介入化疗联合放疗对胃癌肝转移患者免疫调控作用及疗效的影响

摘要

目的: 探讨介入化疗联合放疗对胃癌肝转移患者的免疫调控作用及其疗效.

方法: 胃癌肝转移患者33例分为2组, 对照组(n = 16)采用经肝动脉EAP栓塞化疗方案, 治疗组(n = 17)经肝动脉EAP栓塞化疗方案药物灌注1次后, 再行常规分割外放疗(TD2000-3500cGy). 两组患者在治疗后分别检测免疫调节因子IL-2及TNF-α、IFN-γ的水平, 并观察其近期疗效.

结果: 治疗后治疗组及对照组患者外周血中IL-2及TNF-α、IFN-γ的水平分别为54.7±7.2, 43.1±4.0, 26.6±2.7 ng/L和34.6±5.2, 27.9±3.3, 11.5±1.7 ng/L, 两组数据有显著性差异(P<0.01). 治疗组的近期有效率为94.4%, 0.5及1年生存率均为88.2%. 对照组的近期有效率为62.5%, 0.5及1年生存率为81.3%和43.8%, 治疗组的近期有效率及1年生存率显著高于对照组(P<0.01).

结论: 经肝动脉EAP栓塞化疗方案联合放疗治疗胃癌肝转移患者, 可显著提高患者的近期有效率及1年生存率, 上调免疫调节因子IL-2及TNF-α、IFN-γ的水平.

关键词: 胃癌; 介入化疗; 放疗

Influence of interventional chemotherapy combined with radiotherapy on immunomodulatory mechanism of gastric cancer patients with liver metastasis

Qiang Zhang, Jin-Shui Zhu, Hui-Xiang Yao, Yue-Wu Guo, Li Zhu

Qiang Zhang, Department of Radiotherapy, the Affiliated Sixth People's Hospital of Shanghai Jiaotong University, Shanghai 200233, China

Jin-Shui Zhu, Hui-Xiang Yao, Li Zhu, Department of Gastroenterology, the Affiliated Sixth People's Hospital of Shanghai Jiao Tong University, Shanghai 200233, China

Yue-Wu Guo, Department of Oncology, the Affiliated Sixth People's Hospital of Shanghai Jiao Tong University, Shanghai 200233, China

Correspondence to: Jin-Shui Zhu, Department of Gastroenterology, the Affiliated Sixth People's Hospital of Shanghai Jiao Tong University, 600 Yishan Road, Shanghai 200233, China. zhujs1803@hotmail.com

Received: March 7, 2006
Revised: March 13, 2006
Accepted: March 20, 2006
Published online: April 28, 2006

Abstract

AIM: To explore the immunomodulatory effects and efficacy of liver arterial chemotherapy combined with radiotherapy in the treatment of patients with metastatic hepatocarcinoma from gastric cancer.

METHODS: Thirty-three gastric patients with liver metastasis were divided into 2 groups. Patients in group A were treated with liver arterial chemotherapy in combination with radiotherapy (TD2000-3500cGy) under the guidance of DSA with the regimen of high-dose EAP (VP16 100 mg/m², adriamycin 60 mg/m² + carboplatin 200 mg/m²), while patients in group B received single liver arterial chemotherapy. The levels of Detecting the level of interleukin-2 (IL-2), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) were detected and the short-term efficacy was analyzed.

RESULTS: All the patients could tolerate the side effect. The short-term efficacy rate, 0.5- and 1-year survival rates in group A were 94.4%, 88.2% and 88.2%, respectively, while those in group B were 62.5%, 81.3% and 43.8%, respectively. The short-term efficacy rate and 1-year survival rate were significantly higher in group A (P < 0.01). The levels of IL-2, TNF-α, and IFN-γ were also markedly different between the two groups (54.7 ± 7.2, 43.1 ± 4.0, 26.6 ± 2.7 ng/L vs 34.6 ± 5.2, 27.9 ± 3.3, 11.5 ± 1.7 ng/L, all P < 0.01).

