目的:由于全身毒性和血脑屏障(BBB)通透性的限制,全身治疗胶质母细胞瘤(GBM)的疗效仍然有限。颞顶筋膜瓣(TPFFs)和血管化的颅周皮瓣(PCF)不受血脑屏障(BBB)的限制,因为它们的血管供应来自颈外动脉的分支。血管化TPFF或PCF沿着GBM切除腔的转位可将不受BBB限制的自体组织带到肿瘤床微环境附近。允许由外部循环供给的血管通道向内生长,并提供一种绕过血脑屏障的机制。此外,血管化皮瓣中的循环免疫细胞可以更好地接触肿瘤微环境中的肿瘤相关抗原(TAA)。我们进行了一项首次人体I期试验,评估了新诊断的GBM患者的自体TPFF/PCF内衬切除腔的安全性。
方法:12名患者接受了安全,新诊断GBM的最大手术切除,然后是带蒂的切除腔内衬,自体TPFF或PCF。通过监测不良事件评估安全性。疗效的次要分析被检查为经历无进展疾病(PFS)的患者比例,如神经肿瘤学(RANO)标准和总生存期(OS)中的反应评估所指示的。该研究能够根据这些早期结果确定是否需要进行II期研究。对于这个分析,在最后一次随访时仍存活且未进展的受试者被视为审查,在最后一次随访时仍存活的所有存活患者被视为总生存期审查.为简单起见,我们假设6个月时70%的PFS率被认为是一个令人鼓舞的反应,并为进一步调查该手术提供了依据.
结果:纳入患者的中位年龄为57岁(范围46-69岁)。所有患者均为异柠檬酸脱氢酶(IDH)野生型。平均肿瘤体积为56.6cm3(范围14-145cm3)。在所有患者中,所有增强疾病的切除均被视为总切除(GTR)。3例患者出现III级或以上不良事件。术后即刻未发生IV级或V级严重不良事件,包括癫痫发作。感染,中风,或者肿瘤沿着皮瓣生长。仅在4例(33%)患者中发现了原始肿瘤部位的疾病进展(中位数为23个月,范围8-25个月),其中3人接受了再次手术。在重复手术中对那些植入的皮瓣和肿瘤床活检的组织病理学分析显示,移植的皮瓣内有强大的免疫浸润。重要的是,没有患者表现出肿瘤浸润到植入的皮瓣中的证据。在这份手稿准备的时候,只有4/12(33%)的患者死亡。基于上述统计学考虑,并且包括所有12名患者10/12(83.3%)具有6个月PFS。中位PFS为9.10个月,OS为17.6个月。4/12(33%)的患者存活超过两年,我们目前存活时间最长的患者存活时间为60个月。
结论:这项初步研究表明,沿着GBM切除腔插入带蒂自体TPFF/PCF是安全可行的。基于6个月PFS和OS的令人鼓舞的响应率,有必要进行更大的第二阶段研究来评估和重现安全性,可行性,和功效。前瞻性注册试验的试验注册编号和注册日期:ClinicalTrials.govIDNCT03630289,日期:08/02/2018。
OBJECTIVE: The efficacy of systemic therapies for glioblastoma (GBM) remains limited due to the constraints of systemic toxicity and blood-brain barrier (BBB) permeability. Temporoparietal fascial flaps (TPFFs) and vascularized peri cranial flaps (PCF) are not restricted by the blood-brain barrier (BBB), as they derive their vascular supply from branches of the external carotid artery. Transposition of a vascularized TPFF or PCF along a GBM resection cavity may bring autologous tissue not restricted by the BBB in close vicinity to the tumor bed microenvironment, permit ingrowth of vascular channels fed by the external circulation, and offer a mechanism of bypassing the BBB. In addition, circulating immune cells in the vascularized flap may have better access to tumor-associated antigens (TAA) within the tumor microenvironment. We conducted a first-in-human Phase I
trial assessing the safety of lining the resection cavity with autologous TPFF/PCF of newly diagnosed patients with GBM.
METHODS: 12 patients underwent safe, maximal surgical resection of newly diagnosed GBMs, followed by lining of the resection cavity with a pedicled, autologous TPFF or PCF. Safety was assessed by monitoring adverse events. Secondary analysis of efficacy was examined as the proportion of patients experiencing progression-free disease (PFS) as indicated by response assessment in neuro-oncology (RANO) criteria and overall survival (OS). The
study was powered to determine whether a Phase II
study was warranted based on these early results. For this analysis, subjects who were alive and had not progressed as of the date of the last follow-up were considered censored and all living patients who were alive as of the date of last follow-up were considered censored for overall survival. For simplicity, we assumed that a 70% PFS rate at 6 months would be considered an encouraging response and would make an argument for further investigation of the procedure.
RESULTS: Median age of included patients was 57 years (range 46-69 years). All patients were Isocitrate dehydrogenase (IDH) wildtype. Average tumor volume was 56.6 cm3 (range 14-145 cm3). Resection was qualified as gross total resection (GTR) of all of the enhancing diseases in all patients. Grade III or above adverse events were encountered in 3 patients. No Grade IV or V serious adverse events occurred in the immediate post-operative period including seizure, infection, stroke, or tumor growing along the flap. Disease progression at the site of the original tumor was identified in only 4 (33%) patients (median 23 months, range 8-25 months), 3 of whom underwent re-operation. Histopathological analyses of those implanted flaps and tumor bed biopsy at repeat surgery demonstrated robust immune infiltrates within the transplanted flap. Importantly, no patient demonstrated evidence of tumor infiltration into the implanted flap. At the time of this manuscript preparation, only 4/12 (33%) of patients have died. Based on the statistical considerations above and including all 12 patients 10/12 (83.3%) had 6-month PFS. The median PFS was 9.10 months, and the OS was 17.6 months. 4/12 (33%) of patients have been alive for more than two years and our longest surviving patient currently is alive at 60 months.
CONCLUSIONS: This pilot
study suggests that insertion of pedicled autologous TPFF/PCF along a GBM resection cavity is safe and feasible. Based on the encouraging response rate in 6-month PFS and OS, larger phase II studies are warranted to assess and reproduce safety, feasibility, and efficacy.
TRIAL REGISTRATION NUMBER AND DATE OF REGISTRATION FOR PROSPECTIVELY REGISTERED TRIALS: ClinicalTrials.gov ID NCT03630289, dated: 08/02/2018.