宫颈癌动脉灌注栓塞化疗中新鲜明胶海绵颗粒药物缓释作用的评估
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摘要
【研究背景】
随着新辅助化疗(Neoadjuvant chemotherapy,NACT)概念的提出,国内外学者对化疗在宫颈癌中的作用进行了深入研究,明确了化疗在宫颈癌中的治疗地位,证实无论是术前静脉化疗还是动脉化疗,对局部晚期宫颈癌(locally advancedcervical cancer,LACC)患者都是一个有效的降低肿瘤临床分期的方法,进而可提高手术切除率和改善患者的生存质量。无论是基础研究还是临床疗效,众多文献报道证实了术前动脉化疗较静脉化疗更为有效,能为后续治疗提供更广泛的空间;但不可否认的是仍有部分病例效果不明显,如何进一步提高动脉化疗的疗效是需要进一步研究的问题。我们的前期研究证实,动脉灌注化疗后癌组织内抗癌药物峰浓度及药—时曲线下面积值(area under the time-concentration curve,AUC)均明显高于静脉给药组,但其抗癌药物浓度升高表现为一过性,随着时间的延长而快速下降,抗癌药物在肿瘤组织中保留时间短、清除快、迅速进入全身血液循环,导致抗癌药物与肿瘤细胞不能充分接触,使其疗效受到一定限制。因此寻找可延长肿瘤组织内抗癌药物持续高浓度的方法是提高动脉化疗疗效的有效途径之一。
动脉化疗较静脉化疗相比的另一优势是可同时对靶血管进行栓塞。因此,我们在临床上常将动脉灌注化疗与动脉栓塞相结合,形成动脉灌注后栓塞或动脉栓塞化疗,其目的之一是通过栓塞剂的栓塞作用阻断肿瘤病灶内的血流,使肿瘤细胞缺血缺氧而坏死;目的之二是希望将抗癌药物混合到栓塞剂中,以期达到药物缓释维持癌组织内抗癌药物持续高浓度的目的。在我们的前期动物实验研究发现卡铂与栓塞剂(超液化碘油)混合进行动脉栓塞化疗,癌组织内抗癌药物的AUC值明显高于同等剂量卡铂单纯动脉灌注化疗,从临床药代动力学的角度证实动脉栓塞化疗优于单纯动脉灌注化疗,并且证明超液化碘油作为栓塞剂,不仅具有栓塞作用,还具有不规则的药物缓释作用,达到减慢癌组织内抗癌药物的清除速度、保持较高抗癌药物浓度的效果。但在妇科恶性肿瘤的动脉化疗中尚无证据支持这一点。超液化碘油作为栓塞剂在肝癌的动脉栓塞化疗中已被广泛应用,并获得较好的临床疗效。但一般不建议应用于妇科恶性肿瘤的动脉栓塞化疗,因为女性盆腔动脉具有广泛的交通支,而妇科恶性肿瘤病灶内可能存在动静脉瘘,已有在妇科恶性肿瘤中应用超液化碘油导致肺栓塞甚至死亡的病例。因此我们另需寻找既有良好的栓塞效果、又具有药物缓释作用且能在妇科恶性肿瘤中安全应用的栓塞剂,以期达到延长肿瘤组织内抗癌药物持续高浓度、提高临床疗效的目的。
新鲜明胶海绵(gelatin sponge,GF)颗粒因其性能稳定、制备容易、应用简单、安全可靠、取材方便、经济实惠等优点被广泛应用于盆腔肿瘤的栓塞治疗中,但在以下方面我们还不清楚,需进一步评估:(1)新鲜GF颗粒带药栓塞化疗是否具有药物缓释作用;(2)将抗癌药物按不同比例灌注和栓塞化疗(新鲜GF颗粒与抗癌药物混合),是否会改变抗癌药物在癌组织内的吸收、分布、代谢及排泄。为阐明上述问题,我们设计了本研究课题。
【目的】
通过检测卡铂与新鲜GF颗粒不同方式、不同比例动脉化疗宫颈癌癌组织内铂浓度,获得癌组织内卡铂的临床药代动力学参数,研究各自的临床药代动力学特征,探讨新鲜GF颗粒在动脉灌注/栓塞化疗中有无药物缓释作用;规范新鲜GF颗粒在宫颈癌动脉化疗中的应用方式。
【材料与方法】
选择从2007年11月至2009年1月,就诊南方医院及合作医院符合病例入选标准的局部晚期宫颈癌且肿瘤直径≥4cm的患者27例。忠者年龄29～68岁,平均(46.15±8.47)岁。按照FIGO标准,临床分期为:ⅠB2期6例,ⅡA期7例,ⅡB期10例,ⅢA期2例,ⅢB期2例。鳞癌26例(病理分级:Ⅲ级2例,Ⅱ级10例,Ⅰ级1例,Ⅱ～Ⅲ级9例,Ⅰ～Ⅱ级4例),腺癌1例(病理分级Ⅱ级)。随机分为A、B、C三组,组间临床及病理学资料比较,差异无统计学意义(P＞0.05)。化疗药物选择卡铂400 mg/m~2一次性给药,栓塞剂为新鲜GF颗粒(直径1mm),为保证所有药物全部进入癌组织内,新鲜GF均为一块,不足者用不带药GF颗粒补充栓塞。A组为卡铂400 mg/m~2双侧子宫动脉灌注后+新鲜GF颗粒栓塞;B组为卡铂300 mg/m~2双侧子宫动脉灌注后+(卡铂100mg/m~2+新鲜GF颗粒混合)栓塞;C组为卡铂200mg/m~2双侧子宫动脉灌注后+(卡铂200mg/m~2+新鲜GF颗粒混合)栓塞。手术方法:双侧子宫动脉插管。手术时间的控制:双侧子宫动脉灌注给药时间为20分钟,灌注后取材时间为30分钟,双侧子宫动脉栓塞或栓塞化疗时间为30分钟。取材时间点:灌注后0h、0.17h(即10min)、0.33h(即20min)、0.5h(即30min)、1h(栓塞后即刻)、7h(栓塞后6h)、13h(栓塞后12h)、25h(栓塞后24h)、49h(栓塞后48h),以宫颈活检钳钳取新鲜宫颈癌组织约0.3～0.5g;清洗表面血迹、滤干后置EP管内入-20℃冰箱储存备测。
癌组织内铂浓度用无火焰石墨原子吸收光谱法测定,其检测限为5×10~(-10)g/L,精密度为:3.1-7.5%,线性范围在0.2ug/ml～4.0ug/ml。临床药代动力学参数由非房室模型软件计算获得。
统计方法:采用SPSS13.0进行统计学分析,对计量资料以(?)±s表示。数据分析:Cmax、AUC(梯形法求算)、V_d/F、MRT和CL/F采用单向方差分析;Tmax和t_(1/2)采用多个独立样本非参数检验,多重比较采用Dunnett T3检验,P＜0.05为统计学有意义。
【结果】
1.A、B、C三组癌组织内铂平均药物浓度—时间曲线特征
A、B、C三组癌组织内铂平均药物浓度曲线均为双峰曲线,第一峰值均出现在灌注化疗后即刻,随着时间的延长呈一快速下降;第二峰值出现在栓塞或栓塞化疗后即刻至栓塞后6小时,随着时间的延长呈一缓慢下降曲线。
A组第一峰值为266.96±217.23mg/kg,第二峰值为124.15±138.02mg/kg,两峰值比为2.15:1(P=0.115);B组第一峰值为192.26±129.42 mg/kg,第二峰值为131.86±87.40 mg/kg,两峰值比为1.43:1(P=0.263);C组第一峰值为131.84±116.45 mg/kg,第二峰值为301.36±335.88mg/kg,两峰值比为1:2.29(P=0.172)。
2.A、B、C三组癌组织内铂浓度的临床药代动力学参数分析
(1)药物峰浓度(peak concentration,Cmax):即指给药后单位时间内所达到的最高抗癌药物浓度(铂浓度)值。A组266.97±217.21mg/kg,B组为196.93±126.06mg/kg,C组为332.24±325.75mg/kg,三组差异无统计学意义(F=0.731,P=0.492)。从药物峰浓度的角度表明B、C两组的处理并没有显示出明显的抗癌药物缓释作用。
(2)达峰时间(peak time,Tmax):即指从给药后至峰值的时间,A组为0.00±0.00 h,B组为0.80±2.33 h,C组为0.67±0.50h。A、B两组比较,差异无统计学意义(P=0.674);A、C两组比较,差异有统计学意义(P=0.011);B、C两组比较,差异无统计学意义(P=0.997)。结果表明,C组的处理一定程度上可推迟癌组织内铂浓度的达峰时间。
