Abstract
Objectives
To systematically assess the early detection rate of biochemical prostate cancer recurrence using choline, fluciclovine, and PSMA.
Methods
Under the guidance of the Preferred Reporting Items for Systematic reviews and Meta-Analysis Diagnostic Test Accuracy guidelines, literature that assessed the detection rates (DRs) of choline, fluciclovine, and PSMA in prostate cancer biochemical recurrence was searched in PubMed and EMBASE databases for our systematic review from 2012 to July 15, 2021. In addition, the PSA-stratified performance of detection positivity was obtained to assess the DRs for various methods, including fluciclovine, PSMA, or choline PET/CT, with respect to biochemical recurrence based on different PSA levels.
Results
In total, 64 studies involving 11,173 patients met the inclusion criteria. Of the studies, 12, 7, and 48 focused on choline, fluciclovine, and PSMA, respectively. The pooled DRs were 24%, 37%, and 44%, respectively, for a PSA level less than 0.5 ng/mL (p < 0.001); 36%, 44%, and 60% for a PSA level of 0.5–0.99 ng/mL (p < 0.001); and 50%, 61%, and 80% for a PSA level of 1.0–1.99 ng/mL (p < 0.001). The DR with 18F-labeled PSMA was higher than that with 68Ga-labeled PSMA, and the DR was 58%, 72%, and 88% for PSA levels < 0.5 ng/mL, 0.5–0.9 ng/mL, and 1.0–1.99 ng/mL, respectively.
Conclusion
The DRs of PSMA-radiotracers were greater than those of choline-radiotracers and fluciclovine-radiotracers at the patient level. 18F-labeled PSMA achieved a higher DR than 68Ga-labeled PSMA.
Key Points
• The DRs of PSMA-radiotracers were greater than those of choline-radiotracers and fluciclovine-radiotracers at the patient level.
• 18 F-labeled PSMA achieved a higher DR than 68 Ga-labeled PSMA.
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Introduction
Prostate cancer (PCa) is the most common malignancy of the male genitourinary system worldwide [1]. Radical prostatectomy or radiation therapy remains the most widely used treatment for localized PCa with intermediate and high risks [2]. After definitive therapy, biochemical recurrence (BCR) of PCa still recurs approximately 39–41% of the time [3, 4]. At this stage of the disease, it is still essential to define the location and extent of metastasis and initial recurrence to help urologists make further treatment plans [5]. The detection of subtle or occult recurrence and metastasis after treatment continues to pose a challenge [6]. In this setting, PET/CT is particularly superior to conventional imaging modalities such as CT (computed tomography)/MRI (magnetic resonance imaging) because of its higher detection rate (DR) for low-volume metastatic or locally initial recurrence [7, 8].
To date, of the radiolabels that have been evaluated, 11C-choline and 18F-fluciclovine were approved by the Food and Drug Administration (FDA) in 2012 and 2016 [9]. Prostate-specific membrane antigen (PSMA), a cell surface protein, is highly expressed in the majority of PCa cells and in PCa recurrence [10, 11]. 68Ga- and 18F-labeled PSMA are promising new radiotracers for detecting the BCR of PCa and radio-nuclear therapy. [68Ga]Ga-PSMA-11 was the first PSMA PET tracer that was approved by the FDA [6]. Moreover, 18F-labeled PSMA agents have also been employed in clinical practice.
Previous evidence-based studies have compared the diagnostic performance of choline, fluciclovine, and PSMA PET/CT in PCa patients with BCR, and particularly at a PSA level less than 2 ng/mL6. However, they only concentrated on long-half radionuclides as 18F-labeled PET tracers and compared their diagnostic performance in detecting patients with BCR. To our knowledge, a comprehensive comparative meta-analysis of choline, fluciclovine, and PSMA for detecting PCa patients with BCR and low PSA levels has not been performed. Furthermore, several studies have shown that the higher image resolution of 18F, as a longer half-life nuclide, is slightly better than that of 68Ga [12, 13]. However, evidence-based data based on 18F-labeled and 68Ga-labeled PSMA are still lacking. Therefore, the aims of this meta-analysis were to compare the DRs of radiotracers, including choline, fluciclovine, and PSMA PET/CT, for biochemical recurrence with PSA levels less than 2 ng/mL and to perform subgroup analyses based on 18F-labeled and 68Ga-labeled PSMA.
