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   大连医科大学学报  2022, Vol. 44 Issue (1): 75-79      DOI: 10.11724/jdmu.2022.01.15
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腹腔热灌注化疗治疗胃癌的研究现状
李宗圜1, 王晓盈2, 蒋华2    
1. 大连医科大学 第二临床学院,辽宁 大连 116044;
2. 常州市第二人民医院 肿瘤中心,江苏 常州 213000
摘要:胃癌患者预后差的主要原因是腹膜转移,既往的姑息性手术及全身化疗治疗模式对其疗效差。近年来腹腔热灌注化疗(hyperthermic intraperitoneal chemotherapy,HIPEC)以及围绕其开展的综合治疗模式的临床研究不断进行,证实HIPEC不仅可以预防胃癌根治术后腹膜转移,还可改善部分腹膜转移患者的生活质量,延长生存期。本文从作用机制、药物选择、治疗模式及疗效评价、预后相关生物标记物等方面对HIPEC治疗胃癌的现状进行综述。
关键词腹腔热灌注化疗    胃癌    腹膜转移    
Current status of hyperthermic intraperitoneal chemotherapy in gastric cancer patients
LI Zongyuan1, WANG Xiaoying2, JIANG Hua2    
1. The Second Clinical College, Dalian Medical University, Dalian 116044, China;
2. Cancer Center, Changzhou Second People's Hospital, Changzhou 213000, China
Abstract: The main reason of poor prognosis in gastric cancer patients is peritoneal metastasis. The effectiveness of traditional treatment modality, including systematic chemotherapy and/or palliative surgery, is disappointing due to the poor survival rate and quality of life. In recently years, clinical studies of hyperthermic intraperitoneal chemotherapy (HIPEC) and comprehensive treatment model centering HIPEC have been carried out continuously. It has been confirmed that HIPEC can not only prevent peritoneal metastasis after radical resection of gastric cancer, but also improve both the survival and the quality of life in selected patients with peritoneal metastasis. This article reviews the current status of HIPEC in gastric cancer from the aspects of mechanism, drug selection, treatment model and efficacy evaluation and prognosis related biomarkers.
Keywords: hyperthermic intraperitoneal chemotherapy    gastric cancer    peritoneal metastasis    

胃癌(gastric cancer,GC)是世界第四大常见恶性肿瘤[1],约50%的胃癌相关死亡发生在中国[2]。根治性治疗患者的中位生存期约50个月[3],治疗失败的最主要原因是腹膜转移。腹膜转移发病率高达70%,而平均生存期仅为4个月[4]。腹膜转移是胃癌的终末期表现,姑息性化疗是其标准的治疗方法,但全身化疗的腹膜渗透性差,并不能改善腹膜转移患者的生存[4-5]。自1980年Spratt等[6]首次将腹腔热灌注化疗(hyperthermic intraperitoneal chemotherapy,HIPEC)用于腹膜假性黏液瘤患者后,HIPEC已被逐步推广用于包括胃癌在内的多种恶性肿瘤伴腹膜转移患者的治疗。另外预防性的HIPEC也已被建议作为根治术后腹膜转移高危患者的一种辅助治疗策略[7-8]

1 HIPEC作用机制

肿瘤细胞较正常组织细胞对热疗更敏感,肿瘤细胞在43 ℃持续作用1 h,即可出现不可逆的损害,但正常组织可耐受47 ℃持续1 h。HIPEC的热效应既可通过激活溶酶体、破坏胞质和胞核、干扰能量代谢、损伤DNA修复等对腹膜肿瘤细胞造成损害,又可通过改变肿瘤细胞膜的稳态,促进化疗药物进入癌组织,增加癌细胞对化疗药物的吸收,并且由于“血液-腹膜屏障”的存在,限制了腹腔内的化疗药物吸收入血,从而维持腹腔内高药物浓度。热效应还可通过激活热休克蛋白的方式,诱发自身免疫系统产生抗肿瘤效应。另外,HIPEC腹腔内的大量循环灌注液可将脱落的肿瘤细胞及时杀死或冲刷出体外[9-10]

2 HIPEC治疗胃癌的药物选择

HIPEC治疗胃癌应用最广泛的药物是丝裂霉素C(MMC)和顺铂(CDDP),可以单药,也可联合用药[11-12]。在此基础上联合5-FU、紫杉醇等也有相关研究报道。Murata等[13]对5-FU、CDDP、MMC三药联合用于HIPEC治疗胃癌腹膜转移患者的药物剂量和安全性进行了探索,结果表明MMC、CDDP和5-FU三药联合是安全可行的。有研究者将CDDP、丝裂霉素和紫杉醇三药联合用于胃癌腹膜转移患者的腹腔热灌注化疗,结果证实丝裂霉素、CDDP联合紫杉醇安全可耐受[14]。因此,三药联合能否提高HIPEC疗效的Ⅱ、Ⅲ期临床研究亟待开展。

