No abstract

No abstract

Since one of the most frequent sites of human metastatic cancer is the liver, particularly in colon and rectum carcinoma, there is a special need for the development of an effective therapy. This study describes the parameters for reproducible production of poly lactic acid (PLA) microspheres with an average diameter of 37 microm and labelled with neutron-activated holmium-166 (Emax=1.84 MeV, t1/2=26. 8 h), suitable for use in internal radionuclide therapy of liver metastases. It is demonstrated that holmium-loaded PLA microspheres can be prepared by a relatively simple method, with incorporation of 17.0%+/-0.6% holmium (n=5), and that 20 GBq can be obtained from 400 mg neutron activatable microspheres. In order to produce this high amount of activity, the microspheres must be free of water and irradiation must be performed in a polyethylene vial, with a relatively low neutron flux (5x10(13) cm-2 s-1) within 1 h. Under these well-defined conditions minor surface changes were seen which barely affected total volume and consequently total radioactivity of the microspheres with a diameter of 20-50 microm. Overall structural integrity was maintained in terms of form and size. In vitro analyses showed that >99.3% of 166Ho activity was retained in the microspheres after 192 h incubation in PBS, plasma and leucocytes, while in liver homogenate retention was still 98.4%.

Ho-PLLA-MS used for internal radionuclide therapy can be imaged clearly in vivo with MR imaging.

166 Ho-poly(L-lactic acid) microspheres allow for quantitative imaging with MR imaging or SPECT for microsphere biodistribution assessment after radioembolization. The purpose of this study was to evaluate SPECT-and MR imaging-based dosimetry in the first patients treated with 166 Ho radioembolization. Methods: Fifteen patients with unresectable, chemorefractory liver metastases of any origin were enrolled in this phase 1 study and were treated with 166 Ho radioembolization according to a dose escalation protocol . The contours of all liver segments and all discernible tumors were manually delineated on T2-weighted posttreatment MR images and registered to the posttreatment SPECT images (n 5 9) or SPECT/CT images (n 5 6) and MR imagingbased R 2 * maps (n 5 14). Dosimetry was based on SPECT (n 5 15) and MR imaging (n 5 9) for all volumes of interest, tumor-tonontumor (T/N) activity concentration ratios were calculated, and correlation and agreement of MR imaging-and SPECT-based measurements were evaluated. Results: The median overall T/N ratio was 1.4 based on SPECT (range, 0.9-2.8) and 1.4 based on MR imaging (range, 1.1-3.1). In 6 of 15 patients (40%), all tumors had received an activity concentration equal to or higher than the normal liver (T/N ratio $ 1). Analysis of SPECT and MR imaging measurements for dose to liver segments yielded a high correlation (R 2 5 0.91) and a moderate agreement (mean bias, 3.7 Gy; 95% limits of agreement, 211.2 to 18.7). Conclusion: With the use of 166 Ho-microspheres, in vivo dosimetry is feasible on the basis of both SPECT and MR imaging, which enables personalized treatment by selective targeting of inadequately treated tumors. Radi oembolization is an interventional oncologic treatment during which radioactive microspheres are administered in the arterial vessels supplying the liver and its tumors. The rationale behind this intraarterial liver treatment is that liver tumors are predominantly supplied by arterial blood, in contrast to the nontumorous liver, which relies mainly on the portal vein for its blood supply. Injection of a substance into the hepatic artery will therefore selectively target the tumorous tissue (1). Currently, the commercially available microspheres that are used for radioembolization are labeled with 90 Y. To be able to quantitatively evaluate the optimal and selective distribution of microspheres to the liver tumors, posttreatment imaging is indispensable. For that reason, optimization of posttreatment imaging of 90 Y-microspheres with bremsstrahlung SPECT and PET has recently gained interest (2-5).166 Ho-poly(L-lactic acid) microspheres have been developed at our institute as an alternative to 90 Y-microspheres specifically to be able to visualize the in vivo biodistribution of microspheres after radioembolization. 166 Ho-microspheres can be imaged with both SPECT and MR imaging, using the emission of g-photon radiation and the paramagnetic properties of holmium, respectively (6-10). Exploiting these qualities, multimodal dosimetry becomes feasible,...

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

Rhenium-186 hydroxyethylidene diphosphonate 0S6Re-HEDP) has been used for the palliative treatment of metastatic bone pain. A phase 1 dose escalation study was performed using lS6Re-HEDR Twenty-four patients with hormone-resistant prostate cancer entered the study. Each patient had at least four bone metastases and adequate haematological function. Groups of at least three consecutive patients were treated with doses starting at 1295 MBq and increasing to 3515 MBq (escalated in increments of 555 MBq). Thrombocytopenia proved to be the dose-limiting toxicity, while leucopenia played a minor role. Early death occurred in one patient (10 days after administration) without clear relationship to the ~86Re-HEDP therapy. Transient neurological dysfunction was seen in two cases. Two patients who received 3515 MBq ]S6Re-HEDP showed grade 3 toxicity (thrombocytes 25-50 x 109/1), defined as unacceptable toxicity. After treatment alkaline phosphatase levels showed a transient decrease in all patients (mean: 26% _+ 10% IU/1; range: 11%-44%). Prostate-specific antigen values showed a decline in eight patients, preceded by a temporary increase in three patients. From this study we conclude that the maximally tolerated dose of lS6Re-HEDP is 2960 MBq. A placebo-controlled comparative study on the efficacy of 186Re-HEDP has been initiated.

Noninvasive imaging techniques like magnetic resonance imaging (MRI), computed tomography (CT) and single photon emission computed tomography (SPECT) play an increasingly important role in the diagnostic workup and treatment of cancerous disease. In this context, a distinct trend can be observed towards the development of contrast agents and radiopharmaceuticals that open up perspectives on a multimodality imaging approach, involving all three aforementioned techniques. To promote insight into the potentialities of such an approach, we prepared an overview of the strengths and limitations of the various imaging techniques, in particular with regard to their capability to quantify the spatial distribution of a multimodal diagnostic agent. To accomplish this task, we used a two-step approach. In the first step, we examined the situation for a particular therapeutic anti-cancer agent with multimodal imaging opportunities, viz. holmium-loaded microspheres (HoMS). Physical phantom experiments were performed to enable a comparative evaluation of the three modalities assuming the use of standard equipment, standard clinical scan protocols, and signal-known-exactly conditions. These phantom data were then analyzed so as to obtain first order estimates of the sensitivity and detection limits of MRI, CT and SPECT for HoMS. In the second step, the results for HoMS were taken as a starting point for a discussion of the factors affecting the sensitivity and detection limits of MRI, CT and SPECT for multimodal agents in general. In this, emphasis was put on the factors that must be taken into account when extrapolating the findings for HoMS to other diagnostic tasks, other contrast agents, other experimental conditions, and other scan protocols.