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The Role of PET-CT Imaging in Prostate Cancer
Abstract
Prostate cancer (CaP) is the commonest malignancy to affect men in the UK. Extraprostatic disease detection at staging and in the setting of biochemical recurrence (BCR) is essential in determining treatment strategy. Conventional imaging including computed tomography (CT) and bone scintigraphy (BS) are limited in their ability to detect sites of loco-regional nodal and metastatic bone disease, particularly at clinically relevant low prostate specific antigen (PSA) levels. The use of positron emission tomography-computed tomography (PET-CT) has helped overcome these deficiencies and is leading a paradigm shift in the management of CaP using a wide range of radiopharmaceuticals. Their mechanisms of action, utility in both staging and BCR, and comparative strengths and weaknesses will be covered in this article.
... Indeed, several studies reported pitfalls in the use of PSA serum concentration as an early biomarker for prostate cancer [6][7][8]. Thus, currently the diagnosis of prostate cancer is based on imaging methods including transrectal ultrasound [9], Magnetic Resonance Imaging (MRI) [10], Computer Tomography (CT) [11] and Positron-Emission Tomography (PET) [11][12][13]. However, the final diagnosis and classification of prostate cancer lesions is performed by both histological and immunohistochemical analysis [14]. ...
... Indeed, several studies reported pitfalls in the use of PSA serum concentration as an early biomarker for prostate cancer [6][7][8]. Thus, currently the diagnosis of prostate cancer is based on imaging methods including transrectal ultrasound [9], Magnetic Resonance Imaging (MRI) [10], Computer Tomography (CT) [11] and Positron-Emission Tomography (PET) [11][12][13]. However, the final diagnosis and classification of prostate cancer lesions is performed by both histological and immunohistochemical analysis [14]. ...
... In recent years PET/CT analysis of prostate cancer patients with several radiopharmaceuticals such as 18 F-choline ( 18 F-ethylcholine or 18 F-methylcholine) [15], 11 C-choline PET/CT [16], FDG [17] and PSMA ligand [17,18] acquired a central role in the management of these patients. In fact, PET/CT investigations can be used for both diagnosis and follow-up of patients affected by prostate cancer with an eminent role in the detection of metastatic lesions [19]. ...
Aims of the study:
The study utilizes the prostate-specific membrane antigen-reporting and data system (PSMA-RADS) version 1.0 in a real-world patient scenario in the evaluation of equivocal lesions using the PSMA-RADS categorization for patient management and communication in multidisciplinary team (MDT) meetings.
Methods:
A retrospective analysis of 203 patients who had 18F PSMA PET/CT for either restaging or staging over 12 months was undertaken. The scans were evaluated for local disease, lymph node involvement and distant metastases. The scan findings were classified as suspicious for metastases, and equivocal and benign lesions. Experience with PSMA ligand imaging was considered while classifying the lesions, equivocal lesions were assessed with PSMA-RADS and followed up with complementary imaging and/or clinical follow-up assessment or MDT for further patient management.
Results:
A total of 91 of 203 patients had equivocal lesions. Follow-up assessment was performed in 47 of 91 patients with imaging (n = 36) or MDT discussion (n = 11).On follow-up imaging (n = 36), equivocal lesion was seen in skeletal lesions (n = 24), pelvic lymph nodes (n = 6), both skeletal and pelvic nodes (n = 4), hilar and mediastinal lymph nodes (n = 1) and spleen (n = 1). The patients were reclassified as benign, metastatic with few lesion remained equivocal. Overall follow-up assessment impacted clinical management in 47% patients.
Conclusion:
18F PSMA PET/CT may show equivocal lesions; many of them in the skeleton, a small proportion of which are ultimately proven metastatic. In contrast, a higher proportion of the equivocal nodes in the pelvis end up being metastatic on follow-up. A structured reporting with PSMA-RADS grading helps in the proper classification of lesions and standardization of reports.
We previously demonstrated the ability to detect metastatic prostate cancer using (18)F-DCFBC (DCFBC), a low-molecular-weight radiotracer that targets the prostate-specific membrane antigen (PSMA). PSMA has been shown to be associated with higher Gleason grade and more aggressive disease. An imaging biomarker able to detect clinically significant high-grade primary prostate cancer reliably would address an unmet clinical need by allowing for risk-adapted patient management.
We enrolled 13 patients with primary prostate cancer who were imaged with DCFBC PET prior to scheduled prostatectomy, with 12 of these patients also undergoing pelvic prostate MRI. Prostate DCFBC PET was correlated with MRI and histological and immunohistochemical (IHC) analysis on a prostate segment (12 regions) and dominant lesion basis. There were no incidental extraprostatic findings on PET suspicious for metastatic disease.
MRI was more sensitive than DCFBC PET for detection of primary prostate cancer on a per-segment (sensitivities of 0.17 and 0.39 for PET and MRI for non-stringent analysis and 0.10 and 0.35 for stringent analysis, respectively) and per-dominant lesion analysis (sensitivity of 0.46 and 0.92 for PET and MRI, respectively). However, DCFBC PET was more specific than MRI by per-segment analysis (specificity of 0.96 and 0.89 for PET and MRI for non-stringent analysis and 1.00 versus 0.91 for stringent analysis, respectively) and highly specific for detection of high-grade lesions greater than or equal to 1.1 mL in size (Gleason 8 and 9). DCFBC uptake in tumors was positively correlated with Gleason score (ρ = 0.64, PSMA expression (ρ = 0.47) and PSA (ρ = 0.52). There was significantly lower DCFBC uptake in benign prostatic hypertrophy (BPH) compared to primary tumors (median SUVmax 2.2 versus SUVmax 3.5; P = 0.004).
Although the sensitivity of DCFBC for primary prostate cancer was less than MRI, DCFBC PET was able to detect the more clinically significant high-grade tumors (Gleason score 8 and 9) with higher specificity than MRI. In particular, there was relatively low DCFBC PET uptake in BPH lesions compared to cancer in the prostate, which may allow for more specific detection of primary prostate cancer by DCFBC PET. This study demonstrates the utility of PSMA-based PET for detection of primary prostate cancer, which may be used in conjunction with MRI to guide biopsy and identify clinically significant, aggressive disease non-invasively.
Copyright © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.
Purpose:
Early and accurate localisation of lesions in patients with biochemical recurrence (BCR) of prostate cancer may guide salvage therapy decisions. The present study, XXX, aimed to evaluate the impact of 18F-fluciclovine on management of men with BCR of prostate cancer.
Methods:
Men with a first episode of BCR following curative-intent primary therapy were enrolled at 6 UK sites. Patients underwent 18F-fluciclovine PET/CT according to standardised procedures. Clinicians documented management plans before and after scanning, recording changes to treatment modality as 'major' and changes within a modality as 'other'. The primary outcome measure was record of a revised management plan post-scan. Secondary endpoints were evaluation of optimal PSA threshold for detection, salvage treatment outcome assessment based on 18F-fluciclovine-involvement, and safety.
Results:
18F-Fluciclovine was well tolerated in the 104 scanned patients (median PSA=0.79 ng/mL). Lesions were detected in 58/104 (56%) patients. Detection was broadly proportional to PSA level; ≤1 ng/mL, 1/3 of scans were positive, while 93% scans were positive at PSA >2.0 ng/mL. Sixty-six (64%) patients had a post-scan management change (80% following a positive result). Major changes (43/66; 65%) were: salvage or systemic therapy to watchful waiting (16/66; 24%); salvage therapy to systemic therapy (16/66; 24%); alternative changes to treatment modality (11/66, 17%). The remaining 23/66 (35%) management changes were modifications of the pre-scan plan: most (22/66; 33%) were adjustments to planned brachytherapy/radiotherapy to include a 18F-fluciclovine-guided boost. Where 18F-fluciclovine guided salvage therapy, the PSA response rate was higher than when 18F-fluciclovine was not involved (15/17 [88%] vs 28/39 [72%]).
Conclusions:
18F-Fluciclovine PET/CT located recurrence in the majority of men with BCR, frequently resulting in major management plan changes. Incorporating 18F-fluciclovine PET/CT into treatment planning may optimise targeting of recurrence sites and avoid futile salvage therapy.
Background:
PSMA PET is a promising method for primary lymph node staging in prostate cancer. However, recent systematic reviews have identified only a limited number of studies with histopathology as a reference test.
Methods:
A systematic search was performed in PubMed and the Cochrane Library. An expedited systematic review was performed where we identified diagnostic studies in prostate cancer where a preoperative PSMA PET for primary lymph node staging was compared to histopathology. The trials must have diagnostic data on a patient level.
Results:
Eighteen eligible clinical trials included 969 patients. The median patient number per study was 32 (range 10 to 208). Five trials were prospective, and nine trials had a consecutive enrolment of patients. Sixteen studies used Ga-68-PSMA-11; there was one study with Cu-64-PSMA and one study with F-18-DCDFPyL. Twelve studies used PET/CT, four trials used PET/MR. Most trials included patients with intermediate and high-risk. Diagnostic accuracy varied notably among the studies; sensitivity ranged from 23 to 100%, specificity 67-100%, positive predictive value 20-100%, and negative predictive value 41-100%. Weighted sensitivity was 59%, weighted specificity was 93%. Four studies compared PSMA PET with anatomical imaging (CT or MRI); in all cases, sensitivity and specificity were superior with PSMA PET. Three studies compared PSMA PET with multi-parametric or diffusion-weighted MRI with mixed results.
Conclusions:
PSMA PET showed promising diagnostic accuracy for primary lymph node staging with pathology as reference. Recommendation for PSMA PET for high-risk patients in clinical guidelines should be supported by confirmatory, prospective trials with patient-relevant outcomes.
Purpose
To determine the impact on clinical management of patients with high-risk (HR) prostate cancer at diagnosis and patients with biochemical recurrence (BCR) using a new kit form of ⁶⁸Ga-prostate-specific membrane antigen (PSMA), namely tris(hydroxypyridinone) (THP)-PSMA, with positron emission tomography-computed tomography (PET-CT).
Methods
One hundred eighteen consecutive patients (50 HR, 68 BCR) had management plans documented at a multidisciplinary meeting before ⁶⁸Ga-THP-PSMA PET-CT. Patients underwent PET-CT scans 60-min post-injection of ⁶⁸Ga-THP-PSMA (mean 159 ± 21.2 MBq). Post-scan management plans, Gleason score, prostate-specific antigen (PSA) and PSA doubling time (PSAdt) were recorded.
Results
HR group: 12/50 (24%) patients had management changed (9 inter-modality, 3 intra-modality). Patients with PSA < 20 μg/L had more frequent management changes (9/26, 34.6%) compared with PSA > 20 μg/L (3/24, 12.5%). Gleason scores > 8 were associated with detection of more nodal (4/16, 25% vs 5/31, 16.1%) and bone (2/16, 12.5% vs 2/31, 6.5%) metastases. BCR group: Clinical management changed in 23/68 (34%) patients (17 inter-modality, 6 intra-modality). Forty out of 68 (59%) scans were positive. Positivity rate increased with PSA level (PSA < 0.5 μg/L, 0%; PSA 0.5–1.0 μg/L, 35%; PSA 1.0–5.0 μg/L, 69%; PSA 5.0–10.0 μg/L, 91%), PSAdt of < 6 months (56% vs 45.7%) and Gleason score > 8 (78.9% vs 51.2%).
Conclusions
⁶⁸Ga-THP-PSMA PET-CT influences clinical management in significant numbers of patient with HR prostate cancer pre-radical treatment and is associated with PSA. Management change also occurs in patients with BCR and is associated with PSA and Gleason score, despite lower scan positivity rates at low PSA levels < 0.5 μg/L.
The aim of the study was to prospectively evaluate diagnostic performance of 18F-PSMA-1007 PET/CT in patients with prostate cancer (PCa) after radical treatment and low but rising prostate-specific antigen (PSA) levels.
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).
18F-PSMA-1007 PET/CT was positive in 24/40 patients, which yielded 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.
