博莱霉素和替尼泊苷内化疗治疗脑胶质瘤的临床观察
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摘要
目的初步探讨脑胶质瘤术后经Ommaya囊瘤腔内联合应用博莱霉素及替尼泊苷化疗的安全性与疗效。
方法选取苏州大学附属第一医院神经外科在2010.9.2-2012.9.21期间手术的，具有完整病历资料和随访资料的，经术后病理检查证实为胶质瘤的9例患者，其中WHOII级的星形细胞瘤6例、WHOII级的少突胶质细胞瘤1例， WHO III级的间变性星形细胞瘤（AA）1例，WHO IV级的胶质母细胞瘤（GBM）1例，术中最大程度安全切除肿瘤后于肿瘤残腔内留置Ommaya囊，术后1-4周开始经Ommaya囊瘤腔内给药化疗，用药方案为连续4日分别给予博莱霉素（1ml:7.5mg，d1,d2）、替尼泊苷（1ml:10mg,d3,d4）。间隔21日重复为一个内化疗周期。内化疗后观察其并发症，并通过头颅CT或MRI等随访其疗效，通过美国国立癌症研究所抗癌药物急性与亚急性毒性分级标准评价其不良反应。
结果8例行6周期内化疗后放疗，1例（为GBM）行1周期内化疗后放疗，放疗结束后继续内化疗2周期。随访截止日期为2013年3月21日，随访6月-30月，中位随访18月，无死亡病例，7例稳定，内化疗结束后MRI均表现为肿瘤残腔壁线样强化，境界清楚，无明显占位效应，进一步CT或MRI随访无复发及进展迹象，正常生活。2例进展，其中1例MRI表现为出现新发病灶（约术后六月），另一例（为GBM）MRI表现为局部复发（约术后三月）。所有9例患者除1例出现Ommaya囊处局部皮肤发红皱缩（II-III级毒性反应，考虑为药物渗漏）外，均无与Ommaya囊局部给药相关的癫痫、颅内感染、颅内血肿、堵管或其它严重并发症，均无骨髓抑制、肝肾功能损害、神经毒性等全身或局部不良反应。
结论经Ommaya囊瘤腔内联合应用博莱霉素及替尼泊苷化疗治疗脑胶质瘤相对安全，其短期疗效尚可。因本组样本较少，随访时间较短，其长期疗效有待进一步的随访及大宗随机对照研究证实。
Objective Preliminary explore the safety and efficacy of bleomycin combined withteniposide(VM-26)intratumoral chemotherapy for treating glioma through an Ommayareservoir after the resction of glioma.
Methods9patients were enrolled in our group,who have operated on theneurosurgery department of the first affiliated hospital of Soochow University fromSeptember2,2010to September21,2012,with complete medical records and follow-updata and confirmed by postoperative pathological examination for glioma.6cases wereWHO grade II astrocytomas,1case was WHO grade II oligodendrogliomas,1case wasWHO grade III anaplasic astrocytomas,1case was WHO grade IVglioblastomas(GBM).All9cases placed an Ommaya reservoir in the tumor residual cavityafter maximum safe resection,1-4weeks started intratumoral chemotherapy aftersurgery.Dosage schedule were4consecutive days to deliver bleomycin(1ml:7.5mg，d1,d2)and VM-26(1ml:10mg,d3,d4), respectively.Repeat interval21days as a cycle ofintratumoral chemotherapy.The complication was observed after intratumorachemotherapy.We followed up its curative effect by head CT or MRI etc and evaluated itsadverse reactions by acute and subacute toxicity of anticancer drugs classification standardof the U.S. national cancer institute.
