Prognostic role of interleukin-6 in renal cell carcinoma: a meta-analysis

  • Y. WangEmail author
  • Y. Zhang
Research Article



To evaluate the prognostic role of interleukin-6 (IL-6) in renal cell carcinoma (RCC).


Relevant research articles were obtained from literature databases. Data were extracted from study reports which reported IL-6 levels in relevance to RCC prognosis and random-effects meta-analyses were performed to estimate IL-6 levels, percentage of patients with high IL-6 levels, and hazard/odds ratios between high and low IL-6 levels in survival outcomes.


22 studies (1976 patients; age 59.9 years [95% confidence interval (CI) 58.0, 61.8]; 33% [95% CI 29, 36] females) were included. IL-6 levels in RCC patients ranged from 8.9 ± 13–193 ± 101 picograms per milliliter (pg/ml) which were higher than those of normal healthy individuals (mean difference 13.96 pg/ml [95% CI: 1.52, 26.40]; p = 0.03). Percentage of RCC patients with high IL-6 levels was 48.98% [95% CI 42.94, 55.03] and this rate was greater in advanced (51.73% [95% CI 45.94, 57.53]) than in local (40.75% [95% CI 26.23, 55.27]) RCC. Survival was longer in patients with low compared to high IL-6 levels (MD 9.65 months [95% CI 5.01, 14.29]; p < 0.0006 and hazard ratio 3.03 [95% CI 2.37, 3.70]). Treatment response rate was significantly higher in patients with low IL-6 than high IL-6 levels (odds ratio 5.11 [95% CI 2.21, 11.77]; p < 0.00001). There was a strong correlation between IL-6 and c-reactive protein levels (correlation coefficient 0.622 [95% CI 0.431, 0.760]; p = 0.00001).


IL-6 levels are much variable in RCC patients. High levels of IL-6 in RCC patients are associated with poor survival.


Renal cell carcinoma Interleukin-6 Prognosis Metastasis Survival 




Compliance with ethical standards

Conflict of interest

All the authors have declared that they have no conflict of interest.

Research involving human participants and/or animals

All analyses were based on previous published studies, thus no ethical approval required.

Informed consent

For this type of study, formal consent is not required.