18F-PSMA-1007 PET/CT shows 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-PSMA-1007 also presents excellent sensitivity, specificity and NPV.
Objectives:
First, to review the literature to determine the sensitivity and specificity of 68 Ga-PSMA PET for detecting pelvic lymph node metastases in patients with primary prostate cancer, and the positive predictive value in patients with biochemical recurrence after initial curative treatment. Second, to determine the detection rate and management impact of 68 Ga-PSMA PET in patients with biochemical recurrence after radical prostatectomy.
Materials and methods:
We performed a comprehensive literature search. Search terms used through Medline, Embase and Science Direct were '(PSMA, 68 Ga-PSMA, 68 Gallium-PSMA, Ga-68-PSMA or prostate-specific membrane antigen)' and '(histology, lymph node, staging, sensitivity, specificity, positive predictive value, recurrence, recurrent or detection)'. Relevant abstracts were reviewed and full-text articles obtained where possible. References to and from obtained articles were searched to identify further relevant articles.
Results:
Nine retrospective and two prospective studies describe the sensitivity and specificity of 68 Ga-PSMA PET for detecting pelvic lymph node metastases before initial treatment which ranged from 33.3 to 100% and 80 to 100%, respectively. In eight retrospective studies, the positive predictive value of 68 Ga-PSMA PET in patients with biochemical recurrence before salvage lymph node dissection ranged from 70 to 100%. The detection rate of 68 Ga-PSMA PET in patients with biochemical recurrence after radical prostatectomy in the PSA subgroups <0.2 ng/ml, 0.2-0.49 ng/ml and 0.5-<1.0 ng/ml ranged from 11.3 to 50.0%, 20.0 to 72.7% and 25.0 to 87.5% respectively.
Conclusion:
68 Ga-PSMA PET demonstrates a high specificity for the detection of pelvic lymph node metastases in primary prostate cancer. Furthermore, 68 Ga-PSMA PET has a very high positive predictive value in detecting lymph node metastases in patients with biochemical recurrence. By contrast, sensitivity is only moderate. Therefore, based on the currently available literature, 68 Ga-PSMA PET cannot yet replace pelvic lymph node dissection to exclude lymph node metastases. In the salvage phase, 68 Ga-PSMA PET has both a high detection rate and impact on radiotherapy planning in early biochemical recurrence after radical prostatectomy.
Purpose
⁶⁸Ga-PSMA-11 PET/CT is commonly performed at 1 h post injection (p.i.). However, various publications have demonstrated that most prostate cancer (PC) lesions exhibit higher contrast at later imaging. The aim of this study was to compare the “common” protocol of ⁶⁸Ga-PSMA-11 PET/CT with a modified protocol.
Methods
In 2017, we used the following scanning protocol for ⁶⁸Ga-PSMA-11 PET/CT in patients with recurrent PC: acquisition at 1 h p.i. without further preparations. From 2018, all scans were conducted at 1.5 h p.i. In addition, patients were orally hydrated with 1 L of water 0.5 h p.i. and were injected with 20 mg of furosemide 1 h p.i. Both protocols including 112 patients (2017) and 156 (modified protocol in 2018) were retrospectively compared. Rates of pathologic scans, maximum standardized uptake values (SUVmax), and tumor contrast (ratio lesion-SUVmax/background-SUVmean) as well as average standardized uptake values (SUVmean) of urinary bladder were analyzed.
Results
Both tumor contrast and tracer uptake were significantly (p < 0.001) higher in the novel protocol. Although statistically not significant, the rates of pathologic scans were also higher in the modified protocol: 76.3% vs. 68.8% for all PSA values including 38.9% vs. 25.0% for PSA < 0.5 ng/ml and 60.0% vs. 56.7% for PSA > 0.5–≤ 2.0 ng/ml. Average SUVmean of the urinary bladder was significantly (p < 0.001) lower with the modified protocol.
Conclusions
The modified protocol, which includes a combination of delayed image acquisition at 1.5 h p.i., hydration, and furosemide resulted in higher tumor contrast and seems to have the potential to increase the rates of pathological scans, especially at low PSA levels.
Purpose:
Multiparametric magnetic resonance imaging (mpMRI) with informed targeted biopsies (TGBX) has changed the paradigm of prostate cancer (PCa) diagnosis. Randomized studies have demonstrated a diagnostic benefit of Clinically significant (CS) for TGBX compared to standard systematic biopsies (SBX). We aimed to evaluate whether mpMRI-informed TGBX has superior diagnosis rates of any-, CS-, high-grade (HG)-, and clinically insignificant (CI)-PCa compared to SBX in biopsy-naive men.
Methods:
Data was searched in Medline, Embase, Web of Science, and Evidence-based medicine reviews-Cochrane Database of systematic reviews from database inception until 2019. Studies were selected by two authors independently, with disagreements resolved by consensus with a third author. Overall 1951 unique references were identified, and 100 manuscripts underwent full-text review. Data were pooled using random-effects models. The meta-analysis is reported according to the PRISMA statement. The study protocol is registered with PROSPERO (CRD42019128468).
Results:
Overall 29 studies (13,845 patients) were analyzed. Compared to SBX, use of mpMRI-informed TGBX was associated with a 15% higher rate of any PCa diagnosis (95% CI 10-20%, p<0.00001). This relationship was not affected by the study methodology (p=0.11). Diagnosis of CS and HG PCa were more common in the mpMRI-informed TGBX group (risk difference of 11%, 95% CI 0-20%, p=0.05, and 2%, 95% CI 1-4%; p=0.005, respectively) while there was no difference in diagnosis of CI PCa (risk difference of 0, 95% CI -3 to 3%, p=0.96). Notably, the exclusion of SBX in the mpMRI-informed TGBX arm significantly modified the association between a mpMRI strategy and lower rates of CI PCa diagnosis (p=0.01) without affecting the diagnosis rates of CS- or HG-PCa.
Conclusions:
In comparison to SBX, a mpMRI-informed TGBX strategy results in a significantly higher diagnosis rate of any-, CS-, and HG-PCa. Excluding SBX from mpMRI-informed TGBX was associated with decreased rates of CI-PCa diagnosis without affecting diagnosis of CS- or HG-PCa.
Background:
National Comprehensive Cancer Network guidelines consider 18F-fluciclovine PET-CT for prostate cancer biochemical recurrence localisation after radical prostatectomy, whereas European Association of Urology guidelines recommend prostate-specific membrane antigen (PSMA) PET-CT. To the best of our knowledge, no prospective head-to-head comparison between these tests has been done so far. The aim of this study was to compare prospectively paired 18F-fluciclovine and PSMA PET-CT scans for localising biochemical recurrence of prostate cancer after radical prostatectomy in patients with low prostate-specific antigen (PSA) concentrations (<2·0 ng/mL).
Methods:
This was a prospective, single-centre, open-label, single-arm comparative study done at University of California Los Angeles (Los Angeles, CA, USA). Patients older than 18 years of age with prostate cancer biochemical recurrence after radical prostatectomy and PSA levels ranging from 0·2 to 2·0 ng/mL without any prior salvage therapy and with a Karnofsky performance status of at least 50 were eligible. Patients underwent 18F-fluciclovine (reference test) and PSMA (index test) PET-CT scans within 15 days. Detection rate of biochemical recurrence at the patient level and by anatomical region was the primary endpoint. A statistical power analysis demonstrated that a sample size of 50 patients was needed to show a 22% difference in detection rates in favour of PSMA (test for superiority). Each PET scan was interpreted by three independent masked readers and a consensus majority interpretation was generated (two vs one) to determine positive findings. This study is registered with ClinicalTrials.gov, number NCT02940262, and is complete.
Findings:
Between Feb 26, 2018, and Sept 20, 2018, 143 patients were screened for eligibility, of whom 50 patients were enrolled into the study. Median follow-up was 8 months (IQR 7-9). The primary endpoint was met; detection rates were significantly lower with 18F-fluciclovine PET-CT (13 [26%; 95% CI 15-40] of 50) than with PSMA PET-CT (28 [56%; 41-70] of 50), with an odds ratio (OR) of 4·8 (95% CI 1·6-19·2; p=0·0026) at the patient level; in the subanalysis of the pelvic nodes region (four [8%; 2-19] with 18F-fluciclovine vs 15 [30%; 18-45] with PSMA PET-CT; OR 12·0 [1·8-513·0], p=0·0034); and in the subanalysis of any extrapelvic lesions (none [0%; 0-6] vs eight [16%; 7-29]; OR non-estimable [95% CI non-estimable], p=0·0078).
Interpretation:
With higher detection rates, PSMA should be the PET tracer of choice when PET-CT imaging is considered for subsequent treatment management decisions in patients with prostate cancer and biochemical recurrence after radical prostatectomy and low PSA concentrations (≤2·0 ng/mL). Further research is needed to investigate whether higher detection rates translate into improved oncological outcomes.
Funding:
None.
Purpose:
One of the major challenges for all imaging modalities is accurate detection of prostate cancer (PCa) recurrence. Beyond the established Ga-PSMA, a novel promising PET tracer in PCa imaging is F-fluciclovine. For evaluating the advantages and disadvantages and the comparability, we conducted a prospective head-to-head comparison on F-fluciclovine and Ga-PSMA-11 in patients with biochemical recurrence of PCa.
Methods:
58 patients with biochemical recurrence of PCa after definitive primary therapy were included. Both scans were performed within a time window of mean 9.4 days. All scans were visually analyzed independently on a patient-, region- and lesion-based analysis. All the examinations were performed in the same medical department using identical scanners at any time.
Results:
The overall detection rate for PCa recurrence was 79.3% in F-fluciclovine and 82.8% in Ga-PSMA-11 (P = 0.64). Local recurrence was detected in 37.9% on F-fluciclovine and in 27.6% on Ga-PSMA-11 (P = 0.03). Local pelvic lymph node recurrence was detected on F-fluciclovine versus Ga-PSMA-11 in 46.6% versus 50%, in extrapelvic lymph node metastases in 41.4% versus 51.7% and in bone metastases in 25.9% versus 36.2%. Lesion-based analysis showed identical findings in local pelvic lymph nodes in 39.7%, in extrapelvic lymph nodes in 22.4%, and in bone metastases in 13.8%.
Conclusions:
The advantage of F-fluciclovine is detecting curable localized disease in close anatomical relation to the urinary bladder, whereas Ga-PSMA-11 fails because of accumulation of activity in the urinary bladder. F-fluciclovine is almost equivalent to Ga-PSMA-11 in detecting distant metastases of PCa recurrence.
Background
The aim was to compare the diagnostic accuracy of ⁶⁸Ga-PSMA PET/CT with conventional cross-sectional imaging and diffusion-weighted MRI (DW-MRI) for detecting lymph node metastasis (LNM) to stage prostate cancer patients. Twenty consecutive, newly- diagnosed prostate cancer patients were prospectively enrolled and underwent ⁶⁸Ga-PSMA-11 PET/CT, anatomical MRI or contrast-enhanced CT, and DW-MRI prior to laparoscopic, template-based, extended lymph node dissection. Histopathological findings served as the reference test.
Results
Histopathology showed LNM in 13 of 20 patients (19 high-risk, 1 intermediate risk). Five patients had metastasis-suspected lymph nodes on ⁶⁸Ga-PSMA PET/CT. Patient-based analysis showed that the sensitivity and specificity for detecting LNM were 39% and 100% with ⁶⁸Ga-PSMA PET/CT, 8% and 100% with MRI/CT, and 36% and 83% with DW-MRI, respectively. The positive and negative predictive values were 100% and 49% with ⁶⁸Ga-PSMA PET/C, 100% and 37% with MRI/CT, and 80% and 42% with DW-MRI. Of 573 dissected lymph nodes, 33 were LNM from 26 regions. True-positive LNM on ⁶⁸Ga-PSMA PET/CT was 9–11 mm in diameter, whereas false-negative LNM had a median diameter of 4 mm, with only 3 of 30 lymph nodes being larger than 10 mm. LNM were positive for PSMA by immunostaining.