Results8cases received six cycles of intratumoral chemotherapy followed byradiotherapy.1case(GBM) received1cycle of intratumoral chemotherapy followed byradiotherapy,who continued to receive2cycle of intratumoral chemotherapy after the endof radiotherapy.The deadline of follow-up is March21,2013.The patients were followed up6-30months.The median follow-up time were18months.No deaths.7cases with stabledisease, after six cycles of intratumoral chemotherapy,thin line appearance and high signalintensity areas could be seen in the marginal zone of the tumor cavity on thegadolinium-enhanced T1-weighted MRI,the boundary is clear,but there was no masseffect.Further follow-up with CT or MRI showed no sign of recurrence and progress andhad a normal life.2cases with progressive disease,Of1case new lesions was observed onMRI(about6months after the operation),of1case local recurrence was observed onMRI(about3months after the operation).Except1case appeared local skin redness andshrinkage above the Ommaya reservoir(grade II-III toxicity reaction, considering for drugleakage),all9cases neither had epilepsy, intracranial infection, intracranial hematoma,blocking pipe, or other serious complications which related to the local drug deliverthrough an Ommaya reservoir,nor had systemic or local adverse reactions such asmyelosuppression,liver and kidney function damage, nerve toxicity,and so on.
Conclusion Bleomycin combined with VM-26intratumoral chemotherapy fortreating glioma through an Ommaya reservoir is a relatively safe treatment.Its short-termcurative effect is better.Because this group of samples is less, follow-up time is shorter, itslong-term effect remains to be further followed up and confirmed in large randomizedcontrolled researches.
方法选取苏州大学附属第一医院神经外科在2010.9.2-2012.9.21期间手术的，具有完整病历资料和随访资料的，经术后病理检查证实为胶质瘤的9例患者，其中WHOII级的星形细胞瘤6例、WHOII级的少突胶质细胞瘤1例， WHO III级的间变性星形细胞瘤（AA）1例，WHO IV级的胶质母细胞瘤（GBM）1例，术中最大程度安全切除肿瘤后于肿瘤残腔内留置Ommaya囊，术后1-4周开始经Ommaya囊瘤腔内给药化疗，用药方案为连续4日分别给予博莱霉素（1ml:7.5mg，d1,d2）、替尼泊苷（1ml:10mg,d3,d4）。间隔21日重复为一个内化疗周期。内化疗后观察其并发症，并通过头颅CT或MRI等随访其疗效，通过美国国立癌症研究所抗癌药物急性与亚急性毒性分级标准评价其不良反应。
结果8例行6周期内化疗后放疗，1例（为GBM）行1周期内化疗后放疗，放疗结束后继续内化疗2周期。随访截止日期为2013年3月21日，随访6月-30月，中位随访18月，无死亡病例，7例稳定，内化疗结束后MRI均表现为肿瘤残腔壁线样强化，境界清楚，无明显占位效应，进一步CT或MRI随访无复发及进展迹象，正常生活。2例进展，其中1例MRI表现为出现新发病灶（约术后六月），另一例（为GBM）MRI表现为局部复发（约术后三月）。所有9例患者除1例出现Ommaya囊处局部皮肤发红皱缩（II-III级毒性反应，考虑为药物渗漏）外，均无与Ommaya囊局部给药相关的癫痫、颅内感染、颅内血肿、堵管或其它严重并发症，均无骨髓抑制、肝肾功能损害、神经毒性等全身或局部不良反应。
结论经Ommaya囊瘤腔内联合应用博莱霉素及替尼泊苷化疗治疗脑胶质瘤相对安全，其短期疗效尚可。因本组样本较少，随访时间较短，其长期疗效有待进一步的随访及大宗随机对照研究证实。
Objective Preliminary explore the safety and efficacy of bleomycin combined withteniposide(VM-26)intratumoral chemotherapy for treating glioma through an Ommayareservoir after the resction of glioma.
Methods9patients were enrolled in our group,who have operated on theneurosurgery department of the first affiliated hospital of Soochow University fromSeptember2,2010to September21,2012,with complete medical records and follow-updata and confirmed by postoperative pathological examination for glioma.6cases wereWHO grade II astrocytomas,1case was WHO grade II oligodendrogliomas,1case wasWHO grade III anaplasic astrocytomas,1case was WHO grade IVglioblastomas(GBM).All9cases placed an Ommaya reservoir in the tumor residual cavityafter maximum safe resection,1-4weeks started intratumoral chemotherapy aftersurgery.Dosage schedule were4consecutive days to deliver bleomycin(1ml:7.5mg，d1,d2)and VM-26(1ml:10mg,d3,d4), respectively.Repeat interval21days as a cycle ofintratumoral chemotherapy.The complication was observed after intratumorachemotherapy.We followed up its curative effect by head CT or MRI etc and evaluated itsadverse reactions by acute and subacute toxicity of anticancer drugs classification standardof the U.S. national cancer institute.
