Towards Effective Targeted Alpha Therapy for Neuroendocrine Tumours: A Review.

This review article explores the evolving landscape of Molecular Radiotherapy (MRT), emphasizing Peptide Receptor Radionuclide Therapy (PRRT) for neuroendocrine tumours (NETs). The primary focus is on the transition from ß-emitting radiopharmaceuticals to α-emitting agents in PRRT, offering a critical analysis of the radiobiological basis, clinical applications, and ongoing developments in Targeted Alpha Therapy (TAT). Through an extensive literature review, the article delves into the mechanisms and effectiveness of PRRT in targeting somatostatin subtype 2 receptors, highlighting both its successes and limitations. The discussion extends to the emerging paradigm of TAT, underlining its higher potency and specificity with α-particle emissions, which promise enhanced therapeutic efficacy and reduced toxicity. The review critically evaluates preclinical and clinical data, emphasizing the need for standardised dosimetry and a deeper understanding of the dose-response relationship in TAT. The review concludes by underscoring the significant potential of TAT in treating SSTR2-overexpressing cancers, especially in patients refractory to ß-PRRT, while also acknowledging the current challenges and the necessity for further research to optimize treatment protocols.

Iodine-131 and Iodine-131-Meta-iodobenzylguanidine Dosimetry in Cancer Therapy.

Radioactive iodine was first used for the treatment of benign thyroid disease and thyroid cancer 80 years ago. I-131 mIBG was later developed for the treatment of adult and pediatric neuroendocrine tumors. Physicists were closely involved from the outset to measure retention, to quantify uptake and to calculate radiation dosimetry. As the treatment became widespread, contrasting treatment regimes were followed, either given with empirically derived fixed levels of activity or guided according to the radiation doses delivered. As for external beam radiotherapy, individualized treatments for both thyroid cancer and neuroendocrine tumors were developed based on the aim of maximizing the radiation doses delivered to target volumes while restricting the radiation doses delivered to organs-at-risk, particularly the bone marrow. The challenge of marrow dosimetry has been met by using surrogate measures, often the blood dose for thyroid treatments and the whole-body dose in the case of treatment of neuroblastoma with I-131 mIBG. A number of studies have sought to establish threshold absorbed doses to ensure therapeutic efficacy. Although different values have been postulated, it has nevertheless been conclusively demonstrated that a fixed activity approach leads to a wide range of absorbed doses delivered to target volumes and to normal organs. Personalized treatment planning is now technically feasible with ongoing multicenter clinical trials and investigations into image quantification, biokinetic modelling and radiobiology.

A Systematic Review and Meta-Analysis of the Relationship Between the Radiation Absorbed Dose to the Thyroid and Response in Patients Treated with Radioiodine for Graves' Disease.

Background: Patients with Graves' disease are commonly treated with radioiodine. There remains controversy over whether the aim of treatment should be to achieve euthyroidism or hypothyroidism, and whether treatments should be administered with standard levels of radioactivity or personalized according to the radiation absorbed doses delivered to the thyroid. The aim of this review was to investigate whether a relationship exists between radiation absorbed dose and treatment outcome. Methods: A systematic review and meta-analysis of all reports published before February 13, 2020, were performed using PubMed, Web of Science, OVID MEDLINE, and Embase. Proportion of patients achieving nonhyperthyroid status was the primary outcome. Secondary outcomes were proportion of patients who were specifically euthyroid or hypothyroid. A random-effects meta-analysis of proportions was performed for primary and secondary outcomes, and the impact of the radiation absorbed dose on treatment outcome was assessed through meta-regression. The study is registered with PROSPERO (CRD42020175010). Results: A total of 1122 studies were identified of which 15, comprising 2303 Graves' disease patients, were eligible for the meta-analysis. A strong association was found between radiation absorbed dose and nonhyperthyroid and hypothyroid outcomes (odds ratio [OR] = 1.11 [95% confidence interval {CI} 1.08-1.14] and OR = 1.09 [CI 1.06-1.12] per 10 Gy increase). Higher rates of euthyroid outcome were found for radiation absorbed doses within the range 120-180 Gy when compared with outside this range (n = 1172, OR = 2.50 [CI 1.17-5.35], p = 0.018). A maximum euthyroid response of 38% was identified at a radiation absorbed dose of 128 Gy. Conclusions: The presented radiation absorbed dose-response relationships can facilitate personalized treatment planning for radioiodine treatment of patients with Graves' disease. Further studies are required to determine how patient-specific covariates can inform personalized treatments.

SOLLID - a single centre study to develop methods to investigate the effects of low radiation doses within nuclear medicine, to enable multicentre epidemiological investigations.

There is continuing debate concerning the risks of secondary malignancies from low levels of radiation exposure. The current model used for radiation protection is predicated on the assumption that even very low levels of exposure may entail risk. This has profound implications for medical procedures involving ionising radiation as radiation doses must be carefully monitored, and for diagnostic procedures are minimised as far as possible. This incurs considerable expense. The SOLLID study (ClinicalTrials.gov Identifier: NCT03580161) aims to develop the methodology to enable a large-scale epidemiological investigation of the effect of radiopharmaceutical administrations to patients undergoing diagnostic nuclear medicine procedures. Patients will undergo a series of scans in addition to that acquired as standard of care to enable the radiation doses delivered to healthy organs to be accurately calculated. Detailed analysis will be performed to determine the uncertainty in the radiation dose calculations as a function of the number and type of scans acquired. It is intended that this will inform a subsequent long-term multicentre epidemiological study that would address the question definitively. Secondary aims of the study are to evaluate the range of absorbed doses that are delivered from diagnostic nuclear medicine procedures and to use current risk models to ascertain the relative risks from these administrations.

Bone scan index as metastatic bone disease quantifier and predictor of radium-223-dichloride biochemical response.

OBJECTIVES: This work aims to assess whether the biochemical response of radium-223-dichloride treatment can be predicted based on the pretherapy bone scan, and consequently if bone scan index (BSI) and maximum lesion intensity have a place as alternatives or as complements to extent of bone disease (EOBD) scoring in predicting biochemical response to treatment. Many cases of advanced prostate cancer have evidence of bone metastasis. Accurate EOBD quantification could help predict the response to radium-223-dichloride therapy. Current EOBD score is simple to use but does not consider size, intensity or localisation of lesion BSI might be more suitable for stratification of bone metastases. PATIENTS AND METHODS: Bone scans (n=20) preceding radium-223-dichloride treatment for prostate cancer were assessed retrospectively using automated BSI software (EXINI) and by assessing maximum counts per lesion. Results were then compared to total alkaline phosphatase (ALP) as a measure of biochemical response to therapy using linear regressions and to their EOBD scores using box plot analysis. RESULTS: Moderate correlation was found between ALP response and maximum lesion intensity (R=0.41) and BSI (R=0.46). Strong correlation (R=0.71) was found between baseline ALP and BSI and between lesion number and BSI (R=0.60). Visual assessment of EOBD score was found to correlate well with baseline ALP and maximum ALP response. CONCLUSION: BSI is a useful asset in stratification of patients with metastatic bone disease. It may also have a place in prediction of biochemical response.