Conclusions
The sensitivity of ⁶⁸Ga-PSMA PET/CT was notably better than that of MRI/CT and comparable to that of DW-MRI. Some false positive findings with DW-MRI reduced its specificity and positive predictive value compared with those of ⁶⁸Ga-PSMA PET/CT and MRI/CT.
Background: The use of radiolabeled prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) for biochemical recurrent prostate cancer (BRPCa) is increasing worldwide. Recently, 18F-labeled PSMA agents have become available. We performed a systematic review and meta-analysis regarding the detection rate (DR) of 18F-labeled PSMA PET/CT in BRPCa to provide evidence-based data in this setting. Methods: A comprehensive literature search of PubMed/MEDLINE, EMBASE, and Cochrane Library databases through 23 April 2019 was performed. Pooled DR was calculated on a per-patient basis, with pooled proportion and 95% confidence interval (95% CI). Furthermore, pooled DR of 18F-PSMA PET/CT using different cut-off values of prostate-specific antigen (PSA) was obtained. Results: Six articles (645 patients) were included in the meta-analysis. The pooled DR of 18F-labeled PSMA PET/CT in BRPCa was 81% (95% CI: 71–88%). The pooled DR was 86% for PSA ≥ 0.5 ng/mL (95% CI: 78–93%) and 49% for PSA < 0.5 ng/mL (95% CI: 23–74%). Statistical heterogeneity was found. Conclusions: 18F-labeled PSMA PET/CT demonstrated a good DR in BRPCa. DR of 18F-labeled PSMA PET/CT is related to PSA values with significant lower DR in patients with PSA < 0.5 ng/mL. Prospective multicentric trials are needed to confirm these findings.
Both radiolabelled choline and prostate specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) could be used in patients with biochemical recurrent prostate cancer (BRPCa). We aimed to perform a meta-analysis about the head-to-head comparison of detection rate (DR) between these methods in BRPCa. A comprehensive literature search of studies listed in PubMed/MEDLINE, EMBASE and Cochrane library databases through October 2018 and regarding the head-to-head comparison of DR between ra-diolabelled choline and PSMA PET/CT in BRPCa was carried out. Overall pooled DR was calculated on a per patient-based analysis; subgroup analyses taking into account different prostate-specific antigen (PSA) cutoff values were performed. Five studies (257 BRPCa patients) were included. The meta-analysis provided the following overall DR: 56% [95% confidence interval (95% CI): 37-75%] for radiolabelled choline PET/CT and 78% (95% CI: 70-84%) for radiolabelled PSMA PET/CT. Significant difference of DR was found only in patients with PSA ≤ 1 ng/ml [the DR of radiolabelled choline and PSMA PET/CT were 27% (95% CI: 17-39%) and 54% (95% CI: 43-65%), respectively]. Radiolabelled PSMA PET/CT proved to be clearly superior in detecting BRPCa lesions at low PSA levels (≤ 1 ng/ml) when compared to radiolabelled choline PET/CT. On the other hand, the superiority of radiolabelled PSMA PET/CT was less evident in patients with PSA > 1 ng/ml. More studies and in particular cost-effectiveness analyses comparing these imaging methods are warranted.
Prostate-specific membrane antigen (PSMA) is highly overexpressed in prostate cancer. Many PSMA analog radiotracers for PET/CT prostate cancer staging have been developed, such as 68Ga-PSMA-11. This radiotracer has achieved good results in multiple clinical trials, but because of the superior imaging characteristics of 18F-fluoride, 18F-PSMA-11 was developed. The aim of this study was to evaluate the administration safety and radiation dosimetry of 18F-PSMA-11. Methods: Six patients (aged 62-68 y; mean, 66 ± 2 y) with suspected prostate cancer recurrence after previous treatment were administered 2 MBq of 18F-PSMA-11 per kilogram of body weight and then underwent low-dose PET/CT imaging at 0, 20, 50, 90, and 300 min after injection. To evaluate the safety of administration, vital parameters were monitored. To assess toxicity, full blood count and biochemical parameters were determined. According to the latest International Commission on Radiological Protection recommendations, radiation dosimetry analysis was performed using IDAC-Dose 2.1. For blood activity measurement, small samples of venous blood were collected at various time points after injection. The unbound 18F-fluoride fraction was determined in plasma at 20, 50, and 90 min after administration to evaluate the defluorination rate of 18F-PSMA-11. Results: After injection, 18F-PSMA-11 cleared rapidly from the blood. At 5 h after injection, 29.0% ± 5.9% of the activity was excreted in urine. The free 18F fraction in plasma increased from 9.7% ± 1.0% 20 min after injection to 22.2% ± 1.5% 90 min after injection. The highest tracer uptake was observed in kidneys, bladder, spleen, and liver. No study drug-related adverse events were observed. The calculated mean effective dose was 12.8 ± 0.6 μSv/MBq. Conclusion:18F-PSMA-11 can be safely administered and results in a mean effective dose of 12.8 ± 0.6 μSv/MBq. Therefore, the total radiation dose is lower than for other PSMA PET agents and in the same range as 18F-DCFPyL.
18F-DCFPyL (2-(3-{1-carboxy-5-[(6-18F-fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid), a prostate-specific membrane antigen-targeting radiotracer, has shown promise as a prostate cancer imaging radiotracer. We evaluated the safety, sensitivity, and impact on patient management of 18F-DCFPyL in the setting of biochemical recurrence of prostate cancer. Methods: Subjects with prostate cancer and biochemical recurrence after radical prostatectomy or curative-intent radiotherapy were included in this prospective study. The subjects underwent 18F-DCFPyL PET/CT imaging. The localization and number of lesions were recorded. The uptake characteristics of the 5 most active lesions were measured. A pre- and posttest questionnaire was sent to treating physicians to assess the impact on management. Results: One hundred thirty subjects were evaluated. 18F-DCFPyL PET/CT localized recurrent prostate cancer in 60% of cases with a prostate-specific antigen (PSA) level of ≥0.4 to <0.5, 78% with a level of ≥0.5 to <1.0, 72% with a level of ≥1.0 to <2.0, and 92% with a level of ≥2.0. Many subjects had few lesions (1 lesion in 40.8%, 2 in 8.5%, and 3 in 4.6%). The number of lesions was significantly related to PSA by ANOVA, but there was a large overlap in the PSA values for number of lesion categories. Total lesion uptake was also significantly related to PSA level. A change in treatment intent occurred in 65.5% of subjects, disease stage changed in 65.5%, and management plans changed in 87.3%. Twenty-two subjects reported mild adverse events after the scan; all resolved completely. Conclusion:18F-DCFPyL PET/CT is safe and sensitive for the localization of biochemical recurrence of prostate cancer. This test improved decision making for referring oncologists and changed management for most subjects.
Importance
In retrospective studies, ⁶⁸Ga-PSMA-11 positron emission tomographic (PET) imaging improves detection of biochemically recurrent prostate cancer compared with conventional imaging.
Objective
To assess ⁶⁸Ga-PSMA-11 PET accuracy in a prospective multicenter trial.
Design, Setting, and Participants
In this single-arm prospective trial conducted at University of California, San Francisco and University of California, Los Angeles, 635 patients with biochemically recurrent prostate cancer after prostatectomy (n = 262, 41%), radiation therapy (n = 169, 27%), or both (n = 204, 32%) underwent ⁶⁸Ga-PSMA-11 PET. Presence of prostate cancer was recorded by 3 blinded readers on a per-patient and per-region base. Lesions were validated by histopathologic analysis and a composite reference standard.
Main Outcomes and Measures
Endpoints were positive predictive value (PPV), detection rate, interreader reproducibility, and safety.
Results
A total of 635 men were enrolled with a median age of 69 years (range, 44-95 years). On a per-patient basis, PPV was 0.84 (95% CI, 0.75-0.90) by histopathologic validation (primary endpoint, n = 87) and 0.92 (95% CI, 0.88-0.95) by the composite reference standard (n = 217). ⁶⁸Ga-PSMA-11 PET localized recurrent prostate cancer in 475 of 635 (75%) patients; detection rates significantly increased with prostate-specific antigen (PSA): 38% for <0.5 ng/mL (n = 136), 57% for 0.5 to <1.0 ng/mL (n = 79), 84% for 1.0 to <2.0 ng/mL (n = 89), 86% for 2.0 to <5.0 ng/mL (n = 158), and 97% for ≥5.0 ng/mL (n = 173, P < .001). Interreader reproducibility was substantial (Fleiss κ, 0.65-0.78). There were no serious adverse events associated with ⁶⁸Ga-PSMA-11 administration. PET-directed focal therapy alone led to a PSA drop of 50% or more in 31 of 39 (80%) patients.
Conclusions and Relevance
Using blinded reads and independent lesion validation, we establish high PPV for ⁶⁸Ga-PSMA-11 PET, detection rate and interreader agreement for localization of recurrent prostate cancer.
Trial Registration
ClinicalTrials.gov Identifiers: NCT02940262 and NCT03353740.
68Ga-PSMA-11 PET is used to stage patients with prostate cancer. We performed an updated metaanalysis that separates imaging at the time of diagnosis and at the time of biochemical recurrence and focuses on pathology correlation in both populations. Methods: We searched the MEDLINE and EMBASE databases using the PRISMA statement. Quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies tool 2. In total, 1,811 studies were screened, 58 were analyzed, 41 were included for qualitative synthesis, and 29 were included for quantitative analysis. A random-effect model and a hierarchical summary receiver-operating-characteristic model were used to summarize the sensitivity, specificity, positive predictive value (PPV), negative predictive value, and accuracy for pelvic lymph nodes in initial staging compared with pathology at prostatectomy and the PPV for lesions with pathologic correlation in those with biochemical recurrence. We also summarized the detection rate of 68Ga-PSMA-11 in those with biochemical recurrence stratified by prostate-specific antigen (PSA) at the time of imaging. Results: The metaanalysis of 68Ga-PSMA-11 at initial staging demonstrated a sensitivity and specificity of 0.74 (95% confidence interval [95% CI], 0.51-0.89) and 0.96 (95% CI, 0.85-0.99), respectively, using nodal pathology at prostatectomy as a gold standard. At biochemical recurrence, the PPV was 0.99 (95% CI, 0.96-1.00). The detection rate was 0.63 (95% CI, 0.55-0.70), with a PSA of less than 2.0 and 0.94 (95% CI, 0.91-0.96) with a PSA of more than 2.0. Conclusion:68Ga-PSMA-11 performed well for the localization of metastatic prostate cancer at initial staging and at the time of biochemical recurrence.
Context: In men with prostate cancer (PCa) treated with curative intent, controversy exists
regarding the impact of biochemical recurrence (BCR) on oncological outcomes.
Objective:. To perform a systematic review of the existing literature on BCR after treatment with curative intent for non-metastatic PCa. Objective 1 is to investigate whether oncological outcomes differ between patients with or without BCR. Objective 2 is to study which clinical factors and tumor features in patients with BCR have an independent prognostic impact on oncological outcomes. Evidence acquisition:. Medline, Medline In-Process, Embase, and the Cochrane Central Register of Controlled Trials were searched. For objective 1, prospective and retrospective studies comparing survival outcomes of patients with or without BCR following radical prostatectomy (RP) or radical radiotherapy (RT) were included. For objective 2, all studies with at least 100 participants and reporting on prognostic patient and tumor characteristics in patients with BCR were included. Risk-of-bias and confounding assessments were performed according to the Quality in Prognosis Studies (QUIPS) tool. Both a narrative synthesis and a meta-analysis were undertaken. Evidence synthesis: Overall, 77 studies were included for analysis, of which 14 studies addressed objective 1, recruiting 20 406 patients. Objective 2 was addressed by 71 studies with 29 057, 11 301, and 4272 patients undergoing RP, RT, and a mixed population (mix of patients undergoing RP or RT as primary treatment), respectively. There was a low risk of bias for study participation, confounders, and statistical analysis. For most studies, attrition bias, and prognostic and outcome measurements were not clearly reported. BCR was associated with worse survival rates, mainly in patients with a short prostate-specific antigen doubling time (PSA-DT) and a high final Gleason score after RP, or a short interval to biochemical failure (IBF) after RT and a high biopsy Gleason score. Conclusions: BCR has an impact on survival, but this effect appears to be limited to a subgroup of patients with specific clinical risk factors. A short PSA-DT and a high final Gleason score after RP, and a short IBF after RT and a high biopsy Gleason score are the main factors that have a negative impact on survival. These factors may form the basis of a new BCR risk stratification (European Association of Urology BCR Risk Groups), which needs to be validated formally.
