Renal cell carcinoma (RCC) is the eighth most commonly diagnosed malignancy in the United States and the third most commonly diagnosed genitourinary malignancy (following prostate and bladder cancer).1 According to 2019 data, more than 68,000 new cases of RCC were diagnosed and more than 14,000 individuals died of an RCC-related mortality. Estimates for 2022 show a linear growth in new cases to 79,000; however, a lower death rate of 13,920 is also modeled.2 Rates of RCC diagnoses are not evenly distributed across the United States; people living in southern states such as Oklahoma, Texas, Arkansas, Louisiana, Mississippi, and Alabama are diagnosed at markedly higher rates compared with the rest of the country (median, 21 per 100,000 persons for southern states vs a national median of 17 per 100,000 persons).3 To make matters worse, most cases of RCC-related mortality occur in patients with metastatic RCC,4, 5, 6, 7, 8 with common sites of spread including the lung, bone, liver, and brain.
Checkpoint Inhibition Plus TKI
The management of metastatic RCC has continued to evolve rapidly as immunotherapy has become mainstream as a treatment strategy compared to the historical resistance to cytotoxic chemotherapy and radiation therapy that has plagued the management of RCC. Several phase 3 clinical trials have investigated different combinations of immunotherapy aiming for either dual immune checkpoint inhibition targeting PD-1 (programmed death 1) or targeting PD-L1 (programmed death ligand 1) in conjunction with CTLA-4 (cytotoxic T-lymphocyte associated protein 4).
Alternatively, checkpoint inhibition plus tyrosine kinase inhibition (TKI) via the VEGF (vascular endothelial growth factor) or its receptor, VEGF-R, have been trialed. A recent meta-analysis9 comparing four phase 3 clinical trials with different regimens—CheckMate 214,9 CheckMate 9ER,10 KEYNOTE-426,11 and KEYNOTE-58112 — demonstrated interesting results.
The authors noted that the combination of checkpoint inhibition and TKI (CheckMate 9ER; cabozantinib plus nivolumab) provided maximal overall survival (OS) benefit.9 Despite not being a direct noninferiority trial, these types of meta-analyses further emphasize that the therapeutic development of combination therapies for treatment of metastatic RCC will continue to evolve.
The advent of integrated imaging with positron emission tomography and computed tomography (PET/CT) has allowed clinicians to garner significant anatomical and oncologic information about a given tumor. However, traditional 18F-fluoro-2-deoxy-2-d-glucose (FDG)- PET imaging for RCC has had several limitations. Under normal circumstances, the accumulation of FDG-6-phosphate within the cancer cells occurs because of the higher expression of glucose transporters and low intracellular glucose-6-phosphatase.13 However, in renal cancer, due to excretion of FDG via normal renal parenchyma, the utility of FDG-based PET imaging has been limited.
