Purpose: To investigate the relationships between tumor absorbed dose (TAD) or normal tissue absorbed dose (NTAD) and clinical outcomes in hepatocellular carcinoma (HCC) treated with yttrium-90 glass microspheres. Methods: TARGET was a retrospective investigation in 13 centers across eight countries. Key inclusion criteria: liver-dominant HCC with or without portal vein thrombosis, < 10 tumors per lobe (at least one ≥ 3 cm), Child–Pugh stage A/B7, BCLC stages A–C, and no prior intra-arterial treatment. Multi-compartment pre-treatment dosimetry was performed retrospectively. Primary endpoint was the relationship between ≥ grade 3 hyperbilirubinemia (such that > 15% of patients experienced an event) without disease progression and NTAD. Secondary endpoints included relationships between (1) objective response (OR) and TAD, (2) overall survival (OS) and TAD, and (3) alpha fetoprotein (AFP) and TAD. Results: No relationship was found between NTAD and ≥ grade 3 hyperbilirubinemia, which occurred in 4.8% of the 209 patients. The mRECIST OR rate over all lesions was 61.7%; for the target (largest) lesion, 70.8%. Responders and non-responders had geometric mean total perfused TADs of 225.5 Gy and 188.3 Gy (p = 0.048). Probability of OR was higher with increasing TAD (p = 0.044). Higher TAD was associated with longer OS (HR per 100 Gy increase = 0.83, 95% CI: 0.71–0.95; p = 0.009). Increased TAD was associated with higher probability of AFP response (p = 0.046 for baseline AFP ≥ 200 ng/mL). Conclusion: Real-world data confirmed a significant association between TAD and OR, TAD and OS, and TAD and AFP response. No association was found between ≥ grade 3 hyperbilirubinemia and NTAD. Trial registration number: NCT03295006.

Radioembolization is an established treatment for chemoresistant and unresectable liver cancers. Currently, treatment planning is often based on semi-empirical methods, which yield acceptable toxicity profiles and have enabled the large-scale application in a palliative setting. However, recently, five large randomized controlled trials using resin microspheres failed to demonstrate a significant improvement in either progression-free survival or overall survival in both hepatocellular carcinoma and metastatic colorectal cancer. One reason for this might be that the activity prescription methods used in these studies are suboptimal for many patients. In this review, the current dosimetric methods and their caveats are evaluated. Furthermore, the current state-of-the-art of image-guided dosimetry and advanced radiobiological modeling is reviewed from a physics’ perspective. The current literature is explored for the observation of robust dose-response relationships followed by an overview of recent advancements in quantitative image reconstruction in relation to image-guided dosimetry. This review is concluded with a discussion on areas where further research is necessary in order to arrive at a personalized treatment method that provides optimal tumor control and is clinically feasible.

Background: 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. Methods: 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. Discussion: 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. Trial registration: ClinicalTrials.gov NCT01031784

Purpose As an alternative to technetium-99m-macroaggregated albumin (^99mTc-MAA), a scout dose of holmium-166 (¹⁶⁶Ho) microspheres can be used prior to ¹⁶⁶Ho-radioembolization. The use of identical particles for pre-treatment and treatment procedures may improve the predictive value of pre-treatment analysis of distribution. The aim of this study was to analyze the agreement between ¹⁶⁶Ho-scout and ¹⁶⁶Ho-therapeutic dose in comparison with the agreement between ^99mTc-MAA and ¹⁶⁶Ho-therapeutic dose. Methods Two separate scout dose procedures were performed (^99mTc-MAA and ¹⁶⁶Ho-scout) before treatment in 53 patients. First, qualitative assessment was performed by two blinded nuclear medicine physicians who visually rated the agreement between the ^99mTc-MAA, ¹⁶⁶Ho-scout, and ¹⁶⁶Ho-therapeutic dose SPECT-scans (i.e., all performed in the same patient) on a 5-point scale. Second, agreement was measured quantitatively by delineating lesions and normal liver on FDG-PET/CT. These volumes of interest (VOIs) were co-registered to the SPECT/CT images. The predicted absorbed doses (based on ^99mTc-MAA and ¹⁶⁶Ho-scout) were compared with the actual absorbed dose on post-treatment SPECT. Results A total of 23 procedures (71 lesions, 22 patients) were included for analysis. In the qualitative analysis, ¹⁶⁶Ho-scout was superior with a median score of 4 vs. 2.5 for ^99mTc-MAA (p < 0.001). The quantitative analysis showed significantly narrower 95%-limits of agreement for ¹⁶⁶Ho-scout in comparison with ^99mTc-MAA when evaluating lesion absorbed dose (− 90.3 and 105.3 Gy vs. − 164.1 and 197.0 Gy, respectively). Evaluation of normal liver absorbed dose did not show difference in agreement between both scout doses and ¹⁶⁶Ho-therapeutic dose (− 2.9 and 5.5 Gy vs − 3.6 and 4.1 Gy for ^99mTc-MAA and ¹⁶⁶Ho-scout, respectively). Conclusions In this study, ¹⁶⁶Ho-scout was shown to have a superior predictive value for intrahepatic distribution in comparison with ^99mTc-MAA.

