吴生红, 等. 西妥昔单抗靶向治疗局部晚期食管癌的研究进展 471 食管癌中的应用成为了可能 本文对 EGFR 抑制剂西妥昔单抗在食管癌中的研究进展进行简要综述 1 EGFR 与肿瘤发生 发展及预后的关系 EGFR 是原癌基因 c-erbb1 表达的一种跨膜糖蛋白, 位于第 7 号染色体, 由 28

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1 470 综述 Review 肿瘤 2014 年 5 月第 34 卷第 5 期 TUMOR Vol. 34, May 2014 DOI: /j.issn Copyright 2014 by TUMOR 西妥昔单抗靶向治疗局部晚期食管癌的研究进展 吴生红, 叶明上海交通大学医学院附属仁济医院放疗科, 上海 [ 摘要 ] 食管癌是严重威胁人类健康的恶性肿瘤之一, 同步放 化疗是治疗局部进展期食管癌的标准模式, 但食管癌患者放 化疗后仍有复发早和预后差等特点 表皮生长因子受体 (epithelial growth factor receptor,egfr) 抑制剂西妥昔单抗联合放疗对局部进展期头颈鳞癌的治疗获得了成功 本文根据西妥昔单抗在食管癌二线治疗 一线治疗及新辅助治疗中的应用情况, 对西妥昔单抗治疗食管癌的安全性及疗效进行简要综述, 指出西妥昔单抗联合同步放 化疗治疗局部晚期食管癌具有良好的耐受性和近期疗效, 尤其是在新辅助治疗中的疗效令人振奋, 值得为此开展多中心 Ⅲ 期临床研究 [ 关键词 ] 食管肿瘤 ; 综合疗法 ; 受体, 表皮生长因子 ; 西妥昔单抗 [ 中图分类号 ] R735.1 [ 文献标志码 ] A [ 文章编号 ] (2014) Progress on cetuximab in treatment of locally advanced esophageal cancer WU Sheng-hong, YE Ming Department of Radiotherapy, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai , China [ABSTRACT] Esophageal cancer (EC) is one of the malignant tumours which has a serious threat to human health. Although, concurrent radiochemotherapy is the standard treatment mode of locally advanced esophageal cancer (LAEC), the early recurrence is still common, and the prognosis is poor. Epithelial growth factor receptor (EGFR) inhibitor cetuximab (a monoclonal antibody) combined with radiotherapy is effecive in the treatment of locally advanced head and neck squamous cell carcinoma. This review focuses on the efficacy and safety of cetuximab in second-line and first-line therapies as well as neoadjuvant therapy in the treatment of LAEC, and points out that cetuximab combined with chemoradiation therapy displays a good tolerance and a satisfactory short-term effect, especially in neoadjuvant therapy. A multicenter phase Ⅲ clinical trial of cetuximab plus chemoradiation in neoadjuvant therapy for patients with LAEC needs to be carried out. [KEY WORDS] Esophageal neoplasms; Combined modality therapy; Receptor, epidermal growth factor; Cetuximab [TUMOR, 2014, 34 (05): ] 食管癌是严重威胁人类健康的恶性肿瘤之一, 主要以男性为主, 男 女性的发病比例约为 2 1 