甲状腺未分化癌的靶向治疗进展
作者简介:
殷德涛: 主任医师，二级教授，博士生导师，郑州大学第一附属医院河医院区甲状腺外科主任。中国医师协会外科学分会甲状腺外科医师委员会委员；中国研医会甲状腺委员会常委，青委会副主委；中国中西医结合学会理事；河南省中西医结合学会甲状腺分会主任委员等。Thyroid、Anti-cancer Agents、Archives of Medical Research等杂志特约审稿人；《中国普通外科杂志》《中华医学杂志》《中华实验外科杂志》《中华内分泌外科杂志》《国际外科学杂志》《肿瘤防治研究》等杂志编委或通信编委。作为第一完成人，获河南省科技进步奖二等奖两项，主持国家自然科学基金面上项目一项，省部级科研课题25项，在国家级核心期刊发表学术论著一百余篇，SCl收录期刊发表学术论著二十余篇。荣获河南省高层次人才特殊支持“中原千人计划”学者、河南省优秀专家、河南省学术技术带头人、河南省青年科技专家、河南省高校省级青年骨干教师等荣誉二十余项
。
Progress of Targeted Therapy for Anaplastic Thyroid Cancer
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摘要:
甲状腺未分化癌是一种极其罕见的甲状腺恶性肿瘤，因其侵袭性强、预后差，是目前甲状腺癌的主要致死原因。甲状腺未分化癌的手术难度通常较大，且传统放化疗的意义不够明确，而靶向治疗的出现彻底改变了传统的肿瘤治疗模式。靶向治疗通过特异性作用于肿瘤相关的特定分子和信号通路来实现抗肿瘤效应。与传统化疗相比，靶向治疗可以更精确地攻击肿瘤细胞，并减少对正常细胞的损伤。随着靶向治疗临床试验的深入，发现应用靶向药物治疗对提高甲状腺未分化癌患者总生存期有明显效果，靶向治疗以及肿瘤相关信号通路逐渐成为甲状腺未分化癌治疗的研究热点之一。本文结合现阶段靶向药物在甲状腺未分化癌治疗方面的研究，对甲状腺未分化癌靶向治疗的进展作一综述。
Abstract:Anaplastic thyroid cancer, an extremely rare malignant tumor of the thyroid gland, is a major cause of mortality in thyroid cancer because of its aggressiveness and poor prognosis. Anaplastic thyroid cancer is typically challenging to treat surgically, and the efficacy of traditional radiotherapy and chemotherapy remains unclear. Meanwhile, the emergence of targeted therapy has radically transformed the traditional mode of tumor treatment. Anti-tumor effects can be achieved by specifically targeting tumor-associated molecules and signaling pathways. Compared with conventional chemotherapy, targeted therapy is able to more precisely target tumor cells while minimizing damage to normal cells. With the advancement of clinical trials on targeted therapy, the use of targeted drugs has been observed to significantly improve overall survival of patients with anaplastic thyroid cancer. Targeted therapy and tumor-related signaling pathways have emerged as research hotspots in the treatment of anaplastic thyroid cancer. This article offers an overview of the progress of targeted therapy for anaplastic thyroid cancer, incorporating current research on targeted drugs in the treatment of this condition.
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Key words:
- Anaplastic thyroid cancer /
- Targeted therapy /
- Signaling pathway /
- Genetic mutation
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0 引言
