Methods: We prospectively enrolled 40 consecutive patients after radical treatment (80%—radical prostatectomy, 20%— radiation beam therapy) of PCa and low (0.008 to ≤2.0 ng/ml), rising PSA. Skull to mid-thigh PET/CT imaging was performed 95 (±12) min after injection of 295.5 (±14.1) MBq 18F-PSMA-1007. Detection rate was correlated with PSA levels, Gleason score (GS), and T stage ≥ 3. PET/CT results were verified during 10.3 (±4.7) months follow-up to calculate sensitivity, specificity, negative predictive values (NPV), and positive predictive values (PPV).
Results: 18F-PSMA-1007 PET/CT was positive in 24/40 patients, which yielded an overall detection rate of 60%. Detection rate was 39%, 55% and 100% for PSA < 0.5, 0.5 to <1.0 and 1.0 to ≤2.0 ng/ml, respectively. PET/CT showed metastases in locoregional lymph nodes in 55% of patients, bones in 36% of patients, and local recurrence in 9% of patients. Detection rate was correlated with PSA—a 0.1 ng/ml rise in PSA level increased odds for positive PET/CT by ~30%. PET/CT positivity was independent of GS and T stage. Verification of 40 lesions yielded sensitivity, specificity, PPV, and NPV of 100%, 94.4%, 66.7%, and 100%, respectively.
Conclusions: 18F-PSMA-1007 PET/CT shows a relatively high detection rate in patients with PCa after radical treatment and low, rising PSA levels. Like other PSMA-targeting radiotracers, its detection rate is dependent on PSA levels. 18F-PSMA1007 also presents excellent sensitivity, specificity and NPV.
Rising prostate-specific antigen (PSA) levels after radical treatment (radical prostatectomy or radiotherapy) concern up to 53% of men with prostate cancer (PCa).1 Early diagnosis of relapse is crucial for further management— prompt initiation of salvage treatment tailored to the patient yields very good outcomes. Over 60% of men with biochemical relapse (BCR) who will be treated before PSA rises >0.5 ng/ml will achieve undetectable PSA levels, which corresponds to an 80% chance of being progression-free 5 years later.2–4
18F-prostate-specific membrane antigen (PSMA)- 1007 seems to be one of the most promising radiotracers for diagnosing PCa relapse at low PSA levels. Even though its sensitivity falls with decreasing PSA levels, such as 68GaPSMA-11 and radiocholines, it is reported to reach 61–86% at PSA levels < 0.5 ng/ml, which is superior to other commonly used radiotracers.5–7 Yet, the number of studies assessing 18F-PSMA-1007 diagnostic performance is still rather limited and lacks verification of PET/CT findings.
The aim of our study was to prospectively evaluate detection rate, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 18FPSMA-1007 PET/CT in patients with PCa after radical treatment and low-rising PSA levels.
Materials and Methods
We prospectively enrolled 40 consecutive patients with PCa after  radical prostatectomy with BCR or  radiation beam therapy with PSA levels rising in at least two consecutive measurements. In both groups, PSA levels were ≤2.0 ng/ml. Radiation beam therapy was performed in addition to surgery in 16 (40%) patients. Ten (25%) of the patients received androgen deprivation therapy, yet none of them within 6 months prior to the study. In all patients, 18FPSMA-1007 PET/CT scan was performed. Afterward, during the follow-up period, we gathered data on further therapeutic decisions, results of diagnostic procedures, and clinical outcomes in order to calculate per-lesion sensitivity, specificity, PPV, and NPV of 18F-PSMA-1007 PET/CT. Histopathology or biopsy of prostatic bed or metastases, correlative imaging results, and clinical data (normalisation or > 20% reduction of PSA after salvage therapy) was used as a reference standard. Detailed information on patients, follow-up, and PET/CT scans is presented in Table 1.
Informed consent was obtained from all individual participants included in the study. All procedures performed in the study were in accordance with the ethical standards of the institutional research committee (Military Medical Chamber Ethics Committee in Warsaw, Poland, ref. no. 149/17), with national regulations and with the 1964 Helsinki declaration and its later amendments.