根据 GLOBOCAN 2008 年的统计 [1], 男性食管癌全球发病率位居恶性肿瘤发病率的第 6 位, 为 例 ; 死亡率位居第 5 位, 为 例 在发展中国家, 食管癌发病率位居第 5 位, 为 例 ; 死亡率位居第 4 位, 为 例 ; 发展中国家食管癌的发病率占全球的 80% 以上, 同年死亡人数是新发病例的 85% 以上 这一结果提示, 食管癌是一个在经济相对落后地区具有高发病率和高死亡率的恶性肿瘤 [ 基金项目 ] 上海市卫生局科研课题 ( 编号 : ) Correspondence to: YE Ming( 叶明 ) renjiyeming@gmail.com Received Accepted 在病理类型方面, 与欧美国家的食管腺癌 (Barrett s 食管癌 ) 不同, 发展中国家主要以食管鳞癌为主 基础研究结果表明, 这种高侵袭性和高转移性的特性可能与肿瘤细胞表面的表皮生长因子受体 (epithelial growth factor receptor,egfr) 过表达有关 RTOG 的研究结果奠定了同步放 化疗治疗局部晚期食管癌的标准模式 [2] 近年来, 放射治疗技术的发展降低了肿瘤周围正常组织的损伤并在一定程度上转化成 [3, 了生存获益 4], 但由于食管癌化疗的进展缓慢, 使得这一模式在近 20 年来未能获得长足的进步 随着分子靶向治疗的发展, 尤其是 EGFR 抑制剂西妥昔单抗联合放疗对局部晚期头颈部鳞癌的治疗获得了成功, 使得这一治疗模式在

2 吴生红, 等. 西妥昔单抗靶向治疗局部晚期食管癌的研究进展 471 食管癌中的应用成为了可能 本文对 EGFR 抑制剂西妥昔单抗在食管癌中的研究进展进行简要综述 1 EGFR 与肿瘤发生 发展及预后的关系 EGFR 是原癌基因 c-erbb1 表达的一种跨膜糖蛋白, 位于第 7 号染色体, 由 28 个外显子组成, 相对分子质量为 , 广泛分布于哺乳动物的上皮细胞 成纤维细胞和胶质细胞等细胞的表面, 在细胞的生长 增殖和分化等生理过程中发挥重要的调节作用,EGFR 过表达可使部分肿瘤细胞加速增殖 减缓细胞凋亡及促进肿瘤组织的血管生成, 最终导致肿瘤的侵袭和转移 [5-7] 产生这一结果的可能机制包括 :(1)EGFR 过表达引起下游信号转导增强 ;(2) 突变型 EGFR 或其配体表达增加, 导致 EGFR 持续活化 ; (3) 受体下调机制的破坏, 研究表明非受体酪氨酸激酶 c-src ( 原癌基因产物 ) 可通过抑制受体泛素化和内吞作用而上调 EGFR 水平 ;(4) 异常信号转导通路的激活 ;(5)EGFR 在肿瘤中过表达还可能与活化后降解减少有关 EGFR 过表达的恶性肿瘤对激素 细胞毒性药物或放疗相对不敏感, 预后较差 [8-10] 2 西妥昔单抗的抗肿瘤作用机制 西妥昔单抗是一种人鼠嵌合型单克隆抗体, 具有高亲和力, 能与 EGFR 特异性结合, 阻断配体与受体结合, 抑制 EGFR 活性, 下调内源性 EGFR 水平 西妥昔单抗的抗肿瘤机制还包括抑制酪氨酸激酶活性, 阻断细胞内信号转导途径, 将细胞分裂阻断在 G 1 期, 从而抑制癌细胞的增殖, 诱导癌细胞的凋亡, 并通过减少基质金属蛋白酶 (matrix metalloproteinase,mmp) 血管内皮生长因子 (vascular endothelial growth factor,vegf) 和转化生长因子 β(transforming growth factor-β,tgf-β) 等因子的产生, 抑制肿瘤血管生成和肿瘤的浸润与转移 [11] 西妥昔单抗与药物或放射性核素结合后, 成为靶向生物制剂, 可以提高抗肿瘤药物或放射性核素的药效, 并减少不良反应, 促进放 化疗诱导的细胞凋亡, 抑制受损肿瘤细胞的修复 [12] [13] Kawaguchi 等认为, 西妥昔单抗可以通过抗体依赖的细胞介导的细胞毒作用 (antibody-dependent cell-mediated cytotoxicity,adcc) 治疗 EGFR 过表达的食管鳞状细胞癌 3 西妥昔单抗作为二线治疗方案在转移性或复发性食管癌中的应用 由于局部晚期食管癌同步放 化疗的疗效较差, 目前尚无食管癌的标准二线治疗方案 在已报道的二线化疗研究中, 中位生存期 (overall survival,os) 均未达到 6 个月, 中位无进展生存期 (progression-free survival,pfs) 为 2 ~ 4 个月 [14-16] S0415 研究结果显示, 对化疗失败的 55 例食管腺癌 ( 男性 49 例 女性 6 例 ) 给予西妥昔单抗单药治疗 ( 初始剂量为 400 mg/m 2, 静脉滴注 120 min; 以后剂量为每 次 250 mg/m 2, 静脉滴注 60 min,1 次 / 周, 