Study protocol of a multicenter prospective [¹⁸F]F-FAPI PET-CT imaging study in patients with cancer of unknown primary

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Abstract Background Cancer of unknown primary (CUP) is defined by the presence of metastatic disease without an identified primary tumor despite comprehensive diagnostics. The absence of a known primary tumor creates substantial diagnostic uncertainty for patients and caregivers, and precludes site-specific, evidence-based treatments. Fibroblast activation protein inhibitor (FAPI) PET tracers have recently gained attention as promising alternatives to [ 18 F]fluoro-2-deoxy-d-glucose ([ 18 F]FDG), as they selectively target cancer-associated fibroblasts within the tumor microenvironment and demonstrate low physiological uptake in normal tissues. This favorable biodistribution yields high tumor-to-background contrast, potentially overcoming the limitations of [¹⁸F]FDG and enhancing diagnostic performance in patients with CUP. Methods This investigator-initiated, patient advocacy supported, multicenter, prospective clinical trial evaluates the diagnostic performance of the novel radiotracer [¹⁸F]F-FAPI for primary tumor detection in patients with CUP. Fifty patients (aged ≥ 18 year) diagnosed with CUP after a standard diagnostic work-up, including [ 18 F]FDG PET-CT, will be recruited in six medical centers throughout the Netherlands. Participation in the study involves a single [¹⁸F]F-FAPI PET-CT scan. Images will be centrally interpreted by two independent nuclear medicine physicians or nuclear radiologists, with a consensus report and recommendations provided to the treating physician. A central Truth Panel of multidisciplinary experts will review all pseudonymized clinical data collected up to six months after the [¹⁸F]F-FAPI PET-CT, including whole genome sequencing, pathology, and additional imaging, to assess the clinical impact and added diagnostic value of [¹⁸F]F-FAPI PET-CT. Patient recruitment commenced in July 2024. The study will be completed after the six-month follow-up of the last enrolled participant has been completed. Discussion This study aims to determine the utility of [¹⁸F]F-FAPI PET-CT in identifying the primary tumor in CUP patients with inconclusive results from conventional diagnostics, including [¹⁸F]FDG PET-CT. We hypothesize that [¹⁸F]F-FAPI PET-CT will identify the primary tumor in at least 15% of cases, potentially expediting the diagnostic process, enabling site-specific treatment, and improving patient outcomes. Trial registration Clinicaltrials.gov, NCT06644716. Registered 04 October 2024 Retrospectively registered, https//clinicaltrials.gov/study/NCT06644716.