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

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.