(3)药—时曲线下面积AUC_((0-49h))值(area under the time-concentration,AUC):即指单位时间内卡铂被吸收进入癌组织内的总量。A组为2860.06±2215.97mg·kg~(-1)·h,B组为3776.79±4088.15mg·kg~(-1)·h,C组为4557.50±4536.70mg·kg~(-1)·h,三组差异无统计学意义(F=0.462,P=0.636)。提示卡铂总剂量相同时,被吸收进入癌组织内的量与本实验不同给药方法的关系并不密切,表明B、C两组的处理并没有影响卡铂进入癌组织内的总量。
(4)半衰期(half-life,t_(1/2)):即指消除相时铂浓度下降一半所需的时间,A组为36.94±11.17h,B组为55.01±54.73h,C组为21.17±7.53h。A、B两组比较,差异无统计学意义(P=0.250);A、C两组比较,差异无统计学意义(P=0.314);B、C两组比较,差异有统计学意义(P=0.037)。结果表明,B组的处理可延长癌组织对卡铂的清除速率。
(5)平均滞留时间(mean residence time,MRT):即指抗癌药物卡铂在癌组织内的平均驻留时间,A组为21.16±2.80h,B组为18.14±4.73h,C组17.36±2.71h,三组差异无统计学意义(F=2.874,P=0.076)。结果表明,B、C两组的处理不能延长卡铂在癌组织内的作用时间。
(6)清除率(clearance,CL/F):即指在单位时间内,从癌组织内清除的卡铂的表观分布容积数,A组为0.19±0.14kg·m~(-2)·h~(-1),B组为0.25±0.23kg·m~(-2)·h~(-1),C组0.18±0.17kg·m~(-2)·h~(-1),三组差异无统计学差异(F=0.377,P=0.690)。结果表明,B组、C组的处理方式不能改变癌组织对卡铂的清除速率及代谢过程。
(7)表观分布容积(apparent volume of distribution,V_d/F):即指卡铂在癌组织内分布达到动态平衡时,癌组织内药量与铂浓度相互关系的一个比例常数,反映卡铂在癌组织内分布的广度和深度,同时也反映了癌组织与卡铂结合的能力。A组为9.94±7.40kg·m~(-2),B组为8.55±4.45kg·m~(-2),C组5.79±5.99kg·m~(-2),三组差异无统计学意义(F=1.090,P=0.352)。结果表明,经B、C两组处理后,卡铂在癌组织内分布的广度和深度以及癌组织与卡铂结合的能力没有显著改变。
参考经典的药物缓释剂的临床药代动力学特征及以往带药微球缓释剂动脉栓塞化疗中临床药代动力学参数特征:Cmax降低,Tmax延长,AUC值升高,MRT延长,t_(1/2)延长,CL减慢。综合分析本实验相关临床药代动力学参数:(1)与A、B两组的Tmax相比,C组在一定程度上虽能延迟癌组织内铂浓度的达峰时间,但三组Cmax数值上的差异无统计学意义,说明B、C两组的处理方式不能延缓癌组织对卡铂的吸收速度,即新鲜GF颗粒不具有药物缓释作用。(2)三组AUCJ_((0-49h))值差异无统计学意义,说明B、C两组的处理不能延缓卡铂在癌组织内的释放及增加癌组织对卡铂的吸收量,表明新鲜GF颗粒不具有药物缓释作用。(3)t_(1/2)、MRI及CL/F均反映卡铂在癌组织内消除的过程,三组间差异均无统计学意义,说明B、C两组处理方式并没有延缓卡铂在癌组织内的清除速度及代谢过程,即新鲜GF颗粒不具有药物缓释作用。(4)三组V_d/F差异无统计学意义,说明B、C两组处理没有改变卡铂在癌组织内的分布广度和深度,V_d/F虽不能直接反映新鲜GF颗粒与卡铂混合后是否具有药物缓释作用,但提示B、C两组的处理并没有改变卡铂的生物学特性。由此得出:新鲜GF颗粒不具有药物缓释作用。
【结论】
本实验从临床药代动力学的角度揭示了在卡铂常规剂量下(400mg/m~2),新鲜GF颗粒在宫颈癌的动脉灌注/栓塞化疗中不具有药物缓释作用,仅具有单纯的栓塞作用。因此在宫颈癌动脉化疗中,新鲜GF颗粒的应用以灌注抗癌药物后即刻单纯栓塞为最合适。
【Background】
With the concept of neoadjuvant chemotherapy(NACT),further researches on the role of chemotherapy in cervical cancer had been done by domestic and foreign scholars.The status of chemotherapy in treatment of cervical cancer had been identified.It is confirmed that both preoperative intravenous chemotherapy and transarterial chemotherapy had a down-staging effect to the locally advanced cervical cancer(LACC) to improve the tumor resection rate and the quality of life of the patients.In both basic researches and clinical practices,plenty of studies have confirmed that the intra-arterial chemotherapy which can provide a wider space for subsequent treatment is more effective than the intravenous chemotherapy.But there are still some ineffective cases which propose us to pay more attention to enhance the efficiency of transarterial chemotherapy.In the previous studies we confirmed that the peak value and area under the time-concentration curve(AUC) of anticancer drugs after transarterial chemotherapy were significantly higher than that of intravenous chemotherapy in tumor tissue.But the elevating of concentration of anticancer drugs is transient after the infusion chemotherapy and then decreased quickly.Because the retention of anticancer drugs in tissues is short and it clears quickly and then enter into the blood circulation,therefore the anticancer drugs and tumor cells can not contact with each other fully and thus limits the efficiency.So figuring out a method to prolong the retention of high concentration of anticancer drugs in tumor tissue is an effective way to improve the efficiency of transarterial chemotherapy.
