Prostate cancer

Head-to-head comparison of 99mTc-PSMA and 99mTc-MDP SPECT/CT in diagnosing prostate cancer bone metastasis: a prospective, comparative imaging trial

This study was approved by the ethics committee of Fujian Provincial Hospital (reference number, K2019-10-017), and all methods were carried out following relevant guidelines and regulations. This study was carried out in compliance with the Declaration of Helsinki. Informed consent was obtained from all participants and/or their legal guardians.

Sample size calculation

We conducted a prospective observational study to analyse the difference between 99mTc-PSMA SPECT/CT and 99mTc-MDP SPECT/CT in the detection of bone metastasis in PCa. In this study, the sensitivity and specificity of 99mTc-PSMA and 99mTc-MDP scans were assumed to be greater than 50% (H0 = 50%). Referring to similar published literature on 68 Ga-PSMA and 99mTc-MDP scans78, an H1 = 80% was assumed. PASS 11 software (power analysis and sample size, NCSS, LLC) was used to estimate the required sample size. Assuming α = 0.05 (unilateral), β = 0.1, and a 1:1 ratio between groups, the calculations indicated that at least 46 patients needed to be included in the study. Ultimately, 74 individuals were enrolled in the study.

Patient selection

A total of 74 men were enrolled in this study from October 2019 to November 2021. The inclusion criteria were as follows: (1) PCa confirmed by surgical or puncture histopathology; (2) completion of initial treatment [such as radical prostatectomy (RP), external-beam radiotherapy (EBRT), endocrine therapy, etc.]; (3) biochemical recurrence (defined as: (i) a PSA level ≥ 0.2 μg/L on two consecutive measurements after RP; (ii) after EBRT, any PSA increase > 2 ng/mL higher than the PSA nadir value, regardless of the serum concentration of the nadir)9; and (4) complete medical records, control data and clinical follow-up results. The exclusion criteria were as follows: (1) the presence of sever syndromes that were difficult to manage; (2) active or upcoming participation in other clinical drug trials; (3) lack of regular review or follow-up results; and (4) inability to obtain relevant contrast imaging and clinical data. All eligible patients underwent both 99mTc-PSMA SPECT/CT and 99mTc-MDP SPECT/CT at an average interval of 12.1 days (1–14 days). None of the patients received any antineoplastic therapy between the two scans. The characteristics of the patients are given in Table 1.

Table 1 Patient characteristics.


A PSMA lyophilized kit was provided by Shanghai Engineering Research Center of Molecular Imaging Probes. Before each use, a bottle of lyophilized reagent was selected, and after 5 min, 4 mL 0.9% NaCl solution was added to dissolve the reagent, followed by approximately 5 mL 3.7–4.44 GBq 99mTcO4 solution. The solution was then mixed well and heated in a 100 °C water bath for 10 min. The radiochemical purity (RCP) of the 99mTc-PSMA was assessed by analytical high-performance liquid chromatography (HPLC) on an Agilent 1200 system6. The 99mTc-PSMA was discarded if the RCP was lower than 95%. The 99mTc-MDP was provided by Guangdong CI Pharmaceutical Co., LTD. Fuzhou Branch. Quality control (QC) of 99mTc-MDP was carried out by the manufacturer.

Imaging protocol

For the 99mTc-PSMA scan, all patients were injected intravenously with a dose of 0.74 GBq (20 mCi) 99mTc-PSMA. Whole-body planar imaging and regional (neck-pelvic) SPECT/CT were performed 2 h after injection on a Discovery NM/CT 670Pro (GE, USA) with low energy high resolution collimators. The image acquisition protocol was as follows: (1) Planar imaging: peak energy 140 keV (99mTc) and scan velocity 15 cm/min in a 1025 × 256 matrix. (2) Regional SPECT/CT: camera matrix size 128 × 128, zoom 1.0, rotation 360°, and 30 s/frame for a total of 60 frames. For CT, low-dose CT (130 keV; 60 mAs) was used.

For the 99mTc-MDP scan, a dose of 0.74 GBq (20 mCi) 99mTc-MDP was injected intravenously, and imaging was performed following a delay of 3 to 5 h. The imaging instrument and acquisition protocol were the same as those of the 99mTc-PSMA scan.

