Background: Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) with ¹⁷⁷Lu-labeled PSMA ligands has achieved remarkable results in advanced disease stages of metastatic castration-resistant prostate cancer (mCRPC). However, not all patients benefit from this therapy. Different treatment responses could be explained by tumor heterogeneity triggered by progression and the number of prior treatments. PSMA-negative lesions can be missed on PSMA ligand PET/CT, which subsequently results in an underestimation of tumor burden. Conversely, high FDG uptake may also be an indicator of tumor aggressiveness and thus a poor prognostic marker for response to RLT and overall survival (OS). The aim of this analysis was to investigate the prognostic value of combined PSMA ligand PET/CT and [¹⁸F]fluorodeoxyglucose (FDG) PET/CT for outcome prediction in patients undergoing RLT. Materials and methods: This bicentric analysis included 54 patients with mCRPC who underwent both FDG and PSMA ligand PET/CT imaging before RLT. In all patients, the pattern of PSMA ligand and FDG uptake was visually assessed. Patients with at least one FDG-positive, but PSMA-negative (FDG+/PSMA−) lesions were compared to patients without any FDG+/PSMA− lesions. A log-rank analysis was used to assess the difference in OS between subgroups. Results: Median OS was 11 ± 1.8 months (95% CI 7.4–14.6). A significantly lower OS (p < 0.001) was found in patients with at least one FDG+/PSMA− lesion at baseline PET/CTs (n = 18) with a median OS of 6.0 ± 0.5 months (95% CI: 5.0–7.0 months). In comparison, patients without any FDG+/PSMA− lesions (n = 36) had a median OS of 16.0 ± 2.5 months (95% CI: 11.2–20.8 months). Conclusion: FDG+/PSMA− lesions are a negative predictor of overall survival in patients with mCRPC undergoing RLT. However, it remains to be determined if patients with FDG+/PSMA− lesions should be excluded from PSMA RLT.

Background: Labelled with lutetium-177, the urea-based small molecules PSMA I&T and PSMA-617 are the two agents most frequently used for radioligand therapy (RLT) in patients with advanced metastatic castration-resistant and prostate-specific membrane antigen (PSMA) expressing prostate cancer (mCRPC). In this matched-pair analysis, we aimed to compare the toxicity and efficacy of both agents for PSMA-directed RLT. Materials and methods: A total of 110 mCRPC patients from two centres were accrued, 55 individuals treated with [¹⁷⁷Lu]Lu-PSMA I&T, and a matched cohort of 55 patients treated with [¹⁷⁷Lu]Lu-PSMA-617. Matching criteria included age at the first cycle, Gleason score, prostate-specific antigen (PSA) values, and previous taxane-based chemotherapy. Using common terminology criteria for adverse events (CTCAE v. 5.0), toxicity profiles were investigated (including bone marrow and renal toxicity). Overall survival (OS) between both groups was compared. Results: Toxicity assessment revealed grade III anaemia in a single patient (1.8%) for [¹⁷⁷Lu]Lu-PSMA I&T and five (9.1%) for [¹⁷⁷Lu]Lu-PSMA-617. In addition, one (1.9%) grade III thrombopenia for [¹⁷⁷Lu]Lu-PSMA-617 was recorded. Apart from that, no other grade III/IV toxicities were present. A median OS of 12 months for patients treated with [¹⁷⁷Lu]Lu-PSMA I&T did not differ significantly when compared to patients treated with [¹⁷⁷Lu]Lu-PSMA-617 (median OS, 13 months; P = 0.89). Conclusion: In this matched-pair analysis of patients receiving one of the two agents most frequently applied for PSMA RLT, the rate of clinically relevant toxicities was low for both compounds. In addition, no relevant differences for OS were observed.