When compared with the intravenous chemotherapy,there was another advantage of the emboliszation of target vessel by intra-arteries chemotherapy.Therefore,the transarterial infusion chemotherapy and transcatheter arterial embolization were used together in clinical.On the one hand,embolization could interrupt the tumor blood stream,so the tumor cells may necrosis more.On the other hand,we hope that the anticancer drugs in embolization agent shows a the sustained-release effect in tumor tissue.In our previous animal experiments,we found that in the transarterial chemoembolization(TACE) group with the mixture of carboplatin and lipiodol with the same dosage,both peak concentration and the AUC of platinum in tumor tissue are higher than those of simply transcatheter arterial chemotherapy(TALC) group with platinum.We confirmed that lipiodol plays not only the role of embolization but also as a drug carrier,which can delay the clearance of carboplatin in tumor tissue and maintain a high concentration of drugs.But we also proved that the peak concentration in cancer tissues in TACE group was lower than that of TAC group.So the combination of arterial perfusion and arterial embolization is possibly a theoretical way to prolong the retention of anti-cancer drugs in cancer tissues and may have an effect of improving the efficiency of transarterial chemotherapy.But it is uncertain in transarterial chemotherapy of pelvic tumors.The embolization agent,lipiodol is widely used in transarterial chemoembolization of liver cancer and has a good effect in clinical work.But it is not recommended for gynecologic cancers because there are many communications in pelvic arteries and arteriovenous fistula may exist in malignance tumors.It has been reported that it could cause pulmonary embolism and lead to death.In order to improve clinical efficiency and safety,we have to find a novel agent which own good sustained-releasing effect and good safety.
Gelfoam(GF) has been widely used in embolization therapy of gynecologic malignancy because of its stable composition,easy preparation,simple utilization, safety,and economic benefit.But for the following two points,we are still not for sure: (1) whether GF has drug sustained-release effect;(2)whether the effect of killing cancer cells could be changed if we change the concentration of anticancer drugs in cancer tissues by combining the perfusion with chemoembolization(mixed the GF particle with drugs) with different proportion.In order to clarify the above issues we designed the current study.
【Objective】
The current study was designed to compare the pharmacokinetics of platinum between the embolization after transcatheter arterial chemotherapy and transarterial chemoembolization and then evaluate the sustained-release effect of gelfoam particles of the intra-arterial chemotherapy in cervical cancer.
【Material and Methods】
Twenty-seven patients of locally advanced cervical cancer had been selected(6 stageⅠB2,7 stageⅡA,10 stageⅡB,2 stageⅢA,2 stageⅢB).The patients' ages ranged from 29 to 68 years.Among those patients,26 were squamous cell carcinomas, 1 case was adenocarcinoma,which were all confirmed by pathological test.They were randomized into three groups.Patients in group A were administered with Carboplatin at the dosage of 400 mg/m~2 by infusing,and then embolized with gelfoam particles (1mm in diameter).Patients in group B were administered with Carboplatin at the dosage of 300 mg/m~2 by infusing,and then embolized with the mixture of carboplatin at the dosage of 100 mg/m~2 and gelfoam particles(1mm in diameter).Patients in group C were administered with Carboplatin at the dosage of 200 mg/m~2 by infusing, and then embolized with the mixture of carboplatin at the dosage of 200 mg/m~2 and gelfoam particles(1mm in diameter).Samples from the cervical cancer lesions were collected at different times after infusion in three groups and then analyzed by using graphite-furnace Zeeman atomic absorption spectrometry.
Statistics:The analyses were performed using the software SPSS 13.0.Mean and SD of platinum concentrations in tumor tissue was calculated,and the One-Way ANOVA or K Independent Samples Test was used to statistically assess intergroup differences.Differences among groups were then determined with a Dunnett'T3 test. The level of significance was set at P＜0.05.The pharmacokinetics parameters analysis were conducted by the noncompartment method(Model:Plasma data,BolusⅣAdministration;pharmacokinetics and bioavailability Program Package,Ⅴ2.1).
【Results】
1.The characteristics of the concentration-time curve of platinum in tumor tissue in three groups.
The concentration-time curve of platinum in tumor tissue in three groups was of noncompartmental model.The peak value concentration of platinum in tumor tissues of the three groups were observed immediately after infusion,and then descended quickly.Another peak value of concentration of platinum in tumor tissue of three groups was observed between immediately and 6 hours after embolization and descended slowly.
