J Korean Med Sci.  2024 Nov;39(45):e293. 10.3346/jkms.2024.39.e293.

Sites of Metastasis and Survival in Metastatic Renal Cell Carcinoma: Results From the Korean Renal Cancer Study Group Database

Affiliations
  • 1Department of Urology, Inje University Busan Paik Hospital, Inje University College of Medicine, Busan, Korea
  • 2Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
  • 3Department of Urology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
  • 4Department of Urology, Yeungnam University College of Medicine, Daegu, Korea
  • 5Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
  • 6Department of Urology, Korea University Ansan Hospital, Korea University College of Medicine, Ansan, Korea
  • 7Department of Urology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
  • 8Department of Urology, Center for Urologic Cancer, National Cancer Center, Goyang, Korea
  • 9Department of Urology, College of Medicine, Hanyang University, Seoul, Korea
  • 10Department of Urology, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu, Korea
  • 11Department of Urology, Chung-Ang University Gwangmyeong Hospital, Chung-Ang University College of Medicine, Gwangmyeong, Korea
  • 12Department of Urology, Hallym University Dongtan Sacred Heart Hospital, Hallym University School of Medicine, Hwaseong, Korea
  • 13Department of Urology, Ajou University Hospital, Ajou University School of Medicine, Suwon, Korea
  • 14Department of Urology, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Hwasun, Korea

Abstract

Background
In patients with metastatic renal cell carcinoma (mRCC), sites of metastatic involvement have been reported to be associated with a difference in survival. However, the frequency and survival according to different sites of metastases in Korean patients with mRCC remain unclear. Therefore, this study aimed to assess the frequency of metastatic site involvement and the association between sites of metastatic involvement and survival in Korean patients with mRCC.
Methods
This retrospective study used the multicenter cohort of the Korean Renal Cancer Study Group mRCC database to identify patients who started targeted therapy between December 2005 and March 2018. Data on the frequency of metastatic organ involvement at the time of mRCC diagnosis and oncologic outcomes according to different sites of metastasis were analyzed.
Results
A total of 1,761 patients were eligible for analysis. Of the 1,761 patients, 1,564 (88.8%) had clear cell RCC, and 1,040 (59.1%) had synchronous metastasis. The median number of metastasis sites was 2 (interquartile range [IQR], 1–6). The median age at the initiation of systemic therapy was 60 years (IQR, 29–88), 1,380 (78.4%) were men, and 1,341 (76.1%) underwent nephrectomy. Based on the International Metastatic Renal Cell Carcinoma Database Consortium model, patients were stratified into favorable-, intermediate-, and poor-risk groups with 359 (20.4%), 1,092 (62.0%), and 310 (17.6%) patients, respectively. The lung (70.9%), lymph nodes (37.9%), bone (30.7%), liver (12.7%), adrenal gland (9.8%), and brain (8.2%) were the most common sites of metastasis, followed by the pancreas, pleura, peritoneum, spleen, thyroid, and bowel. Among the most common sites of metastasis (> 5%), the median cancer-specific survival (CSS) ranged from 13.9 (liver) to 29.1 months (lung). An association was observed between liver, bone, and pleural metastases and the shortest median CSS (< 19 months).
Conclusion
In Korean patients with mRCC, metastases to the lung, lymph nodes, bone, liver, adrenal gland, and brain were more frequent than those to other organs. Metastases to the liver, bone, and pleura were associated with poor CSS. The findings of this study may be valuable for patient counseling and guiding future study designs.

Keyword

Carcinoma, Renal Cell; Neoplasm Metastasis; Molecular Targeted Therapy; Survival; Prognosis

Figure

  • Fig. 1 Distribution of renal cell carcinoma metastases by location. (A) Whole cohort (multiple metastases included). (B) Single-organ metastasis in the absence of any other disease sites.