  1. 1.
    Ishibashi K, Koguchi T, Matsuoka K, et al. Interleukin-6 induces drug resistance in renal cell carcinoma. Fukushima J Med Sci. 2018;64:103–10.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Capitanio U, Bensalah K, Bex A, et al. Epidemiology of renal cell carcinoma. Eur Urol. 2019;75:74–84.CrossRefPubMedGoogle Scholar
  3. 3.
    Cohen HT, McGovern FJ. Renal-cell carcinoma. N Engl J Med. 2005;353:2477–90.CrossRefPubMedGoogle Scholar
  4. 4.
    Cho YH, Kim MS, Chung HS, Hwang EC. Novel immunotherapy in metastatic renal cell carcinoma. Investig Clin Urol. 2017;58(4):220–7.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Calvo E, Schmidinger M, Heng DY, Grünwald V, Escudier B. Improvement in survival end points of patients with metastatic renal cell carcinoma through sequential targeted therapy. Cancer Treat Rev. 2016;50:109–17.CrossRefPubMedGoogle Scholar
  6. 6.
    Ghatalia P, Zibelman M, Geynisman DM, Plimack ER. Review of checkpoint inhibitors for the treatment of renal cell carcinoma. Curr Treat Options Oncol. 2017;18(1):7. Scholar
  7. 7.
    Bedke J, Gauler T, Grünwald V, Hegele A, Herrmann E, Hinz S, Janssen J, Schmitz S, Schostak M, Tesch H, Zastrow S, Miller K. Systemic therapy in metastatic renal cell carcinoma. World J Urol. 2017;35(2):179–88.CrossRefPubMedGoogle Scholar
  8. 8.
    Motzer RJ, Bacik J, Schwartz LH, et al. Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. J Clin Oncol. 2004;22(3):454–63.CrossRefPubMedGoogle Scholar
  9. 9.
    Heng DY, Xie W, Regan MM, et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. J Clin Oncol. 2009;27(34):5794–9.CrossRefGoogle Scholar
  10. 10.
    Heng DY, Xie W, Regan MM, et al. External validation and comparison with other models of the international metastatic renal-cell carcinoma database consortium prognostic model: a population-based study. Lancet Oncol. 2013;14(2):141–8.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Shinohara N, Nonomura K, Abe T. A new prognostic classification for overall survival in Asian patients with previously untreated metastatic renal cell carcinoma. Cancer Sci. 2012;103(9):1695–700.CrossRefPubMedGoogle Scholar
  12. 12.
    Okita K, Hatakeyama S, Tanaka T, et al. Impact of disagreement between two risk group models on prognosis in patients with metastatic renal cell carcinoma. Clin Genitourin Cancer. 2019. Scholar
  13. 13.
    Yao X, Huang J, Zhong H, Shen N, Faggioni R, Fung M, Yao Y. Targeting interleukin-6 in inflammatory autoimmune diseases and cancers. Pharmacol Ther. 2014;141(2):125–39.CrossRefPubMedGoogle Scholar
  14. 14.
    Ghandadi M, Sahebkar A. Interleukin-6: a critical cytokine in cancer multidrug resistance. Curr Pharm Des. 2016;22(5):518–26.CrossRefPubMedGoogle Scholar
  15. 15.
    Alberti L, Thomachot MC, Bachelot T, et al. IL-6 as an intracrine growth factor for renal carcinoma cell lines. Int J Cancer. 2004;111:653–61.CrossRefPubMedGoogle Scholar
  16. 16.
    Blay JY, Negrier S, Combaret V, et al. Serum level of interleukin 6 as a prognosis factor in metastatic renal cell carcinoma. Cancer Res. 1992;52:3317–22.PubMedGoogle Scholar
  17. 17.
    Costes V, Liautard J, Picot MC, et al. Expression of the interleukin 6 receptor in primary renal cell carcinoma. J Clin Pathol. 1997;50:835–40.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Dosquet C, Schaetz A, Faucher C, et al. Tumour necrosis factor-alpha, interleukin-1 beta and interleukin-6 in patients with renal cell carcinoma. Eur J Cancer. 1994;30A:162–7.CrossRefPubMedGoogle Scholar
  19. 19.
    Falkensammer CE, Thurnher M, Leonhartsberger N, et al. C-reactive protein is a strong predictor for anaemia in renal cell carcinoma: role of IL-6 in overall survival. BJU Int. 2011;107:1893–8.CrossRefPubMedGoogle Scholar
  20. 20.
    Fu Q, Chang Y, An H, et al. Prognostic value of interleukin-6 and interleukin-6 receptor in organ-confined clear-cell renal cell carcinoma: a 5 year conditional cancer-specific survival analysis. Br J Cancer. 2015;113:1581–9.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Fumagalli L, Lissoni P, Di Felice G, et al. Pretreatment serum markers and lymphocyte response to interleukin-2 therapy. Br J Cancer. 1999;80:407–11.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Hrab M, Olek-Hrab K, Antczak A, et al. Interleukin-6 (IL-6) and C-reactive protein (CRP) concentration prior to total nephrectomy are prognostic factors in localized renal cell carcinoma (RCC). Rep Pract Oncol Radiother. 2013;18:304–9.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Kallio J, Hämäläinen M, Luukkaala T, et al. Resistin and interleukin 6 as predictive factors for recurrence and long-term prognosis in renal cell cancer. Urol Oncol. 2017;35:544.e25–31.CrossRefGoogle Scholar
  24. 24.
    Kim CS, Kim Y, Kwon T, et al. Regulatory T cells and TGF-β1 in clinically localized renal cell carcinoma: comparison with age-matched healthy controls. Urol Oncol. 2015;33(113):e19–25.Google Scholar
  25. 25.
    Ljungberg B, Grankvist K, Rasmuson T. Serum interleukin-6 in relation to acute-phase reactants and survival in patients with renal cell carcinoma. Eur J Cancer. 1997;33:1794–8.CrossRefPubMedGoogle Scholar
  26. 26.
    Negrier S, Perol D, Menetrier-Caux C, et al. Interleukin-6, interleukin-10, and vascular endothelial growth factor in metastatic renal cell carcinoma: prognostic value of interleukin-6–from the groupe francais d’immunotherapie. J Clin Oncol. 2004;22:2371–8.CrossRefPubMedGoogle Scholar
