MPMs的发生。

5. 结论

随着早期诊断和全身治疗的进步,食管癌患者的生存率显著提高;放射治疗虽然可以增强局部控制并可能提高生存率,但也会带来潜在的长期副作用和多原发恶性肿瘤的风险。深入理解其发病机制、熟悉临床特点、规范诊断筛查流程以及制定合理的防治策略,对于改善食管癌放疗后患者的长期生存与生活质量具有极为关键的意义。未来还需要进一步开展大规模、多中心的研究,探索更精准的预测指标与更有效的防治方法,以降低这一并发症的危害。

NOTES

*第一作者。

#通讯作者。

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