至病情恶化或出现严重不良反应, 此为西妥昔单抗的标准治疗方案 ), 中位 OS 为 4.0 个月 [95% 置信区间 (confidence interval,ci): 3.2 ~ 5.9], 中位 PFS 为 1.8 个月 (95% CI:1.7 ~ 1.9), 仅有 20 例 (36%) 患者的 OS 达到或超过 6 个月 (95% CI: 0.24 ~ 0.50) [17] 另一项类似研究( 男性 31 例 女性 4 例, 西妥昔单抗的单药用法与 S0415 研究相同 ) 发现, 中位 OS 为 3.1 个月, 中位 PFS 为 1.6 个月 [18] 上述两项研究的中位 OS 均没有达到 6 个月, 与二线化疗方案的 OS 及 PFS 无明显差异, 表明西妥昔单抗单药二线治疗食管癌疗效欠佳 研究发现, 西妥昔单抗与化疗联合具有协同效应, 并且这一结果在化疗联合西妥昔单抗治疗晚期非小细胞肺癌的 FLEX 研究中得到了证实 [19] [20] Schønnemann 等应用西妥昔单抗联合伊立替康二线治疗 ( 西妥昔单抗 500 mg/m², 伊立替康 180 mg/m², 静脉滴注,1 次 /2 周, 至疾病进展 ) 对铂类耐药的 63 例胃食管结合部腺癌患者, 总有效率 (overall response rate,orr) 为 11%, 疾病稳定 (stable disease,sd) 患者占 37%, 中位 PFS 为 2.8 个月, 中位 OS 为 6.1 个月, 其中出现 1/2 级皮疹患者 (73%) 的 OS 延长至 7.1 个月 研究结果显示, 西妥昔单抗联合伊立替康二线治疗胃食管腺癌的中位 OS 超过 6 个月, 与西妥昔单抗或伊立替康单药比较, 有延长胃食管腺癌 OS 的趋势 AGITG ATTAX2 研究应用西妥昔单抗联合多西紫杉醇二线治疗 38 例多西紫杉醇耐药的胃食管结合部腺癌 ( 西妥昔单抗为标准治疗方案 ; 多西紫杉醇 30 mg/m²,d 1 d 8, 静脉滴注, 每 3 周为 1 个周期, 至疾病进展或出现不可耐受的不良反应 ),6% 的患者达部分缓解 (partial response,pr),43% 的患者达 SD, 中位 PFS 为 2.1 个月, 中位 OS 为 5.4 个月 [21] 由此提示, 西妥昔单抗与多西紫杉醇联合治疗紫杉醇耐药的胃食管结合部腺癌可能有效 4 西妥昔单抗作为一线治疗方案在局部晚期食管癌中的应用 4.1 西妥昔单抗联合化疗一线治疗食管癌西妥昔单抗联合化疗一线治疗食管癌的研究较少, 并且主要集中在胃及胃食管结合部癌 在西妥昔单抗联合 FOLFIRI( 伊立替康 + 亚叶酸钙 + 5- 氟尿嘧啶 ) 或多西紫杉醇 + 顺铂 / 奥沙利铂方案一线治疗胃食管结合部腺癌的研究中, 与单纯化疗比较, 未见 PFS 和 OS 明显延长, 这一结果可能与胃食管腺癌 EGFR 表达率较低有关 [22-24] 在为数不多的食管鳞癌的研究中发现,32 例应用西妥昔单抗联合顺铂 + 5- 氟尿嘧啶和 30 例应用顺铂 + 5- 氟尿嘧啶一线治疗转移性食管鳞癌患者的 ORR 分别为 19% 和 13%(P = 0.73), 疾病控制率分别为 75% 和 57%(P = 0.18), 中位 PFS 分别为 5.9 个月和 3.6 个月 (P = 0.21), 中位 OS 分别为 9.5 个月和 5.5 个月 (P = 0.32) [25] 虽然西妥昔单抗联合顺铂 + 5- 氟尿嘧啶治疗组患者较顺铂 + 5- 氟尿嘧啶治疗组患者的中位 OS 和中位 PFS 均有延长, 但 2 组的 ORR 均 < 20% 作者认为, 可能与入组的病例数有限 交叉用药 ( 顺铂 + 5- 氟尿嘧啶治疗组中 5 例患者出现病情进展,2 例患者再接

3 472 吴生红, 等. 西妥昔单抗靶向治疗局部晚期食管癌的研究进展 受西妥昔单抗单药治疗,3 例患者再接受西妥昔单抗联合顺铂 + 5- 氟尿嘧啶治疗 ) 及 2 组患者性别不均衡 (2 组患者的男 女性比例分别为 23 9 和 29 1) 有关 西妥昔单抗联合化疗药物在已有的研究中都表现出较好的安全性 与西妥昔单抗相关的不良反应主要是痤疮样皮疹, 发生率约为 70% ~ 80%, 颜面部是较常见的发生部位, 在接受西妥昔单抗治疗后 1 ~ 3 周最为严重, 可口服强力霉素 ( 非特异性抗炎样作用 ), 合并感染者选择抗生素治疗, 减少皮疹发生率 多项 Ⅱ 期临床试验发现, 痤疮样皮疹的发生与西 [26, 妥昔单抗缓解患者疾病的程度呈正相关 27] 4.2 西妥昔单抗联合其他靶向药物治疗食管癌西妥昔单抗与其他靶向药物的联合应用目前仍停留在基础研究 [28] 阶段 李静等研究发现, 阿法替尼联合西妥昔单抗对 EGFR T790M 突变所致耐药的非小细胞肺癌原代细胞有 [29] 效 