抗EGFR单抗治疗局部晚期头颈部鳞状细胞癌临床共识（2023年版）

doi:10.19401/j.cnki.1007-3639.2023.01.010

摘要/Abstract

摘要：

头颈部鳞状细胞癌（squamous cell carcinoma of the head and neck，SCCHN）是最常见的一类头颈部肿瘤。由于早期症状不典型，大多数SCCHN患者确诊时已处于局部晚期。以标准剂量顺铂为基础的同期放化疗（chemoradiotherapy，CRT）是局部晚期SCCHN患者的标准非手术治疗模式。但同期CRT的近期和远期毒性问题不容忽视，对于无法耐受标准治疗强度的患者，在治疗策略的选择上要兼顾疗效、器官毒性和器官功能。几乎所有的SCCHN都会存在表皮生长因子受体（epidermal growth factor receptor，EGFR）过表达。抗EGFR单抗通过与EGFR结合，竞争性阻断内源性EGFR天然配体，阻碍EGFR二聚体的形成，抑制肿瘤细胞生长；此外，抗EGFR单抗可通过影响细胞周期、DNA损伤修复及血管生成等多种途径发挥放疗增敏作用。既往Ⅲ期临床研究表明，对比单纯放疗，放疗联合西妥昔单抗可显著改善局部晚期SCCHN患者的局部区域控制，延长总生存期。临床工作中合理地应用抗EGFR单抗仍面临诸多挑战，包括适用人群的判定标准、应用时机、联合方案的选择及不良事件管理等都需要进一步明确和规范。本共识专家组以循证医学证据为基础、相关指南为依据，经充分讨论形成《抗EGFR单抗治疗局部晚期头颈部鳞状细胞癌临床共识（2023年版）》。根据本共识的专家建议，局部晚期SCCHN患者在同期CRT前，应评估患者对标准剂量顺铂治疗的耐受性和治疗毒性。对于无法耐受标准剂量顺铂治疗的患者，或在接受多西他赛+顺铂+5-氟尿嘧啶（TPF）方案诱导化疗后出现顺铂相关毒性的患者，可选择放疗联合西妥昔单抗方案。对于有降期或器官功能保留需求、拟行诱导治疗的患者，标准诱导治疗方案为TPF方案，不能耐受TPF方案毒性的患者，可用西妥昔单抗替代5-氟尿嘧啶，采用TPE方案。安全性方面，放疗联合西妥昔单抗相关常见不良反应包括痤疮样皮疹、口腔黏膜炎、放射性皮炎等，可以通过治疗前预防、治疗过程中早期识别和及时干预进行全面、分级管理。

关键词: 抗EGFR单抗, 局部晚期, 头颈部鳞状细胞癌, 临床共识

Abstract:

Squamous cell carcinoma of the head and neck (SCCHN) is the most common head and neck tumor. Patients are generally diagnosed with advanced stage attributed to no clinically evident symptom at the early stage. For locally advanced SCCHN, cisplatin-based concurrent chemoradiotherapy (CRT) is the standard non-surgical treatment. However, the tolerance to high-dose cisplatin is poor owing to the high prevalence of comorbidities in patients with SCCHN. There are also concerns on the acute and late toxicities of CRT. Epidermal growth factor receptor (EGFR) is proved to be overexpressed in most SCCHN and it is associated with resistance to cytotoxic agents and radiotherapy leading to poor prognosis. Anti-EGFR antibody, which competes with EGFR ligands, can lead to receptor internalization, antibody-receptor complex down-regulation and tumor death. In addition, anti-EGFR antibody can play a role in radiosensitization by affecting cell cycle, DNA damage repair and angiogenesis. Radiotherapy combined with anti-EGFR antibody was demonstrated to improve survival when compared to radiotherapy alone, while consensus on anti-EGFR antibody delivery in the eligible patients, optimal intervention time and the management of adverse effects when combined with radiotherapy are yet warranted. According to the current recommendations, all patients with locally advanced SCCHN should be assessed for the tolerance of standard dose cisplatin prior to CRT. Radiotherapy with cetuximab is an alternative for patients who cannot tolerate. For those who received induction chemotherapy with the purpose of tumor downstaging or organ preservation, the standard regimen is TPF (docetaxel+cisplatin+5-fluorouracil) scheme. TPE scheme, using cetuximab as a substitution for fluorouracil, is an option for toxicities reducing. Managements of skin reactions, oral mucositis and radiation dermatitis are proposed.

