Kramer Kim, Humm John L, Souweidane Mark M, Zanzonico Pat B, Dunkel Ira J, Gerald William L, Khakoo Yasmin, Yeh Samuel D, Yeung Henry W, Finn Ronald D, Wolden Suzanne L, Larson Steven M, Cheung Nai-Kong V
Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
J Clin Oncol. 2007 Dec 1;25(34):5465-70. doi: 10.1200/JCO.2007.11.1807.
Tumors metastasizing to the CNS and leptomeninges (LM) are associated with significant mortality. We tested the toxicity, pharmacokinetics, and dosimetry of intraventricular iodine-131-labeled monoclonal antibody 3F8 (131I-3F8) targeting GD2-positive CNS/LM disease in a phase I clinical trial.
Adequate CSF flow was determined by pretreatment indium-111-DTPA studies. Fifteen patients received a tracer (1 to 2 mCi) and therapeutic injection (10 to 20 mCi) of intra-Ommaya 131I-3F8. 131I-3F8 pharmacokinetics were studied by serial CSF and blood samplings. Dosimetry was based on pharmacokinetics and region of interest (ROI) analyses on whole-body gamma camera scans. Tumor response was determined by clinical, radiographic, and cytologic criteria.
Total absorbed CSF dose was 1.12 to 13.00 Gy by sampling and 1.00 to 13.70 Gy by ROI data. Average dosimetry ratio (Gy/mCi) of the therapy/tracer administration was 0.88 (+/- 0.58) and 1.08 (+/- 0.66) based on CSF pharmacokinetics and ROI analysis, respectively. CSF half-life by sampling was 3 to 12.9 hours. Toxicities included self-limited headache, fever, and vomiting. Dose-limiting toxicity was reached at the 20-mCi dose, when transient elevations in intracranial pressure and chemical meningitis were seen. Three of 13 assessable patients achieved objective radiographic and/or cytologic responses. No late toxicities have been seen in two patients who remain in remission off therapy for more than 3.5 years.
Intra-Ommaya 131I-3F8 was generally well tolerated; the maximum-tolerated dose was 10 mCi. A high CSF-to-blood ratio was achieved. Tracer studies reliably predicted the therapeutic dose to the CSF. Radioimmunoconjugates targeting GD2 may have clinical utility in the treatment of CNS/LM malignancies.
转移至中枢神经系统（CNS）和软脑膜（LM）的肿瘤与显著的死亡率相关。我们在一项I期临床试验中测试了脑室内注射碘-131标记的单克隆抗体3F8（131I-3F8）靶向GD2阳性CNS/LM疾病的毒性、药代动力学和剂量学。
通过预处理铟-111-二乙三胺五乙酸（DTPA）研究确定脑脊液（CSF）流动是否充足。15名患者接受了脑室内奥马亚（Ommaya）131I-3F8的示踪剂注射（1至2毫居里）和治疗性注射（10至20毫居里）。通过连续的CSF和血液采样研究131I-3F8的药代动力学。剂量学基于药代动力学和全身γ相机扫描的感兴趣区域（ROI）分析。根据临床、影像学和细胞学标准确定肿瘤反应。
通过采样，CSF的总吸收剂量为1.12至13.00戈瑞（Gy），通过ROI数据为1.00至13.70 Gy。基于CSF药代动力学和ROI分析，治疗/示踪剂给药的平均剂量学比率（Gy/毫居里）分别为0.88（±0.58）和1.08（±0.66）。通过采样得到的CSF半衰期为3至12.9小时。毒性包括自限性头痛、发热和呕吐。在20毫居里剂量时达到剂量限制性毒性，此时出现颅内压短暂升高和化学性脑膜炎。13名可评估患者中有3名达到了客观的影像学和/或细胞学反应。两名已缓解且停止治疗超过3.5年的患者未出现晚期毒性。
脑室内注射131I-3F8总体耐受性良好；最大耐受剂量为10毫居里。实现了高CSF与血液比率。示踪剂研究可靠地预测了CSF的治疗剂量。靶向GD2的放射免疫缀合物在治疗CNS/LM恶性肿瘤中可能具有临床应用价值。
