经皮肝动脉热化疗灌注联合化疗栓塞治疗原发性肝癌临床应用研究
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摘要
目的探讨热化疗灌注联合化疗栓塞术治疗原发性肝癌的临床应用价值。
方法96例原发性肝癌患者，随机分为两组，治疗组热化疗灌注与化疗栓塞术联合治疗，对照组常温下化疗灌注与化疗栓塞术联合治疗，每组48例。治疗前完善患者各项基本检查，包括：肝功能、肾功能、血常规、凝血四项、肝功能Child评分、并用流式细胞仪检测细胞免疫功能，治疗前患者行多期增强CT扫描(描述肿瘤分型，测量肿瘤大小、个数)，同时治疗前对患者进行KPS评分。化疗栓塞术，均采用经右侧股动脉行超选择性插管化疗栓塞，96例患者分别完成2-4个疗程。治疗组48例患者使用国产HGC-3000肿瘤介入热疗机，先行将盐酸吉西他滨1000mg溶于1200ml生理盐水中，将其加入热疗机灌注桶中，灌注时将药液进入动脉导管入处的温度设定在50-55℃，以0.5-1.0ml/s流率进行热化疗灌注，时间10-37分钟，热化疗灌注后用盐酸吉西他滨200mg+卡铂200mg+超液化碘油(根据肿瘤大小确定用量)进行超选择性肝动脉化疗栓塞。栓塞剂采用超液态碘化油及明胶海绵。对照组将盐酸吉西他滨1000mg溶于1200ml生理盐水中，之后常温下以0.5-1.0ml/s的流率进行化疗灌注，时间10-37分钟，化疗灌注后用盐酸吉西他滨200mg+卡铂200mg+超液化碘油(根据肿瘤大小确定用量)进行超选择性肝动脉化疗栓塞，所用栓塞剂同治疗组。治疗后30天复查多期增强CT扫描，并依据RECIST标准比较两组客观疗效；治疗后对患者进行KPS评分，评估治疗前后患者生活质量改善情况；治疗后第3天复查肝功能、肾功能、血常规、免疫功能（术后七天评估），治疗后第30天复查肝功能、肾功能、血常规，之后比较术前及术后各项观察指标的变化；治疗前后比较两组毒副反应；观察两组患者0.5、1.0、1.5及2.0年生存率，同时比较两组患者的中位生存时间。结果两组丙氨酸转氨酶（ALT）及谷草转氨酶（AST）治疗后3天较治疗前均升高（P<0.05），且对照组高于治疗组（P<0.01），但治疗后30天较治疗前无变化；而两组肾功能治疗前后无明显变化。各组比较结果：治疗组治疗前ALT(43±5)U/L，治疗后三天ALT(84±12)U/L，较治疗前升高(P=0.000),治疗后30天ALT(42±6)U/L，较治疗前无升高(P=0.710)，对照组治疗前ALT(41±3)U/L，治疗后三天ALT(175±10)U/L，(P<0.05)，较治疗前升高，治疗后30天ALT(40±5)U/L，较治疗前差异无统计学意义(P=0.462)。治疗组治疗前AST(44±2)U/L，治疗后三天AST(94±11)U/L，较治疗前升高(P=0.000)，治疗后30天AST(45±1)U/L，较治疗前差异无统计学意义(P=0.202)，对照组治疗前AST(42±1)U/L，治疗后三天AST(173±13)U/L，(P<0.05)，较治疗前明显升高，治疗后30天AST(41±3)U/L，较治疗前差异无统计学意义(P=0.787)。尽管两组ALT和AST热化疗灌注后肝功能暂时升高，给予保肝治疗后，即可恢复至治疗前水平，提示热化疗灌注后患者肝功能短时间内可能一过性升高。近期疗效评价，治疗组CR0例、PR36例、SD7例、PD5例，其所占的比率依此为0%、75.00%、14.58%、10.42%、总有效率75%(36/48)；对照组CR0例，PR19例，SD18例，PD11例，所占比率分别为0%、39.58%、37.5%、22.92%，总有效率39.58%(19/48)，两组差异有显著性(P=0.000)；治疗组生活质量显著改善9例、改善30例、稳定7例、下降2例，所占比率分别为18.75%、62.50%、14.58%、4.17%，KPS评分提高39例，占81.30%；对照组依此为0、24、15和7例，所占比率分别为0%、50.00%、31.25%、14.58%，KPS评分提高共24例，所占比率50.00%，治疗组生活质量改善情况明显优于对照组(P=0.003)。治疗前后患者免疫功能变化：治疗组组免疫功能CD3及调节性T细胞较治疗前升高而CD8较治疗前下降，对照组免疫功能较治疗前无明显变化，且治疗后治疗组免疫功能CD3及调节性T细胞高于对照组，差异有统计学意义（P<0.01）。其各组结果如下：治疗组治疗前CD3(69.35±6.88)%，治疗后(72.23±6.84)%，(P=0.005)；治疗组治疗前CD4(40.67±6.75)%，治疗后(40.89±8.19)%，(P=0.849)；治疗组治疗前CD8(24.18±1.85)%，治疗后(23.56±6.66)%，(P=0.028)；治疗组治疗前CD4/CD8(1.82±0.67)，治疗后(1.85±0.57)，(P=0.194)；治疗组治疗前NK细胞(12.69±4.98)%，治疗后(11.41±4.43)%，(P=0.291)；治疗组治疗前调节性T细胞(11.83±4.09)%，治疗后(14.17±3.92)%，(P=0.002)，对照组治疗前CD3(68.89±5.45)%，治疗后(68.67±5.35)%，(P=0.172)；对照组治疗前CD4(39.89±5.78)%，治疗后(40.01±5.68)%，(P=0.570)；对照组治疗前CD8(23.08±1.75)%，治疗后(23.10±1.70)%，(P=0.854)；对照组治疗前CD4/CD8(1.86±0.56)，治疗后(1.87±0.61)，(P=0.206)；对照组治疗前NK细胞(11.70±5.78)%，治疗后(11.80±5.25)%，(P=0.815)；对照组治疗前调节性T细胞(11.61±3.08)%，治疗后(11.59±3.07)%，(P=0.724)。对照组术前术后各项免疫功能无明显变化，提示治疗组热化疗灌注治疗后患者的免疫状态改善。治疗组患者的中位生存时间为24个月(95%置信区间[CI]为20-29)，对照组患者的中位生存时间为18.9个月(95%置信区间[CI]为18-20)，治疗组较对照组中位生存时间延长；两组毒副反应的发生率无统计学差异。结论热化疗灌注联合介入化疗栓塞术治疗原发性肝癌疗效优于常温下化疗灌注联合介入化疗栓塞术，是治疗原发性肝癌的一种安全、有效的方法。