18F-PSMA-1007 was made with a Trasis AiO (Ans, Belgium) synthesiser. 18F-fluoride was produced in Siemens Eclipse (Knoxville, USA) cyclotron by bombarding enriched 18O-water with protons. It was then collected at anion exchange cartridge (QMA) and released by tetrabutylammonium hydroxide (TBA-HCO3) eluent to reaction vial, where residual traces of water were evaporated at 130 °C for 8 min. Then, PSMA-1007 precursor (ABX, Radeberg, Germany) dissolved in 2 ml of dimethyl sulfoxide was added to the dried complex. Fluorination reaction was processed at 105 °C for 5 min. During labelling, two cleaning cartridges (C18ec and PS-H) were conditioned by rinsing 5% EtOH in water for injection (WFI), EtOH, and again 5% EtOH in WFI. Crude product was trapped on cartridges and rinsed with 5% EtOH in WFI to remove side products. The product was eluted from cartridges by 30%EtOH to the end vial by 0.22 µm sterilising filter and then diluted by phosphate-buffered saline. In the end, quality control was performed. The product does not hold a marketing authorisation and was prepared for the purpose of the study.
PET/CT imaging was performed with a hybrid PET/CT system (Discovery 710, GE Healthcare, Chicago, Illinois, USA). First, a scout view and a non-contrast-enhanced low dose spiral 64-slice CT scan was performed for attenuation correction of PET emission data and anatomic localisation. CT scan was acquired with a tube voltage of 140 kV in the helical mode with a Smart/Auto mA (range: 40–120 mA). The X-ray tube rotation time was 0.6 s. The pitch and table speed were 0.984:1 and 39.37 mm/rot, respectively. The helical thickness was 3.75 mm. For standard type of reconstruction, the slice thickness was 1.25 mm. The GE Adaptive Statistical Iterative Reconstruction with the level of 20% was used to reduce patient radiation dose from CT scans.
Following CT, top-of-the-head to mid-thigh threedimensional (3D) PET was acquired. For each bed position (15.7 cm with 23% bed overlap) a 3-min long acquisition time was used. The emission data were corrected for geometrical response, detector efficiency, system dead time, random coincidences, scatter, and attenuation.
For non-attenuation corrected images, the 3D iterative reconstruction technique (GE VUE Point HD) with 2 iterations/24 subsets and a filter cut-off of 6.4 mm was conducted. The matrix size was 192 × 192. For attenuation, corrected images reconstruction was conducted with a 3D iterative algorithm with time of flight PET reconstruction algorithm (GE VUE Point FX) and a resolution recovery algorithm (GE SharpIR) with 3 iterations/18 subsets and a filter cut-off of 5.5 mm. The matrix size was 256 × 256.
PET/CT images were analysed visually and semiquantitatively with GE Healthcare Advantage Workstation (Chicago, Illinois, USA) by three physicians with at least 4-year experience in nuclear medicine. All disagreements were resolved by consensus. Scans were defined as positive if at least one lesion highly suspicious for malignancy was reported. Identified lesions were grouped according to their localisation (prostate bed, lymph nodes, or bones) and assessed semiquantitatively—maximum standardised uptake values (SUVmax) and tumour-to-background ratios (TBR) were calculated. To measure SUVmax, rectangular regions of interest were drawn around areas with focally increased uptake in axial slices and then adapted to 3D volume of interest. To calculate TBR, lesion uptake was divided by uptake in the thoracic aorta. We also looked for a correlation between PET/CT positivity and PSA level, Gleason score (GS), and T stage ≥ 3.
Statistica 13 software (StatSoft Polska Sp. z o. o. Cracow, Poland) was used for statistical analysis. Descriptive analysis was performed by calculating mean, median, standard deviation, and range. The Shapiro–Wilk test was used to check if samples were normally distributed. Quantitative variables were compared with the Mann–Whitney U test. Percentage variables were compared with the chi-squared test and its modifications and the Fisher test. To evaluate correlation linear and logistic regression were used. A p-value < 0.05 was considered significant.
