How to design a theranostic trial?

The field of nuclear theranostic clinical trials is continuously expanding as an increasing number of novel agents and treatment combinations are explored for treating advanced and metastatic cancers. Moving from 'bench-to-bedside' is oftentimes a complex and lengthy process. The objective of this overview is to explore the basic elements involved in designing clinical trials with a special focus on theranostics in nuclear medicine. The 'bench-to-bedside' journey involves translating basic scientific research into patient-effective treatments. Preclinical studies, a crucial initial step, are a complex process encompassing in vitro experiments, in vivo studies, and animal models to explore hypotheses in humans. Clinical trials follow, with predefined phases assessing safety, effectiveness, and comparisons to existing treatments. This process demands investments in data management, statistics, good clinical practice (GCP) accreditations, and collaborative efforts for funding and sustainable pricing. Theranostics, merging diagnostics and personalized treatment, is at the forefront. Continuous efforts to enhance existing agents involve reducing adverse effects, exploring new indications, and incorporating advanced imaging modalities. Radionuclide therapy, unique with non-uniform distribution and complex radiobiology, plays a distinct role. This article explores trends and challenges in each clinical trial phase in light of the emerging field of theranostics in nuclear medicine, emphasizing meticulous trial design, dosimetry optimization, and the necessity of collaborative stakeholder efforts for successful implementation.

Reduction of [68Ga]Ga-DOTA-TATE injected activity for digital PET/MR in comparison with analogue PET/CT.

BACKGROUND: New digital detectors and block-sequential regularized expectation maximization (BSREM) reconstruction algorithm improve positron emission tomography (PET)/magnetic resonance (MR) image quality. The impact on image quality may differ from analogue PET/computed tomography (CT) protocol. The aim of this study is to determine the potential reduction of injected [68Ga]Ga-DOTA-TATE activity for digital PET/MR with BSREM reconstruction while maintaining at least equal image quality compared to the current analogue PET/CT protocol. METHODS: NEMA IQ phantom data and 25 patients scheduled for a diagnostic PET/MR were included. According to our current protocol, 1.5 MBq [68Ga]Ga-DOTA-TATE per kilogram (kg) was injected. After 60 min, scans were acquired with 3 (≤ 70 kg) or 4 (> 70 kg) minutes per bedposition. PET/MR scans were reconstructed using BSREM and factors ß 150, 300, 450 and 600. List mode data with reduced counts were reconstructed to simulate scans with 17%, 33%, 50% and 67% activity reduction. Image quality was measured quantitatively for PET/CT and PET/MR phantom and patient data. Experienced nuclear medicine physicians performed visual image quality scoring and lesion counting in the PET/MR patient data. RESULTS: Phantom analysis resulted in a possible injected activity reduction of 50% with factor ß = 600. Quantitative analysis of patient images revealed a possible injected activity reduction of 67% with factor ß = 600. Both with equal or improved image quality as compared to PET/CT. However, based on visual scoring a maximum activity reduction of 33% with factor ß = 450 was acceptable, which was further limited by lesion detectability analysis to an injected activity reduction of 17% with factor ß = 450. CONCLUSION: A digital [68Ga]Ga-DOTA-TATE PET/MR together with BSREM using factor ß = 450 result in 17% injected activity reduction with quantitative values at least similar to analogue PET/CT, without compromising on PET/MR visual image quality and lesion detectability.

Evaluation of Hepatocellular Carcinoma Surveillance with Contrast-enhanced MRI in a High-Risk Western European Cohort.

AIM: To investigate the utilization of MRI using a MRI liver protocol with extracellular contrast-enhanced series for hepatocellular carcinoma (HCC) surveillance in high-risk patients. METHODS: Consecutive high-risk patients of a western European cohort who underwent repeated liver MRI for HCC screening were included. Lesions were registered according to the Liver Reporting & Data System (LIRADS) 2018. HCC was staged as very early stage HCC (BCLC stage 0) and more advanced stages of HCC (BCLC stage A-D). Differences in time interval between MRI's for BCLC stage 0 and stage A-D were calculated with the Mann-Whitney U test. The HCC cumulative incidence at one-, three- and five years was calculated with the Kaplan Meier estimator. RESULTS: From 2010 to 2019 a total of 240 patients were included (71% male; median age: 57 years; IQR: 50-64 years) with 1350 MRI's. Most patients (83 %) had cirrhosis with hepatitis C as the most common underlying cause. Patients underwent on average four MRI's (IQR: 3-7). Forty-two patients (17.5%) developed HCC (52 HCC lesions: 43 LIRADS-5, eight LIRADS-4, and one LIRADS-TIV). Eighteen patients (43%) had BCLC stage 0 HCC with a significant shorter screening time interval (10 months; IQR: 6-21) compared to patients with BCLC stage A-D (21 months; IQR: 10-32) (p = 0.03). Thirty seven percent of patients with a LIRADS-3 lesion (n=43) showed HCC development within twelve months (median: 7.4 months). One, three- and five-year HCC cumulative incidence in cirrhotic patients was 1%, 10% and 17%, respectively. CONCLUSION: High-risk patients who underwent surveillance with contrast-enhanced MRI developed HCC in 17.5 % during a follow up period of over 4 years median. Very early stage HCC was seen in compensated cirrhosis after a median time interval of 10 months. Later stages of HCC were related to prolonged screening time interval (median 21 months).

18 F-FDG PET/MRI for restaging esophageal cancer after neoadjuvant chemoradiotherapy.

PURPOSE: The purpose of this study was to investigate whether 18F-fluorodeoxyglucose ( 18 F-FDG) PET/MRI may potentially improve tumor detection after neoadjuvant chemoradiotherapy (nCRT) for esophageal cancer. METHODS: This was a prospective, single-center feasibility study. At 6-12 weeks after nCRT, patients underwent standard 18 F-FDG PET/computed tomography (CT) followed by PET/MRI, and completed a questionnaire to evaluate burden. Two teams of readers either assessed the 18 F-FDG PET/CT or the 18 F-FDG PET/MRI first; the other scan was assessed 1 month later. Maximum standardized uptake value corrected for lean body mass (SUL max ) and mean apparent diffusion coefficient (ADC mean ) were measured at the primary tumor location. Histopathology of the surgical resection specimen served as the reference standard for diagnostic accuracy calculations. When patients had a clinically complete response and continued active surveillance, response evaluations until 9 months after nCRT served as a proxy for ypT and ypN (i.e. 'ycT' and 'ycN'). RESULTS: In the 21 included patients [median age 70 (IQR 62-75), 16 males], disease recurrence was found in the primary tumor in 14 (67%) patients (of whom one ypM+, detected on both scans) and in locoregional lymph nodes in six patients (29%). Accuracy (team 1/team 2) to detect yp/ycT+ with 18 F-FDG PET/MRI vs. 18 F-FDG PET/CT was 38/57% vs. 76/61%. For ypN+, accuracy was 63/53% vs. 63/42%, resp. Neither SUL max (both scans) nor ADC mean were discriminatory for yp/ycT+ . Fourteen of 21 (67%) patients were willing to undergo a similar 18 F-FDG PET/MRI examination in the future. CONCLUSION: 18 F-FDG PET/MRI currently performs comparably to 18 F-FDG PET/CT. Improvements in the scanning protocol, increasing reader experience and performing serial scans might contribute to enhancing the accuracy of tumor detection after nCRT using 18 F-FDG PET/MRI. TRIAL REGISTRATION: Netherlands Trial Register NL9352.