In group A,the first peak value was 266.96±217.23 mg/kg,the second peak value was 124.15±138.02 mg/kg,the ratio between the two values was 2.15:1 (P=0.115);In group B,the first peak value was 192.26±129.42 mg/kg,the second peak value was 131.86±87.40 mg/kg,the ratio between the two value was 1.43:1 (P=0.263);In group C,the first peak value was 131.84±116.45 mg/kg,the second peak value was 301.36±335.88 mg/kg,the ratio between the two value was 1:2.29 (P=0.172).
2.The comparison of the pharmacokinetic parameters of carboplatin in tumor tissue among the three groups.
(1) Peak concentration of platinum:The peak concentration of platinum was 266.97±217.21 mg/kg in group A,it was 196.93±126.06 mg/kg in group B and in group C it was 332.24±325.75 mg/kg.There was no significant difference among three groups.The result maybe indicate that the GF had not the effect of sustained-release.
(2)Peak time:It was 0.00±0.00 h in group A,in group B it was 0.80±2.33 h,and it was 0.67±0.50 h in group C。There was a significant difference between the group A and C(P=0.011),no significant difference was detected in other groups.
(3)Area under the time-concentration,AUC:The AUC represents the total dosage absorbed by tissue after one administration at a certain dose at unit time.In group A,it was 2860.06±2215.97 mg·kg~(-1)·h,it was 3776.79±4088.15 mg·kg~(-1)·h in group B,and in group C it was 4557.50±4536.70 mg·kg~(-1)·h.There was no significant difference among the three groups(P=0.636).
(4)Half-life:It was 36.94±11.17 h in group A,in group B it was 55.01±54.73 h, and in group C it was 21.17±7.53h.The significant difference was detected between the group B and C(P=0.037).No significant difference was observed in other two groups.
(5) Mean residence time,MRT:It was 21.16±2.80 h in group A,in group B it was 18.14±4.73 h,and it was 17.36±2.71 h in group C.There was no significant difference among three groups(P=0.076).
(6) Clearance,CL/F..It was 0.19±0.14 kg·m~(-2)·h~(-1) in group A,in group B it was 0.25±0.23 kg·m~(-2)·h~(-1),and it was 0.18±0.17 kg·m~(-2)·h~(-1) in group C.No difference was detected among the three groups(P=0.690).
(7) Apparent volume of distribution,V_d/F:It was 9.94±7.40 kg·m~(-2) in group A, in the group B it was 8.55±4.45 kg·m~(-2),and it was 5.79±5.99 kg·m~(-2) in group C. There was no significant difference among three groups(P=0.352).
It was observed that there was no significant difference of Cmax,AUC_((0-49h)), MRT,CL/F and V_d/F among the three groups.There was a statistical difference of the peak time(Tmax) between group A and C(P=0.011),which means the treatment in group C could delay the peak time of concentration of carboplatin in tumor tissue comparing to group A.But there was no statistically significant difference between group B and C(P=0.997).There was a statistical difference of the half-life(t_(1/2)) between group B and C(P=0.037),but for the reason for this phenomenon we need further study.But there was no statistically significant difference between group A and C(P=0.314).
The results from the current study suggested that the rate of absorption and distribution of platinum in tumor tissue were almost equal among the three groups.It may suggest that the gelfoam particles have no sustained-release effect of platinum.
【Conclusion】
Gelfoam particles have no sustained-release effect of platinum on the routine dosage(400mg/m~2) in transarterial chemoembolization.It simply displayed the effect of embolism.The optimal method to use the Gelfoam particles in transarterial chemoembolization for cervical cancer is simply embolization after infusion of anticancer drugs.
随着新辅助化疗(Neoadjuvant chemotherapy,NACT)概念的提出,国内外学者对化疗在宫颈癌中的作用进行了深入研究,明确了化疗在宫颈癌中的治疗地位,证实无论是术前静脉化疗还是动脉化疗,对局部晚期宫颈癌(locally advancedcervical cancer,LACC)患者都是一个有效的降低肿瘤临床分期的方法,进而可提高手术切除率和改善患者的生存质量。无论是基础研究还是临床疗效,众多文献报道证实了术前动脉化疗较静脉化疗更为有效,能为后续治疗提供更广泛的空间;但不可否认的是仍有部分病例效果不明显,如何进一步提高动脉化疗的疗效是需要进一步研究的问题。我们的前期研究证实,动脉灌注化疗后癌组织内抗癌药物峰浓度及药—时曲线下面积值(area under the time-concentration curve,AUC)均明显高于静脉给药组,但其抗癌药物浓度升高表现为一过性,随着时间的延长而快速下降,抗癌药物在肿瘤组织中保留时间短、清除快、迅速进入全身血液循环,导致抗癌药物与肿瘤细胞不能充分接触,使其疗效受到一定限制。因此寻找可延长肿瘤组织内抗癌药物持续高浓度的方法是提高动脉化疗疗效的有效途径之一。
