Radioactive holmium poly(L-lactic acid) microspheres for treatment of liver malignancies (2001)

Liver metastases frequently occur during the progression of various solid tumours, especially colorectal cancers, and are the cause of 25-50% of all cancer deaths [1-3]. In particular in patients with colorectal cancer the liver is the main metastatic site. Median survival of patients with liver metastases is approximately 6-12 months, and in the presence of extensive hepatic metastases survival is reported to be less than 6 months with no 5-year survivors [1,4,5]. Systemic chemotherapy results in only limited increase in life span with a median survival of around 1 year. In addition to systemic chemotherapy, local hepatic arterial chemotherapy, chemo-occlusion or combination therapies have resulted in some extension of life span of approximately 12-24 months [5-7]. Although loco-regional chemotherapy showed good palliative properties, a number of side effects such as nausea, vomiting and diarrhoea has been reported. In addition, hepatic toxicity associated with these therapies is often observed [5,8]. Surgery is still the only accepted treatment with curative intention, but only a minority of the patients can be subjected to this treatment [9,10]. Other newly developed surgical modalities like cryo-ablation and radiofrequency ablation have resulted in refinement of the surgical techniques which can be applied to a greater number of patients. Nevertheless, surgical therapies are only possible in approximately 10% of the patients [11,12].&#13;\n&#13;\nExternal beam radiotherapy in the treatment of hepatic malignancies is limited by the radiosensitivity of normal liver tissue, which can tolerate doses of only up to 30 Gy for whole liver irradiation [3,13,14]. Therefore, investigators have searched for ways to utilise the arterial vascularization of hepatic metastases in order to inject local radioactive deposits. Yttrium-90 ( 90 Y) labelled microspheres which can be administered intra-arterially, became available in the late 1980s and resulted in the start of a new safe therapy for treatment of liver cancer [2,15]. Livers of patients can receive up to 150 Gy without developing radiation hepatitis; a safety limit of 80 to 100 Gy is used in most studies [16,17]. The median survival in a study of 17 patients with liver metastases from colorectal cancer treated with 90 Y microspheres was 14 months and there were 3 long-term survivors of 4 years [18]. As important as longevity, the treatment has very little morbidity [8].&#13;\n&#13;\nAlthough studies with 90 Y labelled microspheres, either based on glass or resin, showed promising results, their high density (3.3 g/ml for glass and 1.6 g/ml for resin), apparent non-emission of 90 Y (Emax=2.28 MeV, t1/2=64.1h) for imaging can be considered as disadvantages. Therefore, Mumper et al. [19] proposed the use of poly(L-lactic acid) (PLLA) microspheres loaded with the ß -emitter holmium-166 ( 166 Ho) as alternative for the glass or resin based systems. 166 Ho-loaded microspheres have favourable characteristics above the 90 Y glass and resin based systems because of their relatively low density and biodegradability. Moreover, 166 Ho also emits ? -photons, which makes image-guided radionuclide therapy possible. However, because of the relatively low contents of holmium, 10% (w/w), Mumper et al. were not able to produce a patient dose with sufficient activity.