Purpose: To systematically review all current evidence into the dose-response relation of yttrium-90 and holmium-166 selective internal radiation therapy (SIRT) in primary and secondary liver cancer. Methods: A standardized search was performed in PubMed (MEDLINE), Embase, and the Cochrane Library in order to identify all published articles on dose-response evaluation in SIRT. In order to limit the results, all articles that investigated SIRT in combination with other therapy modalities (such as chemotherapy) were excluded. Results: A total of 3038 records were identified of which 487 were screened based on the full text. Ultimately, 37 studies were included for narrative analysis. Meta-analysis could not be performed due to the large heterogeneity in study and reporting designs. Out of 37 studies, 30 reported a ‘mean dose threshold’ that needs to be achieved in order to expect a response. This threshold appears to be higher for hepatocellular carcinoma (HCC, 100–250 Gy) than for colorectal cancer metastases (CRC, 40–60 Gy). Reported thresholds tend to be lower for resin microspheres than when glass microspheres are used. Conclusion: Although the existing evidence demonstrates a dose-response relationship in SIRT for both primary liver tumours and liver metastases, many pieces of the puzzle are still missing, hampering the definition of standardized dose thresholds. Nonetheless, most current evidence points towards a target mean dose of 100–250 Gy for HCC and 40–60 Gy for CRC. The field would greatly benefit from a reporting standard and prospective studies designed to elucidate the dose-response relation in different tumour types.

Purpose: Transarterial 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. Methods: Six 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. Results: Administration 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. Conclusion: This 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. Registration: Clinicaltrials.gov, identifier NCT04269499, registered on February 13, 2020 (retrospectively registered).

Background: Reliable dosimetry based on SPECT/CT imaging is essential to achieve personalized ¹⁶⁶Ho-radioembolization treatment planning and evaluation. This study quantitatively evaluates multiple acquisition and reconstruction protocols for ¹⁶⁶Ho-SPECT imaging based on data from five Dutch hospitals. We aim to recommend an imaging protocol which harmonizes ¹⁶⁶Ho-SPECT images for reproducible and accurate dosimetry in a multi-scanner and multi-center setting. Methods: Cylindrical and NEMA IEC phantoms, filled with ¹⁶⁶Ho-chloride, were imaged using seven SPECT/CT scanners from two vendors (GE HealthCare and Siemens Healthineers). Data were acquired with a photopeak window centered at 81 keV. Two adjacent scatter windows, and one upper scatter window at 118 keV were used for triple-energy window (TEW) and dual-energy window (DEW) scatter correction, respectively. The TEW and DEW reconstructions used vendor-specific software. Additionally, a vendor-neutral software package with Monte Carlo (MC) scatter correction (Hermes Medical Solutions) was used to study the influence of scanner hardware on the image quality. System sensitivity was measured in projection data of the cylindrical phantom. The axial uniformity in the cylindrical phantom was used to characterize the impact of the scatter correction method. The image quality was evaluated by the coefficient of variation (COV; noise), the contrast recovery coefficients (CRCs) and contrast-to-noise ratios (CNRs). Results: TEW scatter correction resulted in superior uniformity and higher CRCs compared to the DEW (CRC for the largest sphere over all scanners, mean ± SD (range): TEW 0.54 ± 0.07 (0.36–0.65), DEW 0.44 ± 0.04 (0.34–0.51)). DEW resulted in lower noise levels compared to TEW (16% lower on average). The DEW and TEW images resulted in comparable CNRs. The system sensitivities and the vendor-neutral image reconstructions demonstrated differences in hardware between the two vendors, most likely due to the characteristics of the vendor-specific medium energy collimator. Conclusion: This study demonstrates that TEW scatter correction increases the accuracy of ¹⁶⁶Ho-SPECT images compared to DEW, and we henceforth recommend adopting this method in the clinical ¹⁶⁶Ho-dosimetry workflow. Scanner hardware has a substantial impact on the characteristics of the acquired data, and identical reconstruction settings will therefore not automatically lead to harmonized image quality.

Background: Quantitative imaging is a crucial step for dosimetry in radionuclide therapies. Traditionally, SPECT/CT imaging is quantified based on scanner-specific conversion factors or self-calibration, but recently absolute quantification methods have been introduced in commercial SPECT reconstruction software (Broad Quantification, Siemens Healthineers). In this phantom study we investigate the accuracy of three quantification methods for holmium-166 SPECT/CT imaging, and provide recommendations for clinical dosimetry. Methods: One cylindrical phantom, filled with a homogeneous holmium-166-chloride activity concentration solution, was imaged at one time point to determine a scanner-specific conversion factor, and to characterize the spatial dependency of the activity concentration recovery. One Jaszczak phantom with six fillable spheres, 10:1 sphere-to-background ratio, was imaged over a large range of holmium-166 activities (61-3130 MBq). The images were reconstructed with either an ordered subset expectation maximization (OSEM, Flash3D-reconstruction; scanner-specific quantification or self-calibration quantification) or an ordered subset conjugate gradient (OSCG, xSPECT-reconstruction; Broad Quantification) algorithm. These three quantification methods were compared for the data of the Jaszczak phantom and evaluated based on whole phantom recovered activity, activity concentration recovery coefficients (ACRC), and recovery curves. Results: The activity recovery in the Jaszczak phantom was 28–115% for the scanner-specific, and 57–97% for the Broad Quantification quantification methods, respectively. The self-calibration-based activity recovery is inherently always 100%. The ACRC for the largest sphere (Ø60 mm, ~ 113 mL) ranged over (depending on the activity level) 0.22–0.89, 0.76–0.86, 0.39–0.72 for scanner-specific, self-calibration and Broad Quantification, respectively. Conclusion: Of the three investigated quantification methods, the self-calibration technique produces quantitative SPECT images with the highest accuracy in the investigated holmium-166 activity range.