Peptide Receptor Radionuclide Therapy of Neuroendocrine Tumors: Agonist, Antagonist and Alternatives.

Peptide receptor radionuclide therapy (PRRT) today is a well-established treatment strategy for patients with neuroendocrine tumors (NET). First performed already more than 30 years ago, PRRT was incorporated only in recent years into the major oncology guidelines, based on its proven efficacy and safety in clinical trials. Following the phase 3 NETTER-1 trial, which led to the final registration of the radiopharmaceutical Luthatera® for G1/G2 NET patients in 2017, the long-term results of the phase 3 NETTER-2 trial may pave the way for a new treatment option also for advanced G2/G3 patients as first-line therapy. The growing knowledge about the synergistic effect of combined therapies could also allow alternative (re)treatment options for NET patients, in order to create a tailored treatment strategy. The evolving thera(g)nostic concept could be applied for the identification of patients who might benefit from different image-guided treatment strategies. In this scenario, the use of dual tracer PET/CT in NET patients, using both [18F]F-FDG/[68Ga]Ga-DOTA-somatostatin analog (SSA) for diagnosis and follow-up, is under discussion and could also result in a powerful prognostic tool. In addition, alternative strategies based on different metabolic pathways, radioisotopes, or combinations of different medical approaches could be applied. A number of different promising "doors" could thus open in the near future for the treatment of NET patients - and the "key" will be thera(g)nostic!

Guiding principles on the education and practice of theranostics.

PURPOSE: The recent development and approval of new diagnostic imaging and therapy approaches in the field of theranostics have revolutionised nuclear medicine practice. To ensure the provision of these new imaging and therapy approaches in a safe and high-quality manner, training of nuclear medicine physicians and qualified specialists is paramount. This is required for trainees who are learning theranostics practice, and for ensuring minimum standards for knowledge and competency in existing practising specialists. METHODS: To address the need for a training curriculum in theranostics that would be utilised at a global level, a Consultancy Meeting was held at the IAEA in May 2023, with participation by experts in radiopharmaceutical therapy and theranostics including representatives of major international organisations relevant to theranostics practice. RESULTS: Through extensive discussions and review of existing curriculum and guidelines, a harmonised training program for theranostics was developed, which aims to ensure safe and high quality theranostics practice in all countries. CONCLUSION: The guiding principles for theranostics training outlined in this paper have immediate relevance for the safe and effective practice of theranostics.

Peptide receptor radionuclide therapy combinations for neuroendocrine tumours in ongoing clinical trials: status 2023.

A growing body of literature reports on the combined use of peptide receptor radionuclide therapy (PRRT) with other anti-tumuor therapies in order to anticipate synergistic effects with perhaps increased safety issues. Combination treatments to enhance PRRT outcome are based on improved tumour perfusion, upregulation of somatostatin receptors (SSTR), radiosensitization with DNA damaging agents or targeted therapies. Several Phase 1 or 2 trials are currently recruiting patients in combined regimens. The combination of PRRT with cytotoxic chemotherapy, capecitabine and temozolomide (CAPTEM), seems to become clinically useful especially in pancreatic neuroendocrine tumours (pNETs) with acceptable safety profile. Neoadjuvant PRRT prior to surgery, PRRT combinations of intravenous and intraarterial routes of application, combinations of PRRT with differently radiolabelled (alpha, beta, Auger) SSTR-targeting agonists and antagonists, inhibitors of immune checkpoints (ICIs), poly (ADP-ribose) polymerase-1 (PARP1i), tyrosine kinase (TKI), DNA-dependent protein kinase, ribonucleotide reductase or DNA methyltransferase (DMNT) are tested in currently ongoing clinical trials. The combination with [131I]I-MIBG in rare NETs (such as paraganglioma, pheochromocytoma) and new non-SSTR-targeting radioligands are used in the personalization process of treatment. The present review will provide an overview of the current status of ongoing PRRT combination treatments.

Somatostatin receptor subtype expression and radiomics from DWI-MRI represent SUV of [68Ga]Ga-DOTATOC PET in patients with meningioma.

