The present pilot study reports our preliminary experience on the use of 68Ga-PSMA and 68Ga-DOTA-RM2 PET/MRI imaging in high-risk prostate cancer staging.
Few studies have investigated prostate cancer by using both 68Ga-PSMA and 68Ga-DOTA-RM2 PET so far, both in the staging [15] and restaging setting of the disease [18, 19]
In our cohort of patients, differently to all the other published papers, all subjects have been studied by using a hybrid PET/MRI scanner both for 68Ga-PSMA and 68Ga-DOTA-RM2 radiotracers [15, 18, 19].
In fact, among the few published studies that investigated the role of this peculiar multitracer approach in PCa, PET/MRI and PET/CT have been used alternatively for 68Ga-PSMA and 68Ga-DOTA-RM2 PET scans [18, 19] or PET/CT have been adopted as the only hybrid imaging modality [15].
In the setting of PCa staging, Schollhammer and colleagues reported a clinical case of a patient undergoing PET/CT scans with 68Ga-PSMA, 68Ga-RM2 and 18F-Choline, while Fassbender et al. used 68Ga-PSMA PET/CT and 68Ga-Ga-RM2 PET/MRI to study eight patients with primary diagnosis of PCa [15, 24]. The same heterogeneity in terms of type of scanners used for patients’ scanning can be also observed in the few studies assessing the role 68Ga-PSMA and 68Ga-DOTA-RM2 in patients with recurrent PCa. The first study performing a comparative evaluation between these two radiotracers in recurrent PCa is the one by Minamimoto et al. In this pioneering work, comparing the biodistribution of 68Ga-PSMA-11 and 68Ga-RM2 in a small cohort of patients with biochemically recurrent PCa, PET/CT was adopted for 68Ga-PSMA studies while PET/MRI scanner was used for 68Ga-DOTA-RM2 PET acquisitions [18].
Similarly, Baratto et al. recently published a study on the use of 68Ga-PSMA and 68Ga-DOTA-RM2 in a cohort of patients with recurrent PCa, and compared the diagnostic performances of these two radiotracers. They showed that 68Ga-PSMA11 and 18F- DCFPyL might have a complementary role as they detect different sites of disease recurrence. Notably, the group used a PET/MR scanner only for 68Ga-RM2 imaging and regarding PSMA PET/CT scans, 68Ga-PSMA11 or 18F- DCFPyL were alternatively used [19].
The use of a PET/MRI scanner in the staging phase of PCa allows to perform a diagnostic MRI on the pelvic region, thus obtaining all the necessary morphological and multiparametric information for an accurate identification and characterization of the primary tumor. Moreover, the possibility to simultaneously acquire a PET scan with two different radiotracers assessing different metabolic pathways provides additional information regarding primary tumor characteristics, together with a whole-body evaluation of the disease. Differently from other groups that investigated the dual tracer approach of 68Ga-PSMA and 68Ga-DOTA-RM2 in PCa staging, or restaging, using a PET/CT scanner [15, 18, 19], one of the most relevant patients’ advantage in the present study relies on the possibility to have received a diagnostic MRI simultaneously acquired to the PET image acquisition. In fact, MRI is expected to increase the diagnostic accuracy of PET imaging for local staging (ECE and SVI) [25], and the information derived from both modalities could be incorporated into clinical nomograms to significantly enhance the pre-operative staging accuracy [26, 27]. Moreover, MRI shows excellent diagnostic performance in the detection of bone metastases [28]. If used in combination with PET, MRI could provide complementary information on bone disease when PET findings are equivocal or when metastatic lesions do not show significant PSMA uptake. Finally, WB-MRI could be of added value in monitoring the response to loco-regional or systemic treatments [29, 30].
In our cohort of patients, the primary PCa was detected in all patients by all three imaging modalities, with slight differences regarding the multifocality of intra-prostatic findings. Even if the comparison with histological examination was not yet available for the patients included in the study, the different intra-prostatic findings detected by 68Ga-PSMA and 68Ga-DOTA-RM2 might reflect the complementarity of these radiotracers; the same consideration might be applied to lymph nodal and bone localizations. These results enlightening a synergic role of 68Ga-PSMA and 68Ga-DOTA-RM2 in prostate cancer are in line with previous published data [15, 18, 19].
