Jean-Mathieu Beauregard

Background: The tumour sink effect is a phenomenon whereby the sequestration of a radiopharmaceutical in cancer lesions leads to decreased activity concentration in the blood stream and organs. The aim of this sub-analysis of the prospective 3TMPO study (NCT04000776) was to investigate the tumour sink effect on prostate-specific membrane antigen (PSMA) PET imaging in a population of patients with metastatic castration-resistant prostate cancer (mCRPC). Methods: Ninety-seven participants underwent ⁶⁸Ga-PSMA-617 PET/CT imaging. The activity concentration in the kidney, parotid, spleen, liver and blood was expressed as a percentage of injected activity per cubic centimetre (%IA/cm³). The total tumour volume was delineated, and the total lesion fraction (TLF), i.e., the percentage of injected activity sequestered in the tumour, was computed. Participants were stratified into three tumour burden groups: small (TLF < 10%), moderate (10% ≤ TLF < 25%), and large (TLF ≥ 25%). Weight, lean body weight, body surface area, and estimated glomerular filtration rate (eGFR) were investigated as additional factors affecting biodistribution. Results: The TLF ranged from 0.0 to 43.5%. For all healthy tissues, the %IA/cm³ was negatively correlated with TLF (r ranging − 0.33 to − 0.46; P < 0.001). Patients with a large TLF had significantly lower uptake in all organs when compared to those with a small TLF (P < 0.05). Body habitus indices and/or eGFR were negatively correlated with the %IA/cm³ of the parotid, liver and blood (r ranging − 0.23 to − 0.33; P < 0.05). Combining predictive variables, the term [BSA / (1–TLF)] tended to yield the strongest negative correlations with healthy tissues %IA/cm³ (r ranging − 0.33 to − 0.63; P < 0.001). Conclusion: The tumour sink effect was observed in a cohort of mCRPC patients scanned with ⁶⁸Ga-PSMA-617. This finding strongly suggests that patients with a large TLF are likely to receive lower absorbed doses to organs at risk – i.e., be undertreated from a dosimetry perspective – following a fixed-activity regime of ¹⁷⁷Lu-PSMA-617 radiopharmaceutical therapy, as commonly practiced. Individual factors such as body habitus and renal function further impact the biodistribution of PSMA radiopharmaceuticals. Trial registration: NCT04000776, registered on 2019-06-27.

Purpose: We present the results of an open-label, phase I/II study evaluating the safety and efficacy of the novel somatostatin receptor (SSTR) antagonist [¹⁷⁷Lu]Lu-satoreotide tetraxetan in 40 patients with previously treated, progressive neuroendocrine tumours (NETs), in which dosimetry was used to guide maximum administered activity. Methods: This study was conducted in two parts. Part A consisted of 15 patients who completed three cycles of [¹⁷⁷Lu]Lu-satoreotide tetraxetan at a fixed administered activity and peptide amount per cycle (4.5 GBq/300 µg). Part B, which included 25 patients who received one to five cycles of [¹⁷⁷Lu]Lu-satoreotide tetraxetan, evaluated different administered activities (4.5 or 6.0 GBq/cycle) and peptide amounts (300, 700, or 1300 μg/cycle), limited to a cumulative absorbed radiation dose of 23 Gy to the kidneys and 1.5 Gy to the bone marrow. Results: Median cumulative administered activity of [¹⁷⁷Lu]Lu-satoreotide tetraxetan was 13.0 GBq over three cycles (13.1 GBq in part A and 12.9 GBq in part B). Overall, 17 (42.5%) patients experienced grade ≥ 3 treatment‑related adverse events; the most common were lymphopenia, thrombocytopenia, and neutropenia. No grade 3/4 nephrotoxicity was observed. Two patients developed myeloid neoplasms considered treatment related by the investigator. Disease control rate for part A and part B was 94.7% (95% confidence interval [CI]: 82.3–99.4), and overall response rate was 21.1% (95% CI: 9.6–37.3). Conclusion: [¹⁷⁷Lu]Lu-satoreotide tetraxetan, administered at a median cumulative activity of 13.0 GBq over three cycles, has an acceptable safety profile with a promising clinical response in patients with progressive, SSTR-positive NETs. A 5-year long-term follow-up study is ongoing. Trial registration: ClinicalTrials.gov, NCT02592707. Registered October 30, 2015.