Patient summary: This review looks at the risk of death in men who show a rising
prostate-specific antigen (PSA) in the blood test performed after curative surgery or
radiotherapy. For many men, a rising PSA does not mean that they are at a high risk of
death from prostate cancer in the longer term. Men with PSA that rises shortly after
they were treated with radiotherapy or a rapidly rising PSA after surgery and a high tumor grade for both treatment modalities are at the highest risk of death. These factors may
form the basis of a new risk stratification (European Association of Urology Biochemical
Recurrence Risk Groups), which needs to be validated formally.
Recently, prostate-specific membrane antigen (PSMA) targeted PET-imaging has emerged as new method of staging and restaging of prostate cancer. Most published studies have investigated the diagnostic potential of 68Ga-labeled PSMA-agents which are excreted renally. [18F]PSMA-1007 is a novel PSMA-ligand with excellent preclinical characteristics which is only minimally excreted by the urinary tract, a potential advantage for pelvic imaging. The aim of this study was to investigate the diagnostic efficacy of [18F]PSMA-1007 in biochemical recurrence (BCR) after radical prostatectomy (RP). Methods: 251 patients from three academic centers with BCR after radical prostatectomy were evaluated in a retrospective analysis. Patients who had received second line androgen deprivation therapy and/or chemotherapy were excluded, however prior first line ADT exposure was allowed. The median PSA-level was 1.2 ng/ml (range: 0.2-228 ng/mL). All patients underwent a PSMA-PET/CT after injection of 301±46 MBq [18F]PSMA-1007 at 92±26 min post injection. The detection rate of presumed recurrence sites was correlated with PSA-level and original primary Gleason score. A comparison to a subset of patients treated previously with androgen deprivation therapy (ADT) was undertaken. Results: 204 of 251 patients (81.3%) patients had evidence of recurrence on [18F]PSMA-1007 PET/CT. The detection rates were 94.1% (79/84), 90.1% (50/55), 74.5% (35/47) and 61.5% (40/65) for PSA-levels of ≥2, 1-<2, 0.5-<1 and 0.2-<0.5ng/mL, respectively. [18F]PSMA-1007 PET/CT revealed local recurrence in 43.7% (62) of patients. Lymph node metastases were present in the pelvis in 40.6% (102), in the retroperitoneum in 19.5% (49) and in supradiaphragmatic locations in 12.0% (30) of patients. Bone and visceral metastases were detected in 40.2% (101) and 3.6% (9) patients. In higher Gleason score tumors (≤7vs.≥8) detection efficacy trended higher (76.3% vs. 86.7%) but was not statistically significant (P = 0.32). However, detection efficacy was higher in patients who had previously been on ADT (91.7% vs. 78.0%) within 6 months prior to imaging (P = 0.0179). Conclusion: [18F]PSMA-1007 PET/CT offers high detection rates in BCR after radical prostatectomy which is comparable to or better than that published for 68Ga-labelled PSMA-ligands.
We aimed to compare ¹¹C-choline positron emission tomography/computed tomography (PET/CT) with conventional imaging, including pelvic magnetic resonance imaging (MRI), contrast-enhanced chest, abdomen, and pelvic computed tomography (CT), and bone scintigraphy, for prostate cancer restaging. Thirty patients (median prostate-specific antigen [PSA: 11.8 ng/mL]) with suspected recurrent prostate cancer following definitive treatment underwent ¹¹C-choline PET/CT and conventional imaging, including pelvic MRI, contrast-enhanced chest, abdomen, and pelvic CT, and bone scintigraphy. The results were compared with regard to patient- and lesion-based diagnostic performance for local recurrence, and for lymph node and bony metastases using receiver operating characteristic (ROC) analysis and McNemar’s test. Documented local recurrence and node and bony metastases were present in 11 (36.7%), 10 (33.3%), and 17 (56.7%) cases, respectively, of the enrolled patients. Patient-based sensitivity / specificity / accuracy / area under the ROC curve for ¹¹C-choline-PET/CT for diagnosing local recurrence were 90.9% / 94.7% / 93.3% / 0.975 and for conventional imaging were 90.9% / 100% / 96.7% / 1.0. Those who underwent ¹¹C-choline-PET/CT for node metastasis were 90.0% / 95.0% / 93.3% / 0.925 and for conventional imaging were 70.0% / 95.0% / 86.7% / 0.905. Those who underwent ¹¹C-choline-PET/CT for bone metastasis were 94.1% / 92.3% / 93.3% / 0.991 and who underwent conventional imaging were 94.1% / 84.6% / 90.0% / 0.982. No significant differences were observed among them. The lesion-based detection rate of ¹¹C-choline PET/CT for local recurrences and node and bone metastases as compared to conventional imaging was 92.9% (13/14) vs. 92.9% (13/14); 87.1% (27/31) vs. 54.8% (17/31); and 96.9% (219/226) vs. 90.3% (204/226) respectively, with significant differences noted for detection of node and bone lesions (p=0.0044 and p=0.00030, respectively). ¹¹C-choline-PET/CT is more accurate in the detection of recurrent prostate cancer nodes and bony metastatic lesions compared to conventional imaging and has the advantage of restaging the disease in a single step.
PurposeWe studied the usefulness of 68Ga-prostate-specific membrane antigen (PSMA) PET/CT for detecting relapse in a prospective series of patients with biochemical recurrence (BCR) of prostate cancer (PCa) after radical treatment. Methods
Patients with BCR of PCa after radical surgery and/or radiotherapy with or without androgen-deprivation therapy were included in the study. 68Ga-PSMA PET/CT scans performed from the top of the head to the mid-thigh 60 min after intravenous injection of 150 ± 50 MBq of 68Ga-PSMA were interpreted by two nuclear medicine physicians. The results were correlated with prostate-specific antigen (PSA) levels at the time of the scan (PSApet), PSA doubling time, Gleason score, tumour stage, postsurgery tumour residue, time from primary therapy to BCR, and patient age. When available, 68Ga-PSMA PET/CT scans were compared with negative 18F-choline PET/CT scans routinely performed up to 1 month previously. ResultsFrom November 2015 to October 2017, 314 PCa patients with BCR were evaluated. Their median age was 70 years (range 44–92 years) and their median PSApet was 0.83 ng/ml (range 0.003–80.0 ng/ml). 68Ga-PSMA PET/CT was positive (one or more suspected PCa lesions detected) in 197 patients (62.7%). Lesions limited to the pelvis, i.e. the prostate/prostate bed and/or pelvic lymph nodes (LNs), were detected in 117 patients (59.4%). At least one distant lesion (LNs, bone, other organs, separately or combined with local lesions) was detected in 80 patients (40.6%). PSApet was higher in PET-positive than in PET-negative patients (P < 0.0001). Of 88 patients negative on choline PET/CT scans, 59 (67%) were positive on 68Ga-PSMA PET/CT. Conclusion
We confirmed the value of 68Ga-PSMA PET/CT in restaging PCa patients with BCR, highlighting its superior performance and safety compared with choline PET/CT. Higher PSApet was associated with a higher relapse detection rate.
Background
The aim of this study was to prospectively compare the detection rate of ⁶⁸Ga-PSMA versus ¹¹C-Choline in men with prostate cancer with biochemical recurrence and to demonstrate the added value of a tri-modality PET/CT-MRI system.
Methods
We analysed 36 patients who underwent both ¹¹C-Choline PET/CT and ⁶⁸Ga-PSMA PET/CT scanning within a time window of 1-2 weeks. Additionally, for the ⁶⁸Ga-PSMA scan, we used a PET/CT-MRI (3.0 T) system with a dedicated shuttle, acquiring MRI images of the pelvis.
Results
Both scans were positive in 18 patients (50%) and negative in 8 patients (22%). Nine patients were positive with ⁶⁸Ga-PSMA alone (25%) and one with ¹¹C-Choline only (3%). The median detected lesion per patient was 2 for ⁶⁸Ga-PSMA (range 0-93) and 1 for ¹¹C-Choline (range 0-57). Tumour to background ratios in all concordant lesions (n = 96) were higher for ⁶⁸Ga-PSMA than for ¹¹C-Choline (110.3 ± 107.8 and 27.5 ± 17.1, mean ± S.D., for each tracer, respectively P = 0.0001). The number of detected lesions per patient was higher for ¹¹C-Choline in those with PSA ≥ 3.3 ng/mL, while the number of detected lesions was independent of PSA levels for ⁶⁸Ga-PSMA using the same PSA cut-off value. Metastatic pelvic lesions were found in 25 patients (69%) with ⁶⁸Ga-PSMA PET/CT, in 18 (50%) with ¹¹C-Choline PET/CT and in 21 (58%) with MRI (3.0 T). MRI was very useful in detecting recurrence in cases classified as indeterminate by means of PET/CT alone at prostate bed.
Conclusions
In patients with prostate cancer with biochemical recurrence ⁶⁸Ga-PSMA detected more lesions per patient than ¹¹C-Choline, regardless of PSA levels. PET/CT-MRI (3.0 T) system is a feasible imaging modality that potentially adds useful relevant information with increased accuracy of diagnosis.
Purpose:
PSMA-targeted PET in patients with prostate cancer (PCa) has a significant impact on treatment decisions. By far the most frequently used PSMA ligand is68Ga-labelled PSMA-11. However, due to the availability of larger amounts of activity,18F-labelled PSMA ligands are of major interest. The aim of the present study was to evaluate the biodistribution and performance of the novel18F-labelled ligand PSMA-1007 at two different time points.
Methods:
This retrospective analysis included 40 consecutive patients (mean age 68.7 ± 8.1 years) referred for PSMA PET/CT.18F-PSMA-1007 PET/CT was performed for localization of biochemical relapse, primary staging or therapy follow-up. Circular regions of interest were placed on representative slices of the liver, spleen, kidney, abdominal aortic blood pool, bone marrow (fourth lumbar vertebral body), urinary bladder and gluteus muscle at 60 and 120 min after injection. In malignant lesions the maximum standardized uptake (SUVmax) was measured within volumes of interest at both time points. All SUVs at 60 min were compared with those at 120 min after injection.
Results:
The activity in the blood pool, urinary bladder and gluteus muscle was very low and decreased significantly over time (P < 0.001). Uptake in the liver, spleen and kidney showed a significant increase over time and uptake in the bone marrow remained stable. Overall, 135 PCa lesions were detected at 60 min and 136 lesions at 120 min after injection. The median SUVmaxincreased significantly (P < 0.001) from 10.98 to 15.51 between 60 and 120 min.
Conclusion:
PCa lesions show a significant increase in18F-PSMA-1007 uptake at 120 min compared with 60 min after injection. In addition, accumulation of the tracer in the urinary bladder was very low leading to improved contrast of adjacent PCa lesions. Increasing accumulation in the liver may limit the sensitivity of the tracer in detecting liver metastases.
Aim
To prospectively evaluate the clinical impact and the diagnostic performance of FCH-PET/CT in patients with occult biochemical recurrence of prostate cancer (PCa).
Materials and methods
Results of 179 patients (mean PSA = 7.5ng/mL) with negative/inconclusive results of pelvic-MRI and of bone-scintigraphy were analysed. To determine the impact of FCH-PET/CT on diagnostic thinking and on patient management, the referring physicians prospectively filled-in a 1st and 2nd questionnaire related to patient’s planned management before and after FCH-PET/CT. Based on data from a 6-month follow-up after FCH-PET/CT, an independent assessor blinded to results of FCH-PET/CT determined the adequacy of management changes motivated by FCH-PET/CT.