Objective To evaluate the clinical efficacy and safety of thermochemotherapy infusion combinedwith chemoembolization in the treatment of hepatic carcinoma. Methods Ninety-six patients with hepaticcarcinoma, were randomly divided into two groups. Each group had forty-eight patients. In the study group,the patients underwent thermochemotherapy infusion combined with chemoembolization. In the contrastgroup, chemotherapy infusion was followed by chemoembolization. Before the treatment, the patients un-derwent the basic blood examination and other necessary examination, including liver function, renal func-tion, routine analysis of blood, clotting mechanism, immune function, electrocardiogram and score of KPS.At the same time, each patient was performed with enhanced CT scaning, which could describe the tumortype, volumes and numbers. In all patients of the two groups the treatment was applied and was repeated2to4courses. In the study group, forty-eight cases were treated by HGC-3000, which was the hyperthermiamachine for interventional oncology, and made in China. At first,1000mg gemcitabine were dissolved insaline and then were infused into the hyperthermia machine, which could warm the solution to50-55℃before infusioning into the hepatic arteries. The rate of fluid was set to0.5-1.0ml/s. The time was set to10-37minutes. After transhepatic arterial infusion of warmed chemotherapeutic, superselective transcathe-ter arterial chemoembolization was performed with the mixture of200mg gemcitabine,200mg carboplatinand lipiodol. While in the control group,1000mg gemcitabine were dissolved in saline in room temperature,and then the solution were infused into hepatic arteries directly by the rate of fluid of0.5-1.0ml/s. After that,superselective transcatheter arterial chemoembolization was performed with the mixture of200mg gemci-tabine,200mg carboplatin and lipiodol. The dosage of lipiodol was according to the volumes of tumours.Repeated treatment was given after30-40days and continued for two or three times. Examination wereperformed, including the liver function, renal function, routine analysis of blood, clotting mechanism andimmune function, three days and one month after treatment. The volumes of tumor were measured on CTimages, and toxicity were recorded and the patients survival periods were observed. Results Two groups ofalanine aminotransferase (ALT) and aspartate aminotransferase (AST) were higher than pre-treatment after 3days(P<0.05), but there were no changes after30days. No significant difference of renal function be-tween pre-treatment and post-treatment were found in the both groups. In the study group, the levels ofalanine aminotransferase (ALT) were (43±5) U/L, three days after treatment, the levels increased to (84±12)U/L (P=0.000), but thirty days after treatment it showed no difference with pre-treatment (P=0.710). In thecontrol group, the levels of ALT were (41±3) U/L, it was (175±10) U/L three days after treatment, and itwere (40±5) U/L thirty days after treatment. There was significant difference between pre-treatment andpost-treatment in the control group. In the study group, the levels of aspartate aminotransferase (AST) were(44±2) U/L, the levels increased to (94±11) U/L three days after treatment (P=0.000). But thirty days aftertreatment there was no difference with pre-treatment (P=0.202). In the control group, the levels of ASTwere (42±1) U/L, it were (173±13) U/L three days after treatment, and it were (41±3) U/L thirty days aftertreatment. There was significant difference between pre-treatment and post-treatment in the control group.The result of our study indicated as following: CR zero case, PR thirty six cases, SD seven cases, PD fivecases, with the total efficiency being75%(36/48); and that of the control group showed that: CR zero case,PR ninteen cases, SD eighteen cases, PD eleven cases, with the total efficiency being39.58%(19/48).Allof above data showed statistically significant difference in two groups (P=0.000). As to the study group,the mark of Karnofsky had improved for thirty-nine cases, accounting for81.25%(39/48), showed statisti-cally significant difference in two groups also (P=0.003); compared with that of the control group fortwenty four cases, accounting for50%(24/48). In the study group,the immunity state of patients were im-proved after treatment, however, There was no significant difference between pre-treatment andpost-treatment in the control group. In the study group, the CD3was (69.35±6.88)%before treatment, andit was (72.23±6.84)%after treatment,(P=0.005). The CD4was (40.67±6.75)%before treatment, and itwas (40.89±8.19)%, after treatment (P=0.849), The CD8was (24.18±1.85)%before treatment, and it was(23.56±6.66)%, after treatment,(P=0.028). The ratio of CD4/CD8was (1.82±0.67) before treatment,and it was (1.85±0.57) after treatment,(P=0.194). The NK cells were (12.69±4.98)%before treatment,and it was (11.41±4.43)%after treatment,(P=0.291). The Regulatory T cells were (11.83±4.09)%beforetreatment, and it were (14.17±3.92)%after treatment,(P=0.002). In the control group, the CD3was (68.89±5.45)%before treatment and it was (68.67±5.35)%after treatment (P=0.172). The CD4was (39.89± 5.78)%before treatment and it was (40.01±5.68)%after treatment (P=0.570). The CD8was (23.08±1.75)%before treatment and it was (23.10±1.70)%after treatment,(P=0.854). The ratio of CD4/CD8was(1.86±0.56) before treatment and it was (1.87±0.61) after treatment (P=0.206). The NK cells were (11.70±5.78)%before treatment and it was (11.80±5.25)%after treatment (P=0.851). The Regulatory T cellswere (11.61±3.08)%before treatment and it were (11.59±3.07)%after treatment (P=0.724). There wasno significant difference between pre-treatment and post-treatment in the control group. However, in thestudy group, the immunity state of patients were improved after treatment. In the study group, the mediansurvival was24months [95%confidence interval(CI):20-29]. In the control group, the median survival was18.9months [95%confidence interval(CI):18-20]. No significant difference was found in side effect be-tween two groups. Conclusion The transcatheter arterial heated chemotherapy combined with transcatheterarterial chemoembolization for Hepatocellular Carcinoma was better than the transcatheter arterial chemo-therapy combined with transcatheter arterial chemoembolization.
