To the best of our knowledge, no previous study has ever reported a direct prospective head-to-head cost-effectiveness comparison of NaF, FCH and DW-MRI in the detection of bone spread in a homogenous group of PCa patients with first BCR.
The diagnostic performances of NaF, FCH and DW-MRI in this setting have already been published [
7,
9,
30,
31]. The accuracy of NaF in detecting bone metastases was found to be significantly better than that of DW-MRI in a recent prospective comparison of 68 PCa patients with BCR [
7]. Langsteger et al. observed a better lesion-based specificity of FCH compared to that of NaF (96% vs 91%,
p = 0.033) for an equivalent sensitivity of 89% in the context of BCR [
9]. In 2014, a meta-analysis compared the pooled performances of MRI (all variants, including DW-MRI) and choline PET/CT (pooling results of FCH and
11C-choline) in the diagnosis of bone metastases in PCa patients [
30]. Overall, a non-significantly lower sensitivity was found for choline PET/CT compared to MRI, with pooled sensitivities of 87 and 95%, and without a difference in specificity values of 97 and 96% respectively. In 2016, Barchetti et al. performed FCH and DW-MRI in 152 PCa patients with BCR [
31]. They considered the FCH results as the SOT. DW-MRI had a detection rate of 99% in patients presenting with bone spread on FCH [
31]. In the present study, we found that the diagnostic performances of the 3 imaging modalities in detecting bone metastases in PCa patients with BCR were concordant with the reported values of other published studies. Thus, we assumed that our procedures did not favour any imaging strategy in the medico-economic analysis.
Medico-economic analysis
In our study, FCH was always the most cost-effective imaging modality for staging patients with BCR, considering either the on-site reading by local specialists or the central reading by the experts of each imaging modality. PET/CT is often criticized for its higher cost compared to other imaging modalities that can be prescribed to explore PCa. From the point of view of an imaging centre, production costs are higher for the PET/CTs than for MRI (302€ for NaF and 881€ for FCH versus 112€ for DW-MRI), but these differences are only because of the radiotracers’ costs. Of note, no contrast agent was used for MRI in our study, which decreased MRI production costs as gadolinium is frequently injected into patients in routine practice for complementary sequences to DW-MRI. From the point of view of the French healthcare system, the reimbursed amounts for the PET/CTs, which are currently the same regardless of the radiotracer, are also approximately four times higher than those for MRI (Additional file
3). However, as shown in Table
5 and illustrated in Fig.
4, imaging costs have nearly no impact on overall patient care costs, as a difference of only 481€ and 666€ exists between the cheapest strategy (DW-MRI) and the most expensive strategy (FCH) when using on-site and central imaging performances respectively. On the other hand, FCH had higher QALY (0.48 and 0.14 with on-site and central imaging performances respectively) than DW-MRI.
Limitations
The main factor shared by all studies addressing metastatic bone spread is the lack of histological evidence for most metastases, which were mainly characterized on the basis of follow-up data. However, this limitation applied equally to the 3 imaging modalities and it is assumed that it would not have favoured one of them.
The second major limitation of this work was the relatively limited number of included patients due to logistical difficulties in prospectively completing the entire imaging workup in the early 2010s. However, our study was the largest homogenous prospective head-to-head cost-effectiveness comparison of these 3 imaging modalities ever reported. The use of a Markov model of the disease was thus essential to simulate the outcomes of PCa patients with BCR in a larger number of patients on a lifetime horizon.
In this study we did not find significant differences among the 3 imaging modalities by using an analysis that summarized the performance of each imaging modality in detecting bone marrow involvement in a per-patient approach. The results could have been different by using a lesion-based analysis. However, we assume that this per-patient approach did not alter the impact on determining patient management or treatment costs, as in the real world therapeutic decision-making is based on a holistic approach of the patients’ disease (patient-based) and not on a lesion per lesion approach (lesion-based).
We found better interobserver agreement between on-site and masked readings for the PET/CTs than for DW-MRI. The low reproducibility of the DW-MRI readings may be explained by a lack of standardization of the analysis of this modality, which was recently prompted [
32]. Indeed, the definition of bone, node and visceral metastases was settled by the time the study protocol was tailored, based on the available literature at that time, well before recent efforts for harmonization in image acquisition and reporting (MET-RADS criteria) [
32]. Again, these differences in the reading agreement of imaging between on-site local specialists and central experts had almost no impact on the total cost of patient care.
The transition probabilities were extracted from the literature and are sometimes based on 10-year-old studies, whereas new therapeutics, such as second-generation anti-androgens such abiraterone acetate or enzalutamide, are now routinely prescribed to patients and may increase survival. Our model predicted an overall life expectancy of 6.7 years for PCa patients with BCR at the age of 70 years when running the simulation without considering the performance of imaging. This result was consistent with the average life expectancy of the French population of 79.4 for men in 2018 [
19] and validated the model.
This study included patients with first BCR after previous definitive treatment for localized PCa. Some of them were treated with salvage high intensity focalized ultrasound (HIFU) after the imaging workup, through this alternative was not recommended at the time of patient inclusion in the FLUPROSTIC study. However, as HIFU is currently suggested in the EAU guidelines for the treatment of relapse for radiation-recurrent PCa [
10], and as we used real treatment costs for the cost-effectiveness study, we assume our results may be extended to the current context of recurrent PCa. Furthermore, as the health-state costs are the same for the 3 imaging modalities, none were penalized by this point.
We chose to evaluate the medico-economic impact of imaging by considering only their performance in detecting bone metastases, while PCa patient management may be based on the detection of lymph node metastases, especially for oligometastatic patients. Performing a medico-economic analysis regarding the performance of imaging in detecting lymph node metastases would have required the availability of relevant transition probabilities in the literature in this setting which is currently lacking for such data. Such analysis could not have been performed for NaF, which only explores bone metabolism.
Finally, with the advent of PET/CT using ligands of prostate-specific membrane antigen (PSMA) as a radiotracer, the usefulness of such cost-effectiveness highlighting a metabolic radiotracer such as FCH for PCa might be questioned. However, we demonstrated that the imaging modality that was used did not impact the total cost of patient care but influenced QALYs (Fig.
4). Thus, the model we developed could be used to compare the cost-effectiveness of different imaging modalities, including PSMA ligands radiotracers.