M. A. D. Vente

Yttrium-90 microsphere radioembolization for the treatment of liver malignancies: a structured meta-analysis

Radioembolization with yttrium-90 microspheres (90Y-RE), either glass- or resin-based, is increasingly applied in patients with unresectable liver malignancies. Clinical results are promising but overall response and survival are not yet known. Therefore a meta-analysis on tumor response and survival in patients who underwent 90Y-RE was conducted. Based on an extensive literature search, six groups were formed. Determinants were cancer type, microsphere type, chemotherapy protocol used, and stage (deployment in first-line or as salvage therapy). For colorectal liver metastases (mCRC), in a salvage setting, response was 79% for 90Y-RE combined with 5-fluorouracil/leucovorin (5-FU/LV), and 79% when combined with 5-FU/LV/oxaliplatin or 5-FU/LV/irinotecan, and in a first-line setting 91% and 91%, respectively. For hepatocellular carcinoma (HCC), response was 89% for resin microspheres and 78% for glass microspheres. No statistical method is available to assess median survival based on data presented in the literature. In mCRC, 90Y-RE delivers high response rates, especially if used neoadjuvant to chemotherapy. In HCC, 90Y-RE with resin microspheres is significantly more effective than 90Y-RE with glass microspheres. The impact on survival will become known only when the results of phase III studies are published.

Holmium-166 radioembolisation in patients with unresectable, chemorefractory liver metastases (HEPAR trial): a phase 1, dose-escalation study

BACKGROUND The efficacy of radioembolisation for the treatment of liver tumours depends on the selective distribution of radioactive microspheres to tumorous tissue. The distribution of holmium-166 ((166)Ho) poly(L-lactic acid) microspheres can be visualised in vivo by both single-photon-emission CT (SPECT) and MRI. In this phase 1 clinical trial, we aimed to assess the safety and the maximum tolerated radiation dose (MTRD) of (166)Ho-radioembolisation in patients with liver metastases. METHODS Between Nov 30, 2009, and Sept 19, 2011, patients with unresectable, chemorefractory liver metastases were enrolled in the Holmium Embolization Particles for Arterial Radiotherapy (HEPAR) trial. Patients were treated with intra-arterial (166)Ho-radioembolisation in cohorts of three patients, with escalating aimed whole-liver absorbed doses of 20, 40, 60, and 80 Gy. Cohorts were extended to a maximum of six patients if dose-limiting toxicity occurred. Patients were assigned a dose in the order of study entry, with dose escalation until dose-limiting toxicity was encountered in at least two patients of a dose cohort. Clinical or laboratory toxicities were scored according to the National Cancer Institutes Common Terminology Criteria for Adverse Events version 3.0. The primary endpoint was the MTRD. Analyses were per protocol. This study is registered with ClinicalTrials.gov, number NCT01031784. FINDINGS 15 patients underwent (166)Ho-radioembolisation at doses of 20 Gy (n=6), 40 Gy (n=3), 60 Gy (n=3), and 80 Gy (n=3). Mean estimated whole-liver absorbed doses were 18 Gy (SD 2) for the 20 Gy cohort, 35 Gy (SD 1) for the 40 Gy cohort, 58 Gy (SD 3) for the 60 Gy cohort, and 73 Gy (SD 4) for the 80 Gy cohort. The 20 Gy cohort was extended to six patients because of the occurrence of dose-limiting toxicity in one patient (pulmonary embolism). In the 80 Gy cohort, dose-limiting toxicity occurred in two patients: grade 4 thrombocytopenia, grade 3 leucopenia, and grade 3 hypoalbuminaemia in one patient, and grade 3 abdominal pain in another patient. The MTRD was identified as 60 Gy. The most frequently encountered laboratory toxicities (including grade 1) were lymphocytopenia, hypoalbuminaemia, raised alkaline phosphatase, raised aspartate aminotransferase, and raised gamma-glutamyltransferase, which were all noted in 12 of 15 patients. Stable disease or partial response regarding target lesions was achieved in 14 of 15 patients (93%, 95% CI 70-99) at 6 weeks and nine of 14 patients (64%, 95% CI 39-84) at 12 weeks after radioembolisation. Compared with baseline, the average global health status and quality of life scale score at 6 weeks after treatment had decreased by 13 points (p=0·053) and by 14 points at 12 weeks (p=0·048). In all patients, technetium-99m ((99m)Tc)-macro-aggregated albumin SPECT, (166)Ho scout dose SPECT, and (166)Ho treatment dose SPECT showed similar patterns of the presence or absence of extrahepatic deposition of activity. INTERPRETATION (166)Ho-radioembolisation is feasible and safe for the treatment of patients with unresectable and chemorefractory liver metastases and enables image-guided treatment. Clinical (166)Ho-radioembolisation should be done with an aimed whole-liver absorbed dose of 60 Gy.

