Stefan Alexander Koerber

BACKGROUND Salvage radiation therapy (sRT) is often the sole curative option in patients with biochemical recurrence after radical prostatectomy. After sRT, we developed and validated a nomogram to predict freedom from biochemical failure. OBJECTIVE This study aims to evaluate prostate-specific membrane antigen–positron emission tomography (PSMA-PET)–based sRT efficacy for postprostatectomy prostate-specific antigen (PSA) persistence or recurrence. Objectives include developing a random survival forest (RSF) model for predicting biochemical failure, comparing it with a Cox model, and assessing predictive accuracy over time. Multinational cohort data will validate the model’s performance, aiming to improve clinical management of recurrent prostate cancer. METHODS This multicenter retrospective study collected data from 13 medical facilities across 5 countries: Germany, Cyprus, Australia, Italy, and Switzerland. A total of 1029 patients who underwent sRT following PSMA-PET–based assessment for PSA persistence or recurrence were included. Patients were treated between July 2013 and June 2020, with clinical decisions guided by PSMA-PET results and contemporary standards. The primary end point was freedom from biochemical failure, defined as 2 consecutive PSA rises >0.2 ng/mL after treatment. Data were divided into training (708 patients), testing (271 patients), and external validation (50 patients) sets for machine learning algorithm development and validation. RSF models were used, with 1000 trees per model, optimizing predictive performance using the Harrell concordance index and Brier score. Statistical analysis used R Statistical Software (R Foundation for Statistical Computing), and ethical approval was obtained from participating institutions. RESULTS Baseline characteristics of 1029 patients undergoing sRT PSMA-PET–based assessment were analyzed. The median age at sRT was 70 (IQR 64-74) years. PSMA-PET scans revealed local recurrences in 43.9% (430/979) and nodal recurrences in 27.2% (266/979) of patients. Treatment included dose-escalated sRT to pelvic lymphatics in 35.6% (349/979) of cases. The external outlier validation set showed distinct features, including higher rates of positive lymph nodes (47/50, 94% vs 266/979, 27.2% in the learning cohort) and lower delivered sRT doses (<66 Gy in 57/979, 5.8% vs 46/50, 92% of patients; P<.001). The RSF model, validated internally and externally, demonstrated robust predictive performance (Harrell C-index range: 0.54-0.91) across training and validation datasets, outperforming a previously published nomogram. CONCLUSIONS The developed RSF model demonstrates enhanced predictive accuracy, potentially improving patient outcomes and assisting clinicians in making treatment decisions.

Purpose: Due to limited imaging options, the visualization of a local relapse of prostate cancer used to pose a considerable challenge. However, since the integration of ¹⁸F-PSMA-1007-PET/CT into the clinic, a relapsed tumor can now easily be detected by hybrid imaging. The present study aimed to evaluate and map the allocate relapse in a large cohort of prostate cancer patients focusing on individual patient management conclusions for radiation therapy. Procedures: The current study included 135 men with prostate cancer after primary treatment who underwent ¹⁸F-PSMA-1007-PET/CT due to biochemical relapse detecting a local relapse. Imaging data were reassessed and analyzed with regard to relapse locations. For the correlation of tumor foci with clinical data, we used binary logistic regression models as well as the Kruskal–Wallis test and Mann–Whitney test. Results: In total, 69.6% of all patients (mean age: 65 years) underwent prostatectomy while 30.4% underwent radiation therapy. PET imaging detected most frequently a unifocal relapse (72.6%). There was a statistically significantly higher rate of ipsilateral cases among the relapsed tumors. Comparing both treatment approaches, tumors relapsed most commonly within the posterior region after surgery and transition/peripheral zone after radiation therapy, respectively. Conclusions: The present study confirms that ¹⁸F-PSMA-1007-PET/CT is highly suitable for the localization and allocation of a local relapse in patients with prostate cancer. The data enable further optimizing dose prescriptions and target volume delineations of radiation therapy in the future.

Background: Normofractionated radiation regimes for definitive prostate cancer treatment usually extend over 7–8 weeks. Recently, moderate hypofractionation with doses per fraction between 2.2 and 4 Gy has been shown to be safe and feasible with oncologic non-inferiority compared to normofractionation. Radiobiologic considerations lead to the assumption that prostate cancer might benefit in particular from hypofractionation in terms of tumor control and toxicity. First data related to ultrahypofractionation demonstrate that the overall treatment time can be reduced to 5–7 fractions with single doses > 6 Gy safely, even with simultaneous focal boosting of macroscopic tumor(s). With MR-guided linear accelerators (MR-linacs) entering clinical routine, invasive fiducial implantations become unnecessary. The aim of the multicentric SMILE study is to evaluate the use of MRI-guided stereotactic radiotherapy for localized prostate cancer in 5 fractions regarding safety and feasibility. Methods: The study is designed as a prospective, one-armed, two-stage, multi-center phase-II-trial with 68 patients planned. Low- and intermediate-risk localized prostate cancer patients will be eligible for the study as well as early high-risk patients (cT3a and/or Gleason Score ≤ 8 and/or PSA ≤ 20 ng/ml) according to d’Amico. All patients will receive definitive MRI-guided stereotactic radiation therapy with a total dose of 37.5 Gy in 5 fractions (single dose 7.5 Gy) on alternating days. A focal simultaneous integrated boost to MRI-defined tumor(s) up to 40 Gy can optionally be applied. The primary composite endpoint includes the assessment of urogenital or gastrointestinal toxicity ≥ grade 2 or treatment-related discontinuation of therapy. The use of MRI-guided radiotherapy enables online plan adaptation and intrafractional gating to ensure optimal target volume coverage and protection of organs at risk. Discussion: With moderate hypofractionation being the standard in definitive radiation therapy for localized prostate cancer at many institutions, ultrahypofractionation could be the next step towards reducing treatment time without compromising oncologic outcomes and toxicities. MRI-guided radiotherapy could qualify as an advantageous tool as no invasive procedures have to precede in therapeutic workflows. Furthermore, MRI guidance combined with gating and plan adaptation might be essential in order to increase treatment effectivity and reduce toxicity at the same time.