3 HIPEC治疗模式及疗效评价

目前HIPEC用于胃癌的治疗模式主要有以下3种:(1)围手术期预防性HIPEC,即胃癌根治术联合术中或术后的预防性HIPEC治疗,用于未证实腹膜转移的胃癌高风险腹膜转移患者。(2)进展期胃癌伴腹膜转移的HIPEC治疗,即胃癌根治术+细胞减灭术(cytoreductive surgery,CRS)+HIPEC,用于治疗有手术可能的胃癌同时性腹膜转移患者。(3)姑息性的HIPEC,用于治疗晚期胃癌伴腹膜转移、腹腔积液患者,可缓解大量腹水引起的腹胀,改善患者的生活质量。

3.1 围手术期预防性HIPEC

局部进展期胃癌行胃癌根治术后的腹膜转移发生率较高,侵及浆膜、印戒细胞癌和未分化分级(G3/G4)的胃癌是胃癌异时性腹膜转移发生的独立危险因素[15]。Sugarbake等[16]的“肿瘤细胞包埋学说”认为,切除肿瘤组织、切断淋巴管以及肿瘤标本的出血可产生游离的腹腔癌细胞,同时肿瘤侵及浆膜后很可能脱落至腹腔引起腹膜种植转移,该假说是HIPEC预防胃癌异时性腹膜转移的理论基础。

2019年10月,Brenkman等[17]纳入了11项研究,对根治性手术联合预防性HIPEC和单纯手术(SA)的疗效进行了比较。在一项随机和三项非随机对照试验的比较中发现联合组和SA组总生存期分别为32~34.6个月、22~28.2个月,其中一项非随机研究结果最为显著,联合组和SA组总生存期为(33个月vs 22个月,P=0.0142)。两个随机和四个非随机对照研究揭示了有关腹膜复发率的数据,HIPEC组和SA组分别为6.8%~26.7%、14.1%~45%,其中一项非随机研究结果有明显差异(HR=0.2,95%CI:0.068~0.600,P=0.005),提示预防性HIPEC可降低术后腹膜复发率。2019年12月,Reutovich等[18]对HIPEC能否降低可切除浆膜浸润性胃癌患者的异时性腹膜转移(metachronous peritoneal metastases,MPM)风险进行了评估,该研究纳入了154例胃癌(ⅡB~ⅢC期)患者,随机分为HIPEC联合胃癌根治术(HIPEC组,n=76)以及仅接受胃癌根治术(对照组,n=78),3年无进展生存率分别为47%(95%CI:36~61)和27%(95%CI:17~43),P=0.0024。两组MPM的发生率分别为12.8% (16/68)和27.6% (39/55),P<0.001。两组疾病进展率分别为52.9%(36/68)和76.4%(42/55),P=0.009。研究证明HIPEC可降低浆膜浸润性胃癌的异时性腹膜转移风险。

综上,局部进展期胃癌患者根治术后易发生腹膜转移,对这类患者行根治术后联合预防性HIPEC是必要的,尤其适用于伴有浆膜浸润、淋巴结受累、腹膜细胞学阳性的高风险腹膜转移患者。

3.2 进展期胃癌腹膜转移的HIPEC治疗

既往认为进展期胃癌一旦发现同时性腹膜转移,患者将只限于姑息性的全身化疗和支持性治疗,中位总生存期仅为7~15个月,5年生存率只有2%[19]。但近年来对于肿瘤转移病理生理学的研究进展表明腹膜转移是一区域性疾病[20],CRS以及HIPEC便被逐渐开发作为这类患者的新型治疗策略,并且取得了令人满意的疗效,CRS可以减轻肿瘤负荷,HIPEC可以清除腹腔内微转移病灶。

2011年,Yang等[21]的一项前瞻性Ⅲ期随机对照试验结果发布,对CRS+HIPEC治疗进展期胃癌腹膜转移患者的疗效进行了评价,该研究共纳入68例胃癌腹膜转移患者,随机分成CRS组(n=34)和CRS+HIPEC(n=34)组,中位生存时间分别为6.5个月(95%CI:4.8~8.2个月)和11.0个月(95%CI:10.0~11.9个月),P=0.046。严重不良反应的发生比例分别是11.7%(4/34)和14.7%(5/34),P=0.839。结果表明对于胃癌的同时性腹膜转移,CRS联合HIPEC可改善生存期,且安全性尚可。并且经多变量分析发现CRS+HIPEC、同时性腹膜转移、CC评分0~1、全身化疗6周期以上是预后较好的独立预测因素。

2019年5月,Manzanedo等[22]发表了一项关于CRS联合HIPEC治疗进展期胃癌腹膜转移的回顾性多中心研究,接受CRS+HIPEC治疗的腹膜转移患者,中位无病生存期为11.6个月,中位总生存期为21.2个月,1年存活率为79.9%,3年存活率为30.9%。多因素分析显示,PCI≥7是影响OS的唯一独立因素(HR=2.37,95% CI:1.26~4.46,P=0.007)。Chia等[23]和Rihuete Caro等[24]的研究结果同样支持PCI<7的胃癌腹膜转移患者行CRS+HIPEC治疗临床获益更明显。综上所述,胃癌根治术+CRS+HIPEC这一治疗模式对于胃癌同时性腹膜转移患者的疗效是确切的,尤其适用于PCI指数<7以及完整性的CRS(CC-0、CC-1)患者。