No adverse effects were observed after injection of 18FPSMA-1007. Patients did not report any alarming symptoms.
18F-PSMA-1007 PET/CT was positive in 24 (60%) patients. In this group, we identified 136 lesions highly suspicious for malignancy. The most common site of relapse was locoregional lymph nodes (n = 75, 55%), followed by bones (n = 49, 36%) and prostatic bed (n = 12, 9%). Mean ± SD SUVmax values were 5.54 ± 5.99, 3.75 ± 1.76, and 5.87 ± 2.89 for all three locations, respectively. Mean ± SD TBR values for lymph nodes, bones, and prostatic bed were 2.79 ± 2.44, 2.05 ± 0.99, and 3.50 ± 1.95, respectively.
PSA level significantly correlated with positive PET/CT result—the higher the PSA level the higher the odds for a positive scan (OR = 1.31 [1.08–1.60], p = 0.009). Scans were positive: in 39% (7/18) patients with PSA < 0.5 ng/ml, 55% (6/11) with PSA 0.5 to <1.0 ng/ml and in 100% (11/ 11) with PSA 1.0 to ≤2.0 ng/ml. All patients with PSA ≥ 0.9 ng/ml (n = 15, 37.5%) had positive PET/CT scans. We found that a 0.1 ng/ml rise in PSA level increased odds for positive PET/CT by ~30%.
In our study, neither GS ≥ 7 nor T stage ≥ 3 significantly correlated with positive PET/CT result (p = 0.29 and p = 0.79, respectively) (Table 2).
During follow-up period, 40 lesions were verified. Thirty-eight lesions underwent histopathologic examination, one lesion (bone metastasis in scapula) was confirmed in 68Ga-PSMA PET/CT and one lesion (bone metastasis in the sacral bone) was a target for radiotherapy, which led to a PSA level decrease >20% (Fig. 1). Out of 38 lesions that underwent histopathologic examination, 37 were surgically dissected lymph nodes. The remaining one lesion was a prostate gland that was biopsied. Out of six lesions positive in 18F-PSMA-1007 PET/CT, four were truly positive and two were false positive. All 18F-PSMA-1007-negative lesions (n = 34) were truly negative. This resulted in sensitivity and specificity of 100% and 94.4%, respectively. PPV and NPV of 18F-PSMA-1007 PET/CT was 66.7% and 100%, respectively.
Fig. 1 A 69-year-old patient with prostate cancer after radical prostatectomy and adjuvant radiation beam therapy (pT3aN0M0, Gleason score 9) with rising PSA (0.155 ng/ml a week before PET/CT scan). 18F-PSMA-1007 PET/CT (a maximum intensity projection [MIP] image; b, e, h, k transverse PET images; c, f, i, l transverse CT images; d, g, j, m transverse fused PET/CT images) showed a metastasis to the left scapula (a, white arrow; b–d) and metastases to bilateral iliac lymph nodes (a, white arrowheads; e–m). 68Ga-PSMA-11 PET/CT performed subsequently confirmed all the above lesions. Stereotactic radiotherapy to the scapula and external beam radiation therapy to the pelvic lymph nodes led to a PSA decrease to 0.086 ng/ml (>20%)
In our study, we found that 18F-PSMA-1007 PET/CT has a relatively high detection rate in patients with PCa after radical treatment and low, rising PSA levels. We observed that the higher the PSA level the higher the odds for a positive PET/CT scan. On the other hand, GS and T stage ≥ 3 did not significantly correlate with PET positivity. 18FPSMA-1007 also showed excellent sensitivity, specificity, and NPV.
In the present study, 18F-PSMA-1007 detection rate was 60.0%, which is lower than reported in the literature (81.3–95%).1, 2 In the cited studies, however, PSA levels were higher—they ranged from 0.04 to 228 ng/ml with median values of 1.2–1.34 ng/ml. In our study, on the other hand, we selected only patients with PSA ≤ 2.0 ng/ml— median PSA was 0.65 (0.008-2.0) ng/ml. Also, nearly half of the patients (18/40) had very low PSA levels (<0.5 ng/ml).