OBJECTIVE: This retrospective study aimed to analyse the correlation between somatostatin receptor subtypes (SSTR 1-5) and maximum standardized uptake value (SUVmax) in meningioma patients using Gallium-68 DOTA-D-Phe1-Tyr3-octreotide Positron Emission Tomography ([68Ga]Ga-DOTATOC PET). Secondly, we developed a radiomic model based on apparent diffusion coefficient (ADC) maps derived from diffusion weighted magnetic resonance images (DWI MRI) to reproduce SUVmax. METHOD: The study included 51 patients who underwent MRI and [68Ga]Ga-DOTATOC PET before meningioma surgery. SUVmax values were quantified from PET images and tumour areas were segmented on post-contrast T1-weighted MRI and mapped to ADC maps. A total of 1940 radiomic features were extracted from the tumour area on each ADC map. A random forest regression model was trained to predict SUVmax and the model's performance was evaluated using repeated nested cross-validation. The expression of SSTR subtypes was quantified in 18 surgical specimens and compared to SUVmax values. RESULTS: The random forest regression model successfully predicted SUVmax values with a significant correlation observed in all 100 repeats (p < 0.05). The mean Pearson's r was 0.42 ± 0.07 SD, and the root mean square error (RMSE) was 28.46 ± 0.16. SSTR subtypes 2A, 2B, and 5 showed significant correlations with SUVmax values (p < 0.001, R2 = 0.669; p = 0.001, R2 = 0.393; and p = 0.012, R2 = 0.235, respectively). CONCLUSION: SSTR subtypes 2A, 2B, and 5 correlated significantly with SUVmax in meningioma patients. The developed radiomic model based on ADC maps effectively reproduces SUVmax using [68Ga]Ga-DOTATOC PET.

Pretest PSA and Restaging PSMA PET/CT Predict Survival in Biochemically Recurrent Prostate Cancer.

BACKGROUND: A biochemical recurrence (BCR) risk model was created based on pretest prostate specific antigen (PSA) and groupings by restaging prostate specific membrane antigen (PSMA) PET/CT. METHODS: A cohort of 1216 BCR patients were analyzed for overall survival (OS) according to the PSA threshold and restaging PSMA PET/CT. A Cox regression analysis of OS was carried out to detect significant clinical characteristics. RESULTS: In the cohort, 271 patients had a pretest PSA of <0.5 ng/mL and 945 patients had higher PSA values. The restaging PSMA PET/CT was positive for 834 patients and negative for 369. Of 1203 patients, 133 (11%) died, including 19 of the 369 (5%) patients without positive sites on the restaging PSMA PET/CT, 82 of the 711 (12%) with 1-5 positive sites, and 32 of the 123 (26%) with >5 positive sites. In the Cox regression analysis, four variables significantly predicted OS: treatment center, International Society of Urologic Pathology (ISUP) grade, pretest PSA threshold, and the grouping of positive sites on the restaging PSMA PET/CT. CONCLUSIONS: The pretest PSA and PSMA PET/CT were important for the OS of the BCR patients. The findings argue for the new BCR risk model and serve as framework for ongoing trials.

Real-world Outcomes and Predictive Biomarkers for 177Lutetium Prostate-specific Membrane Antigen Ligand Treatment in Metastatic Castration-resistant Prostate Cancer: A European Association of Urology Young Academic Urologists Prostate Cancer Working Group Multi-institutional Observational Study.

