Multicentre quantitative Ga-68 PET/CT performance harmonisation

Purpose Performance standards for quantitative F-18-FDG PET/CT studies are provided by the EANM Research Ltd. (EARL) to enable comparability of quantitative PET in multicentre studies. Yet, such specifications are not available for Ga-68. Therefore, our aim was to evaluate Ga-68-PET/CT quantification variability in a multicentre setting. Methods A survey across Dutch hospitals was performed to evaluate differences in clinical Ga-68 PET/CT study protocols. Ga-68 and F-18 phantom acquisitions were performed by 8 centres with 13 different PET/CT systems according to EARL protocol. The cylindrical phantom and NEMA image quality (IQ) phantom were used to assess image noise and to identify recovery coefficients (RCs) for quantitative analysis. Both phantoms were used to evaluate cross-calibration between the PET/CT system and local dose calibrator. Results The survey across Dutch hospitals showed a large variation in clinical Ga-68 PET/CT acquisition and reconstruction protocols. Ga-68 PET/CT image noise was below 10%. Cross-calibration was within 10% deviation, except for one system to overestimate F-18 and two systems to underestimate the Ga-68 activity concentration. RC-curves for F-18 and Ga-68 were within and on the lower limit of current EARL standards, respectively. After correction for local Ga-68/F-18 cross-calibration, mean Ga-68 performance was 5% below mean EARL performance specifications. Conclusions Ga-68 PET/CT quantification performs on the lower limits of the current EARL RC standards for F-18. Correction for local Ga-68/F-18 cross-calibration mismatch is advised, while maintaining the EARL reconstruction protocol thereby avoiding multiple EARL protocols

Tolerability of concurrent external beam radiotherapy and [ 177Lu]Lu-PSMA-617 for node-positive prostate cancer in treatment naïve patients, phase I study (PROQURE-I trial).

BACKGROUND: Prostate cancer patients with locoregional lymph node disease at diagnosis (N1M0) still have a limited prognosis despite the improvements provided by aggressive curative intent multimodal locoregional external beam radiation therapy (EBRT) with systemic androgen deprivation therapy (ADT). Although some patients can be cured and the majority of patients have a long survival, the 5-year biochemical failure rate is currently 29-47%. [ 177Lu]Lu-PSMA-617 has shown impressive clinical and biochemical responses with low toxicity in salvage setting in metastatic castration-resistant prostate cancer. This study aims to explore the combination of standard EBRT and ADT complemented with a single administration of [ 177Lu]Lu-PSMA-617 in curative intent treatment for N1M0 prostate cancer. Hypothetically, this combined approach will enhance EBRT to better control macroscopic tumour localizations, and treat undetected microscopic disease locations inside and outside EBRT fields. METHODS: The PROQURE-I study is a multicenter prospective phase I study investigating standard of care treatment (7 weeks EBRT and 3 years ADT) complemented with one concurrent cycle (three, six, or nine GBq) of systemic [ 177Lu]Lu-PSMA-617 administered in week two of EBRT. A maximum of 18 patients with PSMA-positive N1M0 prostate cancer will be included. The tolerability of adding [ 177Lu]Lu-PSMA-617 will be evaluated using a Bayesian Optimal Interval (BOIN) dose-escalation design. The primary objective is to determine the maximum tolerated dose (MTD) of a single cycle [ 177Lu]Lu-PSMA-617 when given concurrent with EBRT + ADT, defined as the occurrence of Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 grade three or higher acute toxicity. Secondary objectives include: late toxicity at 6 months, dosimetric assessment, preliminary biochemical efficacy at 6 months, quality of life questionnaires, and pharmacokinetic modelling of [ 177Lu]Lu-PSMA-617. DISCUSSION: This is the first prospective study to combine EBRT and ADT with [ 177Lu]Lu-PSMA-617 in treatment naïve men with N1M0 prostate cancer, and thereby explores the novel application of [ 177Lu]Lu-PSMA-617 in curative intent treatment. It is considered likely that this study will confirm tolerability as the combined toxicity of these treatments is expected to be limited. Increased efficacy is considered likely since both individual treatments have proven high anti-tumour effect as mono-treatments. TRIAL REGISTRATION: ClinicalTrials, NCT05162573 . Registered 7 October 2021

Quantification of biochemical PSA dynamics after radioligand therapy with [177Lu]Lu-PSMA-I&T using a population pharmacokinetic/pharmacodynamic model

Abstract Background There is an unmet need for prediction of treatment outcome or patient selection for [177Lu]Lu-PSMA therapy in patients with metastatic castration-resistant prostate cancer (mCRPC). Quantification of the tumor exposure–response relationship is pivotal for further treatment optimization. Therefore, a population pharmacokinetic (PK) model was developed for [177Lu]Lu-PSMA-I&T using SPECT/CT data and, subsequently, related to prostate-specific antigen (PSA) dynamics after therapy in patients with mCRPC using a pharmacokinetic/pharmacodynamic (PKPD) modelling approach. Methods A population PK model was developed using quantitative SPECT/CT data (406 scans) of 76 patients who received multiple cycles [177Lu]Lu-PSMA-I&T (± 7.4 GBq with either two- or six-week interval). The PK model consisted of five compartments; central, salivary glands, kidneys, tumors and combined remaining tissues. Covariates (tumor volume, renal function and cycle number) were tested to explain inter-individual variability on uptake into organs and tumors. The final PK model was expanded with a PD compartment (sequential fitting approach) representing PSA dynamics during and after treatment. To explore the presence of a exposure–response relationship, individually estimated [177Lu]Lu-PSMA-I&T tumor concentrations were related to PSA changes over time. Results The population PK model adequately described observed data in all compartments (based on visual inspection of goodness-of-fit plots) with adequate precision of parameters estimates (< 36.1% relative standard error (RSE)). A significant declining uptake in tumors (k14) during later cycles was identified (uptake decreased to 73%, 50% and 44% in cycle 2, 3 and 4–7, respectively, compared to cycle 1). Tumor growth (defined by PSA increase) was described with an exponential growth rate (0.000408 h−1 (14.2% RSE)). Therapy-induced PSA decrease was related to estimated tumor concentrations (MBq/L) using both a direct and delayed drug effect. The final model adequately captured individual PSA concentrations after treatment (based on goodness-of-fit plots). Simulation based on the final PKPD model showed no evident differences in response for the two different dosing regimens currently used. Conclusions Our population PK model accurately described observed [177Lu]Lu-PSMA-I&T uptake in salivary glands, kidneys and tumors and revealed a clear declining tumor uptake over treatment cycles. The PKPD model adequately captured individual PSA observations and identified population response rates for the two dosing regimens. Hence, a PKPD modelling approach can guide prediction of treatment response and thus identify patients in whom radioligand therapy is likely to fail

A head-to-head comparison between two commercial software packages for hybrid dosimetry after peptide receptor radionuclide therapy

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