Results8cases received six cycles of intratumoral chemotherapy followed byradiotherapy.1case(GBM) received1cycle of intratumoral chemotherapy followed byradiotherapy,who continued to receive2cycle of intratumoral chemotherapy after the endof radiotherapy.The deadline of follow-up is March21,2013.The patients were followed up6-30months.The median follow-up time were18months.No deaths.7cases with stabledisease, after six cycles of intratumoral chemotherapy,thin line appearance and high signalintensity areas could be seen in the marginal zone of the tumor cavity on thegadolinium-enhanced T1-weighted MRI,the boundary is clear,but there was no masseffect.Further follow-up with CT or MRI showed no sign of recurrence and progress andhad a normal life.2cases with progressive disease,Of1case new lesions was observed onMRI(about6months after the operation),of1case local recurrence was observed onMRI(about3months after the operation).Except1case appeared local skin redness andshrinkage above the Ommaya reservoir(grade II-III toxicity reaction, considering for drugleakage),all9cases neither had epilepsy, intracranial infection, intracranial hematoma,blocking pipe, or other serious complications which related to the local drug deliverthrough an Ommaya reservoir,nor had systemic or local adverse reactions such asmyelosuppression,liver and kidney function damage, nerve toxicity,and so on.
Conclusion Bleomycin combined with VM-26intratumoral chemotherapy fortreating glioma through an Ommaya reservoir is a relatively safe treatment.Its short-termcurative effect is better.Because this group of samples is less, follow-up time is shorter, itslong-term effect remains to be further followed up and confirmed in large randomizedcontrolled researches.
引文
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[13]Preeti Singh Sisodiya.PLANT DERIVED ANTICANCER AGENTS: AREVIEW.International Journal of Research and Development in Pharmacy and LifeSciences,2013,2(2):293-308.
[14]Sklansky BD, Mann-Kaplan RS, Reynolds AF Jr,et al.4'-Demethyl-epipodophyllotoxin-β-d-thenylidence-glucoside(PTG) in the treatment of malignantintracranial neoplasms.Cancer,1974,33:460–467.
[15]Kessinger A, Lemon HM, Foley JF.VM-26as a second drug in the treatment of braingliomas. Can Treat Rep,1979,63:511–512.
[16]卞伟，戴勤弼，童建等.59份人脑胶质瘤组织体外培养的药敏分析.重庆医学,2010,39（18）,2452-2455.
[17]徐荣,华咏,钟平.替尼泊苷诱导脑胶质瘤细胞凋亡的检测指标评估.中国临床神经科学,2010,18（2）,156-160.
[18]刘金龙,陈硕朗,林佳等.胶质瘤显微手术切除加术中问质化疗的临床效果.中华显微外科杂志,2003,26（2）,156-158.
[19]范益民,陈来照,王绍梁等.脑胶质瘤局部VM-26治疗的临床观察.山西医科大学学报，2002,33（3）,254-256.
[20]郑念东,熊献尧,王山等.残瘤腔间质内化疗治疗脑胶质瘤的临床研究.局部手术学杂志.2003,12（3）,212-213.
[21]全兴云.脑恶性胶质瘤术后间质内化疗联合放疗临床观察研究.世界健康文摘,2008,5(3),64-66.
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[29]孙红卫,保建基,付旭东等.博莱霉素缓释化疗在恶性脑胶质瘤中的应用.中国实用神经疾病杂志，2006,9（1）,32-33.
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[23]Tomita T: Interstitial chemotherapy for brain tumors:a review. J Neuro-Oncol,1991,10:57–74.
[24]Nakazawa S, Ohwaki K, Shimura T, Itoh Y, Yajima K. A new treatment of malignantbrain tumor-1: local injection of bleomycin (author’s transl).No ShinkeiGeka.1981,9:1487–1493.
[25]Mette Linnert,Julie Gehl.Bleomycin treatment of brain tumors: anevaluation.Anti-Cancer Drugs,2009,20(3):157-164.
[26]Patchell RA, Regine WF, Ashton P, Tibbs PA,Wilson D, Shappley D, et al.A phase Itrial of continuously infused intratumoral bleomycin for the treatment of recurrentglioblastoma multiforme. J Neurooncol,2002,60:37–42.