Purpose: We aimed to determine the impact of fibroblast activation protein inhibitor (FAPI)–directed molecular imaging on staging and therapeutic management in patients affected with digestive system tumors when compared with guideline-compatible imaging (GCI). Patients and Methods: Thirty-two patients with tumors of the digestive system were included: colon adenocarcinoma, 2/32 (6.3%); hepatocellular carcinoma (HCC), 6/32 (18.8%); pancreatic duct adenocarcinoma (PDAC), 6/32 (18.8%), and gastroenteropancreatic neuroendocrine neoplasms, 18/32 (56.3%). All patients underwent GCI and ⁶⁸Ga-FAPI-04 PET/CT within median 4 days. Staging outcomes and subsequent treatment decisions were compared between GCI and ⁶⁸Ga-FAPI-04 PET/CT. Results: Compared with GCI, ⁶⁸Ga-FAPI-04 PET/CT led to staging changes in 15/32 patients (46.9%). Among those, downstaging was recorded in 3/15 cases (20.0%) and upstaging in the remaining 12/15 patients (HCC, 4/12 [33.3%]; PDAC, 4/12 [33.3%]; neuroendocrine neoplasms, 3/12 [25%]; colon adenocarcinoma, 1/12 [8.3%]). Therapeutic management was impacted in 8/32 patients (25.0%), including 4 instances of major and 4 instances of minor therapeutic changes. The highest proportion of treatment modifications was observed in patients diagnosed with PDAC and HCC in 6/8 (75%). Conclusions: In patients affected with digestive system tumors, ⁶⁸Ga-FAPI-04 PET/CT resulted in staging changes in more than 46% and therapeutic modifications in 25% of the cases, in particular in patients with HCC and PDAC. In clinical routine, such findings may favor a more widespread adoption of FAP-directed imaging in those tumor types.

Background: Quantification of [⁶⁸ Ga]-labeled PSMA PET predicts response in patients with prostate cancer (PC) who undergo PSMA-targeted radioligand therapy (RLT). Given the increasing use [¹⁸F]-labeled radiotracers, we aimed to determine whether the uptake derived from [¹⁸F]PSMA-1007 PET can also identify responders and to assess its prognostic value relative to established clinical parameters. Methods: We retrospectively analyzed 103 patients with metastatic, castration-resistant PC who were treated with [¹⁷⁷Lu]Lu-PSMA I&T. We calculated SUV_mean, SUV_max, PSMA-avid tumor volume (TV), and total lesion PSMA (defined as PSMA-TV*SUV_mean) on pre-therapeutic [¹⁸F]PSMA-1007 PET. Laboratory values for hemoglobin, C-reactive protein (CRP), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), and alkaline phosphatase (AP) were also collected prior to RLT. We performed univariable Cox regression followed by multivariable and Kaplan–Meier analyses with overall survival (OS) serving as endpoint. Last, we also computed a risk factor (RF) model including all items reaching significance on multivariable analysis to determine whether an increasing number of RFs can improve risk stratification. Results: A total of 48 patients died and median OS was 16 months. On univariable Cox regression, SUV_mean, CRP, LDH, hemoglobin, and the presence of liver metastases were significantly associated with OS. On multivariable Cox regression, the following significant prognostic factors for OS were identified: SUV_mean (per unit, HR, 0.91; P = 0.04), the presence of liver metastases (HR, 2.37; P = 0.03), CRP (per mg/dl, HR, 1.13; P = 0.003), and hemoglobin (per g/dl, HR, 0.76; P < 0.01). Kaplan–Meier analysis showed significant separation between patients with a SUV_mean below or above a median SUV_mean of 9.4 (9 vs 19 months, HR 0.57; P = 0.03). Of note, patients with only one RF (median OS not reached) showed longest survival compared to patients with two (11 months; HR 2.43 95% CI 1.07–5.49, P = 0.02) or more than two RFs (7 months; HR 3.37 95% CI 1.62–7.03, P < 0.001). Conclusion: A lower SUV_mean derived from [¹⁸F]PSMA-1007, higher CRP, lower hemoglobin, and the presence of liver metastases are associated with reduced OS in patients undergoing RLT. An early RF model also demonstrated that an increasing number of those factors is linked to worse outcome, thereby emphasizing the importance of clinical and imaging parameters for adequate risk stratification.