Results
FCH-PET/CT localised foci evocative of recurrent PCa in 59% (105/179) of patients. Results of FCH-PET/CT motivated a change in scheduled patient management in 56% (100/179) of patients; which was considered as adequate in 89% (89/100) of patients. FCH-PET/CT also led to the detection of lung cancer in two patients.
Conclusion
FCH PET/CT is a powerful tool to localise the sites of occult biochemical recurrence of PCa, leading to an adequate management change in half of patients.
Purpose[68Ga]Tris(hydroxypyridinone)(THP)-PSMA is a novel radiopharmaceutical for one-step kit-based radiolabelling, based on direct chelation of 68Ga3+ at low concentration, room temperature and over a wide pH range, using direct elution from a 68Ge/68Ga-generator. We evaluated the clinical detection rates of [68Ga]THP-PSMA PET/CT in patients with biochemically recurrent prostate cancer after prostatectomy. Methods
Consecutive patients (n=99) referred for evaluation of biochemical relapse of prostate cancer by [68Ga]THP-PSMA PET/CT were analyzed retrospectively. Patients underwent a standard whole-body PET/CT (1 h p.i.), followed by delayed (3 h p.i.) imaging of the abdomen. PSA-stratified cohorts of positive PET/CT results, standardized uptake values (SUVs) and target-to-background ratios (TBRs) were analyzed, and compared between standard and delayed imaging. ResultsAt least one lesion suggestive of recurrent or metastatic prostate cancer was identified on PET images in 52 patients (52.5%). Detection rates of [68Ga]THP-PSMA PET/CT increased with increasing PSA level: 94.1% for a PSA value of ≥10 ng/mL, 77.3% for a PSA value of 2 to <10 ng/mL, 54.5% for a PSA value of 1 to <2 ng/mL, 14.3% for a PSA value of 0.5 to <1 ng/mL, 20.0% for a PSA value of >0.2 to <0.5, and 22.2% for a PSA value of 0.01 to 0.2 ng/mL. [68Ga]THP-PSMA uptake (SUVs) in metastases decreased over time, whereas TBRs improved. Delayed imaging at 3 h p.i. exclusively identified pathologic findings in 2% of [68Ga]THP-PSMA PET/CT scans. Detection rate was higher in patients with a Gleason score ≥8 (P=0.02) and in patients receiving androgen deprivation therapy (P=0.003). Conclusions
In this study, [68Ga]THP-PSMA PET/CT showed suitable detection rates in patients with biochemical recurrence of prostate cancer and PSA levels ≥ 2 ng /mL. Detections rates were lower than in previous studies evaluating other PSMA ligands, though prospective direct radiotracer comparison studies are mandatory particularly in patients with low PSA levels to evaluate the relative performance of different PSMA ligands.
Introduction: The introduction of 18F-labelled prostate-specific membrane antigen (PSMA) targeted positron emission tomography/computed-tomography (PET/CT) tracers, firstly 18F-DCFPyL and more recently 18F-PSMA-1007, have demonstrated promising results for the diagnostic workup of prostate cancer (PCa). This clinical study presents an intra-individual comparison to evaluate tracer-specific characteristics of 18F-DCFPyL versus 18F-PSMA-1007. Methods: Twelve prostate cancer patients, drug naive or prior to surgery, received similar activities of about 250 MBq 18F-DCFPyL and 18F-PSMA-1007 48 h apart and were imaged 2 h p.i. in the same PET/CT-scanner using the same reconstruction-algorithm. Normal organ biodistribution and tumor uptakes were quantified using SUVmax. Results: PSMA-positive lesions were detected in twelve out of twelve PCa patients. Both tracers, 18F-DCFPyL and 18F-PSMA-1007, detected the identical lesions. No statistical significance could be observed when comparing the SUVmax of 18F-DCFPyL and 18F-PSMA-1007 for local tumor, lymph node metastases and bone metastases. With regard to normal organs, 18F-DCFPyL presented statistically significant higher uptake in kidneys, urinary bladder and lacrimal gland. Vice versa, significantly higher uptake of 18F-PSMA-1007 in muscle, submandibular and sublingual gland, spleen, pancreas, liver and gallbladder was observed. Conclusion: Excellent imaging quality was achieved with both 18F-DCFPyL and 18F-PSMA-1007 resulting in identical clinical findings for the evaluated routine situations. Non-urinary excretion of 18F-PSMA-1007 might present some advantage with regard to delineation of local recurrence or pelvic lymph-node metastasis in selective patients; the lower hepatic background might favor 18F-DCFPyL in very late stages when rare cases of liver metastases can occur.
Purpose:
The purpose of this study was to evaluate (18)F-FACBC PET/CT, PET/MRI, and multiparametric MRI (mpMRI) in detection of primary prostate cancer (PCa).
Methods:
Twenty-six men with histologically confirmed PCa underwent PET/CT immediately after injection of 369 ± 10 MBq (18)F-FACBC (fluciclovine) followed by PET/MRI started 55 ± 7 min from injection. Maximum standardized uptake values (SUVmax) were measured for both hybrid PET acquisitions. A separate mpMRI was acquired within a week of the PET scans. Logan plots were used to calculate volume of distribution (VT). The presence of PCa was estimated in 12 regions with radical prostatectomy findings as ground truth. For each imaging modality, area under the curve (AUC) for detection of PCa was determined to predict diagnostic performance. The clinical trial registration number is NCT02002455.
Results:
In the visual analysis, 164/312 (53%) regions contained PCa, and 41 tumor foci were identified. PET/CT demonstrated the highest sensitivity at 87% while its specificity was low at 56%. The AUC of both PET/MRI and mpMRI significantly (p < 0.01) outperformed that of PET/CT while no differences were detected between PET/MRI and mpMRI. SUVmax and VT of Gleason score (GS) >3 + 4 tumors were significantly (p < 0.05) higher than those for GS 3 + 3 and benign hyperplasia. A total of 442 lymph nodes were evaluable for staging, and PET/CT and PET/MRI demonstrated true-positive findings in only 1/7 patients with metastatic lymph nodes.
Conclusions:
Quantitative (18)F-FACBC imaging significantly correlated with GS but failed to outperform MRI in lesion detection. (18)F-FACBC may assist in targeted biopsies in the setting of hybrid imaging with MRI.
Prostate-specific membrane antigen (PSMA) positron emission tomography (PET) is rapidly being established as arguably the leading contemporary imaging modality in the management of prostate cancer. Outside of its conventional use in the de novo staging of localized disease and detection of biochemical recurrence, additional applications for the use of PSMA PET are emerging. Uptake of PSMA tracers in other genitourinary malignancies, particularly renal cell carcinoma, has led to new fields of investigation. Therapeutic delivery of radiolabelled PSMA small molecules has shown considerable promise in advanced prostate cancer. The ability to use the same molecule for imaging and therapy — theranostics — enables a highly personalized approach. PSMA PET can also have a considerable influence in the selection and guidance of radiotherapy fields for high-risk and recurrent disease. Intriguingly, changes in intensity of PSMA uptake during systemic therapy might provide early response assessment or novel insight into the biological responses of genitourinary malignancies to treatment. An evolving range of radiolabelled PSMA radiopharmaceuticals is emerging in the multiple facets of modern clinical practice.
18F-labelled prostate-specific membrane antigen (PSMA) positron emission tomography (PET) tracers are increasingly used in preference to 68Ga-PSMA-11 for restaging biochemical recurrence (BCR) of prostate cancer. They are associated with longer half-lives, larger scale production and lower positron range compared with their 68Ga-labelled counterparts. Here we describe the efficacy of 18F-labelled radiohybrid PSMA, rhPSMA-7, a novel theranostic PSMA-targeting agent for imaging BCR of prostate cancer. Methods: Datasets from 261 consecutive patients with non-castrate BCR after radical prostatectomy who underwent 18F-rhPSMA-7 PET/CT at our institution between June 2017 and March 2018 were reviewed retrospectively. All lesions suspicious for recurrent prostate cancer were recorded. The detection rate of presumed recurrence sites was correlated with patients' PSA level, primary Gleason score, and prior therapy (androgen deprivation therapy [ADT)] and external beam radiation therapy [EBRT]). Results: The 261 patients had a median PSA level of 0.96 (range, 0.01-400) ng/mL. The median injected activity of 18F-rhPSMA-7 was 336 MBq, with a median uptake time of 76 min. In total, 211 patients (81%) patients showed pathological findings on 18F-rhPSMA-7 PET/CT. The detection rates were 71% (42/59), 86% (44/51), 86% (42/49) and 95% (76/80) at PSA levels of 0.2 to <0.5 ng/mL, 0.5 to <1 ng/mL, 1 to <2 ng/mL and ≥2 ng/mL, respectively. In 32% (7/22) patients with a PSA <0.2 ng/ml suspicious lesions were present. 18F-rhPSMA-7 PET/CT revealed local recurrence in 43% (113) patients. Lymph node metastases were present in the pelvis in 42% (110), in the retroperitoneum in 17% (45) and in a supradiaphragmatic location in 8.0% (21) patients. Bone and visceral metastases were detected in 21% (54) and 3.8% (10) patients, respectively. Detection efficacy was not influenced by prior EBRT (79.1% vs. 82.1%, P = 0.55), ADT within the 6 months preceding imaging (80.6% vs. 80.9%, P = 0.54), nor by primary Gleason score (77.9% for Gleason Score ≤7 vs. 82.6% for Gleason Score ≥ 8, P = 0.38). Conclusion:18F-rhPSMA-7 PET/CT offers superb detection rates in early BCR after radical prostatectomy, especially among patients with low PSA values.
Purpose of the report:
The aim of the study was to prospectively compare performance of F-fluorocholine (FCH) and F-prostate-specific membrane antigen (PSMA)-1007 PET/CT in patients with biochemical relapse (BCR) of prostate cancer and low prostate-specific antigen levels.
Methods:
We prospectively enrolled 40 BCR patients after radical treatment and prostate-specific antigen levels 2.0 ng/mL or less. F-FCH and F-PSMA-1007 PET/CT imaging was performed within a mean interval of 54 ± 21 days. Scans were done 87 ± 10 and 95 ± 12 minutes after injecting 248 ± 35 and 295 ± 14 MBq of F-FCH and F-PSMA-1007, respectively. Rates of negative, equivocal, and positive scan results were compared per patient. Per lesion, findings were grouped as equivocal or highly suggestive of malignancy and then compared for their number, localization (local relapse, lymph nodes, bones), and SUVmax values.
Results:
Positive, equivocal, and negative results were reported in 60%, 27.5%, and 12.5% of F-PSMA-1007 and in 5%, 37.5%, and 57.5% of F-FCH scans, respectively. In 70% of scans, F-PSMA-1007 PET/CT upgraded F-FCH PET/CT results. F-PSMA-1007 scans also showed significantly more lesions (184 vs 63, P = 0.0006). Local relapse, lymph node, and bone lesions accounted, respectively, for 9%, 58%, and 33% of F-PSMA-1007 and 5%, 89%, and 6% F-FCH of PET/CT findings. Highly suspicious lesions accounted for 74% of F-PSMA-1007 and 11% of F-FCH PET/CT findings. In F-PSMA-1007 PET/CT SUVmax values of highly suggestive lesions were significantly higher than in equivocal lesions (median, 3.6 vs 2.5; P < 0.00001).
Conclusions:
In early BCR patients F-PSMA-1007 showed a higher detection rate than F-FCH PET/CT. The former also showed more lesions in total, more highly suggestive lesions and less equivocal lesions.
