益气活血解毒方调控IL-6对铂耐药卵巢癌患者巨噬细胞表型的影响

Effects of Yiqi Huoxue Jiedu Fang on macrophage phenotype in patientswith platinum-resistant ovarian cancer through regulating IL-6

目的观察益气活血解毒方治疗铂耐药卵巢癌患者的无进展生存期(PFS)、生存质量和中医证候变化,探讨益气活血解毒方通过调控白细胞介素(IL)-6水平对巨噬细胞表型的影响。方法使用随机对照方法进行研究,纳入75例气虚血瘀证铂耐药卵巢癌患者。两组均接受西医规范治疗,对照组在此基础上口服中成药西黄解毒胶囊,治疗组口服益气活血解毒方,干预至病情进展、死亡或研究结束。每2月随访1次,评估生存质量和中医证候积分变化。采集受试者外周血,分别在入组时和干预每2个月后检测外周血IL-6和M2型巨噬细胞占巨噬细胞的百分比,进行Person相关性分析。对影响PFS的危险因素进行Cox回归分析。结果两组患者入组时中医证候评分、M2占巨噬细胞百分比、IL-6水平、年龄、分期差异无统计学意义。治疗组中位无进展生存期(median progression free survival,mPFS)为6个月(95%置信区间:4.77-7.23),对照组mPFS为5个月(95%置信区间:3.06-6.94),两组比较差异有统计学意义。两组生存质量、中医证候评分均较治疗前改善,但组间差异无统计学意义。外周血中IL-6<5.5 ng/L时,IL-6水平和M2表型在巨噬细胞中的百分比呈负相关,治疗组治疗后IL-6较治疗前升高,对照组治疗后较治疗前变化无统计学意义;IL-6>5.5 ng/L时,IL-6水平和M2占巨噬细胞百分比呈正相关,治疗组和对照组治疗后IL-6均较治疗前降低。化疗线数多和M2型巨噬细胞占比大为无进展生存时间的危险因素。结论益气活血解毒方能延长晚期铂耐药卵巢癌患者的PFS,提高晚期铂耐药卵巢癌患者的生活质量,改善中医证候。益气活血解毒方可以在一定范围内提高IL-6的水平,提高机体免疫功能。IL-6过高时,益气活血解毒方和西黄解毒胶囊均能降低患者外周血中IL-6水平,缓解免疫抑制。巨噬细胞表型的改变能影响铂耐药卵巢癌患者的无进展生存时间。

Objective To observe the effects of Yiqi Huoxue Jiedu Fang(Qi-Benefiting, Blood-Activating, and Toxin-Eliminating Formula, YQHXJDF) on progression-free survival(PSF), quality of life and pattern changes of traditional Chinese medicine(TCM) in the treatment of platinum-resistant ovarian cancer, and its mechanism through regulating IL-6 level and macrophage phenotype. Methods A randomized controlled trial was conducted in 75 patients with platinum-resistant ovarian cancer with qi deficiency and blood stasis pattern. Both groups received standardized treatment of western medicine, on the basis of which the control group was given Chinese patent medicine-Xihuang Jiedu Jiaonang(Toxin-Eliminating Capsule with American Ginseng and Cow Bezoar, XHJDJN) orally, while the treatment group, YQHXJDF. The intervention was finished with end of the study or progression of the disease followed by death. The peripheral blood of the participants was collected, and the levels of IL-6 and M2 in macrophage percentage were detected at enrollment and 2 months after intervention with Pearson coefficient analysis. There was follow-up once every 2 months to evaluate the quality of life(QoL)and the changes of TCM pattern scores. Cox regression analysis was conducted to identify PFS risk factors. Results There was no statistically significant difference in TCM pattern scores, age, stage, M2 macrophage percentage and IL-6 level between the two groups. The median progression-free survival(mPFS) of the treatment group was 6 months [95% confidence interval(CI),4.77-7.23], and the mPFS of the control group was 5 months(95% CI,3.06-6.94). There was significant difference between the two groups. QoL and TCM pattern score were improved in both groups with no satistical significance between two groups. When IL-6 is lower than 5.5 ng/L, IL-6 level was negatively correlated with M2 macrophage percentage. IL-6 in the treatment group was increased after treatment, but there was no statistically significant difference in the control group before and after treatment;when IL-6 is higher than 5.5 ng/L, the level of IL-6 was positively correlated with M2 macrophage percentage, and the levels of IL-6 in both groups were decreased after treatment. The quality of life in the treatment group was better after intervention than that before intervention. There was no statistically significant difference in the control group before and after treatment. Besides, the quality of life in the treatment group was better than that in the control group. The number of chemotherapy lines and M2 macrophage percentage were risk factors of PFS. Conclusion YQHXJDF could prolong the PFS of patients with advanced platinum-resistant ovarian cancer, improve the quality of life and TCM patterns. It could also improve the level of IL-6 to a certain extent and thus improve immune function. When IL-6 is too high, both YQHXJDF and XHJDJN can reduce the level of IL-6 in peripheral blood and alleviate immunosuppression. The changes of macrophage phenotype seems to influence the PFS.