We hypothesize that low PSA levels may also be the reason for relatively low SUVmax values. It has been reported that SUVmax values are positively correlated with PSA values. According to Rahbar et al., median SUVmax in patients with PSA > 2.0 ng/ml tends to be significantly higher than in patients with lower PSA.7 It has been also shown that SUVmax values are higher the longer the uptake time. In the present study, median time from injection to scanning was 90 min, while in some studies where higher SUVmax values are reported it was up to 120 min.8 Low SUVmax values have surely lowered TBR values. In addition, blood pool activity was the background. As 18FPSMA-1007 presents high plasma protein binding and delayed blood pool clearance, tumour-to-blood ratios are usually low. 5, 9
In accordance with the published data, we showed that 18F-PSMA-1007 PET/CT detection rate seems to be strongly dependent on PSA levels. It seems to be the case for other PSMA radioligands, such as 68Ga-PSMA-11 and 18F-DCFPyL, and radiocholines as well.10–13 On the other hand, GS and T stage ≥ 3 did not seem to correlate with 18F-PSMA-1007 PET/CT positivity.
Data on histopathologic confirmation of 18G-PSMA1007-positive lesions are scarce. In a study by Giesel et al., (309 pelvic lymph nodes were histologically examined) 18FPSMA-1007 PET/CT showed 94.7% sensitivity. In our study, where combined reference standard was used, we verified 40 lesions and yielded sensitivity, specificity, PPV, and NPV of 100%, 94.4%, 66.7%, and 100%, respectively. These values seem comparable with 68Ga-PSMA-11.14–16
In the study, we presented a prospective evaluation of 18F-PSMA-1007 PET/CT diagnostic accuracy in patients with PCa after radical treatment and low (≤2.0 ng/ml), rising PSA levels. It must, however, be stated that despite followup and combined reference standard, not all PSMA-positive lesions have been verified. Another limitation of the study is that the relatively small group of subjects might have been the cause for lack of significance in some statistical analyses.
18F-PSMA-1007 PET/CT presented a relatively high detection rate in patients with PCa after radical treatment and low (≤2.0 ng/ml), rising PSA levels. Scan positivity was strongly dependent on PSA levels. 18F-PSMA-1007 also showed excellent sensitivity, specificity, and NPV.
Compliance with ethical standards
Conflict of interest: The authors declare that they have no conflict of interest.
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Ewa Witkowska-Patena1,2, Agnieszka Giżewska1,2, Mirosław Dziuk1,2, Jolanta Miśko2, Anna Budzyńska1,2, Agata Walęcka-Mazur3
- Department of Nuclear Medicine, Military Institute of Medicine, 128 Szaserów St, 04-141 Warsaw, Poland
- Affidea Mazovian PET/CT Medical Centre, 128 Szaserów St, 04- 349 Warsaw, Poland
- Synektik Pharma, Kielce, Poland
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- Rahbar K, Afshar-Oromieh A, Bögemann M, Wagner S, Schäfers M, Stegger L, et al. 18F-PSMA-1007 PET/CT at 60 and 120 min in patients with prostate cancer: biodistribution, tumour detection and activity kinetics. Eur J Nucl Med Mol Imaging. 2018;45:1329–34.
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Received: 21 September 2019 / Revised: 13 November 2019 / Accepted: 15 November 2019 / Published online: 28 November 2019
© The Author(s), under exclusive licence to Springer Nature Limited 2019
Witkowska-Patena W., Giżewska A., Dziuk M., et al. Diagnostic performance of 18F-PSMA-1007 PET/CT in biochemically relapsed patients with prostate cancer with PSA levels ≤ 2.0 ng/ml. Prostate Cancer and Prostatic Diseases. 2020; 23:343–348
Read an Editorial by Henry Woo (MBBS, DMedSc FRACS: 18F-PSMA-1007 PET/CT for Diagnosis and Detection of Biochemically Recurrent Prostate Cancer - Editorial