Theranostics – i.e., the combination of molecular imaging and radiopharmaceutical therapy of cancer targeting a common biological feature – is a rapidly expanding field owing the recent successes of novel radiopharmaceutical therapies, such as ¹⁷⁷Lu-based prostate-specific membrane antigen radioligand therapy of prostate cancer and peptide receptor radionuclide therapy of neuroendocrine tumours. Despite the ongoing technical developments in imaging-based dosimetry, the existence of tumour absorbed dose-efficacy and organ absorbed dose-toxicity relationships, as well as the high interpatient variability in absorbed doses per unit activity, radiopharmaceutical therapies are still mostly administered in a fixed-activity, one-size-fits-all fashion. This is at odds with the principles of radiation oncology, where the absorbed doses to tissues are prescribed and their delivery is carefully planned and controlled for each individual patient to maximise the clinical benefits. There is a growing body of clinical evidence that dosimetry-based radiopharmaceutical therapy allows to safely optimise tumour irradiation, which translates into improved clinical outcomes. In this narrative review, we will present the reported prospective clinical experience to date on the use of imaging-based dosimetry to personalise radiopharmaceutical therapies.

Background: Dead-time correction is required for accurate quantitative SPECT-based dosimetry in the context of personalised ¹⁷⁷Lu radiopharmaceutical therapy. We aimed to evaluate the impact of applying dead-time correction on the reconstructed SPECT image versus on the acquisition projections before reconstruction. Methods: Data from 16 SPECT/CT acquisitions of a decaying ¹⁷⁷Lu-filled phantom (up to 20.75 GBq) and dual-timepoint SPECT/CT in 14 patients treated with personalised ¹⁷⁷Lu peptide receptor radionuclide therapy were analysed. Dead time was determined based on the acquisition wide-spectrum count rate for each projection and averaged for the entire acquisition. Three dead-time correction methods (DTCMs) were used: the per-projection correction, where each projection was individually corrected before reconstruction (DTCM1, the standard of reference), and two per-volume methods using the average dead-time correction factor of the acquisition applied to all projections before reconstruction (DTCM2) or to the SPECT image after reconstruction (DTCM3). Relative differences in quantification were assessed for various volumes of interest (VOIs) on the phantom and patient SPECT images. In patients, the resulting dosimetry estimates for tissues of interest were also compared between DTCMs. Results: Both per-volume DTCMs (DTCM2 and DTCM3) were found to be equivalent, with VOI count differences not exceeding 0.8%. When comparing the per-volume post-reconstruction DTCM3 versus the per-projection pre-reconstruction DTCM1, differences in VOI counts and absorbed dose estimates did not exceed 2%, with very few exceptions. The largest absorbed dose deviation was observed for a kidney at 3.5%. Conclusion: While per-projection dead-time correction appears ideal for QSPECT, post-reconstruction correction is an acceptable alternative that is more practical to implement in the clinics, and that results in minimal deviations in quantitative accuracy and dosimetry estimates, as compared to the per-projection correction.