Objective: To investigate the lesion detection rate of 18F-DCFPyL-PET/CT, a prostate-specific membrane antigen (PSMA) targeted PET agent, in biochemical relapse prostate cancer patients after primary local therapy. Methods: This is a prospective institutional review board-approved study of 90 patients with documented biochemical recurrence (median PSA 2.5 ng/mL, range 0.21-35.5 ng/mL) with negative conventional imaging after primary local therapies, including radical prostatectomy (n = 38), radiation (n = 27) or combination (n = 25). Patients on androgen deprivation therapy were excluded. Patients underwent whole-body 18F-DCFPyL-PET/CT (299.9±15.5 MBq) at 2 h p.i. PSMA-PET lesion detection rate was correlated with PSA, PSA kinetics and original primary tumor grade. Results: Seventy patients (77.8%) showed a positive PSMA-PET scan, identifying a total of 287 lesions: 37 prostate bed foci, 208 lymph nodes, and 42 bone/organ distant sites; 11 patients had a negative scan and 9 patients showed indeterminate lesions, which were considered negative in this study. The detection rates were 47.6% (n = 10/21), 50% (n = 5/10), 88.9% (n = 8/9), and 94% (n = 47/50) for PSA >0.2 to <0.5, 0.5 to <1.0, 1 to <2.0, and ≥2.0 ng/mL, respectively. In post-surgical patients, PSA, PSAdt and PSAvel correlated with PET results but the same was not true for post-radiation patients. These parameters also correlated with the extent of disease on PET (intrapelvic vs. extrapelvic). There was no significant difference between the rate of positive scans in patients with higher grade vs lower grade primary tumors (Gleason score ≥4+3 vs <3+4). Tumor recurrence was histology confirmed in 40% (28/70) of patients. On a per-patient basis, positive predictive value was 93.3% (95% CI, 77.6-99.2%) by histopathologic validation, and 96.2% (95% CI, 86.3-99.7%) by the combination of histology and imaging/clinical follow-up. Conclusion:18F-DCFPyL-PET/CT imaging offers high detection rates in biochemically recurrent prostate cancer patients; and is positive in about 50% of patients with PSA <0.5 ng/mL, which could substantially impact clinical management. In post-surgical patients, 18F-DCFPyL-PET/CT correlates with PSA, PSAdt and PSAvel suggesting it may have prognostic value. 18F-DCFPyL-PET/CT is highly promising for localizing sites of recurrent prostate cancer.
18F-Prostate-specific membrane antigen (PSMA)-1007 is mainly excreted through the liver. We benchmarked the performance of 18F-PSMA-1007 against three renally excreted PSMA-tracers. Methods: Among 668 patients we selected 27 patients in whom the PET/CT with 68Ga-PSMA-11, 18F-DCFPyL, or 18F-JK-PSMA-7 was interpreted as equivocal or negative or as oligometastatic disease (PET-1). Within <3 weeks, a second PET scan with 18F-PSMA-1007 was performed (PET-2). The confidence in the interpretation of PSMA-positive loco-regional findings was scored on a 5-point scale, first in routine diagnostics (reader 1), then by an independent second evaluation (reader 2). Discordant PSMA-positive skeletal findings were examined by contrast enhanced MRI. Results: For both readers, 18F-PSMA-1007 facilitated the interpretability of 27 loco-regional lesions. In PET-2, the clinical read-out led to a significantly lower number of equivocal loco-regional lesions (P = 0.024), reader 2 reported a significantly higher rate of suspicious lesions that were falsely interpreted as probably benign in PET-1 (P = 0.023). Exclusively on PET-2, we observed a total of 15 PSMA-positive PSMA-spots in the bone marrow of 6 patients (= 22%). None of the 15 discordant spots had a morphological correlate on the corresponding CT or on the subsequent MRI. Thus, 18F-PSMA-1007 exhibits a significantly higher rate of unspecific medullary spots (P = 0.0006). Conclusion:18F-PSMA-1007 may increase confidence to interpret small loco-regional lesions adjacent to the urinary tract. However, it may decrease the interpretability of skeletal lesions.
Purpose of review:
Functional imaging with PET combined with computed tomography (CT) is of emerging interest in prostate cancer (PCa). Development of prostate-specific membrane antigen (PSMA) radiolabelled ligands has thrust PET/CT into the limelight as an alternative to conventional imaging techniques, and the evidence base to support its utility in primary staging of newly diagnosed PCa is rapidly growing. This review focuses on the most recent and important publications evaluating PSMA PET/CT in primary staging of PCa.
Recent findings:
Three recent meta-analyses have reported Ga-PSMA PET/CT to demonstrate superior sensitivity and specificity for pelvic lymph node detection than conventional imaging. A recent systematic review also suggests Ga-PSMA PET/CT to be superior to bone scan for identifying bone metastases. However, the majority of studies are of a retrospective nature, and few provide histopathological correlation of PSMA PET/CT findings. Data from prospective studies are awaited to determine accuracy and management impact of PSMA PET/CT in primary staging.
Summary:
PSMA PET/CT is rapidly altering the landscape of primary staging in PCa. It appears to be superior to conventional imaging for detecting regional and distant metastasis, though caution should be applied given the lack of prospective studies assessing how significant findings should be integrated into patient management. PSMA PET/CT could potentially become the gold standard for primary staging of high-risk PCa if future prospective data can prove its validity in this space.
Aim:
To investigate the diagnostic performance of 18F-fluciclovine positron-emission tomography (PET) or combined PET and computed tomography (PET/CT) for diagnosis of primary cancer, preoperative lymph node (LN) staging, and detection of recurrent disease of prostate cancer (PCa) through a systematic review and meta-analysis.
Materials and methods:
The PubMed and EMBASE databases were searched from the earliest available date of indexing through 31 December 2018, for studies evaluating the diagnostic performance of 18F-fluciclovine PET or PET/CT for the management of PCa patients. The sensitivities, specificities, and positive and negative likelihood ratios (LR+ and LR-) across the studies were calculated and summary receiver operating characteristic curves were constructed.
Results:
Across 13 studies (563 patients), the pooled sensitivity for 18F-fluciclovine PET or PET/CT for diagnosis of primary PCa was 0.87 (95% confidence interval [CI]: 0.77-0.93) and a pooled specificity of 0.84 (95% CI: 0.68-0.93). For LN staging, the pooled sensitivity was 0.56 (95% CI: 0.37-0.74) and a pooled specificity of 0.98 (95% CI: 0.88-1.00). For detection of recurrent disease, the pooled sensitivity was 0.79 (95% CI: 0.60-0.91) and a pooled specificity of 0.69 (95% CI: 0.59-0.77). In meta-regression analysis, no definite variable was the source of the study heterogeneity.
Conclusion:
The current meta-analysis showed the moderate sensitivity and specificity of 18F-fluciclovine PET or PET/CT for the diagnosis of primary cancer, preoperative LN staging, and detection of recurrent PCa. Further large multicentre studies will be necessary to substantiate the diagnostic accuracy of 18F-fluciclovine PET/CT for management of PCa patients.
In preclinical trials, the recently developed tracer 18F-JK-PSMA-7 (2-MeO-18F-DCFPyL) has been demonstrated to show favorable properties regarding clinical performance and radiochemical accessibility. The aim of this study was to evaluate the clinical utility of 18F-JK-PSMA-7 for PET/CT imaging of patients with prostate cancer. Methods: In an Institutional Review Board-approved pilot study, initial clinical utility of PET/CT imaging with 18F-JK-PSMA-7 was directly compared to 68Ga-PSMA-11 PET/CT in a group of 10 patients with prostate cancer. The two PSMA-tracers were administered in each patient less than 3 weeks apart. Next, we analyzed the data of 75 consecutive patients who had undergone clinical 18F-JK-PSMA-7 PET/CT imaging for tumor localization of biochemical recurrence (BCR). Results: The pilot study in 10 patients who were examined with both PSMA-tracers demonstrated that 18F-JK-PSMA-7 was at least equivalent to 68Ga-PSMA-11. Using 18F-JK-PSMA-7, all unequivocally 68Ga-PSMA-11 positive lesions could be also detected by PET/CT and in 4 patients additional suspicious PSMA-positive lesions were identified (one patient changed from PSMA-negative to PSMA-positive). In patients with BCR (after prostatectomy or radiotherapy), the capacity of 18F-JK-PSMA-7 PET/CT to detect any PSMA-positive lesions was 84.8%. The PSA-stratified detection rate of 18F-JK-PSMA-7 after prostatectomy varied between 54.5% (6/11 patients; PSA < 0.5µg/l), 87.5% (14/16 patients; PSA 0.5-2 µg/l) and 90.9% (20/22 patients; PSA > 2µg/l). Conclusion: The tracer 18F-JK-PSMA-7 was found to be safe and clinically useful. We demonstrated that 18F-JK-PSMA-7 was not inferior, when directly compared with 68Ga-PSMA-11 in a pilot study but indeed identified additional PSMA-avid suspicious lesions in oligo-metastasized patients with BCR. In a subsequent analysis of a clinical cohort of BCR patients, 18F-JK-PSMA-7 was useful in tumor localization. 18F-JK-PSMA-7 is recommended for future prospective trials.
Purpose:18F-labeled prostate-specific membrane antigen (PSMA)-ligand positron emission tomography (PET) has several principal advantages compared to 68Ga-PSMA-11. The purpose of this retrospective study was to evaluate the frequency of non-tumor related uptake and the detection efficacy comparing 68Ga-PSMA-11 and 18F-PSMA-1007 PET/computed tomography (CT) in recurrent prostate cancer (PC) patients. Methods and Materials: 102 patients with biochemical recurrent PC after radical prostatectomy undergoing 18F-PSMA-1007 PET/CT imaging were included. On the basis of various clinical variables patients with corresponding 68Ga-PSMA-11 PET/CT scans were matched. All PET/CTs (total n = 204) were reviewed by one nuclear medicine physician. First, all PET positive lesions were noted. Then, lesions suspicious for recurrent PC were differentiated from lesions attributed to benign origin based on known pitfalls and information from CT. For each region, SUVmax of the lesion with the highest PSMA-ligand uptake was noted. Detection rates were determined and SUVmax were compared separately for 68Ga-PSMA-11 and 18F-PSMA-1007. Results: In total, 18F-PSMA-1007 PET and 68Ga-PSMA-11 revealed 369 and 178 PSMA-ligand positive lesions, respectively. 18F-PSMA-1007 PET revealed approximately 5 times more lesions attributed to benign origin compared to 68Ga-PSMA-11 PET (245 vs. 52 lesions, respectively). The most frequent benign lesions observed were ganglia, unspecific LN and bone lesions with 43%, 31%, 24% in 18F-PSMA-1007 and 29%, 42%, 27% in 68Ga-PSMA-11 PET, respectively. SUVmax of lesions attributed to benign origin was significantly higher (p<0.0001) in 18F-PSMA-1007 PET. Further, a similar number of lesions was attributed to recurrent PC (124/369 for 18F-PSMA-1007 PET and 126/178 for 68Ga-PSMA-11 PET). Conclusion: In 18F-PSMA-1007 PET, a considerably higher number of lesions with increased PSMA-ligand uptake attributed to benign lesions is present compared to 68Ga-PSMA-11 PET. This necessitates sophisticated reader training emphasizing known pitfalls and reporting within the clinical context.
Objective:
This multicenter, phase II clinical trial evaluated the diagnostic performance of 18F-fluciclovine, a novel amino acid for positron-emission tomography (PET), for detection of small lymph node metastases with short-axis diameters of 5-10 mm in patients with prostate cancer.
Methods:
Patients with prostate cancer were eligible after screening of laboratory tests and pelvic contrast-enhanced computed tomography (CT). Pelvic region 18F-fluciclovine PET/CT was then acquired within 28 days and dissection of regional lymph nodes was performed within 60 days of pelvic contrast-enhanced CT. Diagnostic performance of 18F-fluciclovine-PET/CT was evaluated by comparison with standard histopathology of lymph nodes.