李子明等研究发现, 西妥昔单抗联合吉非替尼可协同诱导人肺腺癌细胞的凋亡 除 EGFR1 外,EGFR2(HER2/Neu) 与食管癌的发生 发展及预后密切相关 免疫组织化学检测结果显示, 食管鳞癌组织中 HER2/Neu 的阳性表达率为 22% ~ 41% [30-32], 抗 HER2/Neu 抗体曲妥珠单抗也可用 [33, 于治疗食管鳞癌 34] [35] Kawaguchi 等研究发现, 曲妥珠单抗可以通过 ADCC 达到治疗食管鳞癌的作用 体外研究结果显示, 西妥昔单抗联合曲妥珠单抗治疗 EGFR1 和 HER2 过表达的食管鳞癌细胞具有较强的抗肿瘤细胞增殖的效应 [36] 西妥昔单抗可以下调肿瘤细胞表面 EGFR1 的表达水平, 抑制丝裂原活化蛋白激酶 (mitogen-activated protein kinase,mapk)/akt 的磷酸化, 但不能下调 HER2/Neu 的表达水平 当西妥昔单抗联合曲妥珠单抗时, 可以增强抑制 Akt 的磷酸化过程, 对肿瘤细胞增殖的抑制具有协同效应, 使西妥昔单抗联合曲妥珠单抗治疗食管癌成为可能 4.3 西妥昔单抗联合放 化疗治疗局部晚期食管癌西妥昔单抗联合放疗对头颈部鳞癌的治疗获得了成功, 但在食管癌中的应用报道较少 目前认为, 西妥昔单抗联合放疗的抗肿瘤作用机制可能是通过调节细胞周期和增强辐射诱导的细胞凋亡 [37] 同步放 化疗是目前治疗局部晚期食管癌的标准治疗方案, 西妥昔单抗因其作用机制的独特性而成为与同步放 化疗联合应用的研究热点 西妥昔单抗与放 化疗联合治疗局部晚期食管癌的耐受性好, 可以安全地与细胞毒药物及放射治疗联合应用, 与西妥昔单抗相关的不良事件主要是过敏反应 ( 表 1) 表 1 西妥昔单抗联合放化疗治疗食管癌的安全性 Table 1 The safety of cetuximab in combination with chemoradiation for patients with esophageal carcinoma Author Phase Case Pathological type Treatment Adverse reaction Conclusion Safran, Ⅱ 60 SCC = 12) et al [38] ADC (n = 48) Radiation: 50.4 Gy Chemotheray: Cetuximab (400 mg/m 2 d 1, then 250 mg m -2 week -1 ) for 6 weeks; Paclitaxel (50 mg m -2 week -1 ); Carboplatin (AUC=2, once a week) for 6 weeks Yu, et al [39] Ⅱ 55 SCC Radiation: 59.4 Gy Chemotheray: Cetuximab (400 mg/ m 2 d 1 before chemoradiotherapy, and then concurrent 250 mg m -2 week -1 ) for 8 weeks; Paclitaxel (45 mg m -2 week -1 ); Cisplatin (20 mg m -2 week -1 ) for 7 weeks. Hsu, et al [40] Ⅱ 41 SCC Radiation a : Gy Chemotheray: Cetuximab (400 mg/m 2 2 h on d 5, then 250 mg/ m 2 2 h on d 3/week); Paclitaxel (35 mg/m 2 1 h on d 1 and d 4/week); Cisplatin (15 mg/m 2 1 h on d 2 and d 5/week) Chen, Ⅱ 31 SCC Radiation: 59.4 Gy et al [41] Chemotheray: Cetuximab (400 mg m -2 week -1 in week 1, 250 mg m -2 week -1 during weeks 2-8); Paclitaxel (45 mg m -2 week -1 ); Cisplatin (20 mg m -2 week -1 during weeks 2-8). Lledo, Ⅱ 79 SCC (n = 53) et al [42] ADC (n = 25) UD (n = 1) Induction therapy: FOLFOX (two cycles) plus cetuximab (400 mg/ mg 2 on d 1, then 250 mg m -2 week -1 ) Radiation: 50.4 Gy Chemotheray: FOLFOX (three