  27. 27.
    Pilskog M, Bostad L, Edelmann RJ, et al. Tumour cell expression of interleukin 6 receptor α is associated with response rates in patients treated with sunitinib for metastatic clear cell renal cell carcinoma. J Pathol Clin Res. 2018;4:114–23.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Polimeno M, Napolitano M, Costantini S, et al. Regulatory T cells, interleukin (IL)-6, IL-8, vascular endothelial growth factor (VEGF), CXCL10, CXCL11, epidermal growth factor (EGF) and hepatocyte growth factor (HGF) as surrogate markers of host immunity in patients with renal cell carcinoma. BJU Int. 2013;112:686–96.CrossRefPubMedGoogle Scholar
  29. 29.
    Ramsey S, Aitchison M, Graham J, et al. The longitudinal relationship between the systemic inflammatory response, circulating T-lymphocytes, interleukin-6 and -10 in patients undergoing immunotherapy for metastatic renal cancer. BJU Int. 2008;102:125–9.CrossRefPubMedGoogle Scholar
  30. 30.
    Stadler WM, Richards JM, Vogelzang NJ. Serum interleukin-6 levels in metastatic renal cell cancer: correlation with survival but not an independent prognostic indicator. J Natl Cancer Inst. 1992;84:1835–6.CrossRefPubMedGoogle Scholar
  31. 31.
    Thiounn N, Pages F, Flam T, et al. IL-6 is a survival prognostic factor in renal cell carcinoma. Immunol Lett. 1997;58:121–4.CrossRefPubMedGoogle Scholar
  32. 32.
    Tran HT, Liu Y, Zurita AJ, et al. Prognostic or predictive plasma cytokines and angiogenic factors for patients treated with pazopanib for metastatic renal-cell cancer: a retrospective analysis of phase 2 and phase 3 trials. Lancet Oncol. 2012;13:827–37.CrossRefPubMedGoogle Scholar
  33. 33.
    Tsukamoto T, Kumamoto Y, Miyao N, Masumori N, Takahashi A, Yanase M. Interleukin-6 in renal cell carcinoma. J Urol. 1992;148(6):1778–81.CrossRefPubMedGoogle Scholar
  34. 34.
    Walther MM, Johnson B, Culley D, et al. Serum interleukin-6 levels in metastatic renal cell carcinoma before treatment with interleukin-2 correlates with paraneoplastic syndromes but not patient survival. J Urol. 1998;159:718–22.CrossRefPubMedGoogle Scholar
  35. 35.
    Yoshida N, Ikemoto S, Narita K, et al. Interleukin-6, tumour necrosis factor alpha and interleukin-1 beta in patients with renal cell carcinoma. Br J Cancer. 2002;86:1396–400.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Zurita AJ, Jonasch E, Wang X, et al. A cytokine and angiogenic factor (CAF) analysis in plasma for selection of sorafenib therapy in patients with metastatic renal cell carcinoma. Ann Oncol. 2012;23:46–52.CrossRefPubMedGoogle Scholar
  37. 37.
    Rossi JF, Négrier S, James ND, et al. A phase I/II study of siltuximab (CNTO 328), an anti-interleukin-6 monoclonal antibody, in metastatic renal cell cancer. Br J Cancer. 2010;103:1154–62.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Angevin E, Tabernero J, Elez E, et al. A phase I/II, multiple-dose, dose-escalation study of siltuximab, an anti-interleukin-6 monoclonal antibody, in patients with advanced solid tumors. Clin Cancer Res. 2014;20:2192–204.CrossRefPubMedGoogle Scholar
  39. 39.
    Fizazi K, De Bono JS, Flechon A, et al. Randomised phase II study of siltuximab (CNTO 328), an anti-IL-6 monoclonal antibody, in combination with mitoxantrone/prednisone versus mitoxantrone/prednisone alone in metastatic castration-resistant prostate cancer. Eur J Cancer. 2012;48:85–93.CrossRefPubMedGoogle Scholar
  40. 40.
    Ishibashi K, Koguchi T, Matsuoka K, et al. Interleukin-6 induces drug resistance in renal cell carcinoma. Fukushima J Med Sci. 2018;64:103–10.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Mizutani Y, Bonavida B, Koishihara Y, et al. Sensitization of human renal cell carcinoma cells to cis-diamminedichloroplatinum(II) by anti-interleukin 6 monoclonal antibody or anti-interleukin 6 receptor monoclonal antibody. Cancer Res. 1995;55:590–6.PubMedGoogle Scholar
  42. 42.
    Fitzgerald JP, Nayak B, Shanmugasundaram K, et al. Nox4 mediates renal cell carcinoma cell invasion through hypoxia-induced interleukin 6- and 8- production. PLoS One. 2012;7:e30712.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    An H, Zhu Y, Xie H, et al. Increased expression of interleukin-8 is an independent indicator of poor prognosis in clear-cell renal cell carcinoma. Tumour Biol. 2016;37:4523–9.CrossRefPubMedGoogle Scholar
  44. 44.
    Pan D, Xu L, Liu H, et al. High expression of interleukin-11 is an independent indicator of poor prognosis in clear-cell renal cell carcinoma. Cancer Sci. 2015;106:592–7.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Ito H, Shioi K, Murakami T, et al. C-reactive protein in patients with advanced metastatic renal cell carcinoma: usefulness in identifying patients most likely to benefit from initial nephrectomy. BMC Cancer. 2012;12:337.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Federación de Sociedades Españolas de Oncología (FESEO) 2019

Authors and Affiliations

  1. 1.Department of Urologic SurgeryYantai Affiliated Hospital of Binzhou Medical UniversityYantaiChina
  2. 2.Office of Quality Assurance and Safety ManagementYantai Affiliated Hospital of Binzhou Medical UniversityYantaiChina

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