Results:
In a total of 28 patients, 40 regional lymph nodes with short-axis diameters of 5-10 mm were eligible for efficacy evaluation; seven of these showed metastases confirmed by histopathology. The sensitivity of 18F-fluciclovine PET/CT was 57.1% (4/7). All four true positive lymph nodes detected by 18F-fluciclovine PET/CT had a metastatic lesion with a long-axis diameter of ≥7 mm and a high proportion of cancer volume (60-100%) according to pathology evaluation. The specificity, diagnostic accuracy, positive predictive value, and negative predictive value of 18F-fluciclovine PET/CT in lymph node-based analysis were 84.8% (28/33), 80.0% (32/40), 44.4% (4/9), and 90.3% (28/31), respectively. No clinically significant adverse events occurred.
Conclusions:
18F-fluciclovine PET/CT detected small lymph node metastases; however it also showed positive findings in benign lymph nodes. Refinement of the image assessment criteria may improve the diagnostic performance of 18F-fluciclovine PET/CT for small lymph node metastases in patients with prostate cancer.
Background: Gallium-68 and Fluor-18 labeled prostate specific membrane antigen (PSMA) molecules have created new opportunities for the unmet diagnostic needs in prostate cancer. The purpose of this study is to give an overview of the studies that have examined the role of PSMA PET scan in treatment planning in prostate cancer patients with biochemical recurrence. Methods: Medline, Embase, Web of Science, Google Scholar, and Cochrane Central were searched for relevant articles. After excluding the articles that did not fulfill the required criteria, 12 publications that reported the impact of PSMA-PET on the treatment plan in prostate cancer patients with biochemical recurrence (BCR) were included in the review. Results: All the studies in our review emphasized the impact of PSMA PET images on therapy management in prostate cancer patients with biochemical recurrence. Overall, the impact of PSMA PET/CT on therapy management varied between 30-76% among the 1,346 patients included in the review. Upstaging was reported in 32% to 67% of the patients. Patients with low PSA values (< 0.5 ng/ml) also demonstrated positive lesions, which could not have been detected by means of conventional imaging techniques. Important modifications to the original treatment plan included avoidance of systemic therapy (17-40%) and PET-directed local therapy (in up to 60% of the patients). Conclusion: PSMA imaging demonstrated a high clinical impact in patients with BCR with modifications to the original treatment plan among half of the patients. Detecting recurrence in BCR can prevent unnecessary toxicity and lead to individualized therapy.
Prostate cancer (PCa) is the most common cancer in men worldwide, but it exhibits a highly variable biological behavior ranging from indolent to highly aggressive disease. The standard conventional imaging for staging PCa consists of CT, MRI, and bone scans, but this imaging has suboptimal accuracy for extraprostatic tumor detection, particularly in the scenario of early biochemical relapse when the prostate-specific antigen levels are still low indicating a low volume of recurrent disease. This gap between known disease (as indicated by a rising prostate-specific antigen) and the failure to detect it on conventional imaging, has led to the development of novel imaging probes most of which have positron emitting radioactive tags. In the last decade, multiple PET probes have demonstrated promising performance in detecting sites of recurrence and extent of disease in patients with PCa. The landscape of available PET radiotracers is changing rapidly and includes radiolabeled choline, anti1-amino-3- ¹⁸ F-fluorocyclobutane-1-carboxylic acid ( ¹⁸ F-fluciclovine), bombesin, dihydrotestosterone, and prostate-specific membrane antigen (PSMA) ligands, among others. Of these, radiolabeled PSMA-PET agents have shown the most encouraging results in terms of sensitivity and are likely to become universally available for imaging PCa within a few years Other PET radiotracers such as bombesin-based radiotracers and antagonist of gastrin releasing-peptide receptor (RM2) are emerging as possible alternatives for PCa imaging. This review article discusses the current and near-future of PET molecular imaging probes.
Purpose:
The majority of men who undergo pelvic lymph node dissection at radical prostatectomy have benign lymph node histology. The aim of this study was to assess the predictive value of preoperative 68Ga-PSMA (prostate specific membrane antigen) positron emission tomography/computerized tomography to predict histological metastasis on pelvic lymph node dissection performed during radical prostatectomy.
Materials and methods:
We retrospectively reviewed the sensitivity, specificity, and positive and negative predictive values of preoperative staging 68Ga-PSMA positron emission tomography/computerized tomography to identify histological lymph node metastasis in 208 consecutive men who subsequently proceeded with pelvic lymph node dissection at radical prostatectomy.
Results:
Median prostate specific antigen was 7.6 μg/l, the lymph node count was 13 and Gleason score was 4 + 5. On a per patient basis only 21 of the 55 men with metastasis on histological examination were identified on 68Ga-PSMA positron emission tomography/computerized tomography for 38.2% sensitivity. Of the 143 men with no lymph node metastasis on 68Ga-PSMA imaging 34 had metastasis on histology for 80.8% negative predictive value. Specificity was 93.5% and positive predictive value was 67.7%. For the 172 histologically identified malignant lymph node metastases the sensitivity per node was 24.4% and specificity was 99.5%.
Conclusions:
If negative 68Ga-PSMA positron emission tomography/computerized tomography is used as the basis of not performing pelvic lymph node dissection, 80% of men would avoid unnecessary pelvic lymph node dissection. However, 68Ga-PSMA positron emission tomography/computerized tomography has poor sensitivity per node to detect all histologically positive lymph node metastases. Thus, pelvic lymph node dissection remains the gold standard to stage pelvic lymph nodes despite its known limitations and complications.
Context
In patients treated for prostate cancer, a rising serum prostate-specific antigen (PSA) level is a first sign of relapse, but imaging is needed to determine the localization of the recurrence, which may be local, in lymph nodes, and/or metastatic. With the increasing success rate of earlier salvage therapy, the diagnosis has become pertinent when the recurrent PSA level is still very low.
Objective
To systematically review the literature on the role of the existing imaging techniques in patients with early recurrent prostate cancer.
Evidence acquisition
A systematic literature search across the MEDLINE and EMBASE databases was conducted in February 2018, searching for original studies reporting on imaging in a (sub)group of patients with recurrent PSA levels not higher than 5 ng/ml. This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The methodological quality of the studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool.
Evidence synthesis
A total of 98 studies were included in this systematic review, reporting on the role of transrectal ultrasonography (TRUS), computed tomography (CT), bone scintigraphy (BS), single-photon emission CT, multiparametric magnetic resonance imaging (mpMRI), whole-body MRI (wbMRI), and positron emission tomography (PET)-CT/MRI using 18F fluoro-deoxy-glucose, 11C choline, 18F (fluoro)(methyl)choline, 11C acetate, 18F FACBC (fluciclovine) and prostate-specific membrane antigen (PSMA)-based tracers. CT and BS were not sufficiently sensitive in the early recurrence setting. For the detection of local recurrence, TRUS or mpMRI can be used; however, at the lowest PSA levels, few data were available, only after radical prostatectomy, showing a wide range of positivity. TRUS or mpMRI need to be combined with (PET)-CT to assess distant disease, but new techniques such as wbMRI, PET-MRI, or PET-CT allow for an all-in-one approach. At recurrent PSA levels <0.5 ng/ml, detection rates up to 31.3% were reported using ¹¹C choline PET-CT and up to 65.0% using ⁶⁸Ga PSMA-11 PET-CT. At recurrent PSA levels <0.2 ng/ml, detection rates of ⁶⁸Ga PSMA-11 PET-CT ranged from 11.3% to as high as 58.3%.
Conclusions
Detection rates of different imaging techniques depend on the PSA level at the time of imaging. Recent advanced imaging techniques may detect the localization of the recurrence, even when the PSA levels are still very low.
Patient summary
In patients treated for prostate cancer, a rising serum prostate-specific antigen (PSA) level is a sign of recurrence of the disease. Advanced imaging techniques may demonstrate the localization of the recurrence, even when the PSA levels are still very low.
Purpose:
The prospective, multicenter LOCATE trial assessed the impact of positron emission tomography/computed tomography (PET/CT) with 18F-fluciclovine on management plans for patients with biochemical recurrence (BCR) of prostate cancer after curative-intent primary therapy.
Materials and methods:
Men who had undergone curative-intent treatment of histologically confirmed prostate cancer, but who were suspected to have recurrence based on rising prostate-specific antigen (PSA) levels, were enrolled prospectively. Each had negative or equivocal findings on standard-of-care imaging. 18F-Fluciclovine-PET/CT was performed according to standardized protocols. Treating physicians completed a questionnaire regarding the patient's management plan pre- and post-scan, recording changes to treatment modality (e.g., salvage radiotherapy to systemic androgen deprivation therapy) as 'major', and changes within a modality (e.g., modified radiotherapy fields) as 'other'.
Results:
Between June 2016 and May 2017, 213 evaluable patients (median age 67 years; median PSA 1.00 ng/mL) were enrolled. 18F-Fluciclovine-avid lesions were detected in 122/213 (57%) patients. Overall, 126/213 patients (59%) had a change in management post-scan; 98/126 (78%) of these were 'major' and 88/126 (70%) were informed by positive PET/CT findings. The most frequent major changes were from salvage or non-curative systemic therapy to watchful waiting (32/126, 25%), from non-curative systemic therapy to salvage therapy (30/126, 24%) and from salvage therapy to non-curative systemic therapy (11/126, 9%).
Conclusion:
18F-Fluciclovine-PET/CT detected one or more sites of recurrence in the majority of men with BCR, frequently resulting in major changes to their management plans. Future studies will be planned to determine if change of management leads to improved outcomes.
Purpose
Our aim was to evaluate the benefit of early (1 h post-injection (p.i.)) and late (3 h p.i.) [⁶⁸Ga]PSMA-HBED-CC positron emission tomography (PET)/x-ray computed tomography (CT) imaging for detection of biochemical recurrence (BCR) of prostate cancer (PCa).
Procedures
Seventy patients with BCR of the PCa and prostate-specific antigen (PSA) levels of less than 2.0 μg/l were subjected to [⁶⁸Ga]PSMA-HBED-CC PET (mean injected activity 180 MBq). While early imaging contained whole body scans, late imaging was confined to the pelvis and the lower abdomen. Uptake in suspicious lesions was analyzed by peak and maximum standardized uptake values (SUVpeak/max). Tumor-to-background ratios were calculated for all lesions in which the liver served as reference organ. The Wilcoxon matched-pair signed-rank test was used to compare the uptake in suspicious lesions between early and late imaging. Follow-up data were used to validate the existence of the additionally detected lesions.
Results
Forty-four of the 70 patients thus examined were interpreted as PSMA-positive in early and/or late scans while 26 remained without suspicion of PSMA tracer uptake. A total of 70 suspicious lesions were analyzed. Ten tumor-suspicious lesions from seven different patients were better or exclusively visible in the late measurements while three tumor-suspicious lesions from three different patients were better or exclusively visible in the early images. A validation by follow-up data was possible for 11 of these 13 additionally detected lesions. In direct comparison between early and late imaging, the mean SUVmax in PSMA-positive lesions was 74 % higher (p < 0.001) and the mean SUVpeak was 36 % higher (p = 0.001) in the late scans. The SUVmean in the reference regions was decreasing in the late measurements, whereas the mean TBR increased by a factor of 3 (p < 0.001). Taking confirmed lesions only into account, we estimated a 10 % gain in additionally detected PSMA-positive lesions (7/70) within the patient cohort.
Conclusions
The time period between injection and data acquisition influences the detection rate of [⁶⁸Ga]PSMA-HBED-CC PET/CT. In biochemical recurrence with low PSA levels, late [⁶⁸Ga]PSMA-HBED-CC PET/CT imaging offers frequent advantages with regard to lesion contrast.
Purpose:
68Ga ligands targeting prostate-specific membrane antigen (PSMA) are rapidly emerging as a significant step forward in the management of prostate cancer. PSMA is a type II transmembrane protein with high expression in prostate carcinoma cells. We prospectively evaluated the use of 68Ga-PSMA positron emission tomography/computed tomography (PET/CT) in patients with prostate cancer and compared the results to those for technetium-99m (99mTc)-10-metacyloyloxydecyl dihydrogen phosphate (MDP) bone scintigraphy (BS).