[27]沈剑峰,周永庆,詹仁雅等.脑胶质瘤同步内放疗和内化疗的临床研究.中华神经外科杂志，2002,18（1），44-46.
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[29]孙红卫,保建基,付旭东等.博莱霉素缓释化疗在恶性脑胶质瘤中的应用.中国实用神经疾病杂志，2006,9（1）,32-33.
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[31]Voulgaris S,Partheni M,Karamouzis M,et al.Intratumoral Doxorubicin in Patients WithMalignant Brain Gliomas.Am J Clin Oncol (CCT),2002,25(1):60–64.
[32]Itoh Y. Treatment of malignant brain tumor by locally injection ofAdriamycin. NipponIka Daigaku Zasshi,1980,47:527–37.
[33]Nakazawa S, Itoh Y, Shimura T, et al. A new treatment of malignant brain tumors.Local injection of Adriamycin. No Shinkei Geka1983;11:821–7.
[34]莫万彬，杜殆庆，罗毅.阿霉素控缓释局部化疗在颅内恶性肿瘤术中的应用.华夏医学，2006,19（1），65-66.
[35]邓航，莫万彬，罗毅等.阿霉素术中控缓释化疗及术后局部化疗在脑胶质瘤中的应用.重庆医学，2011,40（13），1302-1303.
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[42]Yung WK, Albright RE, Olson J, et al.A phase II study of temozolomide vs.procarbazine in patients with glioblastoma multiforme at first relapse. Br JCancer,2000,83:588–593.
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[44]Brem S,Tyler B,Li k,et al.Local delivery of temozolomide by biodegradable polymersis superior to oral administration in a rodent glioma model.Cancer ChemotherPharmacol,2007,60:643–650.
[45]Jun Dong,Guanghua Zhou,Dongfang Tang,et al.Local delivery of slow-releasingtemozolomide microspheres inhibits intracranial xenograft glioma growth.J CancerRes Clin Oncol.2012,138:2079–2084.
[46]Recinos VR,Tyler B,Sunshine SB, Brem H.Combination Of Local Temozolomide WithLocal BCNU:US,20110313010A1[P].2011-11-22.
[47]Recinos VR,Tyler BM,Bekelis k,et al.Combination of Intracranial Temozolomide WithIntracranial Carmustine Improves Survival When Compared With Either TreatmentAlone in a Rodent Glioma Model.Neurosurgery,2010,66:530-537.
[48]Boiardi A,Eoli M,Pozzi A,et al.Locally delivered chemotherapy and repeated surgerycan improve survival in glioblastoma patients.Ital J Neurol Sci,1999,20:43-48.
[49]付卯宏,王树凯.化疗泵植入治疗颅内恶性肿瘤临床报告.中国实用神经疾病杂志,2009,12（1）,53-55.
[50]Grafield J, Dayan AD. Postoperative intracavitary chemotherapy of malignant gliomas,preliminary study using methotrexate.J Neurosurg,1973,39:315–22.
[51]Nierenberg D, Harbaugh R, Maurer LH, et al. Continuous intratumoral infusion ofmethotrexate for recurrent glioblastoma: a pilotstudy. Neurosurgery1991;28:752–61.
[52]Bouvier G, Penn RD, Kroin JS, et al. Direct delivery of medication into a brain tumorthrough multiple chronically implanted catheters.Neurosurgery，1987，20:286–91.
[53]Boiardi A, Salmaggi A, Pozzi A, et al. Interstitial chemotherapy with mitoxantrone inrecurrent malignant glioma:preliminary data.J Neurooncol,1996,27:157–62.
[54]Boiardi A，Silvani A，Eoli M，et a1．Treatment of recurrent glioblastoma：can localdelivery of mitoxantrone improve survival.J Neurooncol，2008，88：105-113.
[55]Bakshi A，Mukherjee D，Bakshi A，et a1．gamma—Linolenic acid therapy of humangliomas[J]．Nutrition，2003，19：305．
[56]Tali Siegal.Which drug or drug delivery system can change clinical practice for braintumor therapy?.Neuro Oncology,2013,doi:10.1093/neuonc/not016.