We aimed to elucidate the diagnostic potential of the C-X-C motif chemokine receptor 4 (CXCR4)-directed positron emission tomography (PET) tracer ⁶⁸Ga-Pentixafor in patients with poorly differentiated neuroendocrine carcinomas (NEC), relative to the established reference standard ¹⁸F-FDG PET/computed tomography (CT). In our database, we retrospectively identified 11 treatment-naïve patients with histologically proven NEC, who underwent ¹⁸F-FDG and CXCR4-directed PET/CT for staging and therapy planning. The images were analyzed on a per-patient and per-lesion basis and compared to immunohistochemical staining (IHC) of CXCR4 from PET-guided biopsies. ⁶⁸Ga-Pentixafor visualized tumor lesions in 10/11 subjects, while¹⁸F-FDG revealed sites of disease in all 11 patients. Although weak to moderate CXCR4 expression could be corroborated by IHC in 10/11 cases, ¹⁸F-FDG PET/CT detected significantly more tumor lesions (102 vs. 42; total lesions, n = 107; p < 0.001). Semi-quantitative analysis revealed markedly higher ¹⁸F-FDG uptake as compared to ⁶⁸Ga-Pentixafor (maximum and mean standardized uptake values (SUV) and tumor-to-background ratios (TBR) of cancerous lesions, SUV_max: 12.8 ± 9.8 vs. 5.2 ± 3.7; SUV_mean: 7.4 ± 5.4 vs. 3.1 ± 3.2, p < 0.001; and, TBR 7.2 ± 7.9 vs. 3.4 ± 3.0, p < 0.001). Non-invasive imaging of CXCR4 expression in NEC is inferior to the reference standard ¹⁸F-FDG PET/CT.

Introduction: Quantitative evaluation of prostate-specific membrane antigen (PSMA)- targeting positron emission tomography/computer tomography (PSMA PET/CT) remains challenging but is urgently needed for the use of standardized PET-based response criteria, such as the PSMA PET/CT consensus statement or RECIP 1.0. A recent study evaluated the prognostic value of whole-body tumor volume using a semiautomatical method relying on a 50% threshold of maximum lesion standardized uptake value (PSMA_TV50). In the present study, we analyzed the suitability of this approach comparing ¹⁸F-PSMA-1007 to ⁶⁸Ga-PSMA-11 PET/CT scans and the potential of PSMA_TV50 for the prediction of overall survival (OS) in patients before ¹⁷⁷Lu-PSMA-radioligand therapy (PSMA RLT). Moreover, PSMA_TV50 was integrated into the PSMA PET/CT consensus statement as well as RECIP 1.0 and the prognostic value of these response classification systems was compared. Methods: This retrospective study included 70 patients with metastatic castration-resistant prostate cancer undergoing PSMA RLT. 33 patients were monitored by ⁶⁸Ga-PSMA-11 PET/CT and 37 patients by ¹⁸F-PSMA-1007 PET/CT. PET/CT scans before (baseline) and at the end of PSMA RLT after 2-4 cycles (follow-up) were separately analyzed by two readers. PSMA_TV50 at baseline and its change to follow-up (ΔPSMA_TV50; expressed as a ratio) were correlated with OS using Cox proportional hazard regression. The results of both subgroups were compared. The integration of ΔPSMA_TV50 in existing response classification systems was evaluated. To assess and compare the discriminatory strength of these classification systems, Gönen & Heller concordance probability estimates (CPE) were calculated. Results: PSMA_TV50-determination was technically feasible in all examinations. A higher PSMA_TV50 at baseline and a higher ΔPSMA_TV50 were strongly associated with a shorter OS for both ⁶⁸Ga-PSMA-11 (PSMA_TV50: HR 1.29 [1.05 – 1.55], p=0.009; ΔPSMA_TV50: HR 1.83 [1.08 – 3.09], p=0.024) and ¹⁸F-PSMA-1007 (PSMA_TV50: HR 1.84 [1.13 – 2.99], p=0.014; ΔPSMA_TV50: HR 1.23 [1.04 – 1.51], p=0.03). Response assessment provided high discriminatory power for OS for the PSMA PET/CT consensus statement (CPE 0.73) as well as RECIP 1.0 (CPE 0.74). Conclusion: PSMA_TV50 and ΔPSMA_TV50 proved to be predictive of OS not only for ⁶⁸Ga-PSMA-11 but also for ¹⁸F-PSMA-1007 PET/CT scans. Subsequent integration of ΔPSMA_TV50 into the PSMA PET/CT consensus statement and RECIP 1.0 provided equally high prognostic value for both classification systems.