Radioactive holmium loaded poly(L-lactic acid) microspheres for treatment of liver malignancies: Results of a phase I, dose escalation study in patients the HEPAR trial

Aim: Holmium-166 poly(L-lactic acid) microspheres (166Ho-PLLA-MS) have been developed in our Institute for multimodality image-guided radioembolisation of liver malignancy. Dosimetry may be performed with both SPECT and MRI (1), thereby allowing individualised .treatment. The holmium microspheres were investigated in patients, in a first-time-in-men dose-escalation study; the HEPAR study (2). A non-randomized, open label, safety study. In this phase 1 clinical trial we assessed the safety and the maximum tolerated radiation dose (MTRD) of 166Ho-PLLA-MS in patients with liver malignancy. Material(s) and Method(s): Approval for the HEPAR trial was obtained from the institutional ethics committee and all participants provided written informed consent. Patients with unresectable, chemorefractory liver metastases were treated with escalating 166Ho-PLLA-MS doses. The primary endpoint was the MTRD. Secondary endpoints included other toxicity and tumour response (ClinicalTrials.gov, #NCT01031784). Result(s): From November, 2009 to September, 2011, 15 patients (ocular melanoma, n=7; colorectal cancer, n=5; cholangiocarcinoma, n=2; breast cancer, n=1) .were treated with escalating 166Ho-PLLA-MS doses of 20Gy (n=6), 40Gy (n=3), 60Gy (n=3), and 80Gy (n=3). In the 80-Gy cohort, dose limiting toxicity was encountered in two patients: grade 4 thrombocytopenia, grade 3 leukopenia, and grade 3 hypoalbuminemia in one patient, and grade 3 abdominal pain in another patient. The MTRD was thus determined to be 60Gy. Both MR and SPECT imaging allowed for accurate quantitative depiction of the biodistribution of the radioactive holmium microspheres. Discussion and conclusions: 166Ho-PLLA-MS can be administered safely in patients with liver metastases The MTRD in this patient group was 60Gy. The unique imaging possibilities (SPECT and MRI) of 166Ho-PLLAMS will lead to accurate dosimetry directing for optimization of the treatment. 1) Liver tumors: MR imaging of radioactive holmium microspheres-phantom and rabbit study, Radiology. 231:491-499 (2004). 2) Holmium-166 radioembolization for the treatment of patients with liver metastases: design of the phase I HEPAR trial, J Exp Clin Cancer Res. 29:70 (2010).