Opitz Isabelle, Lauk Olivia, Meerang Mayura, Jetter Alexander, Aeschlimann Beat, Seifert Burkhardt, Günther Detlef, Stahel Rolf A, Weder Walter
Department of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland.
Department of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland.
J Thorac Cardiovasc Surg. 2020 Jan;159(1):330-340.e4. doi: 10.1016/j.jtcvs.2019.07.073. Epub 2019 Aug 22.
Intracavitary chemotherapy is a promising concept to improve local tumor control for malignant pleural mesothelioma with reported high morbidity rates. We have demonstrated that administration of cisplatin loaded to fibrin increased local drug concentration and reduced systemic toxicity in preclinical models. We present a phase I trial of intracavitary cisplatin-fibrin after surgical tumor resection.
A total of 12 patients (75% International Mesothelioma Interest Group stage III-IV) were treated with 4 dose levels of intracavitary cisplatin-fibrin (11-44 mg/m body surface area) in a dose-escalating design. Cisplatin-fibrin was sprayed on the resected surfaces after pleurectomy/decortication. Blood and tissue samples were taken to assess toxicity and pharmacokinetics. Patients were regularly followed up.
No dose-limiting toxicity was observed. Major morbidity occurred in 4 patients (33%). The 30-day and 90-day mortality were both 0%. Of 80 adverse events, 9 were classified serious, but none of these were related to study treatment. Local cisplatin concentration in the chest wall tissue was high at all dose levels (median, 46.3 μg/g [12-133 μg/g]). In serum, median cisplatin area under the concentration time curve values were always below renal toxicity levels. The median overall survival with 95% confidence interval was 21 months (10-31 months). In 1 patient with epithelioid malignant pleural mesothelioma (International Mesothelioma Interest Group stage I), there was no sign of relapse 48 months after treatment (44 mg/m body surface area).
The administration of intracavitary cisplatin-fibrin is safe with favorable pharmacokinetics. Although most patients had advanced disease, long-term outcomes are comparable to other multimodal concepts. A confirmation phase II trial is ongoing.
腔内化疗是一种有望改善恶性胸膜间皮瘤局部肿瘤控制的方法，但报道的发病率较高。我们已经证明，在临床前模型中，负载顺铂的纤维蛋白给药可提高局部药物浓度并降低全身毒性。我们开展了一项肿瘤切除术后腔内注射顺铂 - 纤维蛋白的I期试验。
采用剂量递增设计，共12例患者（75%为国际间皮瘤兴趣小组III - IV期）接受了4个剂量水平的腔内顺铂 - 纤维蛋白治疗（11 - 44mg/m体表面积）。胸膜切除术/去皮质术后，将顺铂 - 纤维蛋白喷洒在切除表面。采集血液和组织样本以评估毒性和药代动力学。对患者进行定期随访。
未观察到剂量限制毒性。4例患者（33%）发生主要并发症。30天和90天死亡率均为0%。在80例不良事件中，9例被分类为严重不良事件，但均与研究治疗无关。所有剂量水平下胸壁组织中的局部顺铂浓度均较高（中位数，46.3μg/g [12 - 133μg/g]）。血清中，顺铂浓度 - 时间曲线下面积的中位数始终低于肾毒性水平。中位总生存期及95%置信区间为21个月（10 - 31个月）。1例上皮样恶性胸膜间皮瘤患者（国际间皮瘤兴趣小组I期），在接受44mg/m体表面积治疗后48个月无复发迹象。
腔内注射顺铂 - 纤维蛋白给药安全，药代动力学良好。尽管大多数患者病情已进展，但长期结果与其他多模式治疗方法相当。正在进行确认性II期试验。
