This was a prospective study in PCa patients with suspected bone metastases to evaluate the performance of PSMA PET/CT compared to fluoride PET/CT. The results suggested that PSMA PET/CT was able to detect most of the bone lesions (83%) that were positive on fluoride PET/CT.
The usefulness of PSMA PET/CT has primarily been investigated with a focus on localizing biochemical relapse of PCa [21, 25, 28]. A number of studies (summarized in supplementary table 1) have investigated the diagnostic accuracy of PSMA PET/CT regarding bone metastasis compared to BS [29, 30]. In addition, several studies compared the diagnostic performance of several clinically available imaging modalities in localizing bone spread in PCa patients [31–37]. These studies showed better diagnostic performance of fluoride PET/CT and PSMA PET/CT compared to other modalities such as BS, SPECT/CT, WB-MRI, and choline PET/CT [see supplementary Table 1 for details]. Further, PSMA PET/CT showed additional value with improved specificity but with an overlapping sensitivity in comparison to fluoride PET/CT. The results from this study on comparison of PSMA PET/CT with fluoride PET/CT were also in line with these studies.
One important finding from this study is a higher detection rate of fluoride PET/CT compared to -PSMA PET/CT (699 vs 579 bone lesions). In comparison to our study, a retrospective study with a smaller data set (n=16) conducted by Uprimny et al. also documented higher detection rate of fluoride PET/CT [38]. In that study, the authors observed low uptake of PSMA in osteosclerotic lesions similar to [28], stated as the possible explanation for low detection rate of bone lesions on PSMA PET/CT. In concordance, we also noticed overall low intensity of PSMA uptake in sclerotic bone lesions (Fig. 4). However, PSMA-PET had an influential role with its ability to detect soft-tissue PCa spread. In seven patients without bone disease on both PET scans, the presence of lymph node lesions on PSMA-PET/CT changed the treatment decision. We used 68Ga-PSMA-11 in this study, but the superior sensitivity of 18F-fluoride for bone lesions has been documented for other PSMA-based radiopharmaceuticals [39].
Determining the presence of oligo-metastatic bone lesions, the potential targets for metastatic-directed therapies are clinically relevant as they can be irradiated. In the six patients who were identified with oligo-metastatic bone lesions with both PSMA and fluoride PET/CT, one patient showed additional non-osseous lesions on PSMA PET/CT, altering the treatment plan. The remaining five subjects received radiation therapy. Three additional patients were identified with oligo-metastatic bone status on PSMA PET/CT but had more than five lesions on fluoride PET/CT. In addition to bone lesions, PSMA PET/CT also showed either local relapse or lymph node lesions in these patients which influenced the treatment management. However, this cohort is not large enough to determine the added value of PSMA PET/CT treatment decisions related to oligometastatic disease.
The choice of imaging techniques for restaging of PCa at a given centre depends on local parameters such as cost-effectiveness, accessibility and expertise. Many hospitals around the world still use BS along with an abdominal CE-CT scan as standard-of-care in the diagnostic workup. Although CE-CT has limited sensitivity [40], findings particularly of skeletal lesions from CE-CT together with bone scan findings has clinical implication in many hospitals where access to PET/CT imaging is limited. Hence, comparison of CE-CT findings with PSMA PET/CT is relevant to confirm the better diagnostic performance of the latter. Fluoride PET/CT is generally considered superior to 99mTc-MDP-BS and 99mTc-MDP-SPECT/CT for detection of bone metastasis [35, 41, 42]. In further support, few studies evaluated the impact of fluoride PET/CT on patient prognosis [43, 44]. At our hospital, fluoride PET/CT has been recommended over BS in PCa re-staging to locate early signs of bone disease and is generally performed with CE-CT to detect soft tissue lesions.
Using follow-up scanning we could show that some lesions are detected earlier with fluoride PET/CT than with PSMA PET/CT. In none of these cases did the higher sensitivity of fluoride PET/CT lead to therapy changes and the measured tumour burden was similar for both tracers. However, equivocal skeletal findings on fluoride PET/CT are relatively common and contribute to false positive cases [32, 35], which might require additional diagnostic procedures. In this study, we also found equivocal bones lesions on PSMA PET/CT, but the overall perception is that this is a lesser problem with PSMA than with fluoride PET/CT. In addition, PSMA PET/CT provided additional information in detecting local recurrences and lymph node metastases, thus influencing the management, as seen in 7 subjects in our current study.
Based on this study and the vast literature already published, 68Ga-PSMA PET/CT is a highly relevant first-line imaging modality in recurrent PCa. However, Fluoride PET/CT had a significantly higher detection rate for bone metastases and could be a relevant complement to PSMA-PET in certain scenarios. PSMA-expression might be reduced or absent in dedifferentiated PCa and a discrepancy between PSA levels and PSMA-PET findings should potentially trigger additional imaging with higher sensitivity in biochemical relapses after treatments with curative intent [45]. PSMA PET/CT followed by fluoride PET/CE-CT might also be a relevant combination for ruling out PSMA-negative lesions before treatment with PSMA-targeted radionuclide therapies.
This study has several limitations. It was based on a small group of patients with high suspicion for widespread disease involving bone, introducing some bias. A standard reference, preferably histological reports, to confirm the discrepant findings of PET imaging is missing. However, accessing bone for biopsy collection is neither ethically nor practically possible in all lesions. Follow-up scans with optimal imaging modalities were not available in all patients.