进展期食管胃结合部腺癌(adenocarcinoma of esophagogastric junction, AEG)围手术期腹腔热灌注化疗(hyperthermic intraperitoneal chemotherapy, HIPEC)是减少腹腔复发转移进而提高存活率的有力措施[1]，但其机制尚未完全明确。HIPEC的治疗疗效受到肿瘤细胞内热休克蛋白(heat shock proteins, HSPs)的负向调节[2]。HSP105b是唯一一种癌症中显性阴性突变的HSP，多中心研究结果显示HSP105b的低表达与肿瘤的良好预后之间存在直接联系[3]。HSP105b在胃癌组织中的表达水平与肿瘤的进展、不良预后及辅助化疗后的复发有关[4]，但与HIPEC疗效的相关性未见报道。本研究对进展期AEG肿瘤组织中HSP105b的表达水平与临床病理特征的相关性及与围手术期HIPEC治疗疗效的关系进行分析，进而探讨HIPEC抗肿瘤的可能机制。
1 资料与方法
1.1 一般资料
选择2015年1月—2017年6月安阳市肿瘤医院暨河南科技大学第四附属医院腹部肿瘤外科收治的行经腹R0根治性切除+D2淋巴结清除术的局部进展期Siewert Ⅱ型AEG患者。研究对象的纳入标准：(1)术前活检病理确诊为腺癌；(2)影像学排除远处转移；(3)年龄40~70岁；(4)无手术、化疗禁忌证；(5)无其他恶性肿瘤病史及放化疗史；(6)签署知情同意书，并要求手术治疗；(7)术中确诊侵及浆膜和(或)发现区域肿大淋巴结，而且未发现腹盆腔种植灶。
所有患者术前均签署HIPEC知情同意书、手术同意书、临床试验知情同意书，并获得河南科技大学第四附属医院暨安阳市肿瘤医院生命科学伦理审查委员会审查同意。术中探查后确定是否入组，共入组166例。入组患者按手术先后顺序随机分为2组(各83例)：治疗组(术后24 h内开始给予HIPEC治疗，共2次，余给予常规处理)和对照组(术后仅给予常规处理)。治疗组和对照组患者在年龄、性别、BMI、并发症比率、临床分期、胃切除范围及消化道重建方式等方面的差异均无统计学意义(P > 0.05)。
1.2 诊断和分期
所有病例术后检出淋巴结均≥20枚，手术标本均经病理学检查。根据2016年美国癌症联合会(American Joint Committee on Cancer, AJCC)第8版胃癌TNM分期标准[5]进行术后病理分期，分为Ⅱb期患者38例，Ⅲa~b期患者128例。
1.3 手术治疗
所有患者均经腹行食管胃结合部腺癌R0切除+D2淋巴结清扫，治疗组术中留置腹腔灌注管4根。两组均无围手术期死亡病例。
1.4 预防性HIPEC治疗
治疗组患者术后24 h内连接由广州保瑞医疗技术有限公司生产的BR-TRG-Ⅱ型体腔热灌注治疗系统进行治疗。所有患者均行2次国产紫杉醇注射液(术后第1天75 mg/m2, 术后第2天100 mg/m2)的HIPEC。
1.5 标本的处理及免疫组织化学染色
所有标本用10%甲醛固定，石蜡包埋，4 µm厚连续切片。玻片用多聚-L-赖氨酸涂覆，常规苏木素-伊红(HE)染色，确定病理类型。免疫组织化学染色参照文献[6]所述，切片用1:100稀释的兔抗人HSP105b单克隆抗体(GeneTex, 美国)4℃孵育24 h。
使用免疫反应评分(IRS)对HSP105b染色进行评估，评估表达HSP105b的细胞比例及其相对染色强度。HSP105b染色强度分级如下：0，无染色；1+：浅黄色；2+：棕黄色；3+：棕褐色。根据五个代表性区域的至少1 000个癌细胞，计算HSP105b表达的AEG细胞百分比。阳性细胞百分比：无着色细胞计0分，1%~10%计1分， > 10%~50%计2分， > 50%~100%计3分。两项得分相乘，≤3为低表达，≥4为高表达。以上结果由2名病理学专家(副主任医师或主任医师)阅片判断，存在差异时由2位医师一起审查并协商达成一致。
1.6 术后辅助化疗及随访
术后4周内开始给予辅助化疗(SOX三周方案共6周期)，其中38例仅给予4~5周期化疗(治疗组20例，对照组18例)。术后以电话、短信及门诊相结合的方式进行随访，每3月1次。随访内容：患者的生活质量、并发症情况、反流性食管炎程度、进食量、肿瘤复发转移情况等。随访至≥36月或至确诊肿瘤复发和(或)转移或非肿瘤因素死亡之日。随访截至2019年6月30日。
1.7 统计学方法
采用SPSS22.0统计软件进行分析。正态分布计量资料以(x±s)表示，组间比较采用t检验。计数资料采用χ2检验进行统计分析。采用Kaplan-Meier法绘制生存曲线，并使用Log rank检验比较组间差异。P < 0.05为差异有统计学意义。
2 结果
2.1 围手术期两组并发症的比较
本研究中治疗组的消化道反应较轻，仅有5例患者恶心，无呕吐患者；骨髓抑制发生率也较低，仅4例出现Ⅰ度血小板减少(未做特殊处理，自行缓解)。未出现白细胞减少患者，也未出现高敏感患者，仅有3例出现皮肤一过性皮疹，治疗结束后自行缓解。治疗组切口感染3例(其中1例合并切口裂开)、吻合口瘘4例(其中1例形成腹腔脓肿)、肠梗阻1例；而对照组切口感染2例，吻合口瘘3例(其中1例形成腹腔脓肿)，无肠梗阻患者。经积极治疗后患者均治愈。所有患者均未形成弥漫性腹膜炎。两组在腹腔并发症方面差异无统计学意义(χ2=0.751, P=0.386)。治疗组合并肺部感染者8例，发病比例较高，而对照组仅4例，但差异仍无统计学意义(χ2=1.437, P=0.231)。两组患者均未出现围手术期死亡病例。
2.2 进展期AEG癌组织中HSP105b蛋白表达的临床意义
在癌组织中，HSP105b着色于细胞核中。166例患者中92例呈高表达(55.4%)，而74例呈低表达(44.6%)。在进展期AEG组织中HSP105b蛋白表达水平与临床病理特征的关系，见表 1。HSP105b的蛋白表达水平与患者的年龄、性别、肿瘤分化程度、肿瘤的浸润深度、淋巴结转移情况无明显相关性，而仅与是否存在静脉浸润明显相关(t=4.002, P=0.045)。
