The recent development of quinoline-based PET tracers that act as fibroblast-activation-protein inhibitors (FAPIs) demonstrated promising preclinical and clinical results. FAP is overexpressed by cancer-associated fibroblasts of several tumor entities. Here, we quantify the tumor uptake on ⁶⁸Ga-FAPI PET/CT of various primary and metastatic tumors to identify the most promising indications for future application. Methods: ⁶⁸Ga-FAPI PET/CT scans were requested by various referring physicians according to individual clinical indications that were considered insufficiently covered by ¹⁸F-FDG PET/CT or other imaging modalities. All PET/CT was performed 1 h after injection of 122–312 MBq of ⁶⁸Ga-FAPI-04. We retrospectively identified 80 patients with histopathologically proven primary tumors or metastases or radiologically unequivocal metastatic lesions of histologically proven primary tumors. Tumor uptake was quantified by SUV_max and SUV_mean (60% isocontour). Results: Eighty patients with 28 different tumor entities (54 primary tumors and 229 metastases) were evaluated. The highest average SUV_max (>12) was found in sarcoma, esophageal, breast, cholangiocarcinoma, and lung cancer. The lowest ⁶⁸Ga-FAPI uptake (average SUV_max < 6) was observed in pheochromocytoma, renal cell, differentiated thyroid, adenoid cystic, and gastric cancer. The average SUV_max of hepatocellular, colorectal, head–neck, ovarian, pancreatic, and prostate cancer was intermediate (SUV 6–12). SUV varied across and within all tumor entities. Because of low background in muscle and blood pool (SUV_max < 2), the tumor-to-background contrast ratios were more than 3-fold in the intermediate and more than 6-fold in the high-intensity uptake group. Conclusion: Several highly prevalent cancers presented with remarkably high uptake and image contrast on ⁶⁸Ga-FAPI PET/CT. The high and rather selective tumor uptake may open up new applications for noninvasive tumor characterization, staging examinations, or radioligand therapy.

Prostate specific membrane antigen (PSMA) is a promising target in prostate cancer. Recently we started the first-in-man treatment with an alpha radionuclide labeled PSMA-ligand. While the case series is still ongoing, here we already report in advance about two patients with metastatic prostate cancer, progressive under multiple therapies and in highly challenging clinical situations, who showed complete responses to therapy with ²²⁵Ac-PSMA-617. Methods: ⁶⁸Ga-PSMA-11 PET/CT validated a PSMA-positive tumor phenotype. Activities of 100 kBq/kg body-weight of ²²⁵Ac-PSMA-617 were administered bi-monthly. PSA response and hematological toxicity were measured at least every four weeks. Restaging was again performed with ⁶⁸Ga-PSMA-11 PET/CT. Results: Both patients experienced a PSA decline below measurable and presented with complete imaging response. No relevant hematological toxicity was observed. Xerostomia was the only mentionable clinical side-effect. Conclusion: Targeted alpha therapy with ²²⁵Ac-PSMA-617, yet experimental, obviously offers a high potential to provide significant benefit to patients in critical condition, e. g. with diffuse red marrow infiltration and resistance against other therapies.

Purpose Since the introduction of positron emission tomography (PET) imaging with ⁶⁸Ga-PSMA-HBED-CC (=⁶⁸Ga-DKFZ-PSMA-11), this method has been regarded as a significant step forward in the diagnosis of recurrent prostate cancer (PCa). However, published data exist for small patient cohorts only. The aim of this evaluation was to analyse the diagnostic value of ⁶⁸Ga-PSMA-ligand PET/CT in a large cohort and the influence of several possibly interacting variables. Methods We performed a retrospective analysis in 319 patients who underwent ⁶⁸Ga-PSMA-ligand PET/CT from 2011 to 2014. Potential influences of several factors such as prostate-specific antigen (PSA) level and doubling time (DT), Gleason score (GSC), androgen deprivation therapy (ADT), age and amount of injected tracer were evaluated. Histological verification was performed in 42 patients after the ⁶⁸Ga-PSMA-ligand PET/CT. Tracer uptake was measured in 901 representative tumour lesions. Results In 82.8 % of the patients at least one lesion indicative of PCa was detected. Tumor-detection was positively associated with PSA level and ADT. GSC and PSA-DT were not associated with tumor-detection. The average maximum standardized uptake value (SUV_max) of tumour lesions was 13.3 ± 14.6 (0.7–122.5). Amongst lesions investigated by histology, 30 were false-negative in 4 different patients, and all other lesions (n = 416) were true-positive or true-negative. A lesion-based analysis of sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV) revealed values of 76.6 %, 100 %, 91.4 % and 100 %. A patient-based analysis revealed a sensitivity of 88.1 %. Of 116 patients available for follow-up, 50 received local therapy after ⁶⁸Ga-PSMA-ligand PET/CT. Conclusion ⁶⁸Ga-PSMA-ligand PET/CT can detect recurrent PCa in a high number of patients. In addition, the radiotracer is highly specific for PCa. Tumour detection is positively associated with PSA and ADT. ⁶⁸Ga-PSMA-ligand PET/CT can help delay systemic therapy of PCa.

