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

ABSTRACT: Intra-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.The 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.This 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.

SUBMITTER: Smits ML

PROVIDER: S-EPMC2903532 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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

Smits Maarten L J ML Nijsen Johannes F W JF van den Bosch Maurice A A J MA Lam Marnix G E H MG Vente Maarten A D MA Huijbregts Julia E JE van het Schip Alfred D AD Elschot Mattijs M Bult Wouter W de Jong Hugo W A M HW Meulenhoff Pieter C W PC Zonnenberg Bernard A BA

Journal of experimental & clinical cancer research : CR 20100615

<h4>Background</h4>Intra-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 ca ...[more]

PMID: 20550679

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Project description:PurposeTransarterial radioembolization (TARE) is a treatment for liver tumours based on injection of radioactive microspheres in the hepatic arterial system. It is crucial to achieve a maximum tumour dose for an optimal treatment response, while minimizing healthy liver dose to prevent toxicity. There is, however, no intraprocedural feedback on the dose distribution, as nuclear imaging can only be performed after treatment. As holmium-166 (166Ho) microspheres can be quantified with MRI, we investigate the feasibility and safety of performing 166Ho TARE within an MRI scanner and explore the potential of intraprocedural MRI-based dosimetry.MethodsSix patients were treated with 166Ho TARE in a hybrid operating room. Per injection position, a microcatheter was placed under angiography guidance, after which patients were transported to an adjacent 3-T MRI system. After MRI confirmation of unchanged catheter location, 166Ho microspheres were injected in four fractions, consisting of 10%, 30%, 30% and 30% of the planned activity, alternated with holmium-sensitive MRI acquisition to assess the microsphere distribution. After the procedures, MRI-based dose maps were calculated from each intraprocedural image series using a dedicated dosimetry software package for 166Ho TARE.ResultsAdministration of 166Ho microspheres within the MRI scanner was feasible in 9/11 (82%) injection positions. Intraprocedural holmium-sensitive MRI allowed for tumour dosimetry in 18/19 (95%) of treated tumours. Two CTCAE grade 3-4 toxicities were observed, and no adverse events were attributed to treatment in the MRI. Towards the last fraction, 4/18 tumours exhibited signs of saturation, while in 14/18 tumours, the microsphere uptake patterns did not deviate from the linear trend.ConclusionThis study demonstrated feasibility and preliminary safety of a first in-human application of TARE within a clinical MRI system. Intraprocedural MRI-based dosimetry enabled dynamic insight in the microsphere distribution during TARE. This proof of concept yields unique possibilities to better understand microsphere distribution in vivo and to potentially optimize treatment efficacy through treatment personalization.RegistrationClinicaltrials.gov, identifier NCT04269499, registered on February 13, 2020 (retrospectively registered).

Project description:BackgroundPartition modeling allows personalized activity calculation for holmium-166 (166Ho) radioembolization. However, it requires the definition of tumor and non-tumorous liver, by segmentation and registration of a separately acquired CT, which is time-consuming and prone to error. A protocol including 166Ho-scout, for treatment simulation, and technetium-99m (99mTc) stannous phytate for healthy-liver delineation was proposed. This study assessed the accuracy of automatic healthy-liver segmentation using 99mTc images derived from a phantom experiment. In addition, together with data from a patient study, the effect of different 99mTc activities on the 166Ho-scout images was investigated. To reproduce a typical scout procedure, the liver compartment, including two tumors, of an anthropomorphic phantom was filled with 250 MBq of 166Ho-chloride, with a tumor to non-tumorous liver activity concentration ratio of 10. Eight SPECT/CT scans were acquired, with varying levels of 99mTc added to the non-tumorous liver compartment (ranging from 25 to 126 MBq). For comparison, forty-two scans were performed in presence of only 99mTc from 8 to 240 MBq. 99mTc image quality was assessed by cold-sphere (tumor) contrast recovery coefficients. Automatic healthy-liver segmentation, obtained by thresholding 99mTc images, was evaluated by recovered volume and Sørensen-Dice index. The impact of 99mTc on 166Ho images and the role of the downscatter correction were evaluated on phantom scans and twenty-six patients' scans by considering the reconstructed 166Ho count density in the healthy-liver.ResultsAll 99mTc image reconstructions were found to be independent of the 166Ho activity present during the acquisition. In addition, cold-sphere contrast recovery coefficients were independent of 99mTc activity. The segmented healthy-liver volume was recovered fully, independent of 99mTc activity as well. The reconstructed 166Ho count density was not influenced by 99mTc activity, as long as an adequate downscatter correction was applied.ConclusionThe 99mTc image reconstructions of the phantom scans all performed equally well for the purpose of automatic healthy-liver segmentation, for activities down to 8 MBq. Furthermore, 99mTc could be injected up to at least 126 MBq without compromising 166Ho image quality. Clinical trials The clinical study mentioned is registered with Clinicaltrials.gov (NCT02067988) on February 20, 2014.