CONCLUSION: Liver arterial embolism chemotherapy in combination with radiotherapy can significantly improve the levels of IL-2, TNF-α, and IFN-γ, as well as the short-term efficacy and survival rates.

Key Words: Gastric cancer; Interventional chemotherapy; Radiotherapy

0 引言

胃癌肝转移, 除极少可行手术切除外, 多予全身静脉化疗、介入化疗、射频等姑息性治疗手段[1-2]. 我们采用EAP动脉栓塞化疗方案结合放射治疗胃癌肝转移患者取得良好疗效, 延长了该类患者的生存期, 改善了患者的生活质量, 并初步探讨了该方法治疗胃癌肝转移患者相关的免疫调控机制.

1 材料和方法

1.1 材料

1998-08/2003-12收治胃癌肝转移患者33例, 男25例, 女8例; 黏液腺癌26例, 未分化癌3例, 印戒细胞癌4例; 年龄33-75(平均54.4±3.4)岁. 原发病灶已行手术切除, 并有病理诊断, 经CT及胃镜等检查未发现原发病灶复发及肺、脑、骨等处的非肝外转移, 胃癌肝内转移病灶均经CT及活检病理证实, 为无手术指征或自愿放弃手术者, 并按照生活质量的国际KPS评分标准60-90分, 且治疗前肝功能Child分级为A或B级、均未使用干扰素或白介素-2等调节免疫的生物制品患者, 按照抽信封法随机分成肝动脉高剂量EAP化疗对照组及肝动脉化疗联合低剂量放疗治疗组, 前组16例, 后组17例.

1.2 方法

所有患者均行Seldinger法股动脉穿刺, 插管至肝动脉或视肿瘤分布情况超选进入其供血动脉, 注入化疗药物, 采用EAP方案(VP16 100 mg/m²+adriamycin 60 mg/m²+carboplatin 200 mg/m²), 介入加放疗组剂量为高剂量组的60%-80%. 化疗药物以碘油10-20 mL及少量造影剂均匀混和, 做动脉栓塞. 单纯介入组予每6-7 wk重复一次治疗, 共予2-3个周期, 整个介入治疗时间为12-20 wk. 介入加放疗组在首次介入治疗后2-4 wk内开始肝肿瘤外放疗, 定位时依照碘油肿瘤染色结合CT图像, 若病灶弥漫分布, 予全肝中平面TD2000cGy; 若病灶单一或局限, 设小野照射, TD3000-3500cGy. 放疗分割剂量TD150-155cGy/次, 1次/d, 1-5/wk放疗. 整个介入加放疗治疗时间为5-9 wk. 肿瘤的疗效按WHO实体瘤疗效判定标准评价, 化疗毒性按美国全国各临床肿瘤协作组制定的化疗毒性分级系统评价.

统计学处理 采用SPSS11.5统计软件包进行统计学处理, 率的比较采用χ²检验, 组间数据采用t检验.

2 结果

所有患者均能耐受治疗过程, 主要的副反应为胃肠道反应及Ⅱ-Ⅲ级骨髓抑制, 对症治疗后均能缓解.

两组均在治疗结束后4 wk复查CT, 测量肿瘤长径×横径, 判断肿瘤近期疗效, 结果CR 0 vs 1, PR 16 vs 9, NC 0 vs 9, PD 0 vs 1, 无死亡病例; PR+CR 94.1% vs 62.5%, ^aP<0.05.

免疫因子测定分别于治疗结束后2 d抽取外周血5 mL, 采用ELISA法测定外周血清IL-2、TNF-α、IFNγ水平, 结果见表1.

表1 介入化疗联合化疗治疗胃癌肝转移后外周血清IL-2, TNF-α, IFNγ水平 (mean±SD ng/L).

分组	n	IL-2	TNF-α	IFNγ
对照	16	34.6±5.2	27.9±3.3	11.5±1.7
治疗	17	54.7±7.2b	43.1±4.0b	26.6±2.7b

^bP<0.01 vs 对照组.

治疗结束后0.5、1年随访生存率, 结果分别为88.2% vs 81.3%, P>0.05和88.2% vs 43.8%, P<0.01. 死亡原因均为肿瘤晚期并发症.

