Abstract
Hepatic arterial radioembolization with radioactive holmium-166 loaded poly(L-lactic acid) microspheres (166Ho-PLLA-MS) constitutes the subject of this thesis. This technique represents a potential treatment option for patients with unresectable liver malignancies. 166Ho-PLLA-MS are believed to be an improvement over the already clinically applied yttrium-90 microspheres (90Y-MS) due to the multimodality imaging
... read more
properties of holmium, specifically its capability to be visualized by gamma scintigraphy, magnetic resonance imaging (MRI), and X-ray computed tomography (CT). Several preclinical issues regarding 166Ho-PLLA-MS are addressed. Non-radioactive 165Ho-PLLA-MS are neutron-activated to yield radioactive 166Ho-PLLA-MS, a process which was standardized and validated. Although the PLLA matrix was already impaired after 2 hours of irradiation, after neutron irradiation of up to 7 hours the structural integrity of the 166Ho-PLLA-MS was guaranteed. A toxicity study in non-tumor bearing pigs which were hepatic arterially injected with either 165Ho-PLLA-MS or 166Ho-PLLA-MS revealed that the administration of very high amounts of radioactivity does not result in clinical side effects, provided that the 166Ho-PLLA-MS are deposited exclusively into the liver. In the porcine model it was furthermore assessed that a small scout dose of 166Ho-PLLA-MS could, using scintigraphic imaging, accurately predict the distribution of the treatment dose. The applicability of several dosimetric methods in microsphere radioembolization, i.e., Monte Carlo simulation (MC), the point-kernel convolution (PK) method, and the MIRD (Medical Internal Radiation Scheme) dose estimation scheme were also investigated with respect to 166Ho microsphere radioembolization. It was found that MC is the most accurate method, though very time-consuming. It was concluded that the MIRD scheme was insufficient in this respect. The most practical and still amply accurate method was the PK method. A meta-analysis of the literature on 90Y radioembolization was performed which revealed response rates between 79-91%, depending on cancer type (hepatocellular carcinoma or colorectal liver metastases), disease staging, and whether resin or glass 90Y-MS were used. 166Ho acetylacetonate microspheres (166HoAcAcMS) are proposed as a local ablation device. These 166HoAcAcMS are smaller than the 166Ho-PLLA-MS (8.0 ?m and 30 ?m, respectively) and the Ho content is significantly higher (45% and 17% (w/w), respectively). A feasibility study in a feline patient with inoperable liver cancer was conducted. 166HoAcAcMS were intratumorally injected, under ultrasound guidance. The treatment was well tolerated and the animal’s clinical condition rapidly improved. The treatment was repeated when tumor reoccurrence was suspected. Six months after the first treatment the animal was euthanized and ex-vivo MRI and CT revealed that the 166HoAcAcMS were still present in the liver, which was confirmed by histological examination. Further research on these 166HoAcAcMS is warranted.
show less