方法96例原发性肝癌患者，随机分为两组，治疗组热化疗灌注与化疗栓塞术联合治疗，对照组常温下化疗灌注与化疗栓塞术联合治疗，每组48例。治疗前完善患者各项基本检查，包括：肝功能、肾功能、血常规、凝血四项、肝功能Child评分、并用流式细胞仪检测细胞免疫功能，治疗前患者行多期增强CT扫描(描述肿瘤分型，测量肿瘤大小、个数)，同时治疗前对患者进行KPS评分。化疗栓塞术，均采用经右侧股动脉行超选择性插管化疗栓塞，96例患者分别完成2-4个疗程。治疗组48例患者使用国产HGC-3000肿瘤介入热疗机，先行将盐酸吉西他滨1000mg溶于1200ml生理盐水中，将其加入热疗机灌注桶中，灌注时将药液进入动脉导管入处的温度设定在50-55℃，以0.5-1.0ml/s流率进行热化疗灌注，时间10-37分钟，热化疗灌注后用盐酸吉西他滨200mg+卡铂200mg+超液化碘油(根据肿瘤大小确定用量)进行超选择性肝动脉化疗栓塞。栓塞剂采用超液态碘化油及明胶海绵。对照组将盐酸吉西他滨1000mg溶于1200ml生理盐水中，之后常温下以0.5-1.0ml/s的流率进行化疗灌注，时间10-37分钟，化疗灌注后用盐酸吉西他滨200mg+卡铂200mg+超液化碘油(根据肿瘤大小确定用量)进行超选择性肝动脉化疗栓塞，所用栓塞剂同治疗组。治疗后30天复查多期增强CT扫描，并依据RECIST标准比较两组客观疗效；治疗后对患者进行KPS评分，评估治疗前后患者生活质量改善情况；治疗后第3天复查肝功能、肾功能、血常规、免疫功能（术后七天评估），治疗后第30天复查肝功能、肾功能、血常规，之后比较术前及术后各项观察指标的变化；治疗前后比较两组毒副反应；观察两组患者0.5、1.0、1.5及2.0年生存率，同时比较两组患者的中位生存时间。结果两组丙氨酸转氨酶（ALT）及谷草转氨酶（AST）治疗后3天较治疗前均升高（P<0.05），且对照组高于治疗组（P<0.01），但治疗后30天较治疗前无变化；而两组肾功能治疗前后无明显变化。各组比较结果：治疗组治疗前ALT(43±5)U/L，治疗后三天ALT(84±12)U/L，较治疗前升高(P=0.000),治疗后30天ALT(42±6)U/L，较治疗前无升高(P=0.710)，对照组治疗前ALT(41±3)U/L，治疗后三天ALT(175±10)U/L，(P<0.05)，较治疗前升高，治疗后30天ALT(40±5)U/L，较治疗前差异无统计学意义(P=0.462)。治疗组治疗前AST(44±2)U/L，治疗后三天AST(94±11)U/L，较治疗前升高(P=0.000)，治疗后30天AST(45±1)U/L，较治疗前差异无统计学意义(P=0.202)，对照组治疗前AST(42±1)U/L，治疗后三天AST(173±13)U/L，(P<0.05)，较治疗前明显升高，治疗后30天AST(41±3)U/L，较治疗前差异无统计学意义(P=0.787)。尽管两组ALT和AST热化疗灌注后肝功能暂时升高，给予保肝治疗后，即可恢复至治疗前水平，提示热化疗灌注后患者肝功能短时间内可能一过性升高。近期疗效评价，治疗组CR0例、PR36例、SD7例、PD5例，其所占的比率依此为0%、75.00%、14.58%、10.42%、总有效率75%(36/48)；对照组CR0例，PR19例，SD18例，PD11例，所占比率分别为0%、39.58%、37.5%、22.92%，总有效率39.58%(19/48)，两组差异有显著性(P=0.000)；治疗组生活质量显著改善9例、改善30例、稳定7例、下降2例，所占比率分别为18.75%、62.50%、14.58%、4.17%，KPS评分提高39例，占81.30%；对照组依此为0、24、15和7例，所占比率分别为0%、50.00%、31.25%、14.58%，KPS评分提高共24例，所占比率50.00%，治疗组生活质量改善情况明显优于对照组(P=0.003)。治疗前后患者免疫功能变化：治疗组组免疫功能CD3及调节性T细胞较治疗前升高而CD8较治疗前下降，对照组免疫功能较治疗前无明显变化，且治疗后治疗组免疫功能CD3及调节性T细胞高于对照组，差异有统计学意义（P<0.01）。其各组结果如下：治疗组治疗前CD3(69.35±6.88)%，治疗后(72.23±6.84)%，(P=0.005)；治疗组治疗前CD4(40.67±6.75)%，治疗后(40.89±8.19)%，(P=0.849)；治疗组治疗前CD8(24.18±1.85)%，治疗后(23.56±6.66)%，(P=0.028)；治疗组治疗前CD4/CD8(1.82±0.67)，治疗后(1.85±0.57)，(P=0.194)；治疗组治疗前NK细胞(12.69±4.98)%，治疗后(11.41±4.43)%，(P=0.291)；治疗组治疗前调节性T细胞(11.83±4.09)%，治疗后(14.17±3.92)%，(P=0.002)，对照组治疗前CD3(68.89±5.45)%，治疗后(68.67±5.35)%，(P=0.172)；对照组治疗前CD4(39.89±5.78)%，治疗后(40.01±5.68)%，(P=0.570)；对照组治疗前CD8(23.08±1.75)%，治疗后(23.10±1.70)%，(P=0.854)；对照组治疗前CD4/CD8(1.86±0.56)，治疗后(1.87±0.61)，(P=0.206)；对照组治疗前NK细胞(11.70±5.78)%，治疗后(11.80±5.25)%，(P=0.815)；对照组治疗前调节性T细胞(11.61±3.08)%，治疗后(11.59±3.07)%，(P=0.724)。对照组术前术后各项免疫功能无明显变化，提示治疗组热化疗灌注治疗后患者的免疫状态改善。治疗组患者的中位生存时间为24个月(95%置信区间[CI]为20-29)，对照组患者的中位生存时间为18.9个月(95%置信区间[CI]为18-20)，治疗组较对照组中位生存时间延长；两组毒副反应的发生率无统计学差异。结论热化疗灌注联合介入化疗栓塞术治疗原发性肝癌疗效优于常温下化疗灌注联合介入化疗栓塞术，是治疗原发性肝癌的一种安全、有效的方法。