Several authors have reported sensitivities in the range of 50-60 in the primary diagnostic setting.13,14 Despite its limited role in that setting, FDG-PET can be useful for cross-sectional imaging evaluation of patients with suspected advanced or metastatic disease. In a series of 23 patients, Lee et al demonstrated that the median maximum standardized uptake value (SUVmax) was 2.6 in patients without metastatic disease and significantly higher in those with metastatic disease (5.0), supporting the contention that FDG-PET may be useful in evaluating patients for locally advanced or metastatic disease.15
Other Uses of FDG-PET
Cases supporting other uses for FDG-PET also exist. For example, when evaluating patients suspected to have RCC-related thrombosis, FDG-PET imaging may assist in identifying malignant thrombosis of the inferior vena cava (IVC). In a series of 60 RCC patients, FDG-PET imaging detected 7 of 7 cases of IVC tumor invasion.7 Further adding to the evidence, other studies have shown that FDG-PET can help delineate benign from malignant venous thromboembolism. In patients who have undergone primary treatment, and in whom there is concern for new recurrence or new sites of metastatic disease, a large pooled meta-analysis demonstrated that FDG-PET imaging has a sensitivity of 86% and specificity of 88%.16 As targeted therapy for metastatic RCC continues to evolve, the ability to monitor disease progression has grown equivalently in importance. In a phase 2 series of 44 patients with metastatic clear cell RCC receiving sunitinib treatment, FDG-PET imaging demonstrated on multivariate analysis that high SUVmax and greater PET-positive lesions correlated to a shorter OS.17
What about imaging based on prostate membrane-specific antigen (PSMA)? Despite its name, PSMA is highly expressed in a variety of solid tumors, including RCC.18 This has allowed various authors to investigate the utility of PSMA-based PET imaging in an attempt to overcome the limitations of FDG-PET. In a limited series of 5 patients19 with preexisting metastatic RCC, investigators used imaging with 18F-DCFLPyL (Pylarify®); approved by the US Food and Drug Administration in 2021 for use in the prostate cancer setting. The authors reported that, for cross-sectional imaging, the sensitivity for detecting metastatic RCC with 18F-DCFLPyL was 94.7% compared to 78.9% based on conventional imaging alone. Scans based on gallium-68 have also been investigated.
Most recently, at the 2022 meeting of the American Urological Association (AUA), authors from the department of urology at Ludwig Maximilian University in Germany reported on their experience with 68Ga-EMP-100, a novel ligand targeting tumoral c-MET expression which is commonly elevated in clear cell RCC.3 In a series of 12 patients, the authors demonstrated identification of 87 individual tumor lesions with a median c-MET–positive SUVmax of 4.4, with further positivity at the primary site (SUVmax, ~9). Such tools could improve patient selection, especially for patients undergoing consideration for treatment with cabozantinib, a TKI targeting the MET receptor.
Despite a growing volume of evidence and trials documenting the utility of PET and integrated PET/CT imaging in RCC, the AUA guidelines still do not advise clinicians to use PET-based imaging in the routine evaluation or staging of RCC. Furthermore, the role of PET in routine surveillance of RCC also remains unclear; however, the guidelines do advocate for considering PET-based imaging if traditional imaging is equivocal. Future prospective studies such as the ZIRCON (NCT03849118) phase 3 study evaluating the role of 89Zr-TLX250 may provide further data to elucidate the specific role of PET/ CT imaging in care of patients with RCC.20
Akhil Abraham Saji, MD is a urology resident at New York Medical College / Westchester Medical Center. His interests include urology education and machine learning applications in urologic care. He is a founding and current member of the EMPIRE Urology New York AUA section team.
- Centers for Disease Control and Prevention. Cancer Statistics at a Glance. U.S. Cancer Statistics Data Visualizations Tool, based on 2021 submission data (1999-2019). Accessed September 25, 2022. https://gis.cdc.gov/Cancer/USCS/#/AtAGlance/
- National Cancer Institute, Surveillance, Epidemiology and End Results Program (SEER). Cancer Stat Facts: Kidney and Renal Pelvis Cancer. Accessed September 25, 2022. https://seer.cancer.gov/statfacts/html/kidrp.html
- Partin AW, Dmochowski RR, Kavoussi LR, Peters CA, Wein A, eds. Campbell-Walsh-Wein Urology, 12th ed. Philadelphia: Elsevier; 2020:chapter 104, page 2120. https://www.elsevier.com/books/campbell-walsh-urology/partin/978-0-323-67227-6
- Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7-34. doi: 10.3322/caac.21551
- Figlin RA. Renal cell carcinoma: management of advanced disease. J Urol. 1999;161:381-386. doi:10.1016/S0022-5347(01)61897-4
- Albiges L, Tannir NM, Burotto M, et al. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 4-year follow-up of the phase III CheckMate 214 trial. ESMO Open. 2020;5(6):e001079. doi: 10.1136/esmoopen-2020-001079
- Ferda J, Ferdova E, Hora M, et al. 18F-FDG-PET/ CT in potentially advanced renal cell carcinoma: a role in treatment decisions and prognosis estimation. Anticancer Res. 2013; 33:2665-2672.