For instance, Fassbender et al. in their cohort of 8 patients with primary PCa undergoing 68Ga-PSMA PET/CT and 68Ga-Ga-RM2 PET/MRI, concluded that the qualitative findings of PET scans could provide combined relevant information. In their study, both radiotracers partially showed the same tumor region and, in some cases, different tumor parts, thus providing a better PCa characterization and reflecting the heterogeneous and sometimes polyclonal behaviour that characterize PCa [15]. Similarly, the results reported by Baratto and colleagues, comparing RM2-PET and PSMA-PET in patients with biochemically recurrent PCa and by Iagaru and colleagues in patients with newly diagnosed intermediate- or high-risk prostate cancer suggested that the use of both 68Ga-PSMA and 68Ga-DOTA-RM2 provided different and complementary information on PCa [19, 31]
To investigate the correspondence of the intra-prostatic findings referable to the site of primary tumor across modalities, DICE score between manually segmented primary intra-prostatic tumor volumes on 68Ga-PSMA, 68Ga-DOTA-RM2 PET and MR images were calculated. Volumes of the primary tumors, as defined in all the investigated imaging modalities largely overlap. The highest mean DICE score was the one between 68Ga-PSMA PET and MRI. This may be partially explained by the fact that 68Ga-DOTA-RM2 tumor volumes were generally smaller, and partially by the fact that 68Ga-PSMA PET and MRI were simultaneously acquired, thus being intrinsically co-registered. Conversely, automatic co-registration tool on 3D Slicer, with manual adjustments when needed, was used to overlap 68Ga-DOTA-RM2 PET images to 68Ga-PSMA and MR diagnostic images. A residual component of noise might have hampered the computation of the DICE score, therefore resulting in minor overlap between 68Ga-DOTA-RM2 PET and the other images.
Spearman correlations between multitracer PET and MRI parameters revealed no significant associations between parameters derived from different imaging modalities. This is in contrast with the strong association between 68Ga-PSMA PET and 68Ga-DOTA-RM2 PET SUVmax and SUVmean reported by Minamimoto et al. in 2016 [18]. However, that pioneering work relied on a very small sample (n = 7) of patients presenting with biochemical recurrence. Future studies with larger cohorts of patients are needed to unravel the possible association between semi-quantitative parameters derived from 68Ga-PSMA and 68Ga-DOTA-RM2 PET. Furthermore, concerning the correlation between imaging parameters and clinical data, an inverse correlation was found between 68Ga-DOTA-RM2 SUVmax, SUVmean40, SUVmean50 and PSA level at diagnosis. All the other tested correlations resulted non-significant and this is in line with what is reported by Fassbender et al. [15]. These results have to be interpreted with great caution and more evidence is needed before speculating on the clinical utility of these findings, since our sample was small and quantitative analyses might be susceptible to lack of statistical power. Future studies, with larger samples, will allow to unravel the possible association between semi-quantitative PET, quantitative MRI parameters and clinical data.
Some limitations should be pointed out regarding the present study. First of all, histopathological correlation with the post-surgical specimen was not performed because only a minority of patients have undergone radical prostatectomy so far. Therefore, being the present analysis a pilot study with only a preliminary evaluation of the PET/MRI data, we decided to only consider prostatic biopsies as standard of reference. This aspect, will be certainly improved as soon as all histological data will be available, with a detailed co-registration between imaging and histopathological data and subsequent data analysis.
Another limitation of this study is the low number of patient population. However, besides the fact that the few papers already published on PCa staging and using both 68Ga-PSMA and 68Ga-RM2 PET radiotracers included a number of patients even lower than the one presented in the present paper [15], we consider that these preliminary data are interesting to underlie the potential complementary and synergic role of the two different PET radiotracers together with mpMRI.
To conclude, based on the results of the present study, a potential complementary role of 68Ga-PSMA and 68Ga-DOTA-RM2 in PCa staging can be enlightened, in view of the different findings detected by the two imaging modalities in some of the patients included in our cohort. In fact, the possibility to identify different sites of disease by using a multitracer approach, certainly improves the disease characterization and therefore it may ultimately have impact on patients’ management and follow-up. Moreover, a synergic role of the three imaging modalities, namely 68Ga-PSMA PET, 68Ga-DOTA-RM2 PET and mpMRI for primary PCa characterization has been clearly showed. These findings should be validated on larger cohorts of patients to definitively assess the utility of hybrid 68Ga-PSMA PET/MRI and 68Ga-DOTA-RM2 PET/MRI in the clinical management of PCa.