Objective To evaluate the clinical efficacy and safety of thermochemotherapy infusion combinedwith chemoembolization in the treatment of hepatic carcinoma. Methods Ninety-six patients with hepaticcarcinoma, were randomly divided into two groups. Each group had forty-eight patients. In the study group,the patients underwent thermochemotherapy infusion combined with chemoembolization. In the contrastgroup, chemotherapy infusion was followed by chemoembolization. Before the treatment, the patients un-derwent the basic blood examination and other necessary examination, including liver function, renal func-tion, routine analysis of blood, clotting mechanism, immune function, electrocardiogram and score of KPS.At the same time, each patient was performed with enhanced CT scaning, which could describe the tumortype, volumes and numbers. In all patients of the two groups the treatment was applied and was repeated2to4courses. In the study group, forty-eight cases were treated by HGC-3000, which was the hyperthermiamachine for interventional oncology, and made in China. At first,1000mg gemcitabine were dissolved insaline and then were infused into the hyperthermia machine, which could warm the solution to50-55℃before infusioning into the hepatic arteries. The rate of fluid was set to0.5-1.0ml/s. The time was set to10-37minutes. After transhepatic arterial infusion of warmed chemotherapeutic, superselective transcathe-ter arterial chemoembolization was performed with the mixture of200mg gemcitabine,200mg carboplatinand lipiodol. While in the control group,1000mg gemcitabine were dissolved in saline in room temperature,and then the solution were infused into hepatic arteries directly by the rate of fluid of0.5-1.0ml/s. After that,superselective transcatheter arterial chemoembolization was performed with the mixture of200mg gemci-tabine,200mg carboplatin and lipiodol. The dosage of lipiodol was according to the volumes of tumours.Repeated treatment was given after30-40days and continued for two or three times. Examination wereperformed, including the liver function, renal function, routine analysis of blood, clotting mechanism andimmune function, three days and one month after treatment. The volumes of tumor were measured on CTimages, and toxicity were recorded and the patients survival periods were observed. Results Two groups ofalanine aminotransferase (ALT) and aspartate aminotransferase (AST) were higher than pre-treatment after 3days(P<0.05), but there were no changes after30days. No significant difference of renal function be-tween pre-treatment and post-treatment were found in the both groups. In the study group, the levels ofalanine aminotransferase (ALT) were (43±5) U/L, three days after treatment, the levels increased to (84±12)U/L (P=0.000), but thirty days after treatment it showed no difference with pre-treatment (P=0.710). In thecontrol group, the levels of ALT were (41±3) U/L, it was (175±10) U/L three days after treatment, and itwere (40±5) U/L thirty days after treatment. There was significant difference between pre-treatment andpost-treatment in the control group. In the study group, the levels of aspartate aminotransferase (AST) were(44±2) U/L, the levels increased to (94±11) U/L three days after treatment (P=0.000). But thirty days aftertreatment there was no difference with pre-treatment (P=0.202). In the control group, the levels of ASTwere (42±1) U/L, it were (173±13) U/L three days after treatment, and it were (41±3) U/L thirty days aftertreatment. There was significant difference between pre-treatment and post-treatment in the control group.The result of our study indicated as following: CR zero case, PR thirty six cases, SD seven cases, PD fivecases, with the total efficiency being75%(36/48); and that of the control group showed that: CR zero case,PR ninteen cases, SD eighteen cases, PD eleven cases, with the total efficiency being39.58%(19/48).Allof above data showed statistically significant difference in two groups (P=0.000). As to the study group,the mark of Karnofsky had improved for thirty-nine cases, accounting for81.25%(39/48), showed statisti-cally significant difference in two groups also (P=0.003); compared with that of the control group fortwenty four cases, accounting for50%(24/48). In the study group,the immunity state of patients were im-proved after treatment, however, There was no significant difference between pre-treatment andpost-treatment in the control group. In the study group, the CD3was (69.35±6.88)%before treatment, andit was (72.23±6.84)%after treatment,(P=0.005). The CD4was (40.67±6.75)%before treatment, and itwas (40.89±8.19)%, after treatment (P=0.849), The CD8was (24.18±1.85)%before treatment, and it was(23.56±6.66)%, after treatment,(P=0.028). The ratio of CD4/CD8was (1.82±0.67) before treatment,and it was (1.85±0.57) after treatment,(P=0.194). The NK cells were (12.69±4.98)%before treatment,and it was (11.41±4.43)%after treatment,(P=0.291). The Regulatory T cells were (11.83±4.09)%beforetreatment, and it were (14.17±3.92)%after treatment,(P=0.002). In the control group, the CD3was (68.89±5.45)%before treatment and it was (68.67±5.35)%after treatment (P=0.172). The CD4was (39.89± 5.78)%before treatment and it was (40.01±5.68)%after treatment (P=0.570). The CD8was (23.08±1.75)%before treatment and it was (23.10±1.70)%after treatment,(P=0.854). The ratio of CD4/CD8was(1.86±0.56) before treatment and it was (1.87±0.61) after treatment (P=0.206). The NK cells were (11.70±5.78)%before treatment and it was (11.80±5.25)%after treatment (P=0.851). The Regulatory T cellswere (11.61±3.08)%before treatment and it were (11.59±3.07)%after treatment (P=0.724). There wasno significant difference between pre-treatment and post-treatment in the control group. However, in thestudy group, the immunity state of patients were improved after treatment. In the study group, the mediansurvival was24months [95%confidence interval(CI):20-29]. In the control group, the median survival was18.9months [95%confidence interval(CI):18-20]. No significant difference was found in side effect be-tween two groups. Conclusion The transcatheter arterial heated chemotherapy combined with transcatheterarterial chemoembolization for Hepatocellular Carcinoma was better than the transcatheter arterial chemo-therapy combined with transcatheter arterial chemoembolization.
引文
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