- Staehler M, Schott M, Tamalunas A, et al. first in-human results of 68GA-EMP-100 PET for imaging C-MET expression in renal cell carcinoma. J Urol. 2022;207(5S suppl):e348. Abstract PD18-11. doi: 10.1097/JU.0000000000002556.11
- Nocera L, Karakiewicz PI, Wenzel M, et al. Clinical outcomes and adverse events after first-line treatment in metastatic renal cell carcinoma: a systematic review and network meta-analysis. J Urol. 2022;207:16-24. doi: 10.1097/JU.0000000000002252
- Motzer RJ, Choueiri TK, Powles T, et al. Nivolumab + cabozantinib (NIVO+CABO) versus sunitinib (SUN) for advanced renal cell carcinoma (aRCC): outcomes by sarcomatoid histology and updated trial results with extended follow-up of CheckMate 9ER. J Clin Oncol. 2021;39(6 suppl). Abstract 308. doi: 10.1200/JCO.2021.39.6_suppl.308
- Powles T, Plimack ER, Soulières D, et al: Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow up from a randomised, open-label, phase 3 trial. Lancet Oncol. 2020;21(12):1563-1573. doi: 10.1016/S1470-2045(20)30436-8
- Motzer R, Alekseev B, Rha SY, et al; for the CLEAR Trial Investigators. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021;384(14):1289-1300. doi: 10.1056/nejmoa2035716
- Liu Y, Ghesani NV, Zuckier LS. Physiology and pathophysiology of incidental findings detected on FDG-PET scintigraphy. Semin Nucl Med. 2010;40(4):294-315. doi: 10.1053/ j.semnuclmed.2010.02.002
- Wang HY, Ding HJ, Chen JH, et al. Meta-analysis of the diagnostic performance of [18F] FDG-PET and PET/CT in renal cell carcinoma. Cancer Imaging. 2012;12(3):464-474. doi: 10.1102/1470-7330.2012.0042
- Lee H, Hwang KH, Kim SG, Koh G, Kim JH. Can Initial 18F-FDG PET-CT imaging give information on metastasis in patients with primary renal cell carcinoma? Nucl Med Mol Imaging. 2014;48(2):144-152. doi: 10.1007/s13139-013-0245-1
- Ma H, Shen G, Liu B, Yang Y, Ren P, Kuang A. Diagnostic performance of 18F-FDG PET or PET/CT in restaging renal cell carcinoma: a systematic review and meta-analysis. Nucl Med Commun. 2017;38(2):156-163. doi: 10.1097/MNM.0000000000000618
- Kayani I, Avril N, Bomanji J, et al. Sequential FDG-PET/CT as a biomarker of response to sunitinib in metastatic clear cell renal cancer. Clin Cancer Res. 2011;17(18):6021-6028. doi: 10.1158/1078-0432.CCR-10-3309
- Baccala A, Sercia L, Li J, Heston W, Zhou M. Expression of prostate-specific membrane antigen in tumor-associated neovasculature of renal neoplasms. Urology. 2007;70(2):385- 390. doi: 10.1016/j.urology.2007.03.025
- Rowe SP, Gorin MA, Hammers HJ, et al. Imaging of metastatic clear cell renal cell carcinoma with PSMA-targeted ¹⁸F-DCFPyL PET/CT. Ann Nucl Med. 2015;29(10):877-882. doi: 10.1007/s12149-015-1017-z
- Campbell SC, Clark PE, Chang SS, Karam JA, Souter L, Uzzo RG. Renal mass and localized renal cancer: evaluation, management, and follow-up: AUA guideline: part I. J Urol. 2021;206(2):199-208. doi: 10.1097/JU.0000000000001911