动脉化疗较静脉化疗相比的另一优势是可同时对靶血管进行栓塞。因此,我们在临床上常将动脉灌注化疗与动脉栓塞相结合,形成动脉灌注后栓塞或动脉栓塞化疗,其目的之一是通过栓塞剂的栓塞作用阻断肿瘤病灶内的血流,使肿瘤细胞缺血缺氧而坏死;目的之二是希望将抗癌药物混合到栓塞剂中,以期达到药物缓释维持癌组织内抗癌药物持续高浓度的目的。在我们的前期动物实验研究发现卡铂与栓塞剂(超液化碘油)混合进行动脉栓塞化疗,癌组织内抗癌药物的AUC值明显高于同等剂量卡铂单纯动脉灌注化疗,从临床药代动力学的角度证实动脉栓塞化疗优于单纯动脉灌注化疗,并且证明超液化碘油作为栓塞剂,不仅具有栓塞作用,还具有不规则的药物缓释作用,达到减慢癌组织内抗癌药物的清除速度、保持较高抗癌药物浓度的效果。但在妇科恶性肿瘤的动脉化疗中尚无证据支持这一点。超液化碘油作为栓塞剂在肝癌的动脉栓塞化疗中已被广泛应用,并获得较好的临床疗效。但一般不建议应用于妇科恶性肿瘤的动脉栓塞化疗,因为女性盆腔动脉具有广泛的交通支,而妇科恶性肿瘤病灶内可能存在动静脉瘘,已有在妇科恶性肿瘤中应用超液化碘油导致肺栓塞甚至死亡的病例。因此我们另需寻找既有良好的栓塞效果、又具有药物缓释作用且能在妇科恶性肿瘤中安全应用的栓塞剂,以期达到延长肿瘤组织内抗癌药物持续高浓度、提高临床疗效的目的。
新鲜明胶海绵(gelatin sponge,GF)颗粒因其性能稳定、制备容易、应用简单、安全可靠、取材方便、经济实惠等优点被广泛应用于盆腔肿瘤的栓塞治疗中,但在以下方面我们还不清楚,需进一步评估:(1)新鲜GF颗粒带药栓塞化疗是否具有药物缓释作用;(2)将抗癌药物按不同比例灌注和栓塞化疗(新鲜GF颗粒与抗癌药物混合),是否会改变抗癌药物在癌组织内的吸收、分布、代谢及排泄。为阐明上述问题,我们设计了本研究课题。
【目的】
通过检测卡铂与新鲜GF颗粒不同方式、不同比例动脉化疗宫颈癌癌组织内铂浓度,获得癌组织内卡铂的临床药代动力学参数,研究各自的临床药代动力学特征,探讨新鲜GF颗粒在动脉灌注/栓塞化疗中有无药物缓释作用;规范新鲜GF颗粒在宫颈癌动脉化疗中的应用方式。
【材料与方法】
选择从2007年11月至2009年1月,就诊南方医院及合作医院符合病例入选标准的局部晚期宫颈癌且肿瘤直径≥4cm的患者27例。忠者年龄29～68岁,平均(46.15±8.47)岁。按照FIGO标准,临床分期为:ⅠB2期6例,ⅡA期7例,ⅡB期10例,ⅢA期2例,ⅢB期2例。鳞癌26例(病理分级:Ⅲ级2例,Ⅱ级10例,Ⅰ级1例,Ⅱ～Ⅲ级9例,Ⅰ～Ⅱ级4例),腺癌1例(病理分级Ⅱ级)。随机分为A、B、C三组,组间临床及病理学资料比较,差异无统计学意义(P＞0.05)。化疗药物选择卡铂400 mg/m~2一次性给药,栓塞剂为新鲜GF颗粒(直径1mm),为保证所有药物全部进入癌组织内,新鲜GF均为一块,不足者用不带药GF颗粒补充栓塞。A组为卡铂400 mg/m~2双侧子宫动脉灌注后+新鲜GF颗粒栓塞;B组为卡铂300 mg/m~2双侧子宫动脉灌注后+(卡铂100mg/m~2+新鲜GF颗粒混合)栓塞;C组为卡铂200mg/m~2双侧子宫动脉灌注后+(卡铂200mg/m~2+新鲜GF颗粒混合)栓塞。手术方法:双侧子宫动脉插管。手术时间的控制:双侧子宫动脉灌注给药时间为20分钟,灌注后取材时间为30分钟,双侧子宫动脉栓塞或栓塞化疗时间为30分钟。取材时间点:灌注后0h、0.17h(即10min)、0.33h(即20min)、0.5h(即30min)、1h(栓塞后即刻)、7h(栓塞后6h)、13h(栓塞后12h)、25h(栓塞后24h)、49h(栓塞后48h),以宫颈活检钳钳取新鲜宫颈癌组织约0.3～0.5g;清洗表面血迹、滤干后置EP管内入-20℃冰箱储存备测。
癌组织内铂浓度用无火焰石墨原子吸收光谱法测定,其检测限为5×10~(-10)g/L,精密度为:3.1-7.5%,线性范围在0.2ug/ml～4.0ug/ml。临床药代动力学参数由非房室模型软件计算获得。
统计方法:采用SPSS13.0进行统计学分析,对计量资料以(?)±s表示。数据分析:Cmax、AUC(梯形法求算)、V_d/F、MRT和CL/F采用单向方差分析;Tmax和t_(1/2)采用多个独立样本非参数检验,多重比较采用Dunnett T3检验,P＜0.05为统计学有意义。
【结果】
1.A、B、C三组癌组织内铂平均药物浓度—时间曲线特征
A、B、C三组癌组织内铂平均药物浓度曲线均为双峰曲线,第一峰值均出现在灌注化疗后即刻,随着时间的延长呈一快速下降;第二峰值出现在栓塞或栓塞化疗后即刻至栓塞后6小时,随着时间的延长呈一缓慢下降曲线。
A组第一峰值为266.96±217.23mg/kg,第二峰值为124.15±138.02mg/kg,两峰值比为2.15:1(P=0.115);B组第一峰值为192.26±129.42 mg/kg,第二峰值为131.86±87.40 mg/kg,两峰值比为1.43:1(P=0.263);C组第一峰值为131.84±116.45 mg/kg,第二峰值为301.36±335.88mg/kg,两峰值比为1:2.29(P=0.172)。
2.A、B、C三组癌组织内铂浓度的临床药代动力学参数分析
(1)药物峰浓度(peak concentration,Cmax):即指给药后单位时间内所达到的最高抗癌药物浓度(铂浓度)值。A组266.97±217.21mg/kg,B组为196.93±126.06mg/kg,C组为332.24±325.75mg/kg,三组差异无统计学意义(F=0.731,P=0.492)。从药物峰浓度的角度表明B、C两组的处理并没有显示出明显的抗癌药物缓释作用。
(2)达峰时间(peak time,Tmax):即指从给药后至峰值的时间,A组为0.00±0.00 h,B组为0.80±2.33 h,C组为0.67±0.50h。A、B两组比较,差异无统计学意义(P=0.674);A、C两组比较,差异有统计学意义(P=0.011);B、C两组比较,差异无统计学意义(P=0.997)。结果表明,C组的处理一定程度上可推迟癌组织内铂浓度的达峰时间。
(3)药—时曲线下面积AUC_((0-49h))值(area under the time-concentration,AUC):即指单位时间内卡铂被吸收进入癌组织内的总量。A组为2860.06±2215.97mg·kg~(-1)·h,B组为3776.79±4088.15mg·kg~(-1)·h,C组为4557.50±4536.70mg·kg~(-1)·h,三组差异无统计学意义(F=0.462,P=0.636)。提示卡铂总剂量相同时,被吸收进入癌组织内的量与本实验不同给药方法的关系并不密切,表明B、C两组的处理并没有影响卡铂进入癌组织内的总量。
(4)半衰期(half-life,t_(1/2)):即指消除相时铂浓度下降一半所需的时间,A组为36.94±11.17h,B组为55.01±54.73h,C组为21.17±7.53h。A、B两组比较,差异无统计学意义(P=0.250);A、C两组比较,差异无统计学意义(P=0.314);B、C两组比较,差异有统计学意义(P=0.037)。结果表明,B组的处理可延长癌组织对卡铂的清除速率。
(5)平均滞留时间(mean residence time,MRT):即指抗癌药物卡铂在癌组织内的平均驻留时间,A组为21.16±2.80h,B组为18.14±4.73h,C组17.36±2.71h,三组差异无统计学意义(F=2.874,P=0.076)。结果表明,B、C两组的处理不能延长卡铂在癌组织内的作用时间。
(6)清除率(clearance,CL/F):即指在单位时间内,从癌组织内清除的卡铂的表观分布容积数,A组为0.19±0.14kg·m~(-2)·h~(-1),B组为0.25±0.23kg·m~(-2)·h~(-1),C组0.18±0.17kg·m~(-2)·h~(-1),三组差异无统计学差异(F=0.377,P=0.690)。结果表明,B组、C组的处理方式不能改变癌组织对卡铂的清除速率及代谢过程。
(7)表观分布容积(apparent volume of distribution,V_d/F):即指卡铂在癌组织内分布达到动态平衡时,癌组织内药量与铂浓度相互关系的一个比例常数,反映卡铂在癌组织内分布的广度和深度,同时也反映了癌组织与卡铂结合的能力。A组为9.94±7.40kg·m~(-2),B组为8.55±4.45kg·m~(-2),C组5.79±5.99kg·m~(-2),三组差异无统计学意义(F=1.090,P=0.352)。结果表明,经B、C两组处理后,卡铂在癌组织内分布的广度和深度以及癌组织与卡铂结合的能力没有显著改变。