Prostate-specific membrane antigen (PSMA) is an excellent target for radionuclide therapy of metastasized castration-resistant prostate cancer (mCRPC). Besides high affinity and long tumor retention, the DOTA-conjugated ligand PSMA-617 has low kidney uptake making it an excellent choice for therapeutic application. We retrospectively report our experience with ¹⁷⁷Lu-PSMA-617 targeted radionuclide therapy in a case series of mCRPC patients resistant to other treatments. Methods: Patients with PSMA-positive tumor phenotypes were selected by molecular imaging. 30 patients received 1-3 cycles of ¹⁷⁷Lu-PSMA-617. During therapy pharmacokinetics and radiation-dosimetry were evaluated. Blood cell count was checked every two weeks after the first and every four weeks after succeeding cycles. PSA was determined every four weeks. Radiological restaging was performed after three cycles. Results: 21/30 patients had a PSA response; in 13/30 the PSA decreased >50%. After 3 cycles 8/11 patients achieved a sustained PSA response (>50%) for over 24 weeks which also correlated with radiological response (decreased lesion number and size). Normally, acute hematotoxicity was mild. Diffuse bone marrow involvement was a risk factor for higher grade myelosuppression but could be identified by PSMA-imaging in advance. Xerostomia, nausea and fatigue occurred sporadically (<10%). Clearance of non-tumor-bound tracer is predominantly renal and widely completed by 48h. Safety dosimetry reveals kidney doses of approx. 0.75 Gy/GBq, red-marrow 0.03 Gy/GBq, salivary glands 1.4 Gy/GBq; irrespective of tumor burden and consistent on subsequent cycles. Mean tumor absorbed dose ranged 6-22 Gy/GBq during cycle-1. Conclusion: ¹⁷⁷Lu-PSMA-617 is a promising new option for therapy of mCRPC and deserves more attention in larger prospective trials.

The aim of this study was to develop a treatment protocol for ²²⁵Ac-PSMA-617 α-radiation therapy in advanced-stage, metastatic castration-resistant prostate cancer patients with prostate-specific membrane antigen (PSMA)–positive tumor phenotype. Methods: A dosimetry estimate was calculated on the basis of time–activity curves derived from serially obtained ¹⁷⁷Lu-PSMA-617 scans extrapolated to the physical half-life of ²²⁵Ac, assuming instant decay of unstable daughter nuclides. Salvage therapies empirically conducted with 50 (n = 4), 100 (n = 4), 150 (n = 2), and 200 kBq/kg (n = 4) of ²²⁵Ac-PSMA-617 were evaluated retrospectively regarding toxicity and treatment response. Eight of 14 patients received further cycles in either 2- or 4-mo intervals with identical or deescalated activities. Results: Dosimetry estimates for 1 MBq of ²²⁵Ac-PSMA-617 assuming a relative biologic effectiveness of 5 revealed mean doses of 2.3 Sv for salivary glands, 0.7 Sv for kidneys, and 0.05 Sv for red marrow that are composed of 99.4% α, 0.5% β, and 0.1% photon radiation, respectively. In clinical application, severe xerostomia became the dose-limiting toxicity if treatment activity exceeded 100 kBq/kg per cycle. At 100 kBq/kg, the duration of prostate-specific antigen decline was less than 4 mo, but if therapy was repeated every 2 mo patients experienced additive antitumor effects. Treatment activities of 50 kBq/kg were without toxicity but induced insufficient antitumor response in these high-tumor-burden patients. Remarkable antitumor activity by means of objective radiologic response or tumor marker decline was observed in 9 of 11 evaluable patients. Conclusion: For advanced-stage patients, a treatment activity of 100 kBq/kg of ²²⁵Ac-PSMA-617 per cycle repeated every 8 wk presents a reasonable trade-off between toxicity and biochemical response.