Image analysis

Image processing was performed on workstations (Xeleris, General Electric, Waukesha, WI). All images were anonymized and analysed by 3 senior nuclear medicine physicians. On SPECT/CT, areas with higher imaging agent uptake than normal tissue after excluding physiological uptake and traumatic fracture were considered “imaging positive bone lesions”. Areas with abnormal SPECT/CT findings but no imaging agent uptake on the corresponding site of SPECT were considered negative lesions. The flow diagram is shown in Fig. 1.

Figure 1
figure 1

Image analysis flowchart.

Interpretation of the degree of uptake of the positive lesion imaging agent by semiquantitative evaluation

(1) For the 99mTc-PSMA scan, the region of interest (ROI) of the lesions was delineated on whole-body plane imaging, and a mirror ROI was delineated on the liver, avoiding the gallbladder to the greatest extent possible. Then, the ratio of focus to liver (F/L) was calculated; if F/L > 1, the lesion was regarded as having high uptake (score: 3); if F/L = 1, it was regarded as having moderate uptake (score: 2); and if F/L < 1, it was regarded as having mild uptake (score: 1). (2) For the 99mTc-MDP scan, the ROI of the lesions was delineated on whole-body plane imaging, and the mirror ROI was delineated on the contralateral part (if the lesion was located in the spine, the adjacent vertebrae were delineated), and the ratio of focus to contralateral (F/CL) was calculated. If F/CL ≥ 2, lesion uptake was regarded as high (score 3); if F/L was 1.5–2, it was regarded as moderate (score: 2); and if F/L was 1–1.5, it was regarded as mild (score: 1).

Diagnostic criteria for “typical metastasis” and “equivocal metastasis”

(1) Diagnostic criteria for “typical metastasis” (i) typical metastatic changes (increased bone density and/or destruction of bone structure, with or without surrounding soft tissue mass) on CT (fused with SPECT) of the lesion and an imaging score of 1–3. (ii) lack of typical benign or metastatic changes on CT (fused with SPECT) and an imaging score of 2–3. (2) Diagnostic criteria for “equivocal metastasis”: (iii) no typical benign or metastatic changes on CT (fused with SPECT) and an imaging score of 1.

Validation criteria for bone metastases

The pathological criteria for bone metastasis are difficult to obtain; thus, the clinical diagnosis method reported in a previous study was used7. All patients were followed up for at least 6 months (or until death). Serum PSA was reviewed every 3 months for all patients. Subsequent therapeutic schedule options depended on the patient’s condition, including radical prostatectomy, local radiation therapy, chemotherapy, abiraterone, etc. 99mTc-PSMA and 99mTc-MDP imaging were routinely performed every 6 months to describe changes in activity on bone lesions. Future imaging modalities (CT, magnetic resonance (MR), positron emission tomography (PET)/CT, PET/MR, etc.) were selected according to their respective clinical needs and were not bound by a specific protocol. For patients with BR, 18F-FDG PET/CT was performed annually. One of these patients was found left supraclavicular fossa lymph node metastases both by 18F-FDG PET/CT and 99mTc-PSMA SPECT/CT at follow-up one year later.The material was assessed by the specialists involved in the study (nuclear medicine physicians and urologists) to determine the affected bone regions and overall metastatic status. Patients who met at least two of the following conditions were clinically diagnosed with bone metastasis: (1) two or more imaging scans suggestive of bone metastases; (2) symptoms of bone pain and imaging examination suggesting bone metastasis at the site of bone pain, which was relieved after antitumor therapy; (3) a reduction in size or activity for positive metastases after antitumor therapy on imaging examination; and (4) PSA ≥ 100 ng/mL, suggesting distant metastasis10.

Statistical analysis

Data analysis was performed using SPSS 19.0 software (statistical product and service solutions, Chicago, IL). The sensitivity and specificity of the two imaging methods were calculated, and using receiver operating characteristic (ROC) curve analysis, the area under the ROC curve (AUC) was calculated, compared and analysed between the two methods. The Wilcoxon signed-rank test was used to analyse the difference between the proportion of “typical metastasis” versus “equivocal metastasis” as detected by the two imaging methods. The Wilcoxon rank-sum test was used to analyse the difference in the number of bone metastatic lesions detected by the two imaging methods. Binary logistic regression analysis and ROC curve analysis were used to calculate the predictors and optimal critical values of the positive results of the two imaging methods. P < 0.05 was considered statistically significant.