Narsinh Kazim H, Kumar Karishma, Bankiewicz Krystof, Martin Alastair J, Berger Mitchell, Clarke Jennifer, Taylor Jennie, Bush Nancy Ann Oberheim, Molinaro Annette M, Aghi Manish, Butowski Nicholas
Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
Department of Radiology & Biomedical Imaging, San Francisco, CA, USA.
J Neurooncol. 2025 Mar;172(1):219-227. doi: 10.1007/s11060-024-04904-y. Epub 2025 Jan 6.
Irinotecan demonstrates anti-tumor efficacy in preclinical glioma models but clinical results are modest due to drug delivery limitations. Convection enhanced delivery (CED) improves drug delivery by increasing intratumoral drug concentration. Real-time magnetic resonance imaging of infusate delivery during CED may optimize tumor coverage. This phase 1 trial examines the safety and tolerability of liposomal irinotecan and gadolinium delivered via CED using real-time MRI guidance in recurrent high-grade glioma patients.
Initially, a 3 + 3 dose-escalating, single dose trial was planned with 4 cohorts based on a fixed drug dose and volume. After 9 patients, a protocol amendment allowed for variable volume and dose of the study agent based on tumor size. The amended design specified 'personalized' drug volume but fixed concentration of 20 mg/mL of liposomal irinotecan in the first cohort escalating to 40 mg/mL in the second cohort.
Eighteen patients with recurrent WHO grade 3 or 4 gliomas (diameter 1-4 cm) were treated. Based on the tumor volume, the total dose of liposomal irinotecan was 20-680 mg in a total volume of 2-17 ml. Technical challenges were overcome by real-time MRI guidance and protocol amendment. The only dose-limiting toxicity (DLT) was a grade 3 stroke. Safety and survival information is presented.
CED of liposomal irinotecan using real-time MRI in patients with recurrent high-grade glioma is feasible. Image-guidance allowed for improved placement of CED cannulas and optimal tumor coverage. Our results warrant further study with repeat CED dosing.
伊立替康在临床前胶质瘤模型中显示出抗肿瘤疗效，但由于药物递送限制，临床结果并不理想。对流增强递送（CED）通过提高肿瘤内药物浓度来改善药物递送。在CED过程中对输注液递送进行实时磁共振成像可能会优化肿瘤覆盖范围。这项1期试验研究了在复发性高级别胶质瘤患者中，使用实时MRI引导通过CED递送脂质体伊立替康和钆的安全性和耐受性。
最初，计划进行一项3+3剂量递增的单剂量试验，根据固定的药物剂量和体积分为4个队列。9名患者入组后，方案修订允许根据肿瘤大小调整研究药物的体积和剂量。修订后的设计规定了“个性化”药物体积，但第一个队列中脂质体伊立替康的浓度固定为20mg/mL，第二个队列中升至40mg/mL。
18例复发性世界卫生组织3级或4级胶质瘤（直径1-4cm）患者接受了治疗。根据肿瘤体积，脂质体伊立替康的总剂量为20-680mg，总体积为2-17ml。通过实时MRI引导和方案修订克服了技术挑战。唯一的剂量限制性毒性（DLT）是3级中风。给出了安全性和生存信息。
在复发性高级别胶质瘤患者中使用实时MRI进行脂质体伊立替康的CED是可行的。图像引导有助于改善CED套管的放置并实现最佳肿瘤覆盖。我们的结果值得进一步研究重复进行CED给药。