Patients and methods:
A total 113 patients with biopsy-proven prostate cancer referred for standard-of-care BS were prospectively enrolled onto this study. 68Ga-PSMA PET/CT was performed after BS. Metastasis diagnosed on each technique was compared against a final diagnosis based on CT, magnetic resonance imaging, skeletal survey, clinical follow-up, and histologic correlation.
Results:
Ninety-one bone lesions were interpreted as bone metastases in 25 men undergoing 68Ga-PSMA PET/CT compared to only 61 lesions in 19 men undergoing 99mTc-MDP BS. Of the 7 bone scans that missed skeletal metastases, 54% of these missed lesions were due to either marrow or lytic skeletal metastases. The median standardized uptake value in all malignant bone lesions was 13.84. 68Ga-PSMA PET/CT showed significantly higher sensitivity and accuracy than BS (96.2% vs. 73.1%, and 99.1% vs. 84.1%) for the detection of skeletal lesions. For extraskeletal lesions, 68Ga-PSMA PET/CT showed an additional 96 unexpected lesions with a median standardized uptake value of 17.6.
Conclusion:
68Ga-PSMA PET/CT is superior to and can potentially replace bone scan in the evaluation for skeletal metastases in the clinical and trial setting because of its ability to detect lytic and bone marrow metastases.
Introduction
Accurate staging of patients with prostate cancer is important for therapeutic decision making. Relapse following surgery or radiotherapy of curative intent is not uncommon and, in part, represents a failure of staging with current diagnostic imaging techniques to detect disease spread. Prostate‐specific‐membrane‐antigen (PSMA) positron emission tomography / computed tomography (PET/CT) is a new whole body scanning technique that enables visualisation of prostate cancer with high contrast. The hypotheses of this study are that (a) PSMA‐PET/CT has improved diagnostic performance compared to conventional imaging, (b) PSMA‐PET/CT should be used as a first‐line diagnostic test for staging, (c) the improved diagnostic performance of PSMA‐PET/CT will result in significant management impact and (d) there are economic benefits if PSMA‐PET/CT is incorporated into the management algorithm.
Trial methodology
This is a prospective, multi‐centre study in which patients with untreated high‐risk prostate cancer will be randomised to Gallium‐68‐PSMA11‐PET/CT or conventional imaging, consisting of computer tomography of the abdomen/pelvis and bone scintigraphy with SPECT/CT. Inclusion criteria are newly diagnosed prostate cancer patients with select high‐risk prostate cancer defined as International Society of Urological Pathology (ISUP) grade group ≥ 3 (primary Gleason grade 4, or any Gleason grade 5), PSA ≥ 20ng/mL or clinical stage ≥ T3. Patients with negative, equivocal or oligometastatic disease on first line‐imaging will cross‐over to receive the other imaging arm. The primary objective is to compare the accuracy of PSMA‐PET/CT to conventional imaging for detecting nodal or distant metastatic disease. Histopathologic, imaging and clinical follow‐up at six months will define the primary endpoint according to a pre‐defined scoring system. Secondary objectives include comparing management impact, the number of equivocal studies, the incremental value of second‐line imaging in patients who cross‐over, the cost of each imaging strategy, radiation exposure, inter‐observer agreement and safety of PSMA‐PET/CT. Longer term follow‐up will also assess the prognostic value of a negative PSMA‐PET/CT.
Outcome & Significance
This trial will provide data to establish whether PSMA‐PET/CT should replace conventional imaging in the primary staging of select high‐risk localised prostate cancer patients, or whether it should be used to provide incremental diagnostic information in selected cases.
Trial registration
The proPSMA study is registered in the Australian and New Zealand Clinical Trial Registry (ANZCTR Trial No. 12617000005358).
Trial Funding
This clinical trial is funded by a grant from the The Movember Foundation through Prostate Cancer Foundation of Australia's Research Program.
This article is protected by copyright. All rights reserved.
Aim:
To evaluate the efficacy of single time point half-body (skull base to thighs) fluorine-18 choline positron-emission tomography (PET) in combination with computed tomography (CT) compared to a triple-phase acquisition protocol in the detection of prostate carcinoma recurrence.
Materials and methods:
Consecutive choline PET-CT studies performed at a single tertiary referral centre in patients with biochemical recurrence of prostate carcinoma between September 2012 and March 2017 were reviewed retrospectively. The indication for the study, imaging protocol used, imaging findings, whether management was influenced by the PET-CT, and subsequent patient outcome were recorded.
Results:
Ninety-one examinations were performed during the study period; 42 were carried out using a triple-phase protocol (dynamic pelvic imaging for 20 minutes after tracer injection, half-body acquisition at 60 minutes and delayed pelvic scan at 90 minutes) between 2012 and August 2015. Subsequently following interim review of diagnostic performance, a streamlined protocol and appropriate-use criteria were introduced. Forty-nine examinations were carried out using the single-phase protocol between 2015 and 2017. Twenty-nine (69%) of the triple-phase studies were positive for recurrence compared to 38 (78%) of the single-phase studies. Only one patient who had a single-phase study would have benefited from a dynamic acquisition, they have required no further treatment or imaging and are currently under prostate-specific antigen (PSA) surveillance.
Conclusion:
Choline PET-CT remains a useful tool for the detection of prostate recurrence when used in combination with appropriate-use criteria. Removal of dynamic and delayed acquisition phases reduces study time without adversely affecting accuracy. Benefits include shorter imaging time which improves patient comfort, reduced cost, and improved scanner efficiency.
Objective:
The purpose of this article is to review the diagnostic performance of MRI for the detection of pelvic lymph node (LN) metastasis in patients with bladder and prostate cancer.
Materials and methods:
MEDLINE and EMBASE were searched up to January 13, 2017. We included diagnostic accuracy studies that used MRI for pelvic LN detection in patients with bladder or prostate cancer, using histopathologic analyses published since 2000 as the reference standard. Two independent reviewers assessed the methodologic quality using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. Sensitivity and specificity of all studies were calculated. Per-patient and per-LN results were pooled and plotted in a hierarchic summary ROC plot. Metaregression, sensitivity, and subgroup analyses were performed.
Results:
Twenty-four studies (2928 patients) were included. Pooled per-patient sensitivity (n = 21) was 0.56 (95% CI, 0.42-0.69) with a specificity of 0.94 (95% CI, 0.90-0.96). Per-LN pooled estimates (n = 9) showed consistent results: sensitivity of 0.57 (95% CI, 0.29-0.82) and specificity of 0.97 (95% CI, 0.94-0.98). At metaregression analysis, type of cancer, magnet field strength, and use of ultrasmall superparamagnetic particles of iron oxide (USPIO) were significant factors affecting heterogeneity (p ≤ 0.01). Sensitivity analyses showed that specificity estimates were comparable (range, 0.87-0.95), but sensitivity estimates showed significant differences. Studies that used USPIO (n = 4) had higher sensitivity (0.86; 95% CI, 0.62-0.96) than did those not using USPIO (n = 17; 0.46; 95% CI, 0.35-0.58).
Conclusion:
MRI shows high specificity but poor and heterogeneous sensitivity for detecting pelvic LN metastasis in patients with bladder and prostate cancer. Using USPIO can improve sensitivity.
The study aims to investigate the presence of physiological prostate-specific membrane antigen (PSMA)-ligand uptake on positron-emission-tomography (PET) in cervical, coeliac and sacral ganglia of the sympathetic trunk as a pitfall for lymph node metastases in prostate cancer imaging. Methods: 407 patients who underwent "Glu-NH-CO-NH-Lys" radio-labeled with [68Ga]gallium N,N-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N-diacetic acid (68Ga-PSMA-HBED-CC) PET (combined with a diagnostic computed tomography (CT)) were retrospectively analyzed. The number of PSMA PET-positive cervical, coeliac and sacral ganglia was determined and the configuration and maximum standardized uptake value (SUVmax) of each ganglion was measured. In addition, the configuration and SUVmax of adjacent lymph node metastases in the respective region (cervical, coeliac or sacral) were determined. Results: PSMA-ligand uptake above background was detected in 401 (98.5%) patients in any peripheral ganglia, in 369 (92%) patients in cervical ganglia, in 363 (89%) patients in coeliac ganglia, and in 183 (46%) patients in sacral ganglia. The PSMA-ligand uptake was highest in coeliac (mean SUVmax 2.9±0.8 vs. cervical (mean SUVmax 2.4±0.6) and sacral (mean SUVmax 1.7±0.5), both p<0.0001) ganglia. Intra-individually there was a statistically significant, but weak to moderate correlation between the PSMA-ligand uptake in cervical vs. coeliac ganglia (R=0.34, p<0.0001), cervical vs. sacral (R=0.52, p<0.0001) and coeliac vs. sacral (R=0.16, p<0.05). The PSMA-ligand uptake was significantly more intense in adjacent lymph node metastases compared to the respective ganglia (cervical: 18.0±16.2 vs. 2.4±0.6, p<0.0001; coeliac: 13.5±12.3 vs. 2.9±0.8, p<0.0001; sacral: 13.4±11.6 vs. 1.7±0.5, p<0.0001). Furthermore, ganglia predominantly exhibit a band-shaped (71.2%), followed by a teardrop (26.8%) and only rarely a nodular configuration (2.0%). Conversely, lymph node metastases are only rarely band-shaped (1.1%), but more often show teardrop (40.3%) or nodular appearance (58.6%) (p<0.00001). Conclusion: PSMA-ligand uptake in ganglia along the sympathetic trunk as assessed by 68Ga-PSMA-HBED-CC PET represents an important pitfall in prostate cancer PET imaging. The PSMA-ligand uptake is higher in coeliac ganglia compared to cervical or sacral ganglia and the level of PSMA-ligand uptake seems to be patient-related. For the differentiation between lymph node metastases and sympathetic ganglia both intensity of PSMA-ligand-uptake as well as exact localization and configuration of the respective lesion should be examined carefully.
Purpose:
[68Ga]Trishydroxypyridinone (THP)-prostate-specific membrane antigen (PSMA) is a novel tracer that can be labeled in one step by cold reconstitution of a kit with unprocessed generator eluate, targeting PSMA via the lysine-urea-glutamate (KuE) motif. The aim of this study was to evaluate the human imaging characteristics of [68Ga]THP-PSMA.
Procedures:
[68Ga]THP-PSMA positron emission tomography (PET)/x-ray computed tomography (CT) was performed in 25 patients with biochemical recurrence after radical prostatectomy for prostate cancer. Urinary and biliary excretion and tumor lesion uptake were quantified using standardized uptake values (SUVs). Imaging characteristics were assessed in terms of non-target organ uptake, background activity, target-to-background ratios (TBRs) of tumor lesions, and frequency of bladder halo artifacts. Findings were compared to a matched cohort of 25 patients undergoing PET/CT with the established agent [68Ga]PSMA I&T.
Results:
Physiologic uptake of [68Ga]THP-PSMA was significantly lower in salivary glands (P < 0.0001), liver (P < 0.0001), spleen (P < 0.0001), and kidneys (P < 0.0001) than with [68Ga]PSMA I&T. While biliary tracer excretion of [68Ga]THP-PSMA was negligible, urinary tracer excretion of [68Ga]THP-PSMA was fast, and significantly higher than for [68Ga]PSMA I&T, contributing to a higher frequency of bladder artifacts. Malignant lesion uptake of [68Ga]THP-PSMA assessed as either SUV or TBR was significantly lower than with [68Ga]PSMA I&T.
Conclusion:
[68Ga]THP-PSMA yields suitable in vivo uptake characteristics. The simplified synthesis method for [68Ga]THP-PSMA may facilitate wider application and higher patient throughput with PSMA imaging. However, direct intraindividual comparison studies are needed to assess the relative performance of [68Ga]THP-PSMA vs other PSMA ligands in terms of clinical detection rate and image quality.