Materials and methods
Search strategy
This meta-analysis was performed in accordance with the PRISMA-DTA statement [14]. Two reviewers searched the library databases of PubMed and Embase that involved the DR of PET/CT using choline, fluciclovine, and PSMA agents between 2012 and July 2021. The search terms included the following: prostatic neoplasms, prostate cancer, recurrence, biochemical recurrence, 18F-choline, 11C-choline, fluoromethylcholine, [18F]fluciclovine, [18F]FACBC, [18F]PSMA-1007, [18F]DCFPyl, [18F]DCFBC, [68Ga]Ga-PSMA-11, [18F]PSMA-11, [68Ga]Ga-PSMA-I&T, [68Ga]Ga-THP-PSMA, [64Cu]Cu-PSMA-617, [18F]JK-PSMA-7, and [68Ga]Ga-HBED-CC. To expand our search, the lists of references from the retrieved articles were also checked. Two reviewers independently reviewed the references in the included studies.
Study selection
Both retrospective and prospective studies involving males with PCa with BCR who underwent PET/CT using choline, fluciclovine, and PSMA agents between 2012 and July 2021 were included. In addition, single-arm trials, comparative, single-center, multicenter, and clinical trials were also included. Studies were excluded as follows: abstracts, comments, letters, conference records, case reports, reviews, and meta-analyses, non-English articles, studies for staging purposes, and studies assessing specific types of metastatic disease, such as that of bones or lymph nodes. If the studies included patients from the same group, the largest sample was reviewed.
Data extraction and quality assessment
Two reviewers independently extracted and confirmed the data. Information was recorded from each study, including year of publication, radiotracer, imaging protocols, country of origin, study design (prospective or retrospective, multicenter or single center), patient age, sample size, treatment, PSA stratified into tiers (PSA level less than 0.5 ng/mL ng/mL, 0.5–0.99 ng/mL, and 1–1.99 ng/mL), and DR. We used the revised Quality Assessment of Studies of Diagnostic Accuracy, which was included in the QUADAS-2 tool for quality assessment [15]. Each item was judged as “yes,” “no,” or “unclear.” Any disagreements were resolved by consensus.
Statistical analysis
The pooled estimates with 95% CIs were the DRs of PSA-stratified patients with biochemical recurrence after treatment. The pooled estimates for the DRs of different radiotracers were compared using a chi-square test. Forest plots with 95% confidence intervals were used to visually assess the results. The inconsistency index (I2) was used to assess statistical heterogeneity of the included studies. The Cochrane Q with p < 0.05, and I2 > 50% indicated significant heterogeneity. A random-effects model was applied, and marked heterogeneity was observed. Statistical significance was set at a p-value less than 0.05. Egger’s test and funnel plot tests were conducted to assess the publication bias. The open-source statistical software R was used to conduct all statistical analyses (version 3.6.3; www.r-project.org/). The QUADAS quality evaluation was conducted using RevMan (version 5.3).
Results
Literature search
Figure 1 presents an overview of the inclusion process. Initially, 1759 total articles were identified through PubMed and Embase databases using the search terms and keywords (1396 in PubMed, and 363 in Embase). In total, 324 duplicate records were removed. After screening titles and abstracts, 1345 records were excluded; 900 because they were not relevant to the study; 90 as they were abstracts or conference records; 180 as they were letters, reviews, or meta-analyses; and 175 as they were case reports and comments.
Of the remaining studies, 90 full-texts were reviewed, and 64 studies were included in this meta-analysis. Of these, 48 studies focused on the performance of PSMA PET/CT for patients with BCR. Seven and 12 studies were included for fluciclovine and choline PET/CT, respectively. Of these, two studies evaluated both PSMA and choline [16, 17], and one study evaluated both chorine and fluciclovine [18]. The characteristics of the included articles are presented in Tables 1, 2 and 3. Figure 2 shows the proportion of different tracers in the included studies under PSA stratification.
Publication bias and heterogeneity and quality assessment
A symmetrical funnel-shaped distribution of PSA < 0.5 ng/mL (p = 0.96) and PSA levels of 0.5–1.0 ng/mL (p = 0.12) indicated that there was no significant publication bias. However, publication bias was found in the cohorts with PSA levels of 1–1.99 ng/mL (p < 0.001). The Egger test was used to quantify significant asymmetry.