Project description:PurposeIn intra-arterial hepatic radioembolization using Holmium-166 (166 Ho) microspheres, a predicted lung-absorbed dose of more than 30 Gy is a contraindication for therapy. Therefore, scout imaging by means of quantitative SPECT of the lungs after a low-dose pretreatment session is essential. Earlier we showed the superiority of Monte Carlo-based iterative SPECT reconstructions over conventional reconstructions due to its quantitative nature, required for dosimetry, at the cost of substantial computation times. In clinical routine, however, the limited available time between scout imaging and therapy constrains its application. To reduce computation times, we investigated the minimum number of iterations required to guarantee a clinical acceptable accuracy in lung dose estimation using patient and phantom data.Methods166 Ho scout SPECT data (range: 222-283 MBq) were used from 10 patients. SPECT images were Monte Carlo-based OSEM reconstructed (effective iterations: 240). Additionally, the 4D XCAT anthropomorphic phantom was used to mimic studies with an injected scout activity of 250 MBq and with varying lung-absorbed doses ranging from 0.9 to 225 Gy for a therapeutic dosage of 15 GBq. These studies were reconstructed in the same way as the patient data, and were also reconstructed using a clinically available, standard OSEM algorithm for comparison. Lung-absorbed dose was determined using VOI analysis as a function of iterations.ResultsThe estimated lung-absorbed dose in nine patients ranged upon MC-based OSEM convergence from 0 to 0.26 Gy for a therapeutic dosage. One patient had an estimated lung absorbed-dose for a therapeutic dosage of 20.3 Gy upon MC-based OSEM convergence, or 18.4 Gy after 40 iterations (-9%). The phantom data showed that the lung-absorbed dose upon OSEM convergence was underestimated by 15% as compared to the actual simulated lung dose, and the dose after 40 iterations was underestimated by 9% as compared to the dose upon convergence. Both underestimations were irrespective of the magnitude of the lung-absorbed dose (0.9 to 225 Gy) and thus can be easily corrected for. The quantitative accuracy of the MC-based OSEM reconstructions (40 iterations, before convergence) outperformed the clinical OSEM reconstruction while estimating the lung dose.ConclusionsThe number of effective iterations necessary for quantitative estimation of the lung dose using MC-based OSEM can be reduced from 240 to 40. The resulting sixfold reduction in calculation time enables processing of the scout images before therapy administration.

Project description:PurposeTo study the impact of transarterial Yttrium-90 radioembolization (TARE) in combination with second-line systemic chemotherapy for colorectal liver metastases (CLM).MethodsIn this international, multicenter, open-label phase III trial, patients with CLM who progressed on oxaliplatin- or irinotecan-based first-line therapy were randomly assigned 1:1 to receive second-line chemotherapy with or without TARE. The two primary end points were progression-free survival (PFS) and hepatic PFS (hPFS), assessed by blinded independent central review. Random assignment was performed using a web- or voice-based system stratified by unilobar or bilobar disease, oxaliplatin- or irinotecan-based first-line chemotherapy, and KRAS mutation status.ResultsFour hundred twenty-eight patients from 95 centers in North America, Europe, and Asia were randomly assigned to chemotherapy with or without TARE; this represents the intention-to-treat population and included 215 patients in the TARE plus chemotherapy group and 213 patients in the chemotherapy alone group. The hazard ratio (HR) for PFS was 0.69 (95% CI, 0.54 to 0.88; 1-sided P = .0013), with a median PFS of 8.0 (95% CI, 7.2 to 9.2) and 7.2 (95% CI, 5.7 to 7.6) months, respectively. The HR for hPFS was 0.59 (95% CI, 0.46 to 0.77; 1-sided P < .0001), with a median hPFS of 9.1 (95% CI, 7.8 to 9.7) and 7.2 (95% CI, 5.7 to 7.6) months, respectively. Objective response rates were 34.0% (95% CI, 28.0 to 40.5) and 21.1% (95% CI, 16.2 to 27.1; 1-sided P = .0019) for the TARE and chemotherapy groups, respectively. Median overall survival was 14.0 (95% CI, 11.8 to 15.5) and 14.4 months (95% CI, 12.8 to 16.4; 1-sided P = .7229) with a HR of 1.07 (95% CI, 0.86 to 1.32) for TARE and chemotherapy groups, respectively. Grade 3 adverse events were reported more frequently with TARE (68.4% v 49.3%). Both groups received full chemotherapy dose intensity.ConclusionThe addition of TARE to systemic therapy for second-line CLM led to longer PFS and hPFS. Further subset analyses are needed to better define the ideal patient population that would benefit from TARE.

Dataset Information

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

Publications

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

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