BACKGROUND: The European Association of Urology guidelines include the lutetium-177 (177Lu) PSMA-617 prostate-specific membrane antigen (PSMA) ligand as a therapy option for metastatic castration-resistant prostate cancer (mCRPC). A major challenge in clinical practice is to pursue a personalized treatment approach based on robust predictive biomarkers. OBJECTIVE: To assess the performance of 177Lu PSMA in real-world practice and to elaborate clinical biomarkers for evaluating treatment responses. DESIGN, SETTING, AND PARTICIPANTS: We conducted a retrospective observational study including 233 patients with mCRPC treated with 177Lu PSMA in eight high-volume European centers. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Baseline characteristics and clinical parameters during and after 177Lu PSMA treatment were documented. Correlations to treatment response were analyzed using χ2 and log-rank tests, with differences between groups with and without disease progression calculated using a Mann-Whitney U test. Univariate and multivariate-adjusted hazard ratios (HRs) were measured using Cox proportional hazards models. RESULTS AND LIMITATIONS: A prostate-specific antigen (PSA) decrease of ≥30% was observed in 41.7%, 63.5%, and 77.8% of patients after the first, second, and third treatment cycle, respectively. Restaging performed via PSMA positron emission tomography-computed tomography revealed that 33.7% of patients had an imaging-based response, including two patients with a complete response, while 13.4% had stable disease. The median time to progression was 5 mo and the median time until the start of a consecutive antineoplastic therapy was 8.5 mo. Of importance, a PSA decrease ≥30% after the first two cycles of 177Lu PSMA (1 cycle: p = 0.0003; 2 cycles: p = 0.004), absolute PSA after the first three cycles (1 cycle: p = 0.011; 2 cycles: p = 0.0005; 3 cycles: p = 0.002), and a PSA doubling time >6 mo (p = 0.009) were significantly correlated to treatment response. Furthermore, gamma-glutamyl transferase ≤31 U/L at the start of 177Lu PSMA therapy was correlated with 1.5 times higher risk of progression for patients without but not with visceral metastases (p = 0.046). CONCLUSIONS: 177Lu PSMA is an effective treatment option in mCRPC in the real-world setting. A PSA decrease ≥30% after the first two cycles is an early marker of response that can be easily implemented in clinical practice. PATIENT SUMMARY: 177Lu PSMA is a radioactive agent approved for treatment of advanced prostate cancer. We reviewed its use outside of clinical trials for patients treated at eight European centers. We found that 177Lu PSMA is an effective treatment option in real-world practice. A PSA (prostate-specific antigen) decrease of ≥30% after the first two therapy cycles is an early indicator of response to treatment and can be used in personalizing treatments for patients.

Joint EANM/SNMMI procedure guideline for the use of 177Lu-labeled PSMA-targeted radioligand-therapy (177Lu-PSMA-RLT).

Prostate-specific membrane antigen (PSMA) is expressed by the majority of clinically significant prostate adenocarcinomas, and patients with target-positive disease can easily be identified by PSMA PET imaging. Promising results with PSMA-targeted radiopharmaceutical therapy have already been obtained in early-phase studies using various combinations of targeting molecules and radiolabels. Definitive evidence of the safety and efficacy of [177Lu]Lu-PSMA-617 in combination with standard-of-care has been demonstrated in patients with metastatic castration-resistant prostate cancer, whose disease had progressed after or during at least one taxane regimen and at least one novel androgen-axis drug. Preliminary data suggest that 177Lu-PSMA-radioligand therapy (RLT) also has high potential in additional clinical situations. Hence, the radiopharmaceuticals [177Lu]Lu-PSMA-617 and [177Lu]Lu-PSMA-I&T are currently being evaluated in ongoing phase 3 trials. The purpose of this guideline is to assist nuclear medicine personnel, to select patients with highest potential to benefit from 177Lu-PSMA-RLT, to perform the procedure in accordance with current best practice, and to prepare for possible side effects and their clinical management. We also provide expert advice, to identify those clinical situations which may justify the off-label use of [177Lu]Lu-PSMA-617 or other emerging ligands on an individual patient basis.

Imaging Fibrosis.

Tissue injury in nonmalignant human disease can develop from either disproportionate inflammation or exaggerated fibrotic responses. The molecular and cellular fundamental of these 2 processes, their impact on disease prognosis and the treatment concept deviates fundamentally. Consequently, the synchronous assessment and quantification of these 2 processes in vivo is extremely desirable. Although noninvasive molecular techniques such as 18F-fluorodeoxyglucose PET offer insights into the degree of inflammatory activity, the assessment of the molecular dynamics of fibrosis remains challenging. The 68Ga-fibroblast activation protein inhibitor-46 may improve noninvasive clinical diagnostic performance in patients with both fibroinflammatory pathology and long-term CT-abnormalities after severe COVID-19.

Correction: von Eyben et al. A Risk Model for Patients with PSA-Only Recurrence (Biochemical Recurrence) Based on PSA and PSMA PET/CT: An Individual Patient Data Meta-Analysis. Cancers 2022, 14, 5461.

In the original publication [...].

Preliminary Clinical Experience with Cholecystokinin-2 Receptor PET/CT Using the 68Ga-Labeled Minigastrin Analog DOTA-MGS5 in Patients with Medullary Thyroid Cancer.