The forest plots revealed strong heterogeneity for the fluciclovine cohort, as the I2 was 64%, 70%, and 72% for a PSA level < 0.5 ng/mL (p < 0.05), 0.5–0.9 ng/mL (p < 0.01), and 1.0–1.99 ng/mL (p < 0.01), respectively. The I2 was 78%, 66%, and 78% for a PSA level < 0.5 ng/mL (p < 0.01), 0.5–0.9 ng/mL (p < 0.01), and 1.0–1.99 ng/mL (p < 0.01), respectively, in the choline cohort. I2 values of the overall pooled DR were 81%, 78%, and 75% for a PSA level < 0.5 ng/mL (p < 0.01), 0.5–0.9 ng/mL (p < 0.01), and 1.0–1.99 ng/mL (p < 0.01), respectively, in the PSMA cohort. The quality assessment of the included studies is shown in Fig. 3. QUADAS-2 revealed that the majority of included studies were at a moderate risk of bias. Because all studies had consistent qualified patient selection criteria, patient selection was not considered the major potential source of bias. For the reference standard, some articles were marked as unclear or high levels because of the lack of consistent reference standards and clinical follow-up times.
Detection rates of choline, [18F]fluciclovine, and PSMA PET/CT
Pooled DRs of choline, 18F-fluciclovine, and PSMA were 24% (95% CI: 11%, 37%), 37% (95% CI: 0%, 49%), and 47% (95% CI: 42%, 52%) for PSA levels < 0.5 ng/mL (p < 0.001), respectively (Fig. 4); 36% (95% CI: 27%, 44%), 44% (95% CI: 32%, 56%), and 60% (95% CI: 54%, 65%) for a level of 0.5–0.9 ng/mL (p < 0.001) (Fig. 5); and 50% (95% CI: 39%, 61%), 61% (95% CI: 46%, 100%), and 80% (95% CI: 76%, 100%) for a level of 1–1.99 ng/mL (p < 0.001), respectively (Fig. 6).
Comparison of 18F-labeled vs 68Ga-labeled PSMA studies
Table 4 shows the results of the point estimates of the pooled DRs for the difference between 18F-labeled and 68Ga-labeled PSMA. The DR with 18F-labeled PSMA was higher than that with 68Ga-labeled PSMA. In addition, the DR showed an increasing magnitude with an increase in the PSA level, which was significant for all PSA levels.
Discussion
Whereas other meta-analyses have investigated the diagnostic roles of tracers applied in PCa with BCR [2, 6, 7, 78, 79], to our knowledge, this is the first comparative meta-analysis that focuses on all three relevant tracers for the early detection of this disease. This meta-analysis showed a higher pooled DR for PCa with BCR using PSMA compared to that with fluciclovine and choline PET/CT for three PSA levels, and we observed a significant difference. These results are in accordance with a previous meta-analysis that included only 18F-labeled choline, fluciclovine, and PSMA, which reported that PSMA was better than choline and fluciclovine [6]. A meta-analysis recently showed that there is a trend but no significant difference when the PSA level is < 0.5 ng/mL and 0.5–0.9 ng/mL. However, our study found an absolute statistical difference when comparing the DRs of PSMA and fluciclovine. A possible reason for this is the limited number of studies. In general, PET/CT imaging is more likely to be negative with low PSA values.
Radiation therapy remains the gold standard for intermediate- and high-risk, localized prostate cancer. While these are effective forms of management, approximately 30–40% of cancers still recur following treatment, manifesting as a rising prostate-specific antigen (PSA). The key issue for patients with BCR is the early and correct identification of recurrent or metastatic disease. Conventional imaging modalities consisting of CT, bone scan, and MRI have been used for patients with PCa, but their diagnostic performance in detecting minimal or occult lesions is limited. At this stage of the disease, it is important to determine the location and extent of metastases to determine the next course of management. PET is an established, non-invasive, molecular imaging modality that uses different radiolabeled tracers, a combination of a radionuclide and a biologically active molecule, targeted to specific receptors to localize disease. PET/CT has a higher detection rate of intra-prostatic tumors that might have clinical implications regarding focal therapy such as radiotherapy and surgical planning. The current study has demonstrated that PSMA-based tracer PET/CT imaging seems to be a promising tool and shows clear superiority in the detection of PCa with BCR and PSA when compared to choline- and fluciclovine-based tracers. In clinical practice, choline PET/CT is the most commonly used radioactive tracer [17]. Significantly, choline PET/CT exhibits a higher DR only at high PSA levels [80]. A previous study has shown that the DR of PCa with BCR and PSA < 1.5 ng/mL was only below 30% when using choline-based tracers PET/CT [81, 82], which is in accordance with our findings.