表 1 进展期AEG患者临床病理特征与HSP105b表达水平的关系Table 1 Relation between HSP105b expression and clinicopathological characteristics of patients with advanced AEG
2.3 HSP105b表达强度及是否接受HIPEC治疗对无瘤生存率的影响
所有患者36月内非肿瘤死亡7例，其中HSP105b高表达者4例，HSP105b低表达者3例；治疗组4例，对照组3例。HSP105b高表达患者1、2年无瘤生存率分别为89.1%、65.2%，与低表达患者的93.2%、73.0%相比，差异无统计学意义(χ2=3.121, P=0.092; χ2=3.248, P=0.071)；而HSP105b高表达患者的3年无瘤生存率为42.4%，明显低于低表达患者的52.7%，差异有统计学意义(χ2=35.508, P < 0.001)，见图 1。治疗组及对照组各83例，治疗组3年无瘤生存率为54.2%，明显高于对照组的39.8%，差异有统计学意义(χ2=4.622, P=0.032)，见图 2。在治疗组中，HSP105b高表达者47例，低表达者36例，而在对照组中，HSP105b高表达者45例，低表达者38例，其3年无瘤生存率见图 3。各组的3年无瘤生存率从高到低依次为治疗组-低表达(66.7%)、治疗组-高表达(49.8%)、对照组-低表达(47.4%)、对照组-高表达(35.6%)，且均P < 0.05。
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图 1 HSP105b高表达和低表达患者的3年无瘤生存率Figure 1 Three-year disease-free survival rate between patients with high and low HSP105b expression![]()
图 2 治疗组与对照组3年无瘤生存率Figure 2 Three-year disease-free survival rates between treatment group and control group![]()
图 3 HSP105b表达高低及HIPEC治疗对3年无瘤生存率的影响Figure 3 Influence of HSP105b expression and HIPEC treatment on 3-year disease-free survival rate of patients3 讨论
AEG是中国常见的消化道恶性肿瘤之一，根治性手术切除是目前唯一可以治愈的方法[7]。进展期AEG最主要的播散途径是腹腔种植转移。由于手术前/中腹腔微转移的存在，即使行根治性切除，仍有较多患者术后会出现腹腔复发转移[8]。而围手术期给予HIPEC可通过热化疗的协同作用和大容量灌注冲刷作用有效杀灭和清除腹腔内残留的癌细胞和微小转移灶、预防腹膜转移癌，对提高进展期AEG患者的整体疗效具有重要意义[9]。但HIPEC的具体机制尚未明了。
热休克蛋白是一组高度保守的分子伴侣蛋白，可以防止蛋白质结构的错误折叠[10]。本研究结果显示肿瘤组织中的HSP105b蛋白表达水平高低与患者的年龄、性别、肿瘤的分化程度、浸润深度、淋巴结转移情况无明显相关，而仅与是否存在静脉浸润明显相关。说明HSP105b的表达水平与肿瘤的静脉浸润能力密切相关，这与在胃腺癌中的研究结果相一致[4]。
与低表达组相比，进展期AEG患者HSP105b高表达组1年、2年无瘤生存率无明显差异，而3年无瘤生存率则明显下降，这与既往在肺腺癌[11]、结直肠癌[12]、胃癌[13]中的研究结果相一致。因此，可以确定进展期AEG癌组织中HSP105b的高表达与患者的远期预后不良有关。
我们对进展期AEG患者随机分组，分别给予围手术期HIPEC治疗(治疗组)和仅给予常规处理(对照组)。结果显示治疗组的2年、3年无瘤生存率均明显高于对照组。可以看出进展期AEG患者根治术后给予围手术期HIPEC治疗可以减少术后腹腔复发转移的机率，减缓肿瘤复发转移速度，充分证实了HIPEC治疗的必要性。根据是否给予了HIPEC治疗和肿瘤组织中HSP105b表达的高低分成4组，计算其3年无瘤生存率。结果显示，HSP105b低表达患者给予HIPEC治疗可以获得最佳的治疗疗效(3年无瘤生存率最高)。说明HSP105b低表达可以加强HIPEC治疗的疗效，而高表达可以增加肿瘤细胞热化疗抵抗[13]，但其具体分子机制有待后继研究。本试验不良反应较少，且未出现严重不良反应，与前期的研究结果一致，具有较高安全性[14]。
综上所述，HSP105b蛋白的高表达预示着不良预后，而且HSP105b高表达增加了癌细胞的热化疗抵抗。因此，癌组织中HSP105b的蛋白表达水平可作为进展期AEG患者预后因素及预测HIPEC疗效的有效生物标志物：HSP105b低表达的进展期AEG患者应优选围手术期HIPEC治疗，而对于HSP105b高表达患者将在后继的研究中结合其他分子表型选择敏感的个体化治疗方案。
Competing interests: The authors declare that they have no competing interests.利益冲突声明：所有作者均声明不存在利益冲突。作者贡献：殷德涛：文章主题设定、撰写及修改刘维豪：文章撰写、修改及编辑 -
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