参考经典的药物缓释剂的临床药代动力学特征及以往带药微球缓释剂动脉栓塞化疗中临床药代动力学参数特征:Cmax降低,Tmax延长,AUC值升高,MRT延长,t_(1/2)延长,CL减慢。综合分析本实验相关临床药代动力学参数:(1)与A、B两组的Tmax相比,C组在一定程度上虽能延迟癌组织内铂浓度的达峰时间,但三组Cmax数值上的差异无统计学意义,说明B、C两组的处理方式不能延缓癌组织对卡铂的吸收速度,即新鲜GF颗粒不具有药物缓释作用。(2)三组AUCJ_((0-49h))值差异无统计学意义,说明B、C两组的处理不能延缓卡铂在癌组织内的释放及增加癌组织对卡铂的吸收量,表明新鲜GF颗粒不具有药物缓释作用。(3)t_(1/2)、MRI及CL/F均反映卡铂在癌组织内消除的过程,三组间差异均无统计学意义,说明B、C两组处理方式并没有延缓卡铂在癌组织内的清除速度及代谢过程,即新鲜GF颗粒不具有药物缓释作用。(4)三组V_d/F差异无统计学意义,说明B、C两组处理没有改变卡铂在癌组织内的分布广度和深度,V_d/F虽不能直接反映新鲜GF颗粒与卡铂混合后是否具有药物缓释作用,但提示B、C两组的处理并没有改变卡铂的生物学特性。由此得出:新鲜GF颗粒不具有药物缓释作用。
【结论】
本实验从临床药代动力学的角度揭示了在卡铂常规剂量下(400mg/m~2),新鲜GF颗粒在宫颈癌的动脉灌注/栓塞化疗中不具有药物缓释作用,仅具有单纯的栓塞作用。因此在宫颈癌动脉化疗中,新鲜GF颗粒的应用以灌注抗癌药物后即刻单纯栓塞为最合适。
【Background】
With the concept of neoadjuvant chemotherapy(NACT),further researches on the role of chemotherapy in cervical cancer had been done by domestic and foreign scholars.The status of chemotherapy in treatment of cervical cancer had been identified.It is confirmed that both preoperative intravenous chemotherapy and transarterial chemotherapy had a down-staging effect to the locally advanced cervical cancer(LACC) to improve the tumor resection rate and the quality of life of the patients.In both basic researches and clinical practices,plenty of studies have confirmed that the intra-arterial chemotherapy which can provide a wider space for subsequent treatment is more effective than the intravenous chemotherapy.But there are still some ineffective cases which propose us to pay more attention to enhance the efficiency of transarterial chemotherapy.In the previous studies we confirmed that the peak value and area under the time-concentration curve(AUC) of anticancer drugs after transarterial chemotherapy were significantly higher than that of intravenous chemotherapy in tumor tissue.But the elevating of concentration of anticancer drugs is transient after the infusion chemotherapy and then decreased quickly.Because the retention of anticancer drugs in tissues is short and it clears quickly and then enter into the blood circulation,therefore the anticancer drugs and tumor cells can not contact with each other fully and thus limits the efficiency.So figuring out a method to prolong the retention of high concentration of anticancer drugs in tumor tissue is an effective way to improve the efficiency of transarterial chemotherapy.
When compared with the intravenous chemotherapy,there was another advantage of the emboliszation of target vessel by intra-arteries chemotherapy.Therefore,the transarterial infusion chemotherapy and transcatheter arterial embolization were used together in clinical.On the one hand,embolization could interrupt the tumor blood stream,so the tumor cells may necrosis more.On the other hand,we hope that the anticancer drugs in embolization agent shows a the sustained-release effect in tumor tissue.In our previous animal experiments,we found that in the transarterial chemoembolization(TACE) group with the mixture of carboplatin and lipiodol with the same dosage,both peak concentration and the AUC of platinum in tumor tissue are higher than those of simply transcatheter arterial chemotherapy(TALC) group with platinum.We confirmed that lipiodol plays not only the role of embolization but also as a drug carrier,which can delay the clearance of carboplatin in tumor tissue and maintain a high concentration of drugs.But we also proved that the peak concentration in cancer tissues in TACE group was lower than that of TAC group.So the combination of arterial perfusion and arterial embolization is possibly a theoretical way to prolong the retention of anti-cancer drugs in cancer tissues and may have an effect of improving the efficiency of transarterial chemotherapy.But it is uncertain in transarterial chemotherapy of pelvic tumors.The embolization agent,lipiodol is widely used in transarterial chemoembolization of liver cancer and has a good effect in clinical work.But it is not recommended for gynecologic cancers because there are many communications in pelvic arteries and arteriovenous fistula may exist in malignance tumors.It has been reported that it could cause pulmonary embolism and lead to death.In order to improve clinical efficiency and safety,we have to find a novel agent which own good sustained-releasing effect and good safety.
