Utility of PSMA PET/CT in Staging and Restaging of Renal Cell Carcinoma: A Systematic Review and Metaanalysis

Visual Abstract

Renal cell carcinoma (RCC) accounts for 4% of the global cancer burden and 90% of all primary renal malignancies (1,2).RCC is the most lethal genitourinary cancer, as it often remains undetected during its early stages because of a lack of specific symptoms.Approximately 20%-30% of the patients present with metastases at initial diagnosis (2).Accurate staging and characterization of metastases are crucial for planning the treatment of patients with RCC.Conventional imaging techniques such as ultrasound, contrast-enhanced CT, MRI, and bone scintigraphy have been used for the diagnosis and staging of RCC (3,4).The current gold standard modality for evaluating metastatic disease in patients with inconclusive radiologic findings or for surveillance is contrast-enhanced CT using 18 F-FDG PET/CT.However, this technique is not sensitive or comprehensive enough to detect early metastatic lesions and is associated with false-negative results, particularly in small lesions (e.g., ,1 cm) or low-grade tumors (5).Approximately 25% of patients experience metastases after undergoing surgery for a seemingly resectable condition (6).Therefore, there is a need for a more sensitive modality for early detection and timely management of patients with metastatic RCC.Recent reports on the superiority of prostatespecific membrane antigen (PSMA)-targeted PET imaging over the conventional modalities for prostate cancer at initial staging and recurrence have increased interest in exploring its utility for RCC (7)(8)(9).
PSMA is a type II transmembrane glycoprotein highly expressed in prostate cancer cells, as well as in the endothelial cells within the neovasculature of multiple solid tumors, including RCC (10,11).Clear cell RCC (ccRCC) is the most common RCC subtype and is generally the most aggressive, although there are numerous other subtypes with varying aggressiveness, including chromophobe RCC and papillary RCC (12).PSMA expression varies greatly across RCC subtypes.PSMA is strongly expressed in ccRCC (76.2%-88%) compared with chromophobe RCC (31.2%-60%) and is rarely detectable in papillary RCC (13)(14)(15).With high levels of neovascularity and increased PSMA expression, patients with ccRCC are potential candidates for PSMA PET/CT.
The most widely used PSMA-targeted PET imaging probes are 68 Ga-and 18 F-labeled.Compared with 68 Ga, 18 F has a longer halflife and higher target-to-background resolution (16).Multiple preliminary studies have investigated the clinical utility of PSMA PET/CT in RCC using different PSMA-directed radiotracers and shown promising results (17)(18)(19)(20)(21). Reviews on the role of PSMA PET/CT in the evaluation and management of RCC have also been published (22)(23)(24).However, there is a lack of metaanalysis in the available literature that would give better insight into the role of PSMA PET/CT in assessing RCC.In this report, we have provided a systematic review on the utility of PSMA PET/CT in staging and restaging of RCC and performed a metaanalysis on the detection rate of PSMA PET/CT in staging or evaluation of primary RCC and restaging of metastatic or recurrent RCC.

Search Strategy
A systematic literature review was conducted on August 25, 2023, according to the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines (25).The search was performed in PubMed, Embase, and abstract proceedings of major scientific meetings (Society of Nuclear Medicine and Molecular Imaging, European Association of Nuclear Medicine) to identify relevant published studies without any restrictions on language, publication date, or publication status.The search strategy was based on the following combination of keywords: (A) "renal cell carcinoma" OR "RCC" AND (B) "PSMA" OR "prostate-specific membrane antigen."Institutional review board approval was not required since it was a retrospective analysis of previously published studies.

Criteria for Study Consideration
Clinical studies investigating the utility of PSMA PET/CT imaging in staging or restaging of patients with RCC (ccRCC or non-ccRCC) were included.Index tests included 18 F-DCFPyL, 18 F-PSMA-1007, 68 Ga-PSMA-11, or 68 Ga-P16-093 PET/CT scans.The inclusion criteria included all studies that provided the lesion-based detection rate for any PSMA radiotracers in patients with RCC.