Background: Dead-time correction is required for accurate quantitative SPECT-based dosimetry in the context of personalised ¹⁷⁷Lu radiopharmaceutical therapy. We aimed to evaluate the impact of applying dead-time correction on the reconstructed SPECT image vs. on the acquisition projections before reconstruction. Methods: Data from 16 SPECT/CT acquisitions of a decaying ¹⁷⁷Lu-filled phantom (up to 20.75 GBq) and dual-timepoint SPECT/CT in 14 patients treated with personalised ¹⁷⁷Lu peptide receptor radionuclide therapy were analysed. Dead-time was determined based on the acquisition wide-spectrum count rate for each projection and averaged for the entire acquisition. Three dead-time corrections methods (DTCMs) were used: the per-projection correction, where each projection was individually corrected before reconstruction (DTCM1, the standard of reference); and two per-volume methods using the average dead-time correction factor of the acquisition applied to all projections before reconstruction (DTCM2), or to the SPECT image after reconstruction (DTCM3). Relative differences in quantification were assessed for various VOIs on the phantom and patient SPECT images. In patients, the resulting dosimetry estimates for tissues of interest were also compared between DTCMs.Results: Both per-volume DTCMs (DTCM2 and DTCM3) were found to be equivalent, with VOI count differences not exceeding 0.8%. When comparing the per-volume post-reconstruction DTCM3 vs. the per-projection pre-reconstruction DTCM1, differences in VOI counts and absorbed dose estimates did not exceed 2%, with very few exceptions. The largest absorbed dose deviation was observed for a kidney at 3.5%. Conclusion: While per-projection dead-time correction appears ideal for QSPECT, post-reconstruction correction is an acceptable alternative that is more practical to implement in the clinics and that results in minimal deviations in quantitative accuracy and dosimetry estimates, as compared to the per-projection correction.

Objective: To determine the prevalence of intra‐patient inter‐metastatic heterogeneity based on positron emission tomography (PET)/computed tomography (CT) in patients with metastatic castration‐resistant prostate cancer (mCRPC) and to determine the prevalence of neuroendocrine disease in these patients and their eligibility for radioligand therapies (RLTs). Patients and Methods: This multicentre observational prospective clinical study will include 100 patients with mCRPC from five Canadian academic centres. Patients with radiological or biochemical progression and harbouring at least three metastases by conventional imaging will be accrued. Intra‐patient inter‐metastatic heterogeneity will be determined with triple‐tracer imaging using fluorine‐18 fluorodeoxyglucose ( ¹⁸ F‐FDG), gallium‐68‐( ⁶⁸ Ga)‐prostate‐specific membrane antigen (PSMA)‐617 and ⁶⁸ Ga‐DOTATATE, which are a glucose analogue, a PSMA receptor ligand and a somatostatin receptor ligand, respectively. The ⁶⁸ Ga‐PSMA‐617 and ¹⁸ F‐FDG PET/CT scans will be performed first. If at least one PSMA‐negative/FDG‐positive lesion is observed, an additional PET/CT scan with ⁶⁸ Ga‐DOTATATE will be performed. The tracer uptake of individual lesions will be assessed for each PET tracer and patients with lesions presenting discordant uptake profiles will be considered as having inter‐metastatic heterogeneous disease and may be offered a biopsy. Expected Results: The proposed triple‐tracer approach will allow whole‐body mCRPC characterisation, investigating the inter‐metastatic heterogeneity in order to better understand the phenotypic plasticity of prostate cancer, including the neuroendocrine transdifferentiation that occurs during mCRPC progression. Based on ⁶⁸ Ga‐PSMA‐617 or ⁶⁸ Ga‐DOTATATE PET positivity, the potential eligibility of patients for PSMA and DOTATATE‐based RLT will be assessed. Non‐invasive whole‐body determination of mCRPC heterogeneity and transdifferentiation is highly innovative and might establish the basis for new therapeutic strategies. Comparison of molecular imaging findings with biopsies will also link metastasis biology to radiomic features. Conclusion: This study will add novel, biologically relevant dimensions to molecular imaging: the non‐invasive detection of inter‐metastatic heterogeneity and transdifferentiation to neuroendocrine prostate cancer by using a multi‐tracer PET/CT strategy to further personalise the care of patients with mCRPC.