3.3 姑息性HIPEC

胃癌异时性腹膜转移以及不可手术的晚期患者常伴有大量恶性腹水,导致患者生存质量下降。Facchiano等[25]对5例不能切除的胃癌腹膜转移继发恶性腹水患者行HIPEC治疗,发现5例患者腹水及相关症状均完全消退,没有发生与手术相关的术后死亡,且随访至患者死亡为止并无腹水再发。Randle等[26]的一项回顾性研究显示HIPEC对于恶性腹水的控制率可高达93%(288/310)。并且Orgiano等[27]发现随HIPEC次数增加,腹水减少更为显著。Yarema等[28]的研究表明姑息性HIPEC治疗可控制恶性腹水、缓解腹胀,提高晚期患者生存质量,却无生存获益。

但Hotopp等[29]在胃癌腹膜转移患者中采用FLOT方案的新辅助化疗联合CRS+HIPEC,发现这种模式可延长晚期患者生存期。Mielko等[30]应用HIPEC转化术治疗胃癌腹膜转移患者,即开始并无手术机会的患者接受新辅助化疗+根治术+CRS+HIPEC+术后化疗,结果表明这一模式对于分期较低的ypT2和P3以下(根据日本腹膜疾病严重程度分类)的腹膜转移患者是具有生存获益的。因此针对晚期胃癌腹膜转移患者开发基于HIPEC的综合治疗方式是未来的研究方向。

4 预后相关生物标记物

Zunino等[31]证实HIPEC可以通过增加热休克蛋白90(HSP90)的暴露诱导抗癌免疫反应,意味着接受HIPEC治疗后HSP90表达高的患者预后好。Zhang等[32]分析了接受CRS+HIPEC治疗的进展期胃癌患者的mi-RNA表达谱,发现治疗后的患者miRNA-218上调8倍余。在人胃癌细胞(SGC7901)中上调miRNA-218的表达,结果表明miRNA-218上调后明显抑制了肿瘤细胞增长,因此miRNA-218表达增加可反映HIPEC的长期疗效。Grazioso等[33]发现小鼠胃癌模型肿瘤转移相关基因经HIPEC处理后表达下调,其中包括:大肠腺瘤性息肉病(APC);整合素基因的β3亚单位(ITGB3);趋化因子基质细胞衍生因子-1受体(CXCR4);脾脏酪氨酸激酶(SYK);血管内皮生长因子受体3/FMS相关的酪氨酸激酶4(VEGFR3/FLT4);Ⅳ型胶原α2链(COL4A2);C端结合蛋白1(CTBP1)。结果表明,以上基因表达下降可提示HIPEC治疗后的小鼠肿瘤转移发生率降低,但还需进一步的临床试验证明此结论。Kooten等[34]回顾性分析了C-反应蛋白(CRP)对CRS+HIPEC术后短期并发症的预测能力,研究纳入181例患者,根据严重不良事件(SAE)分级标准分为SAE≥3组(n=50)以及SAE<3组(n=131),比较两组患者的CRP水平。结果显示,SAE≥3的患者在术后第2~5天CRP水平明显升高(P值依次为0.023、0.001、0.002、0.002),并且术后第3天CRP>166 mg/L和术后第4天CRP>116 mg/L与SAE ≥3的风险最高。可见,CRP水平在术后第2天开始持续升高、术后第3天CRP>166 mg/L或术后第4天CRP>116 mg/L提示发生高级别SAE的风险较大。

5 结语及展望

目前胃癌有效治疗手段有限,HIPEC是提高胃癌患者疗效的有效手段之一。诸多临床研究表明,HIPEC对于腹膜高转移风险的胃癌患者以及胃癌同时性腹膜转移患者(PCI<7)的疗效是肯定的。但对胃癌异时性腹膜转移、腹膜肿瘤负荷较高以及不可手术的晚期腹膜转移患者,HIPEC的疗效并不乐观。同时,在基础研究方面我们目前不仅缺乏有效靶点提高HIPEC疗效,还缺乏较为准确的预测性生物标记物。因此开发基于HIPEC的综合治疗(联合新辅助化疗、系统化疗、免疫治疗、靶向治疗等)、探讨HIPEC的分子机制、寻求相关的预后生物标记物等都是未来可期的研究策略。

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文章信息

李宗圜, 王晓盈, 蒋华
LI Zongyuan, WANG Xiaoying, JIANG Hua
腹腔热灌注化疗治疗胃癌的研究现状
Current status of hyperthermic intraperitoneal chemotherapy in gastric cancer patients
大连医科大学学报, 2022, 44(1): 75-79.
Journal of Dalian Medical University, 2022, 44(1): 75-79.
通信作者
蒋华,教授。E-mail:czeyjh@njmu.edu.cn.

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