Selection of Studies, Data Extraction, and Study Outcome
All records identified through the electronic search were initially screened for eligibility based on the title and abstract.Two of the authors performed this screening, which excluded review articles, editorials, and irrelevant citations.The full texts of the potentially relevant publications were retrieved and independently checked by the 2 authors for predefined inclusion criteria.
The 2 authors independently extracted the following data from each included study: bibliographic details, patient demographics and disease characteristics, index tests, number of patients, tumor histopathology, and detection rates.The overall pooled detection rate with 95% CIs was estimated among all included studies.In addition, subgroup analysis was performed to estimate the detection rate of 18 F-DCFPyL and 68 Ga-PSMA PET/CT in patients with metastatic RCC and to compare the performance of PSMA PET/CT relative to other conventional imaging modalities, when feasible (only 2 studies).

Statistical Analysis and Data Synthesis
A lesion-based metaanalysis of single proportions was performed to calculate the pooled detection rate of PSMA PET/CT in patients with RCC using meta package (version 6.5-0) in R version 4.3.1.Forest plots of detection rates were created to display variations in the results of the individual studies.Logit transformation with the inverse variance method was used to perform a metaanalysis of proportions.The I 2 index was calculated to quantify heterogeneity.I 2 lies between 0% and 100%, with respective values of approximately 25%, 50%, and 75% indicating low, moderate, and high heterogeneity.To deal with heterogeneity, random-effect assumptions were used for synthesizing metaanalytic data (26).Funnel plots were used to assess publication bias.

Search Results and Study Characteristics
Using the comprehensive search strategy outlined in the methods section, we identified 145 articles, of which 114 were excluded by initial screening of title and abstract.The full texts of the remaining 31 studies were reviewed, and 22 studies were excluded.In total, 9 articles were included in the final metaanalysis and quantitative synthesis (Fig. 1).
Supplemental Tables 1 and 2 (16-21,27-51) summarize the published literature on the utility of PET/CT imaging using different PSMA-directed radiotracers, including 12 articles on 18 F-based tracers ( 18 F-DCFPyL, 18 F-PSMA-1007) and 19 articles on 68 Ga-based tracers ( 68 Ga-PSMA-11, 68 Ga-P16-093), in patients with RCC (31 studies, including case reports and case series) (supplemental materials are available at http://jnm.snmjournals.org).In these studies, PSMA PET/CT was performed for staging and restaging of RCC, evaluation of primary RCC lesions, or other purposes (e.g., prostate cancer restaging) with incidental detection of RCC metastases.All Studies.Nine articles, including 152 patients (133 ccRCC, 19 other RCC subtypes), provided information on the lesion-level detection rate of PSMA PET/CT performed for either staging and evaluation of primary RCC lesions or restaging of metastatic or recurrent RCC.The forest plot representing the pooled data from all included studies is depicted in Figure 2. The estimated pooled  lesion-level detection rate of PET/CT with any PSMA radiotracer was 0.83 (95% CI, 0.67-0.92).There was high heterogeneity among the included studies (I 2 5 81%).
Subgroup analysis was based on the clinical indication (restaging of metastatic RCC vs. staging or evaluation of primary RCC), histopathology (all subtypes of RCC vs. studies that included solely ccRCC), and type of radiotracer ( 18 F-vs. 68Gabased PSMA radiotracers), when feasible.
Restaging of Metastatic or Recurrent RCC.Seven articles, including 90 patients (87 ccRCC, 3 other RCC subtypes), provided information on the lesion-level detection rate of PSMA PET/CT in restaging of metastatic or recurrent RCC (Fig. 3).The estimated pooled lesion-level detection rate of any type of PSMA radiotracer was 0.87 (95% CI, 0.73-0.95).Limiting the cases to studies that included solely ccRCC pathology resulted in a pooled detection rate of 0.85 (95% CI, 0.64-0.95).There was substantial heterogeneity among the included studies, with an I 2 of 76%.
The lowest detection rate has been reported by Sawicki et al. (50%), with all PET-negative metastases being subcentimeter pulmonary nodules in 1 patient (39).This study was identified as a possible source contributing to the high heterogeneity.Exclusion of this study from the analysis significantly improved the study heterogeneity (leave-one-out method), with a pooled detection rate of 0.91 (95% CI, 0.83-0.95;I 2 5 42%) (Supplemental Fig. 1).
Staging or Evaluation of Primary RCC Lesions.Three studies, including 62 patients (48 ccRCC, 14 other subtypes), reported the lesion-level detection rate of 68 Ga-PSMA PET/CT in the staging or evaluation of primary RCC lesions.Only malignant lesions and their PSMA PET positivity data were included in the analysis.The pooled detection rate of PSMA PET/CT for primary RCC was 0.74 (95% CI, 0.57-0.86),with an I 2 of 38%.In other words, approximately 74% (46/62) of primary RCC lesions were PSMApositive (Fig. 4).