PET/CT with the new 68Ga-labeled minigastrin analog DOTA-dGlu-Ala-Tyr-Gly-Trp-(N-Me)Nle-Asp-1-Nal-NH2 (68Ga-DOTA-MGS5) was performed on patients with advanced medullary thyroid cancer (MTC) to evaluate cholecystokinin-2 receptor expression status. Methods: Six patients with advanced MTC underwent PET/CT with 68Ga-DOTA-MGS5. From the images acquired 1 and 2 h after injection, preliminary data on the biodistribution and tumor-targeting properties were evaluated in a retrospective analysis. Results: In total, 87 lesions with increased radiotracer uptake considered malignant were detected (2 local recurrences, 8 lymph node lesions, 27 liver lesions, and 50 bone lesions). In general, radiotracer accumulation in lesions was higher at 2 h than at 1 h after injection (mean SUVmax, 7.2 vs. 6.0, respectively; mean SUVmean, 4.4 vs. 3.6, respectively). Conclusion: The preliminary results clearly demonstrate the potential of 68Ga-DOTA-MGS5 PET/CT in detecting local recurrence and metastases in patients with advanced MTC.

[111In]In-CP04 as a novel cholecystokinin-2 receptor ligand with theranostic potential in patients with progressive or metastatic medullary thyroid cancer: final results of a GRAN-T-MTC Phase I clinical trial.

INTRODUCTION: Medullary thyroid cancer (MTC) is a rare malignant tumour of the parafollicular C-cells with an unpredictable clinical course and currently suboptimal diagnostic and therapeutic options, in particular in advanced disease. Overexpression of cholecystokinin-2 receptors (CCK2R) represents a promising avenue to diagnostic imaging and targeted therapy, ideally through a theranostic approach. MATERIALS AND METHODS: A translational study (GRAN-T-MTC) conducted through a Phase I multicentre clinical trial of the indium-111 labelled CP04 ([111In]In-CP04), a CCK2R-seeking ligand was initiated with the goal of developing a theranostic compound. Patients with proven advanced/metastatic MTC or short calcitonin doubling time were enrolled. A two-step concept was developed through the use of low- and high-peptide mass (10 and 50 µg, respectively) for safety assessment, with the higher peptide mass considered appropriate for therapeutic application. Gelofusine was co-infused in a randomized fashion in the second step for the evaluation of potential reduction of the absorbed dose to the kidneys. Imaging for the purpose of biodistribution, dosimetry evaluation, and diagnostic assessment were performed as well as pre-, peri-, and postprocedural clinical and biochemical assessment. RESULTS: Sixteen patients were enrolled. No serious adverse events after application of the compound at both peptide amounts were witnessed; transient tachycardia and flushing were observed in two patients. No changes in biochemistry and clinical status were observed on follow-up. Preliminary dosimetry assessment revealed the highest dose to urinary bladder, followed by the kidneys and stomach wall. The effective dose for 200 MBq of [111In]In-CP04 was estimated at 7±3 mSv and 7±1 mSv for 10 µg and 50 µg CP04, respectively. Administration of Gelofusine reduced the dose to the kidneys by 53%, resulting in the organ absorbed dose of 0.044±0.019 mSv/MBq. Projected absorbed dose to the kidneys with the use of [177Lu]Lu-CP04 was estimated at 0.9±0.4 Gy/7.4 GBq. [111In]In-CP04 scintigraphy was positive in 13 patients (detection rate of 81%) with superior diagnostic performance over conventional imaging. CONCLUSION: In the present study, [111In]In-CP04 was shown to be a safe and effective radiopharmaceutical with promising theranostic characteristics for patients with advanced MTC.

A Multi-Disciplinary Approach to Diagnosis and Treatment of Radionecrosis in Malignant Gliomas and Cerebral Metastases.

Radiation necrosis represents a potentially devastating complication after radiation therapy in brain tumors. The establishment of the diagnosis and especially the differentiation from progression and pseudoprogression with its therapeutic implications requires interdisciplinary consent and monitoring. Herein, we want to provide an overview of the diagnostic modalities, therapeutic possibilities and an outlook on future developments to tackle this challenging topic. The aim of this report is to provide an overview of the current morphological, functional, metabolic and evolving imaging tools described in the literature in order to (I) identify the best criteria to distinguish radionecrosis from tumor recurrence after the radio-oncological treatment of malignant gliomas and cerebral metastases, (II) analyze the therapeutic possibilities and (III) give an outlook on future developments to tackle this challenging topic. Additionally, we provide the experience of a tertiary tumor center with this important issue in neuro-oncology and provide an institutional pathway dealing with this problem.

Imaging Properties and Tumor Targeting of 68Ga-NeoBOMB1, a Gastrin-Releasing Peptide Receptor Antagonist, in GIST Patients.