cycles) plus cetuximab (250 mg m -2 week -1 for 6 weeks) Dermatologic toxicity (including a painful, pruritic acneiform rash) of grade 3: 23%; Hypersensitivity reactions of grade 3/4: 5%; Esophagitis of grade 3 or 4: 12 % or 3% Neutropenia of grade 3: 32.7%; Anemia of grade 3: 1.8%; Rash of grade 1/2: 92.7%; Mucositis of grade 1/2: 45.5%; Fatigue of grade 1/2: 41.8%; Nausea of grade 1/2: 38.2% Leukopenia of grade 3/4: 64%; Neutropenia of grade 3/4: 18%; Esophagitis of grade 3/4: 9%; Infection of grade 3/4: 9%; Rash of grade 3: 3%; Hypomagnesemia of grade 3 or grade 4: 0% or 6% Esophagitis of grade 3/4: 9.7%; Hematological toxicity (including neutropenia, anemia and thrombocytopenia) of grade 3/4: 29.0%; Cutaneous toxicity of grade 3/4: 16.1% Neutropenia of grade 3 or grade 4: 7.6% or 28.4%; Febrile neutropenia of grade 3 or grade 4: 0 or 2.7%; Mucitis of grade 3 or grade 4: 1.3% or 5.4%; Diarrhea of grade 3 or grade 4: 3.8% or 2.7%; Dysphagiaesophagitis of grade 3 or grade 4: 1.3% or 13.5%; Rash of grade 3 or grade 4: 7.6% or 10.8% Cetuximab can be safely administered with chemoradiation for esophageal cancer Cetuximab can be safely administered with chemoradiation for Chinese patients with esophageal cancer Adding cetuximab to paclitaxel/cisplatin twice weekly-based CCRT prior to esophagectomy is a safe treatment for locally advanced ESCC The regimen of definitive chemoradiation plus cetuximab has an acceptable safety profile in Chinese patients with ESCC Chemoradiotherapy with FOLFOX plus cetuximab has an acceptable toxicity profile in patients with locally advanced esophageal cancer a When the accumulated radiation dose reached 40 Gy, the feasibility of esophagectomy was evaluated for all patients. In patients for whom esophagectomy was not feasible, CCRT was continued to a radiation dose of Gy. FOLFOX: Oxaliplatin + folinic acid + 5-fluorouracil; SCC: Squamous cell carcinomas; ADC: Adenocarcinoma; UD: Undifferentiated; CCRT: Concurrent chemoradiotherapy; ESCC: Esophageal squamous cell carcinoma; AUC: Area under the curve.