Gelfoam(GF) has been widely used in embolization therapy of gynecologic malignancy because of its stable composition,easy preparation,simple utilization, safety,and economic benefit.But for the following two points,we are still not for sure: (1) whether GF has drug sustained-release effect;(2)whether the effect of killing cancer cells could be changed if we change the concentration of anticancer drugs in cancer tissues by combining the perfusion with chemoembolization(mixed the GF particle with drugs) with different proportion.In order to clarify the above issues we designed the current study.
【Objective】
The current study was designed to compare the pharmacokinetics of platinum between the embolization after transcatheter arterial chemotherapy and transarterial chemoembolization and then evaluate the sustained-release effect of gelfoam particles of the intra-arterial chemotherapy in cervical cancer.
【Material and Methods】
Twenty-seven patients of locally advanced cervical cancer had been selected(6 stageⅠB2,7 stageⅡA,10 stageⅡB,2 stageⅢA,2 stageⅢB).The patients' ages ranged from 29 to 68 years.Among those patients,26 were squamous cell carcinomas, 1 case was adenocarcinoma,which were all confirmed by pathological test.They were randomized into three groups.Patients in group A were administered with Carboplatin at the dosage of 400 mg/m~2 by infusing,and then embolized with gelfoam particles (1mm in diameter).Patients in group B were administered with Carboplatin at the dosage of 300 mg/m~2 by infusing,and then embolized with the mixture of carboplatin at the dosage of 100 mg/m~2 and gelfoam particles(1mm in diameter).Patients in group C were administered with Carboplatin at the dosage of 200 mg/m~2 by infusing, and then embolized with the mixture of carboplatin at the dosage of 200 mg/m~2 and gelfoam particles(1mm in diameter).Samples from the cervical cancer lesions were collected at different times after infusion in three groups and then analyzed by using graphite-furnace Zeeman atomic absorption spectrometry.
Statistics:The analyses were performed using the software SPSS 13.0.Mean and SD of platinum concentrations in tumor tissue was calculated,and the One-Way ANOVA or K Independent Samples Test was used to statistically assess intergroup differences.Differences among groups were then determined with a Dunnett'T3 test. The level of significance was set at P＜0.05.The pharmacokinetics parameters analysis were conducted by the noncompartment method(Model:Plasma data,BolusⅣAdministration;pharmacokinetics and bioavailability Program Package,Ⅴ2.1).
【Results】
1.The characteristics of the concentration-time curve of platinum in tumor tissue in three groups.
The concentration-time curve of platinum in tumor tissue in three groups was of noncompartmental model.The peak value concentration of platinum in tumor tissues of the three groups were observed immediately after infusion,and then descended quickly.Another peak value of concentration of platinum in tumor tissue of three groups was observed between immediately and 6 hours after embolization and descended slowly.
In group A,the first peak value was 266.96±217.23 mg/kg,the second peak value was 124.15±138.02 mg/kg,the ratio between the two values was 2.15:1 (P=0.115);In group B,the first peak value was 192.26±129.42 mg/kg,the second peak value was 131.86±87.40 mg/kg,the ratio between the two value was 1.43:1 (P=0.263);In group C,the first peak value was 131.84±116.45 mg/kg,the second peak value was 301.36±335.88 mg/kg,the ratio between the two value was 1:2.29 (P=0.172).
2.The comparison of the pharmacokinetic parameters of carboplatin in tumor tissue among the three groups.
(1) Peak concentration of platinum:The peak concentration of platinum was 266.97±217.21 mg/kg in group A,it was 196.93±126.06 mg/kg in group B and in group C it was 332.24±325.75 mg/kg.There was no significant difference among three groups.The result maybe indicate that the GF had not the effect of sustained-release.
(2)Peak time:It was 0.00±0.00 h in group A,in group B it was 0.80±2.33 h,and it was 0.67±0.50 h in group C。There was a significant difference between the group A and C(P=0.011),no significant difference was detected in other groups.
(3)Area under the time-concentration,AUC:The AUC represents the total dosage absorbed by tissue after one administration at a certain dose at unit time.In group A,it was 2860.06±2215.97 mg·kg~(-1)·h,it was 3776.79±4088.15 mg·kg~(-1)·h in group B,and in group C it was 4557.50±4536.70 mg·kg~(-1)·h.There was no significant difference among the three groups(P=0.636).
(4)Half-life:It was 36.94±11.17 h in group A,in group B it was 55.01±54.73 h, and in group C it was 21.17±7.53h.The significant difference was detected between the group B and C(P=0.037).No significant difference was observed in other two groups.
(5) Mean residence time,MRT:It was 21.16±2.80 h in group A,in group B it was 18.14±4.73 h,and it was 17.36±2.71 h in group C.There was no significant difference among three groups(P=0.076).
(6) Clearance,CL/F..It was 0.19±0.14 kg·m~(-2)·h~(-1) in group A,in group B it was 0.25±0.23 kg·m~(-2)·h~(-1),and it was 0.18±0.17 kg·m~(-2)·h~(-1) in group C.No difference was detected among the three groups(P=0.690).
(7) Apparent volume of distribution,V_d/F:It was 9.94±7.40 kg·m~(-2) in group A, in the group B it was 8.55±4.45 kg·m~(-2),and it was 5.79±5.99 kg·m~(-2) in group C. There was no significant difference among three groups(P=0.352).
It was observed that there was no significant difference of Cmax,AUC_((0-49h)), MRT,CL/F and V_d/F among the three groups.There was a statistical difference of the peak time(Tmax) between group A and C(P=0.011),which means the treatment in group C could delay the peak time of concentration of carboplatin in tumor tissue comparing to group A.But there was no statistically significant difference between group B and C(P=0.997).There was a statistical difference of the half-life(t_(1/2)) between group B and C(P=0.037),but for the reason for this phenomenon we need further study.But there was no statistically significant difference between group A and C(P=0.314).
The results from the current study suggested that the rate of absorption and distribution of platinum in tumor tissue were almost equal among the three groups.It may suggest that the gelfoam particles have no sustained-release effect of platinum.