  • Fig. 2 OS for patients with mRCC. (A) OS according to the IMDC risk groups. (B) OS according to the number of metastatic organs. (C) OS according to histological subtypes.OS = overall survival, mRCC = metastatic renal cell carcinoma, IMDC = International Metastatic Renal Cell Carcinoma Database Consortium, RMST = restricted mean survival time, CI = confidence interval, RCC = renal cell carcinoma.

  • Fig. 3 CSS based on the site of metastatic involvement in metastatic renal cell carcinoma. Survival time is presented in ascending order of median survival. Patients with multiple sites of metastatic involvement were included in the analyses of all groups according to their metastases. CSS was calculated from the time of diagnosis of metastatic disease to death from cancer or censored at the time of the last follow-up. The adjusted HR was reported by comparing involved with non-involved sites of metastasis, adjusted by International Metastatic Renal Cell Carcinoma Database Consortium risk groups and the number of metastatic organs. An adjusted HR > 1 indicates worse CSS.CSS = cancer-specific survival, HR = hazard ratio, RMST = restricted mean survival time, CI = confidence interval.

  • Fig. 4 Survival for single-organ metastasis in the absence of any other sites of disease. (A) Cancer-specific survival. (B) Progression-free survival of first-line targeted therapy.RMST = restricted mean survival time, CI = confidence interval, mRCC = metastatic renal cell carcinoma.