Holmium-166 radioembolization for the treatment of patients with liver metastases : design of the phase I HEPAR trial

BackgroundIntra-arterial radioembolization with yttrium-90 microspheres ( 90Y-RE) is an increasingly used therapy for patients with unresectable liver malignancies. Over the last decade, radioactive holmium-166 poly(L-lactic acid) microspheres ( 166Ho-PLLA-MS) have been developed as a possible alternative to 90Y-RE. Next to high-energy beta-radiation, 166Ho also emits gamma-radiation, which allows for imaging by gamma scintigraphy. In addition, Ho is a highly paramagnetic element and can therefore be visualized by MRI. These imaging modalities are useful for assessment of the biodistribution, and allow dosimetry through quantitative analysis of the scintigraphic and MR images. Previous studies have demonstrated the safety of 166Ho-PLLA-MS radioembolization ( 166Ho-RE) in animals. The aim of this phase I trial is to assess the safety and toxicity profile of 166Ho-RE in patients with liver metastases.MethodsThe HEPAR study (Holmium Embolization Particles for Arterial Radiotherapy) is a non-randomized, open label, safety study. We aim to include 15 to 24 patients with liver metastases of any origin, who have chemotherapy-refractory disease and who are not amenable to surgical resection. Prior to treatment, in addition to the standard technetium-99m labelled macroaggregated albumin ( 99mTc-MAA) dose, a low radioactive safety dose of 60-mg 166Ho-PLLA-MS will be administered. Patients are treated in 4 cohorts of 3-6 patients, according to a standard dose escalation protocol (20 Gy, 40 Gy, 60 Gy, and 80 Gy, respectively). The primary objective will be to establish the maximum tolerated radiation dose of 166Ho-PLLA-MS. Secondary objectives are to assess tumour response, biodistribution, performance status, quality of life, and to compare the 166Ho-PLLA-MS safety dose and the 99mTc-MAA dose distributions with respect to the ability to accurately predict microsphere distribution.DiscussionThis will be the first clinical study on 166Ho-RE. Based on preclinical studies, it is expected that 166Ho-RE has a safety and toxicity profile comparable to that of 90Y-RE. The biochemical and radionuclide characteristics of 166Ho-PLLA-MS that enable accurate dosimetry calculations and biodistribution assessment may however improve the overall safety of the procedure.Trial registrationClinicalTrials.gov NCT01031784

Radionuclide liver cancer therapies: from concept to current clinical status.

Primary and secondary liver cancer have longtime been characterized by an overall poor prognosis since the majority of patients are not candidates for surgical resection with curative intent, systemic chemotherapy alone has rarely resulted in long-term survival, and the role of conventional external beam radiation therapy has traditionally been limited due to the relative sensitivity of the liver parenchyma to radiation. Therefore, a host of new treatment options have been developed and clinically introduced, including radioembolization techniques, which are the main topic of this paper. In these locoregional treatments liver malignancies are passively targeted because, unlike the normal liver, the blood supply of intrahepatic tumors is almost uniquely derived from the hepatic artery. These internal radiation techniques consist of injecting either yttrium-90 ((90)Y) microspheres, or iodine-131 ((131)I) or rhenium-188 ((188)Re) labeled lipiodol into the hepatic artery. Radioactive lipiodol is used exclusively for treatment of primary liver cancer, whereas (90)Y microsphere therapy is applied for treatment of both primary and metastatic liver cancers. Favorable clinical results have been achieved, particularly when (90)Y microspheres were used in conjunction with systemic chemotherapy. The main advantages of radiolabeled lipiodol treatment are that it is relatively inexpensive (especially (188)Re-HDD-lipiodol) and that the administration procedure is somewhat less complex than that of the microspheres. Holmium-166 ((166)Ho) loaded poly(L-lactic acid) microspheres have also been developed and are about to be clinically introduced. Since (166)Ho is a combined beta-gamma emitter and highly paramagnetic as well, it allows for both (quantitative) scintigraphic and magnetic resonance imaging.