Key words: Anti-EGFR monoclonal antibody, Locally advanced, Squamous cell carcinoma of the head and neck, Clinical consensus

中图分类号:

R739.91

许婷婷, 胡超苏, 李宝生. 抗EGFR单抗治疗局部晚期头颈部鳞状细胞癌临床共识（2023年版）[J]. 中国癌症杂志, 2023, 33(1): 81-94.

XU Tingting, HU Chaosu, LI Baosheng. Clinical consensus on the treatment of locally advanced squamous cell carcinoma of the head and neck with anti-EGFR monoclonal antibody (2023 edition)[J]. China Oncology, 2023, 33(1): 81-94.

图/表 3

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表2

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基于欧洲专家共识的放疗联合西妥昔单抗相关放射性皮炎的分级管理建议"

分级	评判标准	基于分级的处理意见
1级	轻微红或干性脱皮	每周随访1次
2级	中度红斑和（或）干性脱皮；斑片状湿性脱皮，或局限于皮肤褶皱的非出血性结痂	每周随访2次 ① 干性脱皮无结痂：短期（1 ~ 2周）使用糖皮质激素乳膏，怀疑二重感染的使用抗生素； ② 皮肤褶皱湿性脱皮：每天使用糖皮质激素乳膏（1 ~ 2周）减轻炎症反应，出现任何双重感染迹象时，局部使用针对金黄色葡萄球菌的抗生素。如二重感染加重，考虑全身使用抗生素，软锌制剂可用于皮肤皱襞，但应在放疗前将其去除以避免辐射剂量学问题，也可以使用伊红； ③ 皮肤褶皱的非出血性结痂：同②的处理，此外，凝胶可用于结痂处
3级	湿性脱皮或出血性结痂；皮肤皱襞以外的非出血性结痂，但大部分局限于皮肤皱襞；轻微擦伤引起的出血；需要口服抗生素的二重感染	评估每天随访的必要性，密切监测局部或全身感染，如发生在<50 Gy，考虑短暂中断治疗 ① 无结痂的湿性脱皮：外用抗菌剂，短期（1 ~ 2周）使用糖皮质激素乳膏，怀疑二重感染的使用抗生素，口服抗生素无效的考虑改静脉使用，软锌制剂可用于皮肤皱襞，但应在放疗前将其去除以避免辐射剂量学问题，也可以使用伊红； ② 有结痂的湿性脱皮：外用抗菌剂，怀疑二重感染的使用抗生素，口服抗生素无效的考虑改静脉使用，凝胶可用于结痂处，避免皮肤外伤以防止重复感染，如果使用水胶体敷料，在进行放疗剂量测定时应考虑敷料的厚度。放疗结束后可使用水纤维敷料
4级	危及生命；广泛的出血性结痂或溃疡（面积>50%）；受累部位大量自发性出血（>40%受累部位）；全真皮质皮肤坏死或溃疡或任何大小的溃疡，伴有广泛组织、肌肉、骨骼或支撑结构的坏死，伴有或不伴有全层皮肤受损；有皮肤移植指征；需要静脉滴注抗生素的多重感染性溃疡	同时中断放疗和西妥昔单抗，西妥昔单抗需中断至皮炎恢复至2级或以下；严重二重感染口服抗生素无效的考虑静脉给药；住院治疗

表3

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患者因素	不宜使用标准剂量顺铂治疗	需谨慎使用顺铂治疗
年龄/岁	NA	>70
ECOG PS评分	≥2	≥1
营养不良	NA	PG-SGA评分≥3分
合并症
肾功能不全	Ccr<50 mL/min	Ccr：50 ~ 60 mL/min
神经系统疾病	≥2级	1级
既往听力丧失/耳鸣	≥2级	1级
心功能不全	NYHA心功能分级≥Ⅱ级	NYHA心功能分级Ⅰ级
HIV/AIDS	NA	CD4⁺T淋巴细胞计数<200/μL
治疗史
既往铂类药物治疗（包括诱导化疗）	NA	顺铂累积剂量≥200 mg/m²

出现次数	剂量调整
第1次	暂停西妥昔单抗治疗≤21 d直到皮疹降至2级。如改善，可重新开始250 mg/m²西妥昔单抗治疗；如无改善，暂停治疗。
第2次	暂停西妥昔单抗治疗≤21 d直到皮疹降至2级。如改善，调整剂量为200 mg/m²西妥昔单抗治疗；如无改善，暂停治疗。
第3次	暂停西妥昔单抗治疗≤21 d直到皮疹降至2级。如改善，调整剂量为150 mg/m²西妥昔单抗治疗；如无改善，暂停治疗。
第4次	永久性停用西妥昔单抗。