Publication Bias
Qualitative evaluation using funnel plots revealed relatively symmetric plots suggestive of a low probability of publication bias (Fig. 7).

DISCUSSION
In this study, we systematically reviewed all the available literature on the utility of PSMA PET/CT imaging in staging or restaging of RCC (supplemental tables) and performed a metaanalysis on the eligible relevant studies when feasible.To our knowledge, this was the first metaanalysis assessing the detection rate of PSMA PET/CT in this patient population.Our results revealed the potential role of PSMA PET/CT in the staging or evaluation of primary RCC lesions and in the restaging of metastatic or recurrent RCC, with a pooled detection rate of 0.74 (95% CI, 0.57-0.86)and 0.87 (95% CI, 0.73-0.95),respectively.Our subgroup analysis revealed that both 68 Gabased (7 studies) and 18 F-based (2 studies) PSMA radiotracers have a high detection rate for evaluation of metastatic RCC (17)(18)(19)(20)(21)36,37,39,41).
We found high heterogeneity among the included studies (I 2 .75%).The heterogeneous study types, differences in the radiotracers used across studies, and mixed patient populations, including both ccRCC and non-ccRCC and different stages of the disease, could have contributed to the high heterogeneity.In Sawicki et al. (detection rate, 50%), all PET-negative metastases were subcentimeter pulmonary nodules in 1 patient (39).This study was identified as a source of heterogeneity.Pulmonary nodules are prone to have decreased tracer activity, which at least partially is explained by breathing-related motion degradation.Furthermore, the subcentimeter size of nodules limits PET resolution because of partialvolume effects, although with targeted radiotracers, it is possible to drive contrast resolution to overcome spatial resolution limitations.Redoing the metaanalysis after exclusion of this study resulted in improved heterogeneity (I 2 5 42%).Primary versus metastatic disease status was identified as another source of heterogeneity, and subgroup analysis on this population improved the heterogeneity (I 2 5 38%).In addition, most of those studies were conducted retrospectively and  lacked pathologic proof of disease at the site of radiotracer uptake; this factor could have contributed to heterogeneity.Demirci et al. ( 50) and Rowe et al. (17) were the first to report the utility of PSMA-targeted radiotracers for imaging patients with ccRCC using 68 Ga-PSMA-11 and 18 F-DCFPyL, respectively.Subsequently, multiple small-scale preliminary studies demonstrated promising results for PSMA PET/CT in staging and restaging of RCC, with the main advantage being the possibility of detecting distant metastasis (23).Patients with metastatic RCC have a poor prognosis, with a 5-y survival rate of only 12% (12).Therefore, accurate staging and assessment of metastases are crucial for managing patients and determining the treatment strategy.Siva et al. ( 41), Raveenthiran et al. (20), and Guhne et al. (37) examined the diagnostic utility of 68 Ga-PSMA PET/CT for evaluating disease extent in patients with metastatic RCC.In a retrospective series of 8 patients with oligometastatic RCC, Siva et al. demonstrated higher uptake on 68 Ga-PSMA than on 18 F-FDG PET, suggesting 68 Ga-PSMA PET to be a more sensitive modality than 18 F-FDG PET for diagnostic evaluation of metastatic RCC (41).Raveenthiran et al. examined the effectiveness of 68 Ga-PSMA PET/CT, compared with conventional imaging, in guiding management decisions (20).
ccRCC accounts for over 75% of RCC diagnoses (12) and has strong PSMA expression relative to other RCC subtypes (13).A retrospective case series of 38 patients with 68 Ga-PSMA PET/CT for staging or restaging of RCC revealed the strongest detection rate in patients with ccRCC and a clinical management change in 43.8% of primary staging cases and 40.9% of restaging cases (20).Guhne et al. demonstrated molecular PSMA expression in all PET-positive lesions, with no correlation between histopathologic findings (extent and intensity of PSMA expression) and PET/CT parameters (SUV max , SUV mean , lesion-to-muscle ratio) in patients with metastatic ccRCC; however, this lack of correlation was because most lung metastases showed low tracer uptake (37).Seven of our included studies evaluated the role of PSMA PET/CT in patients with metastatic or recurrent RCC, with a pooled detection rate of 87%.Most included patients in these studies had ccRCC pathology (87 ccRCC, 3 other subtypes).In addition, our subgroup analysis on studies that included only ccRCC patients did not show a significant change in the detection rate of PSMA PET/CT.Thus, the presence of a different tumor histopathology is not likely to significantly affect our results in this analysis.