In our study, 18F-fluciclovine also showed a higher DR than choline (37% vs 24% for 0.2–0.5 ng/mL, 44% vs 36% for 0.5–1.0 ng/mL). Similarly, in a prospective study, the authors showed that the overall performance with [18F]FACBC, a relatively new radiotracer, was higher than that of 11C-choline, and they found that this difference in DR was particularly significant for PCa with BCR and a PSA level < 1 ng/mL18. Furthermore, current EAU guidelines recommend that choline PET/CT only be used for non-early PCa recurrence with serum PSA levels > 1 ng/mL [83]. Afshar-Oromieh et al calculated the detection rate of [68Ga]Ga-PSMA-11 to be 46% (32/69) for PSA < 0.2 ng/mL, 46% (50/108) for 0.2–0.5 ng/mL, and 73% (87/119) for 0.5–1.0 ng/mL [43]. In addition, a higher detection rate of PCa with BCR with low PSA levels was suggested by other research [59]. Considering these aspects, PSMA should be the preferred tracer choice, especially for patients with low PSA (≤ 2.0 ng/mL).
However, PSMA PET/CT is an increasingly used tracer for patients with BCR and achieves a high DR for early PCa recurrence (PSA ≤ 2.0 ng/mL) [84]. Furthermore, the strength of evidence was limited by publication bias, multiple reference standards, and a lack of consistent clinical follow-up times. In particular, our meta-analyses also performed subgroup analyses based on 18F-labeled and 68Ga-labeled PSMA. We observed statistically significant differences when comparing 18F-labeled and 68Ga-labeled PSMA (PSA < 0.5 ng/mL: 58% vs 44%, p < 0.01; PSA level 0.5–1.0 ng/mL: 72% vs 56%, p < 0.01; PSA 1.0–1.99 ng/mL: 88% vs 78%, p < 0.01). To date, to our knowledge, this is the first evidence-based study to evaluate the DRs of 18F-labeled and 68Ga-labeled PSMA. Recently, there have been multiple meta-analyses showing that the summary DR of 18F-labeled PSMA in patients with BCR was approximately 49% for PSA < 0.5 ng/mL [1, 78, 85], which is slightly better than the 44.9% detection rate of 68Ga-PSMA in a recent prospective study [73]. Compared to 18F-PSMA, 68Ga-PSMA ligands have a short half-life (68 min), and thus are inconvenient for transport [86]. Moreover, they are characterized by a lower signal-to-noise ratio for images [87], limiting its clinical application in detecting occult or metastatic lesions in the prostate bed. However, 18F-PSMA analogs seemed to be more favorable due to their longer half-life and a higher physical spatial resolution, and [18F]PSMA-1007, as a second-generation 18F-labeled PSMA tracer, demonstrated high labeling yields, better tumor uptake, and hepatobiliary excretion, making it an ideal PSMA-target tracer for diagnostic imaging in patients with BCR. Accordingly, this might explain why some authors considered [18F]DCFPyL to be a good replacement for recurrent PCa.
Our meta-analysis has several limitations. First, significant heterogeneity was observed in all cohorts. Second, because the sample size was limited, retrospective, single-institutional studies accounted for a large amount, which might be one of the reasons for the selection bias. Additionally, the different PET/CT scanners, radiotracers, patient populations, and various treatment modes increased the risk of bias and significant heterogeneity.
In conclusion, our meta-analysis revealed that PSMA-radiotracers demonstrate a potentially promising DR with low PSA levels in biochemically recurrent PCa. PSMA has a relatively higher DR than fluciclovine and choline in PCa patients with BCR and with PSA < 2.0 ng/mL. Additionally, 18F-labeled PSMA achieved a higher DR than 68Ga-labeled PSMA.
Abbreviations
- BCR:
-
Biochemical recurrence
- CT:
-
Computed tomography
- DR:
-
Detection rate
- MRI:
-
Magnetic resonance imaging
- PCa:
-
Prostate cancer
- PSA:
-
Prostate-specific antigen
- PSMA:
-
Prostate-specific membrane antigen
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Ma, W., Mao, J., Yang, J. et al. Comparing the diagnostic performance of radiotracers in prostate cancer biochemical recurrence: a systematic review and meta-analysis. Eur Radiol 32, 7374–7385 (2022). https://doi.org/10.1007/s00330-022-08802-7
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DOI: https://doi.org/10.1007/s00330-022-08802-7