4 吴生红, 等. 西妥昔单抗靶向治疗局部晚期食管癌的研究进展 473 [41] Chen 等研究发现, 发生 2 级或 2 级以上痤疮样皮疹患者较 1 级或无皮疹发生患者可获得更高的完全缓解 (complete response,cr) 率 (P = 0.003) 和更长的 PFS(P = 0.022) 因此, 痤疮样皮疹的发生可能成为临床上判断疗效的重要指标 [26] 西妥昔单抗与放 化疗同步根治性治疗局部晚期食管 [43] 鳞癌的 ORR 为 80% ~ 100% Meng 等开展的开放性 多中心 Ⅱ 期临床研究结果显示, 西妥昔单抗与放 化疗同步治疗食管鳞癌 (n = 45) 的临床缓解率为 97.8%, 其中 29 例患者达 CR,15 例患者达 PR,1 年 PFS 率和 OS 率分别为 84.3% 和 93.3%,2 年 PFS 率和 OS 率分别为 74.9% [41] 和 80.0% Chen 等研究结果显示, 西妥昔单抗与放 化疗同步治疗食管鳞癌的 ORR 为 100%(n = 29),CR 率为 69.0%(n = 20),1 年和 2 年的 PFS 率分别为 85% 和 75.1% 合并淋巴结转移患者的 1 年 PFS 率低于无淋巴结转移患者, 差异有统计学意义 (78.7% vs 92.3%,P = 0.038); EGFR 过表达患者 (n = 16,55.2%) 的 CR 率为 75%, EGFR 低表达或不表达患者 (n = 13,44.8%) 的 CR 率为 61.5%,2 组之间差异有统计学意义 (P = 0.024), 但 2 组 之间的 PFS 差异无统计学意义 (P = 0.133), 提示西妥昔单抗的介入, 未能明显改善食管鳞癌患者的近期疗效 笔者目前尚未查阅到大样本远期疗效的报道 5 西妥昔单抗联合放 化疗在食管癌新辅助治疗中的应用 新辅助放 化疗已成为治疗局部晚期食管癌的趋势 [44] Agarwala 等对 36 例食管癌患者于手术前进行西妥昔单抗联合放疗, 结果手术切除率为 72.2%, 病理完全缓解 (pathological complete response,pcr) 率达 50% 类似的 Ⅱ 期临床研究结果显示,pCR 率为 48%(n = 39) [45] 由于上述 2 项研究的意向性分析结果显示,pCR 率分别为 36% 和 36.6%, 加之临床上缺乏类似的大样本研究, 因此, 西妥昔单抗联合放疗在食管癌新辅助治疗中的疗效有待进一步证实 多项前瞻性 多中心 Ⅱ 期临床研究证实, 西妥昔单抗联合放 化疗 ( 序贯或同步 ) 于手术前治疗局部晚期食管鳞癌能降低疾病分期, 提高局部控制率和手术完全切除率, 获得更高的 pcr 率 (23% ~ 68%)( 表 2) 表 2 手术前西妥昔单抗联合放 化疗治疗局部晚期食管癌的近期疗效 Table 2 The short-term response to cetuximab plus chemoradiation for patients with locally advanced esophageal carcinoma before operation Author Phase Case Number of resection Treatment Hsu, et al [40] Ⅱ Radiation a : Gy; Cetuximab (400 mg m -2 2 h on d 5, then 250 mg m -2 2 h on d 3/week); Paclitaxel (35 mg m -2 1 h on d 1 and d 4/week); Cisplatin (15 mg m -2 1 h on d 2 and d 5/week), and then followed by surgical operation Suntharalingam, Ⅱ Concurrent radiation: 50.4 Gy; Cetuximab (400 mg/mg 2 on d 1, et al [46] then 250 mg m -2 week -1 ) for 6 weeks; Paclitaxel (50 mg m -2 week -1 ); Carboplatin (AUC=2, once a week) for 6 weeks, and then followed by surgical operation Fillos, et al [47] Ⅱ 15 7 Concurrent radiation: 50.4 Gy; Cetuximab (200 mg m - 2 week - 1 ); Docetaxel (25-30 mg m - 2 week - 1 ); Cisplatin (25-30 mg m - 2 week - 1 ) for 6 8 weeks Patients were scheduled 4-6 weeks later for surgery followed by the same chemotherapy regimen for total of 16 weeks Wanebo, et al [48] Ⅱ Concurrent radiation: 50.4 Gy; Cetuximab (400 mg/m 2 on d 1, then 250 mg m -2 week -1 ) for 6 weeks; Paclitaxel (50 mg m -2 week -1 ); Carboplatin (AUC=2, once a week) for 6 weeks, and then followed by surgical operation Kim, et al [49] Ⅱ Concurrent radiation: 50.4 Gy; Cetuximab (400 mg/m 2 in week 1 before radiotherapy, then 250 mg m -2 week -1 ) for 6 weeks; Irinotecan (40 mg m -2 week -1 ) and capecitabine (1 650 mg m - 2 d - 1 for 5 d/week) for 5 weeks from the first day during radiotherapy, and