Does whole-body bone SPECT/CT provide additional diagnostic information over [18F]-FCH PET/CT for the detection of bone metastases in the setting of prostate cancer biochemical recurrence?

Background To assess whether whole-body (WB) bone SPECT/CT provides additional diagnostic information over [18F]-FCH PET/CT for the detection of bone metastases in the setting of prostate cancer biochemical recurrence (PC-BR). Methods Patients referred for a PC-BR and whom benefited from a WB bone SPECT/CT and FCH PET/CT were retrospectively included. Tests were classified as positive, equivocal, or negative for bone metastases. A best valuable comparator (BVC) strategy including imaging and follow-up data was used to determine the metastatic status in the absence of systematic histological evaluation. Results Between January 2011 and November 2017, 115 consecutive patients with a PC-BR were evaluated. According to the BVC, 30 patients had bone metastases and 85 patients did not present with bone lesions. The sensitivity, specificity, positive and negative predictive values were respectively 86.7% [69.3–96.2], 98.8% [93.6–100.0], 96.3% [78.7–99.5], and 95.5% [89.4–98.1] for WB bone SPECT/CT and 93.3% [77.9–99.2], 100.0% [95.8–100.0], 100.0 and 97.7% [91.8–99.4] for FCH PET/CT. There was no significant difference in diagnostic accuracy of bone metastases between WB Bone SPECT/CT (AUC 0.824 [0.74–0.90]) and FCH PET/CT (AUC 0.829 [0.75–0.90], p = 0.41). Conclusion Despite good performances for the diagnosis of bone metastases in PC-BR, WB bone SPECT/CT does not provide additive diagnostic information over concomitant FCH PET/CT.


Introduction
Prostate cancer (PC) is the most common form of male cancer in Europe, representing about 400,000 new cases / year in Europe [1,2] and the third leading cause of death in men over 50 yearsold [3]. After initial postdiagnostic radical treatments, follow-up is performed through physical examination and blood prostate specific antigen (PSA) assessment [4].
However, biochemical recurrence (BR) occurs in 20-50% of patients within 10 years following local treatment [5]. BR can be defined by two consecutive rising PSA values > 0.2 ng/mL after radical prostatectomy (RP) or > 2 ng/mL above the nadir after external beam radiotherapy (EBRT) [6]. While PSA is a very sensitive tool to detect relapse, it is not suitable for the characterization of disease extension [7]. For patients presenting with biochemical recurrence, determining whether the disease is locally confined or systemically spread is of paramount importance for the selection of the most appropriate therapeutic strategy between local salvage treatment or systemic treatment.
Bone represents the second most common metastatic site of PC [8]. Bone metastasis represents an independent prognostic factor [9,10] and an indication for a systemic therapy [11]. Bone scan (BS) scintigraphy and 18 F-Choline (FCH) positron emission tomography (PET/CT) are currently available for routine diagnosis use in nuclear medicine for patients with biochemical recurrence of PC. 99 m-Technetium ( 99m Tc) labeled diphosphonate BS is a low-cost and widely available whole-body nuclear imaging test with good sensitivity [12]. However, planar BS has a relatively poor specificity due to the unspecific bone uptake related to osteoblastic activity and potentially leading to false positive results. BS is now supplemented with a single photon emission computed tomography fused with a low-dose CT scan (SPECT/ CT) [13,14], thatimproves the lesion-to-background ratio, allows anatomic lesion localization, removes the superimposition of anatomical structures and provides morphological data, thereby increasing the specificity and positive predictive value of BS [15,16].
FCH currently represents the most commonly used PET tracer for the evaluation of patient with PC [17,18]. Choline uptake is increased in PC cells due to tumoral cell proliferation and the subsequent increase in the activity of choline kinase [19,20]. In addition to bone metastases, FCH PET/CT also allows the detection of local recurrence, lymph node or visceral metastases. FCH is the only available PET tracer considered as a reference in current clinical practice in France for the evaluation of patients with BR of PC [21]. Indeed, prostate-specific membrane antigen (PSMA) PET/CT, which might be considered now as the gold-standard in the setting of PC is still not available for routine use in France [22].
Bone scan is still currently performed by a number of institutions for the detection of bone metastases in BR of PC. Many studies discourage BS in patients with PSA < 10 ng/ml, because of insufficient diagnostic performance and very low detection rate [11,23]. Nevertheless, these studies did not evaluate the potential of systematic whole-body (WB) bone SPECT/CT.
The aim of this study was to assess whether wholebody (WB) bone SPECT/CT provides additional diagnostic information over [18F]-FCH PET/CT for the detection of bone metastases in the setting of prostate cancer biochemical recurrence.