【Conclusion】
Gelfoam particles have no sustained-release effect of platinum on the routine dosage(400mg/m~2) in transarterial chemoembolization.It simply displayed the effect of embolism.The optimal method to use the Gelfoam particles in transarterial chemoembolization for cervical cancer is simply embolization after infusion of anticancer drugs.
引文
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[7]陈莉婷,陈春林,刘萍等.介入治疗前后宫颈癌组织局部Fas/Fasl系统动态变化的研究[J].实用妇产科杂志,2006,22(8):472-474.
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[10]陈春林,谭道彩,梁立治.动、静脉灌注化疗子宫颈癌组织药物浓度的比较[J].中华妇产科杂志1995;30(5):298.
[11]张玉勤,葛勇前,蔡数模,等.动脉及静脉注射化疗药物的血浆及组织药物浓度变化特征[J].中华肿瘤杂志,2002,24(2):344-347.
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[13]王卫,陈春林,刘萍,等.超选择子宫动脉与外周静脉灌注化疗宫颈癌组织内铂浓度的研究[J].肿瘤治疗与预防,2008,21(4):390-393.
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[16]陈春林,孙明晖,谭道彩,等.比较卡铂盆腔动脉化疗栓塞与单纯动脉灌注化疗的动物实验研究[J].癌症,2004,23(11):1405-1408.
[17]吴鹏,朱正纲,叶正宝,等.5-氟尿嘧啶-2'-脱氧核苷经胃左动脉介入灌注后的药代动力学实验研究[J].外科理论与实践,2004,9(2):135-139.
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[19]安潇,肖湘生.基于微透析技术的支气管动脉灌注卡铂的药物代谢动力学研究[J].首都医科大学学报,2007,28(6):737-742.
[20]王良忠,李宁毅,马霖,等.氟尿嘧啶和卡铂周围静脉给药与舌动脉灌注栓塞后药代动力学实验研究[J].齐鲁医学杂志,2006,21(3):193-196.
[21]韩国宏,郭庆林,郭宇良,等.阿霉素不同剂型经肝动脉给药治疗肝癌的体内药动力学研究[J].癌症,1998,17(3):194-196.
[22]程宇慧,廖工铁,侯世祥,等.颈外动脉栓塞化疗用氟尿嘧啶白蛋白微球的研制[J].中国药学杂志,1993,28(8):479-481.
[23]Fujiware K,Hayakawa K,Nagata Y et al.Experimental embolization of rabbit renal arteries to compare the effects of poly Lactic acid microspheres with and without epirubicin release against intraarterial injection[J].Cardiovas Intervent Radiol,2000,23:218-223.
[24]于开涛,封兴华.介入栓塞用微球制剂的应用和研究进展[J].介入放射学杂 志,2002,11(2):132-134.
[25]关良,张纪,刘晔,张水英,张薇.顺铂缓释剂瘤内治疗大鼠C6胶质瘤实验观察[J].中华神经外科杂志,2000,16(2):91-93.
[26]Lewis AL,Gonzalez MV,Lloyd AW,et al,DC Bead:invitro characterization of a drug-delivery device for transarterial chemoembolization[J].J Vasc Interv Radiol,2006,17:335-342.
[27]Maurizio G,Claudio V,Pietro Q,et al.Transarterial Chemoembolization for Hepatocellular Carcinoma with Drug-Elutiong Microspheres:Preliminary Results from an Italian Multicentre Study[J].Cardiovasc Intervent Radiol,2008,31:1141-1149.
[28]王新霞,龚纯贵,赵卫红,等.微球在肝肿瘤介入治疗中的应用[J].药学实践杂志,2008,26(4):245-248.
[29]陈春林,刘萍,主编.妇产科放射介入治疗学[M].北京,2003,78-104.
[30]李麟荪,李彦豪,张金山,等.临床介入治疗学[M].第1版:南京:江苏科学技术出版社,1994,157-891.
[31]李向东,刘增荣,董毅,等.支气管动脉栓塞治疗大咯血的临床应用[J].现代医用影像学,2006,15(1):39-40.
[32]王建华,王小林,颜志平.腹部介入放射学.上海医科大学出版社,1998:180-183.
[33]Greenwood LH,Glickman MG;Schwartz PE,et al.Obstetric and nonmalignant gynecologic bleeding:treatment with angiographic embolization[J].Radiology 1987,164:155-159.
[34]Stancato-Pasik A,Katz R,Mitty HA,et al.Uterine artery embolization of myomas:preliminary results of gelatin sponge pledgets as the embolic agent[J].Min Invas Tber Allied Technol,1999,8:393-396.
[35]Jerry.Pharmacologic rationale for regional drug delivery[J].J Clinical Oncology,1984;2:498.
[36]Rose PG.Locally advanced cervical cancer[J].Curr Opin Obstet Gynecol,2001,13(1):65-70.
[37]魏毅利,方建玲.局部晚期宫颈癌综合治疗方法探讨[J].实用肿瘤学杂 志,2008,22(3):224-228.
[38]Frei E 3 rd.Clinical cancer research:an embattled species[J].Cancer,1982,50:1979-1992.
[39]李金枝,杨兴升,赵俊红.宫颈癌新辅助化疗的Meta分析[J].国际妇产科学杂志,2008,35(5):379-383.
[40]Benedetti-Panici P,Greggi S,Colombo A,et al.Neoadjuvant chemotherapy and radical surgery versus exclusive radiotherapy in locally advanced squamous cell cervical cancer:results from the Italian multicenter randomized study[J].J Clin Oncol,2002;20:179-188.
[41]Ki KD,Song DH,Tong SY,et al.Neoadjuvant chemotherapy in bulky stage ⅠB-ⅡA cervical cancer:results of a quick course with vincristine,bleomycin,and cisplatin[J].Gynecol Cancer.2009,19(1):50-53.
[42]董杰,董长江.Ⅱb-Ⅲb期宫颈癌术前介入联合手术治疗及其临床意义[J].现代肿瘤医学,2004,12:41-42.
[43]赵月霞,韩东亮,刘峰.晚期宫颈癌放疗配合动脉栓塞化疗的应用[J].实用妇产科杂志,2008,24(7):431-433.
[44]Stewart DJ,Mikhael NZ,Nair RC,et al.Platinum concentrations in human autopsy tumor samples[J].Am J Clin Oncol.1988 Apr;11(2):152-158.
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