Two of the included studies provided a direct comparison of PSMA PET/CT ( 18 F-DCFPyL) and conventional imaging in metastatic ccRCC and support a higher detection rate of PSMA PET/CT, with a pooled detection rate of 0.92 (95% CI, 0.76-0.97)versus 0.63 (95% CI, 0.50-0.74),respectively (17,19).Rowe et al. prospectively analyzed 5 patients with metastatic ccRCC and identified 29 lesions on at least one modality.Of these, 18 metastatic lesions were identified on conventional imaging, whereas 28 sites were identified on 18 F-DCFPyL PET/CT, 17 of which corresponded to the disease site seen on conventional imaging.The study reported a higher detection rate (97% vs. 62%) and higher sensitivity (94.7% vs. 78.9%)for 18 F-DCFPyL PET/CT than for conventional imaging in the detection of metastatic lesions (17).Meyer et al. conducted a prospective study to evaluate the clinical utility of 18 F-DCFPyL PET/CT in patients with presumed oligometastatic ccRCC based on conventional imaging.In total, 33 metastatic sites of disease were identified in 17 oligometastatic ccRCC patients, of which 29 sites were detected on 18 F-DCFPyL PET/CT and 21 metastatic lesions were identified on conventional imaging.Seventeen of 21 (81%) metastatic lesions detected on conventional imaging had radiotracer uptake.In 4 patients (28.6%), 12 lesions not detected on conventional imaging were identified on 18 F-DCFPyL PET/CT, and 3 of these patients were no longer considered oligometastatic.The detection rates of 18 F-DCFPyL PET/CT and conventional imaging for identifying sites of metastatic disease were reported as 87.9% and 63.4%, respectively (19).Rhee et al. reported a sensitivity of 92% for 68 Ga-PSMA PET/CT in detecting RCC metastatic lesions, compared with 68.6% for conventional CT (18).A recent study compared the utility of 68 Ga-PSMA PET/CT in ccRCC and non-ccRCC and reported that 68 Ga-PSMA PET/CT had accuracy and sensitivity superior to conventional imaging in the detection of metastatic lesions in ccRCC (40).
The major limitations of the current analysis are high heterogeneity among the studies, lack of definitive indications for the application of PSMA PET/CT in RCC patients, the small number of patients analyzed, lack of data on the location and size of RCC lesions, and the retrospective nature of most of the studies included in the analysis.Despite these limitations, our preliminary results shed light on the potential role of PSMA PET/CT in the detection and characterization of metastatic RCC.Large prospective trials with robust inclusion criteria and pathologic confirmation of lesions would be of value to validate the diagnostic efficiency of  PSMA PET/CT in RCC, particularly in patients at high risk for metastatic disease at initial staging, response assessment, or surveillance monitoring; in patients with oligometastatic disease; and in patients who can potentially be considered for future radioligand PSMAtargeted therapy.

CONCLUSION
Our metaanalysis showed the detection potential of PSMA PET/CT in staging primary RCC lesions and restaging metastatic or recurrent RCC.Although our findings are based on small-scale studies with high heterogeneity, the preliminary results suggest merit in the use of PSMA PET/CT in RCC, particularly when performed for restaging of metastatic or recurrent disease.

DISCLOSURE
Research funding was provided by Lantheus.No other potential conflict of interest relevant to this article was reported.

FIGURE 2 .
FIGURE 2. Lesion-based detection rate of PSMA PET/CT in staging and restaging of RCC (all included studies).

FIGURE 3 .
FIGURE 3. Lesion-based detection rate of PSMA PET/CT in restaging of patients with metastatic or recurrent RCC.

FIGURE 4 .
FIGURE 4. Detection rate of PSMA PET/CT in staging or evaluation of primary RCC.

FIGURE 5 .
FIGURE 5. Lesion-based detection rate of 68 Ga-based PSMA radiotracers in restaging of patients with metastatic RCC.

FIGURE 6 .
FIGURE 6. Lesion-based detection rate of 18 F-DCFPyL PSMA in restaging of metastatic RCC (A), in comparison with conventional imaging modalities (B).