Study design and patients
We conducted a single-center retrospective study at the Grenoble Alpes University Hospital. From January 2011 to November 2017, a total of 386 consecutive patients were addressed in the nuclear medicine department to perform a FCH PET/CT in the setting of biochemical recurrence of PC. We included patients with biochemical recurrence of a histologically proven PC who benefited from whole-body BS coupled to a double field of view (FOV) SPECT/CT and a FCH PET/CT within 3 months, and for whom data on initial tumor and follow-up were available (Fig. 1). Such data were available since both tests were systematically performed for patients referred to our center for BR of PC. Data concerning the initial tumor (PSA at the diagnosis, Gleason score, TNM stage), the initial treatment of PC, the kinetics of PSA (PSA nadir, at least two values of PSA before the WB bone SPECT/CT with their date) and the follow up (clinical evaluation, biological and imaging data) were collected for all patients using our institution database. Data from patients followed in other institutions were collected through their corresponding prescribing physicians and medical biology laboratories by phone or email. The PSA doubling time was calculated using the most recent PSA values (with a minimum of 2 and up to 6 values) and the least squares fitting-exponential methodology (www.doubling-time.com). The study was approved by the local ethics committee.

Whole-body bone SPECT/CT
Three hours after the intravenous administration of 7.4 MBq/Kg (0.2 mCi/Kg) (a minimum of 550 MBq) of 99mTc-methylene diphosphonate, planar whole-body images in anterior and posterior projections were obtained using a dual-head SPECT/CT camera Symbia-T2 (Siemens). A SPECT/CT of two FOV from the cervical spine to the proximal part of the thighs and therefore encompassing belts and the whole spine (whole-body bone SPECT/CT), was then performed in all patients. The camera was equipped with low-energy high-resolution (LEHR) collimators. Images were acquired on a 128 × 128 pixel matrix using 64 projections of 25 s each with 180°rotation for each camera head. SPECT data were reconstructed using an ordered subset expectation maximization (OSEM) algorithm (5 iterations over 8 subsets). A low-dose CT scan of the same zone was obtained for attenuation correction and anatomical localization. Data were acquired with exposure of 130 kV, a pitch of 1.85 with rotation time of 1.5 s and collimation of 2 × 2.5 mm, and reconstructed to images using 3 mm-thick slices.

18F-Choline PET/CT
PET/CT images were acquired on a PET∕ CT Discovery-690 (GE Healthcare) after intravenous administration of 3.7 MBq/Kg (0.1 mCi/Kg) of FCH. Image acquisition consisting of a low dose CT scan followed by dynamic PET images of the pelvis over 10 min (10 × 1 min frames) was started immediately following tracer injection in order to overcome urinary bladder activity. Sixty minutes after injection, a whole-body PET/CT acquisition (from the skull to the proximal part of the thighs) was performed with an acquisition time of 2 min per bed positions. Unenhanced CT scan of the same zone was performed for attenuation correction and localization (120 kV, current modulation, 0.8 s/rotation, 3.75 mm reconstructed section thickness, 512 × 512 matrix). To limit the contribution of urinary elimination on FCH images, all patients received an intravenous injection of a diuretic (Furosemide 20 mg) and were asked to urinate before whole-body acquisition.

Image interpretation
All the images from WB bone SPECT/CT and FCH PET/CT were analyzed by two blinded nuclear medicine physicians and were reviewed on a dedicated workstation. When a lesion was differentially classified, the expertise of a third nuclear medicine physician was used to resolve the discrepancy. Planar BS was visualized in anterior and posterior views whereas SPECT/CT and PET/ CT acquisitions were evaluated in transverse, coronal and sagittal planes. The morphological data from CT scans were also studied for anatomical localization and detection of bone lesions. Each patient was classified as having malignant lesion, equivocal lesion, benign finding or a normal exam from WB bone SPECT/CT analysis. The lesions were classified as equivocal in the event that no consensus could be reached due to the lack of an alternative test. On FCH PET/CT, each focal or diffuse abnormal tracer uptake was classified as positive, equivocal or negative for bone involvement. Pathological focal uptake of FCH from the prostatic or visceral regions and lymph nodes was also studied.
As histological proof of bone metastases was absent in most cases, a best valuable comparator (BVC) was used as the gold standard, as previously described in other comparative imaging studies [24,25]. BVC was determined collegially (nuclear medicine physician, urologist, oncologist, radiotherapist) using all available imaging data (current and follow-up) as well as the 6-month clinical and biological evolution.

Statistical analysis
Continuous variables were reported as medians and interquartile ranges (IQRs) and categorical variables as frequencies and percentages. Baseline characteristics were compared according to WB bone SPECT/CT results using the chi-square test ( ) were presented using 95% confidence intervals (Cis) based on binomial distributions. Equivocal tests were considered negative upon single analysis since such tests did not prevent from performing additional investigations in order to identify secondary bone lesions. Receiver-operating characteristics (ROC) analysis were also obtained for each test with calculation of the area under the curve (AUC) and statistical comparison of ROC curves.
A two-sided p value < 0.05 was considered statistically significant. All analyses were performed using Stata Special Edition version 14.0 (Stata Corp, College Station, TX).