Zusammenfassung Hintergrund Klinische Studien zeigen für die Lokaltherapie von Primarius und Metastasen urologischer Tumoren im metastasierten Stadium Vorteile gegenüber einer alleinigen Systemtherapie und definieren ein potenziell kuratives oligometastasiertes Stadium. Fragestellung Bildgebungsmodalitäten zur sensitiven lokalen und systemischen Diagnostik von urologischen Tumoren im oligometastasierten Stadium werden verglichen. Material und Methode Es wird eine Übersicht über und Zusammenfassung von vergleichenden Studien zu Gütekriterien unterschiedlicher Bildgebungsmodalitäten zusammengestellt. Ergebnisse Abhängig vom betroffenen Organsystem und der Tumorentität bestimmen konventionelle Bildgebungsmodalitäten wie Computertomographie (CT) und Knochenszintigraphie weiterhin die Praxis in Deutschland. Die Hybridbildgebung (PET [Positronenemissionstomographie]/CT) konnte sich in den vergangenen Jahren aufgrund überlegener Gütekriterien in der Onkologie und insbesondere beim Prostatakarzinom durch neue Liganden (PSMA, „prostate-specific membrane antigen“) etablieren. Bei allen Entitäten ist die Entwicklung neuer Bildgebungsliganden (z. B. FAP-Liganden [„fibroblast activated protein“]) und deren klinische Anwendung Gegenstand aktueller Forschung. Schlussfolgerungen Die Entwicklung sensitiverer Bildgebungen durch neue Liganden besonders in der Nuklearmedizin legt die Grundlage zur exakten Definition oligometastasierter Stadien. Hierdurch werden Lokaltherapien möglich, die eine Progression oder Systemtherapie hinauszögern, aber auch kurative Therapieoptionen durch Behandlung sämtlicher Tumorlokalisationen ermöglichen können.

A fibroblast activation protein (FAP) is an atypical type II transmembrane serine protease with both endopeptidase and post-proline dipeptidyl peptidase activity. FAP is overexpressed in cancer-associated fibroblasts (CAFs), which are found in most epithelial tumors. CAFs have been implicated in promoting tumor cell invasion, angiogenesis and growth and their presence correlates with a poor prognosis. However, FAP can generally be found during the remodeling of the extracellular matrix and therefore can be detected in wound healing and benign diseases. For instance, chronic inflammation, arthritis, fibrosis and ischemic heart tissue after a myocardial infarction are FAP-positive diseases. Therefore, quinoline-based FAP inhibitors (FAPIs) bind with a high affinity not only to tumors but also to a variety of benign pathologic processes. When these inhibitors are radiolabeled with positron emitting radioisotopes, they provide new diagnostic and prognostic tools as well as insights into the role of the microenvironment in a disease. In this respect, they deliver additional information beyond what is afforded by conventional FDG PET scans that typically report on glucose uptake. Thus, FAP ligands are considered to be highly promising novel tracers that offer a new diagnostic and theranostic potential in a variety of diseases.

Purpose: A high expression of fibroblast activation protein (FAP) was observed in multiple sarcomas, indicating an enormous potential for PET/CT using ⁶⁸Ga-radiolabeled inhibitors of FAP (FAPI). Therefore, this retrospective study aimed to evaluate the role of the novel hybrid imaging probe for sarcomas as a first clinical evaluation. Methods: A cohort of 15 patients underwent ⁶⁸Ga-FAPI-PET/CT for staging or restaging. The acquisition of PET scans was performed 60 min after administration of 127 to 308 MBq of the tracer. The uptake of ⁶⁸Ga-FAPI in malignant tissue as well as in healthy organs was quantified by standardized uptake values SUVmean and SUVmax. Results: Excellent tumor-to-background ratios (> 7) could be achieved due to low background activity and high SUVmax in primary tumors (median 7.16), local relapses (median 11.47), and metastases (median 6.29). The highest uptake was found for liposarcomas and high-grade disease (range 18.86–33.61). A high SUVmax (> 10) was observed for clinically more aggressive disease. Conclusion: These preliminary findings suggest a high potential for the clinical use of ⁶⁸Ga-FAPI-PET/CT for patients diagnosed with sarcoma.