Neutron activation of holmium poly(L-lactic acid) microspheres for hepatic arterial radioembolization: a validation study

Poly(L-lactic acid) microspheres loaded with holmium-166 acetylacetonate (166Ho-PLLA-MS) are a novel microdevice for intra-arterial radioembolization in patients with unresectable liver malignancies. The neutron activation in a nuclear reactor, in particular the gamma heating, damages the 166Ho-PLLA-MS. The degree of damage is dependent on the irradiation characteristics and irradiation time in a particular reactor facility. The aim of this study was to standardize and objectively validate the activation procedure in a particular reactor. The methods included light- and scanning electron microscopy (SEM), particle size analysis, differential scanning calorimetry, viscometry, thermal neutron flux measurements and energy deposition calculations. Seven hours-neutron irradiation results in sufficient specific activity of the 166Ho-PLLA-MS while structural integrity is preserved. Neutron flux measurements and energy deposition calculations are required in the screening of other nuclear reactors. For the evaluation of microsphere quality, light microscopy, SEM and particle size analysis are appropriate techniques.

Microbrachytherapy using holmium-166 acetylacetonate microspheres: a pilot study in a spontaneous cancer animal model

PURPOSE Holmium-166 acetylacetonate microspheres ((166)Ho-AcAc-MS) are proposed as an intratumoral radioablation device. This article presents a pilot study in housecats with unresectable liver cancer. Feasibility and tolerability of intratumoral administrations of (166)Ho-AcAc-MS was investigated. METHODS AND MATERIALS Three cats with unresectable liver tumors of different histotype were included. One cat had hepatocellular carcinoma (HCC), one had cholangiocarcinoma (CC), and one had a malignant epithelial liver tumor (MELT) of unspecified histotype. (166)Ho-AcAc-MS were injected percutaneously under ultrasound guidance into the tumors. Followup consisted of physical examinations and hematologic and biochemical analyses. RESULTS (166)Ho-AcAc-MS were administered to three liver tumor-bearing cats. The treatment was well tolerated and the clinical condition, that is body weight, alertness, mobility, and coat condition of the animals improved markedly. Most biochemical and hematologic parameters normalized shortly after treatment. Life of all cats was extended and associated with a good quality of life. The HCC cat that received 33-Gy tumor-absorbed dose was euthanized 6 months after the first administration owing to disease progression. The MELT cat received 99-Gy tumor dose and was euthanized 3 months posttreatment owing to bacterial meningitis. The CC cat received 333Gy and succumbed 4 months after the first treatment owing to the formation of a pulmonary embolism. CONCLUSIONS Percutaneous intratumoral injection of radioactive (166)Ho-AcAc-MS is feasible in liver tumor-bearing cats. The findings of this pilot study indicate that (166)Ho-AcAc-MS may constitute safe brachytherapeutic microspheres and warrant studies to confirm the clinical utility of this novel brachytherapy device.

Regional brain perfusion in 12 cats measured with technetium-99m-ethyl cysteinate dimer pinhole single photon emission computed tomography (SPECT)

With the use of perfusion tracers, in vivo examination of the regional cerebral blood flow in cats can be performed with single photon emission computed tomography (SPECT). Reliable perfusion data of normal, healthy cats are necessary for future clinical studies or other research use. Therefore, this dataset of the regional perfusion pattern of the normal feline brain was created. Twelve cats were used in this study. Technetium-99m-ethyl cysteinate dimer (99mTc-ECD) was injected intravenously and the acquisition, using a triple head gamma camera equipped with three multi-pinhole collimators (pinhole SPECT), was started 40 mins after tracer administration under general anaesthesia. Nineteen regions of interest were defined using 7T magnetic resonance images of the feline brain and a topographical atlas. Regional counts were normalised to the counts of two reference regions: the total brain and the cerebellum. The highest tracer uptake was noticed in the subcortical structures, and the lowest in the frontal cortex and the cerebellum. Also left–right asymmetry in the temporal cortex and a rostrocaudal gradient of 5% were observed.