Background: Gastrin-releasing peptide receptors (GRPRs) are molecular imaging targets in multiple malignancies. Recently, NeoBOMB1, a 68Ga-labelled antagonist to GRPRs, was developed for PET. Here we report the outcome of a Phase I/IIa clinical trial (EudraCT 2016-002053-38) describing diagnostic properties and covariates influencing uptake of 68Ga-NeoBOMB1 in oligometastatic gastrointestinal stromal tumor (GIST) patients. Methods: Nine patients with advanced GIST using PET/CT (computed tomography) were included. After kit-based 68Ga-NeoBOMB1 preparation with a licensed 68Ge/68Ga generator, 3 MBq/kg body weight were injected intravenously. PET/CT included dynamic and static PET scans 5, 12 and 18 min and 1, 2, and 3−4 h post injection (first six patients) and static PET scans 2 and 3−4 h post injection (last three participants). Tumor targeting was assessed on a per-lesion and per-patient basis. Results: Six patients showed visible radiotracer uptake in at least one tumor lesion. Seventeen out of 37 tumor lesions exhibited significant 68Ga-NeoBOMB1 uptake (median SUVmax 11.8 [range 2.8−51.1] 2 h p.i. and 13.2 [range 2.5−53.8] 3−4 h p.i) and improved lesion-to-background contrast over time. Five lesions (13.5%) were identified only by 68Ga-NeoBOMB1-PET, with no correlation on contrast-enhanced CT. Three patients showed no radiotracer accumulation in any lesions. Tracer uptake correlated with male sex (p < 0.0001), higher body mass index (p = 0.007), and non-necrotic lesion appearance (p = 0.018). There was no association with whole-lesion contrast enhancement, hepatic localization, mutational status, or disease duration. Conclusions: 68Ga-NeoBOMB1-PET exhibits variable tumor uptake in advanced-stage GIST patients, correlating with lesion vitality based on CT contrast uptake, opening the possibility of a theragnostic approach in selected cases.

A Risk Model for Patients with PSA-Only Recurrence (Biochemical Recurrence) Based on PSA and PSMA PET/CT: An Individual Patient Data Meta-Analysis.

An individual patient meta-analysis followed 1216 patients with PSA-only recurrence (biochemical recurrence, BCR) restaged with [68Ga]Ga-PSMA-11 PET/CT before the salvage treatment for median 3.5 years and analyzed the overall survival (OS). A new risk model included a good risk group with a prescan PSA < 0.5 ng/mL (26%), an intermediate risk group with a prescan PSA > 0.5 ng/mL and a PSMA PET/CT with 1 to 5 positive sites (65%), and a poor risk group with a prescan PSA > 0.5 ng/mL and a PSA PET/CT with > 5 positive sites (9%) (p < 0.0001, log rank test). The poor risk group had a five-year OS > 60%. Adding a BCR risk score by the European Association of Urology did not significantly improve the prediction of OS (p = 0.64). In conclusion, the restaging PSMA PET/CT markedly predicted the 5-year OS. The new risk model for patients with PSA-only relapse requires a restaging PSMA PET/CT for patients with a prescan PSA > 0.5 ng/mL and has a potential use in new trials aiming to improve the outcome for patients with PSA-only recurrence who have polysites prostate cancer detected on PSMA PET/CT.

Enhancing Clinical Diagnosis for Patients With Persistent Pulmonary Abnormalities After COVID-19 Infection: The Potential Benefit of 68 Ga-FAPI PET/CT.

PATIENTS AND METHODS: Six post COVID-19 patients suspected for pulmonary fibrosis were scheduled for dual-tracer PET/CT with 18 F-FDG and 68 Ga-fibroblast activation protein inhibitor (FAPI)-46. The uptake of 68 Ga-FAPI-46 in the involved lung was compared with a control group of 9 non-COVID-19 patients. Clinical data and PET/CT imaging were collected and analyzed. RESULTS: PET/CT revealed in all 6 pulmonary impaired patients the reduced glucose avidity on 18 F-FDG and clear positivity on 68 Ga-FAPI-46 PET/CT in comparison to the control group. CONCLUSIONS: Enhancing fibrotic repair mechanisms, 68 Ga-FAPI PET/CT may improve noninvasive clinical diagnostic performance in patients with long-term CT abnormalities after severe COVID-19. Although this study shows promising results, additional studies in larger populations are required to establish a general diagnostic guideline.