Results
From January 2011 to November 2017, 115 patients were evaluated by both WB bone SPECT/CT and FCH PET/CT for a biochemical recurrence of PC. All data were available except the nadir PSA that was missing for two patients. Patients' characteristics are summarized in Table 1. The median age of the population was 73.2 years (range 56-89). Ten (8.7%), 29 (25.2%), and 76 (66.1%) patients were respectively classified at low-risk, intermediate-risk and high-risk according to D'AMICO initial staging classification.
FCH PET/CT also identified hypermetabolic lymph nodes in 45 (41.5%) patients and local recurrence either in the prostate gland or bed in 35 (32%) patients. One patient had a metastatic lung extension in addition to bone involvement. FCH PET/CT identified the site of relapse for 85 patients among the 115 patients, which represents a detection rate of 74%.
Among patients with bone lesions on WB bone SPEC T/CT (true positive), 9 had a single bone lesion, 8 had an oligometastatic disease (between 2 and 5 lesions) and 9 had a high bone metastatic volume (> 5 lesions). More bone lesions were detected using FCH PET/CT but only five patients switched group. Specifically, 2 false-negative WB bone SPECT/CT had bone involvement (single lesion and high metastatic tumoral volume) identified using FCH PET/CT; 1 patient was reclassified from single to oligometastatic lesions; 1 patient with equivocal lesions upon WB Bone SPECT/CT presented with oligometastatic lesions upon FCH PET/CT; and 1 patient was a WB bone SPECT/CT false-positive (Table 1).

Characteristics associated with the positivity of wholebody bone SPECT/CT
In univariate analysis, patients with a positive WB bone SPECT/CT had a significantly higher initial Gleason score (p < 0.01). The median PSA value at the time of WB bone SPECT/CT was significantly higher for patients with positive WB bone SPECT/CT (12.5 ng/mL) compared with those with negative WB bone SPECT/ CT (4.4 ng/mL, p < 0.001). A PSA threshold of 10 ng/ml was significantly associated with positive WB bone SPEC T/CT (p < 0.001). The median PSAdt of patients with positive WB bone SPECT/CT was significantly shorter than those with negative test (3.8 versus 7.6 months respectively, p < 0.001). The PSAdt threshold of 6 months Patients with a positive WB bone SPECT/CT had higher rates of PSAdt ≤6 months (77.8% vs. 39.8%). Interestingly, a significant interaction was observed between trigger PSA and PSAdt for the odds of the WB bone SPECT/CT results: compared with patients with a PSAdt > 6 months, patients with a shorter PSAdt and with a trigger PSA lower than 10 ng/ml had higher rates of positive WB bone SPECT/CT (OR = 4.4, CI95 [1.1-21.2], p = 0.03) ( Table 4).

Discussion
The main result of this study is that bone scan with systematic double FOV SPECT/CT (WB bone SPECT/CT) has good diagnostic performances for the detection of bone metastases in comparison to FCH PET/CT in patients with BR of PC, but that it does not provide additional diagnostic information. To the best of our knowledge, this is the first study to evaluate the diagnostic performances of bone scan complemented by a systematic WB bone SPECT/CT in patients with BR of PC.

Clinical setting
The detection of bone metastases induces radical changes in the prognosis and therapeutic management of patients with BR of PC, thereby justifying the clinical relevance of powerful corresponding diagnostic tools. WB bone SPECT/CT is a low-cost, widely available and frequently used first intention clinical test for the detection of bone metastases in PC. However, the use of WB bone SPECT/CT has been recently questioned, especially in patients with a PSA < 10 ng/mL [4]. FCH PET/CT is   [2.4-9.9]) observed in the present study was lower than values from previously published studies addressing the performances of bone scan in biochemically recurrent disease [26][27][28]. Although such value might appear elevated with respect to the diagnostic criteria for BR, it is likely explained by the fact that PSA was determined at the time considered as the most relevant for recurrence localization using FCH PET/CT, as indicated by a FCH PET/CT detection rate (74%) similar to that observed in previously published studies [21].