3 讨论

一般认为, 肝脏的血供70%-80%来自于门静脉, 20%-30%来自于腹腔动脉分支的肝动脉, 原发性肝癌及转移性肝癌的血供约90%则来自肝动脉[3], 经肝动脉注入高剂量化疗药物可提高血药浓度, 直接作用于肿瘤细胞, 避免了多次全身静脉化疗后存在严重的骨髓抑制, 如外周血粒细胞下降导致继发感染等不利后果. 近年来动脉介入化疗治疗原发及转移性肝癌发展迅速[4], 而在消化道肿瘤发生肝转移的患者中, 原发于胃的病例所占比例较大[5], 这使得我们必须探究更为有效、简便的治疗手段. 采用经肝动脉高剂量EAP栓塞化疗方案较以往的动脉灌注化疗治疗效果有了明显的提高, 主要体现在提高了胃癌肝转移患者的近期有效率及1年生存率. 其机制可能与混合于碘油中的化疗药相对集中于肿瘤分布区, 缓慢释放, 栓塞物阻断了肿瘤组织肝动脉的血供[6], 同时增加了胃癌患者对联合放疗的敏感性有关. 有研究证实在动脉介入化疗的基础上进行放射治疗, 利用卡铂、VP16的放疗增敏特性可有疗效相加作用, 其机制包括药物抑制放射损伤的修复, 使细胞同步化, 降低乏氧细胞的比例等, 因而化疗药物往往能增加放疗的肿瘤治疗效果[7]. 根据碘油肿瘤染色, 可在透视下直接观察到肝内肿瘤位置, 提高放疗靶区定位的精确度, 减轻对正常肝组织的损伤[8].

我们前期研究报道了高剂量EAP动脉化疗对晚期胃癌有效[9], 而采用高剂量EAP肝动脉化疗联合低剂量的放射线治疗胃癌肝转移患者, 在保证肿瘤局控率的前提下, 使严重的骨髓抑制发生率得以避免, 显著上调了患者治疗后的免疫调节因子IL-2、TNF-α、IFNγ的水平, 已有研究表明免疫调节因子的水平是胃癌的重要预后因素[10-12]. 本研究说明动脉介入化疗结合放疗较之单纯介入化疗有利于胃癌肝转移患者机体免疫功能的恢复, 提高了晚期胃癌伴肝转移患者的近期有效率和1年生存率, 改善了患者的生活质量.

肝脏组织对放疗剂量耐受不高, 放射区域内的正常肝组织损伤限制了放疗的进一步实施, 而放射剂量过低使得肿瘤局部控制差强人意[13]. 如能采用三维适形放疗, 或者调强放疗技术, 则有望提高靶区放疗剂量, 降低放射性肝炎的发生率, 从而取得更好的肿瘤局控率[14-15], 最近还有应用质子束照射胃癌肝转移的报道[16]. 但对于晚期胃癌患者而言, 肿瘤局控率的提高往往并不意味着生存期的延长, 多项随机对照研究认为经肝动脉灌注化疗并不一定能够取得生存期的延长[17], 这可能提示多处器官的转移和基础疾病的恶化对长期生存的影响尤为重要[18]. 新药在化疗方案中的应用也应引起我们更多的关注[19]. 故患者动脉介入化疗结合放疗后免疫调节因子水平的改善是否意味着长期生存率的提高, 尚待进一步随访观察.

评论

背景资料

虽然介入栓塞化疗和外放疗在临床治疗转移性肝癌的应用已有大量文章报道, 但是本文试图通过介入栓塞化疗合并外放疗的方法来减少治疗时间, 进而达到减轻患者负担--不论是身体上的还是经济上的目的. 本文报道的免疫学检测指标均是成熟的已经临床普遍应用的指标, 通过对比可以证实介入栓塞化疗合并外放疗的方法较之多次介入栓塞化疗的方法对人体免疫水平的损伤更轻微, 这也许是该方法在临床应用的优势, 当然, 这需要多个科室的无私协作.

备注

编辑:潘伯荣 电编:张敏

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