Reference

1. Capitanio U, Bensalah K, Bex A, Boorjian SA, Bray F, Coleman J, et al. Epidemiology of renal cell carcinoma. Eur Urol. 2019; 75(1):74–84. PMID: 30243799.
2. Park EH, Jung KW, Park NJ, Kang MJ, Yun EH, Kim HJ, et al. Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2021. Cancer Res Treat. 2024; 56(2):357–371. PMID: 38487832.
3. Motzer RJ. New perspectives on the treatment of metastatic renal cell carcinoma: an introduction and historical overview. Oncologist. 2011; 16:Suppl 2. (Suppl 2):1–3.
4. Dabestani S, Marconi L, Kuusk T, Bex A. Follow-up after curative treatment of localised renal cell carcinoma. World J Urol. 2018; 36(12):1953–1959. PMID: 29767327.
5. Choueiri TK, Motzer RJ. Systemic therapy for metastatic renal-cell carcinoma. N Engl J Med. 2017; 376(4):354–366. PMID: 28121507.
6. Navani V, Heng DY. Immunotherapy in renal cell carcinoma. Lancet Oncol. 2023; 24(11):1164–1166. PMID: 37844599.
7. Ljungberg B, Albiges L, Abu-Ghanem Y, Bedke J, Capitanio U, Dabestani S, et al. European Association of Urology guidelines on renal cell carcinoma: the 2022 update. Eur Urol. 2022; 82(4):399–410. PMID: 35346519.
8. Motzer RJ, Jonasch E, Agarwal N, Alva A, Baine M, Beckermann K, et al. Kidney cancer, version 3.2022, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2022; 20(1):71–90. PMID: 34991070.
9. Bianchi M, Sun M, Jeldres C, Shariat SF, Trinh QD, Briganti A, et al. Distribution of metastatic sites in renal cell carcinoma: a population-based analysis. Ann Oncol. 2012; 23(4):973–980. PMID: 21890909.
10. Chandrasekar T, Klaassen Z, Goldberg H, Kulkarni GS, Hamilton RJ, Fleshner NE. Metastatic renal cell carcinoma: patterns and predictors of metastases-a contemporary population-based series. Urol Oncol. 2017; 35(11):661.e7–661.e14.
11. Dudani S, de Velasco G, Wells JC, Gan CL, Donskov F, Porta C, et al. Evaluation of clear cell, papillary, and chromophobe renal cell carcinoma metastasis sites and association with survival. JAMA Netw Open. 2021; 4(1):e2021869. PMID: 33475752.
12. Wei H, Miao J, Cui J, Zheng W, Chen X, Zhang Q, et al. The prognosis and clinicopathological features of different distant metastases patterns in renal cell carcinoma: analysis based on the SEER database. Sci Rep. 2021; 11(1):17822. PMID: 34497343.
13. Royston P, Parmar MK. Restricted mean survival time: an alternative to the hazard ratio for the design and analysis of randomized trials with a time-to-event outcome. BMC Med Res Methodol. 2013; 13(1):152. PMID: 24314264.
14. Bukavina L, Bensalah K, Bray F, Carlo M, Challacombe B, Karam JA, et al. Epidemiology of renal cell carcinoma: 2022 update. Eur Urol. 2022; 82(5):529–542. PMID: 36100483.
15. Riihimäki M, Thomsen H, Sundquist K, Sundquist J, Hemminki K. Clinical landscape of cancer metastases. Cancer Med. 2018; 7(11):5534–5542. PMID: 30328287.
16. Riihimäki M, Thomsen H, Hemminki A, Sundquist K, Hemminki K. Comparison of survival of patients with metastases from known versus unknown primaries: survival in metastatic cancer. BMC Cancer. 2013; 13(1):36. PMID: 23356713.
17. Chen SC, Kuo PL. Bone metastasis from renal cell carcinoma. Int J Mol Sci. 2016; 17(6):987. PMID: 27338367.
18. Choueiri TK, Escudier B, Powles T, Mainwaring PN, Rini BI, Donskov F, et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015; 373(19):1814–1823. PMID: 26406150.
19. Choueiri TK, Powles T, Burotto M, Escudier B, Bourlon MT, Zurawski B, et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2021; 384(9):829–841. PMID: 33657295.
20. Grünwald V, Eberhardt B, Bex A, Flörcken A, Gauler T, Derlin T, et al. An interdisciplinary consensus on the management of bone metastases from renal cell carcinoma. Nat Rev Urol. 2018; 15(8):511–521. PMID: 29904105.
21. Mekhail TM, Abou-Jawde RM, Boumerhi G, Malhi S, Wood L, Elson P, et al. Validation and extension of the Memorial Sloan-Kettering prognostic factors model for survival in patients with previously untreated metastatic renal cell carcinoma. J Clin Oncol. 2005; 23(4):832–841. PMID: 15681528.
22. Motzer RJ, Bukowski RM, Figlin RA, Hutson TE, Michaelson MD, Kim ST, et al. Prognostic nomogram for sunitinib in patients with metastatic renal cell carcinoma. Cancer. 2008; 113(7):1552–1558. PMID: 18720362.
23. McKay RR, Kroeger N, Xie W, Lee JL, Knox JJ, Bjarnason GA, et al. Impact of bone and liver metastases on patients with renal cell carcinoma treated with targeted therapy. Eur Urol. 2014; 65(3):577–584. PMID: 23962746.