(90)Y resin radioembolization is an emerging treatment in patients with liver-dominant metastatic neuroendocrine tumors (mNETs), despite the absence of level I data. The aim of this study was to evaluate the efficacy of this modality in a meta-analysis of the published literature. A comprehensive review protocol screened all reports in the literature. Strict selection criteria were applied to ensure consistency among the selected studies: human subjects, complete response data with time interval, resin microspheres, more than 5 patients, not a duplicate cohort, English language, and separate and complete data for resin-based (90)Y treatment of mNET if the study included multiple tumor and microsphere types. Selected studies were critically appraised on 50 study criteria, in accordance with the research reporting standards for radioembolization. Response data (Response Evaluation Criteria in Solid Tumors) were extracted and analyzed using both fixed and random-effects meta-analyses. One hundred fifty-six studies were screened; 12 were selected, totaling 435 procedures for response assessment. Funnel plots showed no evidence of publication bias (P = 0.841). Critical appraisal revealed a median of 75% of desired criteria included in selected studies. Very high between-study heterogeneity ruled out a fixed-effects model. The random-effects weighted average objective response rate (complete and partial responses, CR and PR, respectively) was 50% (95% confidence interval, 38%-62%), and weighted average disease control rate (CR, PR, and stable disease) was 86% (95% confidence interval, 78%-92%). The percentage of patients with pancreatic mNET was marginally associated with poorer response (P = 0.030), accounting for approximately 23% of the heterogeneity among studies. The percentage of CR and PR correlated with median survival (R = 0.85; P = 0.008). This meta-analysis confirms radioembolization to be an effective treatment option for patients with hepatic mNET. The pooled data demonstrated a high response rate and improved survival for patients responding to therapy.

Neuroblastoma is the most common extracranial solid malignancy in children. At diagnosis, approximately 50% of patients present with metastatic disease. These patients are at high risk for refractory or recurrent disease, which conveys a very poor prognosis. During the past decades, nuclear medicine has been essential for the staging and response assessment of neuroblastoma. Currently, the standard nuclear imaging technique is meta-[¹²³I]iodobenzylguanidine ([¹²³I]mIBG) whole-body scintigraphy, usually combined with single-photon emission computed tomography with computed tomography (SPECT-CT). Nevertheless, 10% of neuroblastomas are mIBG non-avid and [¹²³I]mIBG imaging has relatively low spatial resolution, resulting in limited sensitivity for smaller lesions. More accurate methods to assess full disease extent are needed in order to optimize treatment strategies. Advances in nuclear medicine have led to the introduction of radiotracers compatible for positron emission tomography (PET) imaging in neuroblastoma, such as [¹²⁴I]mIBG, [¹⁸F]mFBG, [¹⁸F]FDG, [⁶⁸Ga]Ga-DOTA peptides, [¹⁸F]F-DOPA, and [¹¹C]mHED. PET has multiple advantages over SPECT, including a superior resolution and whole-body tomographic range. This article reviews the use, characteristics, diagnostic accuracy, advantages, and limitations of current and new tracers for nuclear medicine imaging in neuroblastoma.