then followed by surgical operation De Vita, et al [50] Ⅱ FOLFOX-4 for 8 weeks; Concurrent cetuximab (400 mg/m 2 in week 1 before radiotherapy, then 250 mg m -2 week -1 ) for 8 weeks and then radiation (50.4 Gy ); Cetuximab (250 mg m -2 week -1 ) during radiotherapy and further 4 weeks during restaging; Surgery was planned 4 weeks after completion of restaging Ruhstaller, et al [51] ⅠB/Ⅱ Two 3-week cycles of induction chemoimmunotherapy (cisplatin: 75 mg/m 2 d 1; docetaxel: 75 mg/m 2 d 1; cetuximab: 250 mg/m 2 on d 1, d 8 and d 15, and 400 mg/m 2 loading dose on d 1), followed by chemoimmunoradiation therapy [radiation (45 Gy) plus concurrent cisplatin (25 mg/m 2 ) and cetuximab (250 mg/m 2 ) weekly for 5 weeks] and surgery Outcomes pcr: 26% ; R 0 resection rate: Not reported; ORR: Not reported; One-year PFS: 69%; One-year OS: 66% pcr: 43% ; R 0 resection rate: Not reported; ccr: 67% pcr: 57% ; R 0 resection rate: 100%; ORR: 53% pcr: 45% ; R 0 resection rate: 70%; ORR: 67% pcr: 23.1% ; R 0 resection rate: 100%; ORR: 92% ; Three-year DFS: 80.0%; Three-year OS: 94.7% pcr: 27% ; R 0 resection rate: 70%; ORR: 47.5% ; One-year OS: 67%; Three-year OS: 42% pcr or near pcr: 68% ; R 0 resection rate: 100%; ORR: Not reported a When the accumulated radiation dose reached 40 Gy, the feasibility of esophagectomy was evaluated for all patients; FOLFOX-4: Oxaliplatin (85 mg/m 2 d 1) + folinic acid (200 mg/m 2 as a 2-h infusion on d 1 and d 2) + 5-fluorouracil (400 mg/ m 2 bolus on d 1 and d 2 followed by 5-fluorouracil 600 mg/m 2 as a 22-h continuous infusion on d 1 and d 2), repeated every 2 weeks. AUC: Area under the curve; pcr: Pathological complete response; ccr: Clinical complete response; ORR: Objective response rate; PFS: Progression-free survival; OS: Overall survival; DFS: Disease-free survival.

5 474 吴生红, 等. 西妥昔单抗靶向治疗局部晚期食管癌的研究进展 进一步的研究表明, 获得 pcr 的患者较未获得 pcr [48] 的患者有更长的生存期 Wanebo 等应用西妥昔单抗联合紫杉醇 + 卡铂方案的新辅助化疗, 同步放疗治疗 57 例局部晚期食管癌或食管胃结合部腺癌患者 结果显示, 手术切除率为 77.2%(44/57),45%(20/44) 的患者获得了 pcr 或接近 pcr,25%(11/44) 的患者获得了 PR,30% (13/44) 的患者手术后仍有残留 ; 未接受手术治疗的 13 例患者中,6 例不适合手术治疗,7 例患者拒绝接受手术治 [50] 疗 ;35%(20/57) 的患者临床分期降低 De Vita 等于手术前应用西妥昔单抗联合 FOLFOX-4 方案 ( 奥沙利铂 + 5- 氟尿嘧啶 + 亚叶酸钙 ) 诱导化疗后, 再给予西妥昔单抗联合放疗治疗 41 例食管癌患者 (13 例腺癌,28 例鳞癌 ), 最终共有 30 例患者接受手术治疗, 手术完全切除率达 80% (24/30),pCR 率为 27%(8/30), 中位 OS 为 17.3 个月,3 [52] 年 OS 率为 42% 值得注意的是,Lee 等手术前应用西妥昔单抗联合放 化疗治疗 19 例局部晚期食管癌 (18 例腺癌,1 例鳞癌 ), 其中 18 例患者放 化疗后接受手术治疗, R 0 切除率达 89%(16/18), 中位 PFS 为 10 个月, 中位 OS 为 31 个月, 仅有 16.7%(3/18) 的患者达到 pcr, 提示手术前应用西妥昔单抗联合放 化疗治疗局部晚期食管腺癌 [50] 的疗效较差 De Vita 等研究发现, 达到 pcr 患者的病理类型均为食管鳞癌, 提示西妥昔单抗联合放 化疗作为新辅助方案治疗局部晚期食管癌具有较好的前景, 且食管鳞癌患者的近期疗效可能优于食管腺癌患者, 但单因素分析结果显示二者生存时间之间的差异无统计学意义,3 年 OS 分别为 57% 和 41%(P = 0.573) 