24. Fidler IJ. The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat Rev Cancer. 2003; 3(6):453–458. PMID: 12778135.
25. Gerlinger M, Rowan AJ, Horswell S, Math M, Larkin J, Endesfelder D, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012; 366(10):883–892. PMID: 22397650.
26. Bourlon MT, Amini A, Kavanagh BD, Flaig TW. Pancreatic metastases from renal cell carcinoma treated with stereotactic body radiation therapy. Oncology (Williston Park). 2014; 28(11):1008–1012. PMID: 25560737.
27. Duarte C, Hu J, Beuselinck B, Panian J, Weise N, Dizman N, et al. Metastatic renal cell carcinoma to the pancreas and other sites-a multicenter retrospective study. EClinicalMedicine. 2023; 60:102018. PMID: 37304495.
28. Shin TJ, Song C, Jeong CW, Kwak C, Seo S, Kang M, et al. Metastatic renal cell carcinoma to the pancreas: clinical features and treatment outcome. J Surg Oncol. 2021; 123(1):204–213. PMID: 33047324.
29. Morgenstern L, Rosenberg J, Geller SA. Tumors of the spleen. World J Surg. 1985; 9(3):468–476. PMID: 4040300.
30. Lam KY, Tang V. Metastatic tumors to the spleen: a 25-year clinicopathologic study. Arch Pathol Lab Med. 2000; 124(4):526–530. PMID: 10747308.
31. Lee SS, Morgenstern L, Phillips EH, Hiatt JR, Margulies DR. Splenectomy for splenic metastases: a changing clinical spectrum. Am Surg. 2000; 66(9):837–840. PMID: 10993611.
32. Moez R, Rami B, Hassen K. Metachronous splenic metastasis from renal cell carcinoma: a case report. J Surg Case Rep. 2021; 2021(10):rjab449. PMID: 34703573.
33. Jiang W, Shi H, Zhang L, Zhang J, Bi X, Wang D, et al. Responses to targeted therapy among organs affected by metastasis in patients with renal cell carcinoma are organ-specific. Urol J. 2020; 18(5):512–518. PMID: 33084003.
34. Heffess CS, Wenig BM, Thompson LD. Metastatic renal cell carcinoma to the thyroid gland: a clinicopathologic study of 36 cases. Cancer. 2002; 95(9):1869–1878. PMID: 12404280.
35. Alt AL, Boorjian SA, Lohse CM, Costello BA, Leibovich BC, Blute ML. Survival after complete surgical resection of multiple metastases from renal cell carcinoma. Cancer. 2011; 117(13):2873–2882. PMID: 21692048.
36. Jackson G, Fino N, Bitting RL. Clinical characteristics of patients with renal cell carcinoma and metastasis to the thyroid gland. Clin Med Insights Oncol. 2017; 11:1179554917743981. PMID: 29242703.
37. Choi SY, Yoo S, You D, Jeong IG, Song C, Hong B, et al. Prognostic factors for survival of patients with synchronous or metachronous brain metastasis of renal cell carcinoma. Clin Genitourin Cancer. 2017; 15(6):717–723. PMID: 28552571.
38. Takemura K, Lemelin A, Ernst MS, Wells JC, Saliby RM, El Zarif T, et al. Outcomes of patients with brain metastases from renal cell carcinoma receiving first-line therapies: results from the international metastatic renal cell carcinoma database consortium. Eur Urol. 2024; Forthcoming. DOI: 10.1016/j.eururo.2024.01.006.
39. Hirsch L, Martinez Chanza N, Farah S, Xie W, Flippot R, Braun DA, et al. Clinical activity and safety of cabozantinib for brain metastases in patients with renal cell carcinoma. JAMA Oncol. 2021; 7(12):1815–1823. PMID: 34673916.
40. Psutka SP, Master VA. Role of metastasis-directed treatment in kidney cancer. Cancer. 2018; 124(18):3641–3655. PMID: 29689599.
41. Lewis AR, Lohse CM, Lyon TD, Cheville J, Leibovich BC, Sharma V, et al. Survival outcomes of metastasis-directed therapy for solitary sites of metastatic clear cell renal cell carcinoma. J Clin Oncol. 2023; 41(6):suppl. 674.
42. Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar B, Choueiri TK, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018; 378(14):1277–1290. PMID: 29562145.
43. Motzer RJ, Powles T, Burotto M, Escudier B, Bourlon MT, Shah AY, et al. Nivolumab plus cabozantinib versus sunitinib in first-line treatment for advanced renal cell carcinoma (CheckMate 9ER): long-term follow-up results from an open-label, randomised, phase 3 trial. Lancet Oncol. 2022; 23(7):888–898. PMID: 35688173.
44. Grünwald V, Powles T, Eto M, Kopyltsov E, Rha SY, Porta C, et al. Phase 3 CLEAR study in patients with advanced renal cell carcinoma: outcomes in subgroups for the lenvatinib-plus-pembrolizumab and sunitinib arms. Front Oncol. 2023; 13:1223282. PMID: 37664025.
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