Phase I clinical trial of lobaplatin combined with image-guided volume-modulated arc radiation therapy in locally advanced cervical cancer

Background: We aimed to determine the maximum tolerable dose (MTD) and dose-limiting toxicity (DLT) of weekly lobaplatin combined with concurrent radiotherapy using image-guided volumetric modulated arc therapy (VMAT), and brachytherapy in locally advanced cervical cancer (LACC) patients. Methods: Patients with clinical stage IB3-IVA cervical cancer were enrolled and received image-guided volume-modulated arc radiation therapy and brachytherapy combined with concurrent weekly lobaplatin following a standard 3+3 dose escalation design. Patients received 45 Gy in 25 fractions to the pelvis and 60 Gy in 25 fractions to the involved pelvic and para-aortic lymph nodes. High-dose-rate intracavitary brachytherapy was conducted weekly during the 4th or 5th week of radiation at a dose of 28 Gy in 4 fractions. The starting weekly dose of lobaplatin 8 mg/m2, which was subsequently successively increased by 2 mg/m2 for a total of 5 levels. The primary endpoints were the MTD and DLT of weekly lobaplatin. DLTs were defined as follows: 1) grade 4 hematologic toxicity, febrile neutropenia, or grade 3 or higher thrombocytopenia with bleeding; 2) grade 3 or higher nonhematologic toxicity (except nausea, vomiting, or alopecia); and 3) less than 3 cycles of lobaplatin due to treatment-related toxicity. This study is registered with chictr.org, ChiCTR2000040113, and is now complete. Findings: Between December 30 and October 19, 21 patients were enrolled in this study. All patients completed image-guided volume-modulated arc radiotherapy and brachytherapy per protocol. Three patients experienced DLTs: grade 3 fatigue at 14 mg/m2, two cycles of chemotherapy at 16 mg/m2, and grade 3 fatigue at 16 mg/m2. Grade 3 hematologic toxicities were observed only at 14 mg/m2 and 16 mg/m2, with 7 patients (33.3%) having leukopenia and 1 (4.8%) having neutropenia. The only severe and dose-limiting nonhematologic toxicity was Grade 3 fatigue. The MTD of weekly lobaplatin was 14 mg/m2. Interpretation: In this phase I clinical trial, the MTD of weekly lobaplatin combined with image-guided volume-modulated arc radiation therapyand brachytherapy for LACC was found to be 14 mg/m2. Considering the hematologic and nonhematologic toxicities, we recommend a weekly dose of 12 mg/m2 of lobaplatin when combined with pelvic and/or para-aortic radiotherapy in patients with LACC. Trial Registration: This study is registered with chictr.org, ChiCTR2000040113 Funding: Clinical Trials Foundation of Peking University Cancer Hospital and Clinical Research Fund for Distinguished Young Scholars of Peking University Cancer Hospital. Declaration of Interest: We declare no competing interests. Ethical Approval: This study was reviewed and approved by the Institutional Review Board of Peking University Cancer Hospital. Written informed consent was obtained from all patients.