西妥昔单抗联合同步放 化疗治疗局部晚期食管癌, 尤其是在新辅助治疗中的疗效较好, 其机制目前仍不明确 可能的原因包括 :(1) 虽然部分临床研究没有报道 EGFR 的表达水平, 但前期的基础研究和部分临床研究结果显示, 食管癌的表皮生长因子呈高表达, 可能与应用西妥昔单抗提高疗效相关 [10] ;(2) 西妥昔单抗联合放 化疗具有协同 [12, 39, 效应, 且安全性好, 能获得更高的抗肿瘤效应 40] ;(3) 与其他恶性肿瘤的新辅助治疗的优点相似, 通过降低临床分期提高手术切除率 ( 尤其是 R 0 率 ), 早期用药可能消除隐匿性微转移灶, 减少手术后的转移和复发, 对改善患者的预后至关重要, 并且肿瘤血管未被手术破坏, 可增强化疗效果 不同的是, 更多的研究支持西妥昔单抗通过诱导肿瘤细胞的凋亡而非直接杀灭肿瘤细胞而发挥抗肿瘤作用 ; 联合西妥昔单抗后, 肿瘤患者的临床缓解率提高, 尤其是能获得更高的 PR 和 SD, 而不是更高的 CR 因此, 同步放 化疗联合西妥昔单抗靶向治疗后再进行手术切除, [13, 29, 患者能获得较好的近期疗效 45] 6 结语 西妥昔单抗治疗晚期结直肠癌和头颈癌, 使患者生存获得了改善, 在治疗局部晚期食管癌中的作用仅仅初露端倪, 虽然部分研究结果存在差异, 但从已有的结果可以获 得的印象是西妥昔单抗联合同步放 化疗治疗局部晚期食管癌具有良好的耐受性和近期疗效, 尤其是在新辅助治疗中的疗效令人振奋, 值得为此开展多中心 Ⅲ 期临床研究 ; 而在晚期食管癌中, 与化疗的联合应用由于受到样本量小 病理类型不均质以及治疗方案多样性的影响而使治疗结果参差不齐, 需要做进一步的研究 [ 参考文献 ] [1] Jemal A, Bray F, Center MM, et al. Global cancer statistics[j]. CA Cancer J Clin, 2011, 61(2): [2] C o o p e r J S, G u o M D, H e r s k o v i c A, e t a l. Chemoradiotherapy of locally advanced esophageal cancer: long-term follow-up of a prospective randomized trial (RTOG 85-01). Radiation Therapy Oncology Group[J]. JAMA, 1999, 281(17): [3] Gong G, Wang R, Guo Y, et al. Reduced lung dose during radiotherapy for thoracic esophageal carcinoma: VMAT combined with active breathing control for moderate DIBH[J]. Radiat Oncol, 2013, 8:291. [4] Pepek JM, Willett CG, Czito BG. Technical considerations in radiation therapy for gastroesophageal junction cancer[j]. Semin Radiat Oncol, 2013, 23(1): [5] Huang CW, Tsai HL, Chen YT, et al. The prognostic values of EGFR expression and KRAS mutation in patients with synchronous or metachronous metastatic colorectal cancer[j]. BMC cancer, 2013, 13(1):599. [6] Yang YL, Xu KL, Zhou Y, et al. Correlation of epidermal growth factor receptor overexpression with increased epidermal growth factor receptor gene copy number in esophageal squamous cell carcinomas[j]. Chin Med J (Engl), 2012, 125(3): [7] Chang AY, Wang M. Molecular mechanisms of action and potential biomarkers of growth inhibition of dasatinib (BMS ) on hepatocellular carcinoma cells[j]. BMC Cancer, 2013, 13(1):267. [8] Box C, Peak J, Rogers S, et al. EGFR signaling in invasion, angiogenesis and metastasis[m]// Haley JD, William JG. EGFR signaling networks in cancer therapy. New York: Humana Press, 2008: [9] Wang Q, Zhu H, Xiao Z, et al. Expression of epidermal growth factor receptor is an independent prognostic factor for esophageal squamous cell carcinoma[j]. World J Surg Oncol, 2013, 11(1):278. [10] Kato H, Arao T, Matsumoto K, et al. Gene amplification of EGFR, HER2, FGFR2 and MET in esophageal squamous cell carcinoma[j]. Int J Oncol, 2013, 42(4): [11] Paletta-Silva R, Rocco-Machado N, Meyer-Fernandes JR.

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