Diagnostic performance of whole-body bone SPECT/CT
Among the papers published studying the performance of bone scan in prostate cancer, none evaluated the performances of systematic whole-body bone SPECT/CT in BR of PC. These previously published studies rather evaluated the performances of planar bone scintigraphy an out-of-date procedure [29,30], or the performances of non-systematic SPECT/CT indicated on the basis of planar scintigraphic findings [31,32].  [30]. However, an optimal strategy taking into account both the medical and medico-economical perspectives obviously requires the classification of equivocal studies as negative since all equivocal cases require an additional test to establish a reliable diagnosis.
Accordingly, when considering equivocal WB bone SPECT/CT as negative, the results of Picchio et al. point at the suboptimal performances of planar bone scintigraphy (sensitivity, 70%; specificity, 100%) with respect to those observed in the present study using WB bone SPECT/CT (sensitivity, 86.7%; specificity, 98.8%). Overall, the diagnostic performances of WB bone SPECT/CT are superior to those described in the literature for planar BS [33][34][35][36][37][38]. The rate of positive WB bone SPECT/ CT that we observed (27 patients, 23.5%) appears relatively high compared to that found in previous studies with planar BS (6 to 14%) [26,28,29] and similar to those of Moreira et al. (20-26%) [39]. However, details regarding the acquisition protocol (planar with or without SPECT/CT) were not provided by the authors of the latter study. Furthermore, we noticed a relatively low equivocal examination rate, with only 7 patients (6%) classified as doubtful for the presence of bone metastases, while the remaining patients were immediately categorized as positive or negative. These results are in accordance with those of Helyar et al. who reported an 8% rate of equivocal lesions according to SPECT/CT and a significantly reduced rate of equivocal lesions in comparison with that of planar BS alone [40].
No significant difference was observed for the detection of bone metastases in comparison with FCH PET/ CT (AUC 0.824 for WB Bone SPECT/CT vs 0.829 for FCH PET/CT, p = 0.41). These AUCs are comparable with those obtained by Pyka et al. [24] for bone SPECT/ CT, even though a small number of patients benefited from a bone SPECT/CT in this study. More bone lesions were detected by FCH PET/CT than by WB bone SPEC T/CT in the present study. However, the data from both tests were mostly in accordance regarding the classification of bone metastasis patients into the subgroups of single metastatic lesion, oligometastatic lesions, and patients with high bone metastatic volume.
Our results are deprived of any ambiguity since 74% of patients (85/115) benefited from FCH PET/CT which

Perspective
A current clinical problem consists in the detection of early recurrence which may still be accessible to local therapy and which may develop in the setting of low PSA levels. In the present study, the detection rate of bone lesions by WB bone SPECT/CT was low for PSA levels between 1 and 2 ng/mL and < 1 ng/mL, suggesting the suboptimal performances of the test in this setting. PSMA has recently become a very promising target for the diagnostic and therapeutic management of patients with PC. PSMA-PET/CT was shown to outperform planar BS and bone SPECT/CT for the detection of bone metastases [24,40] and FCH PET/CT for the number of detected bone metastases and for the overall number of identified recurrence sites [22], especially in patients presenting with low, < 2 ng/mL PSA levels. Indeed, the AUC of WB bone SPECT/CT and FCH PET/CT were comparable in our study and both were equivalent to the AUC observed by Pyka et al. [24] for WB bone SPECT/CT whereas the authors found a significantly better AUC for PSMA PET/CT.

Limitations
There are several limitations to the present study. First, this is a single-centered and retrospective study.
However, the bias caused by retrospective design remains acceptable in comparison with previously published data on planar bone scan scintigraphy versus choline PET/CT ( 11 C or 18 F). For instance, patients being included over an initial population in our study represented (115/386) 29.8% versus (78/6266) 1.2% in the study by Picchio et al. [30].
Second, patients were referred for FCH PET/CT in the setting of BR of PC, implying the presence of high PSA levels with respect to the biological definition of BR.
A third limitation to be considered is the choice of FCH as the comparison test rather than the goldstandard PSMA-PET/CT. However, PSMA-PET/CT is not available yet in France and could therefore not be used as a reference in our study. The implications of our study are therefore limited to those countries with no access yet to PSMA-PET/CT in clinical routine or to those centers with no access to a 68Ga generator. Such situations are unfortunately still dominant worldwide, which in our opinion underlines the relevance of our study.
Fourth, systematic histological confirmation of bone lesions is impracticable and unethical when not impacting patient management. In the absence of histological evidence, others have used morphological or functional imaging modalities and follow-up as gold standards [32,35,41,42]. In the present study, the BVC includes some clinical judgment or interpretation and is not totally independent of our diagnostic tests, which may lead to an inclusion bias and an overestimation of diagnostic performances. However, the BVC as a gold-standard appears as the best alternative to systematic histological analysis.
Finally, the choice of the frequency and timing of PSA measurements were left to treating physicians, which could have led to more variability in the assessment of PSAdt while however reflecting more accurately the clinical reality.

Conclusion
Despite good performances for the diagnosis of bone metastases in prostate cancer biochemical recurrence, whole-body bone SPECT/CT does not provide additive diagnostic information over concomitant FCH PET/CT.  Percentages are expressed in relation to the total number of patients. Equivocal bone lesions were classified as negative