Does diabetes mellitus play an independent prognostic role in kidney cancer?
Editorial Commentary

Does diabetes mellitus play an independent prognostic role in kidney cancer?

Johannes Breyer

Department of Urology, University of Regensburg Caritas St. Josef Medical Center, Regensburg, Germany

Correspondence to: Johannes Breyer. Department of Urology, University of Regensburg Caritas St. Josef Medical Center, Landshuter Str. 65 93053 Regensburg, Germany. Email: johannes.breyer@ukr.de.

Provenance: This is an invited article commissioned by the Section Editor Dr. Xiao Li (Department of Urology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China).

Comment on: Nayan M, Jalali S, Kapoor A, et al. Diabetes and kidney cancer survival in patients undergoing nephrectomy: A Canadian multi-center, propensity score analysis. Urol Oncol 2019;37:576.e11-576.e16.


Submitted Dec 09, 2019. Accepted for publication Dec 13, 2019.

doi: 10.21037/atm.2019.12.85


Kidney cancer accounts for about 2% of all carcinomas with an incidence of 403,262 new cases in 2018 and 175,098 dying from the tumor (1). Due to the improved and more frequent use of imaging, incidence is rising about 2% over the last two decades with more small and localized tumors being diagnosed (2).

Smoking, obesity and hypertension have been identified as modifiable risk factors for renal cell carcinoma (RCC) (3,4).

The role of diabetes mellitus (DM) as an independent risk factor and prognostic factor of RCC remains unclear (3,4). There is evidence that diabetes may be a risk factor for RCC. Ribback et al. could show that long-term hyperglycemia can induce carcinogenesis in renal tubule cells in vitro (5). In a meta-analysis, Bao et al. described an increased risk for diabetic patients to develop RCC, independent of obesity, smoking and alcohol consumption (6). But there was no association to carcinoma-specific survival (CSS) in this meta-analysis. In a single-center propensity score analysis of over 1,000 patients with RCC, no correlation of DM with survival of RCC could be shown (7). In a retrospective analysis on the influence of metabolic syndrome on the outcome of localized RCC, DM as single component of metabolic syndrome had no independent influence on survival (8).

However, there is data that underlines a negative prognostic impact of diabetes in RCC patients. Chen et al. could show a worse recurrence-free survival (RFS), CSS and overall survival (OS) for diabetes in another meta-analysis (9). Patel et al. could also show a significant worse survival for DM in patients with T1a kidney cancer (10). In a retrospective analysis of 571 patients with T1 RCC DM was the best predictor for worse long-term OS without influencing RFS or CSS (11).

Nayan et al. performed a multi-center propensity score analysis of patients with localized RCC undergoing surgical treatment in 16 centers in Canada between 1989 and 2017 (12). The entire cohort consists of a retrospective cohort (1989−2011) and a prospective cohort (2011−2017) with a median follow-up of 26.6 months. After excluding patients with previous RCC and with missing data, 4,828 patients could be included in the final analysis, 20% of those having DM. There were 901 deaths with 299 from RCC. Diabetic patients were older, had more comorbidities and a higher amount of clear cell carcinoma. After propensity score matching, all characteristics were balanced. No correlation between DM and CSS (HR 1.13, 95% CI: 0.78−1.62) and OS (HR 1.14, 95% CI: 0.94−1.38) after propensity score matching could be found (12).

There is substantial merit in this study. As outlined above, data concerning the prognostic role of DM in RCC is conflicting. Since DM is often accompanied by multiple other diseases such as hypertension, increased BMI and older age, it is very important to exclude this bias when analyzing survival in these patients. Kriegmair et al. showed that metabolic syndrome is associated with survival in RCC but not DM as a single factor (8). The strength of the study at hand is that there is individual retrospective and prospective multi-center patient data of a large cohort over a large time span.

Another interesting finding of the analysis of Nayan et al. is that there is a correlation between DM and clear cell histology, which has been described earlier (7) and deserves a closer look on the underlying mechanisms in future studies.

However, there are a few limitations to this study. The median follow-up is rather short and it would be interesting, to determine how diabetes influences long-term survival. Furthermore, there is no information on the severity of the diabetes, i.e., Glucose and HbA1c levels. However, a previous study did not show any correlation with the severity of diabetes (7).

Furthermore, there is no information on the treatment of diabetes in this study. There is data on the effect of the antidiabetic drug metformin on the outcome of RCC (13-15). Metformin might influence prognosis via suppression of the mTOR-pathway (16). Hakimi et al. could find no impact on the use of metformin at the time of renal surgery for RCC on RFS and CSS (13). Hamieh et al. also did not find an effect of the use of metformin on OS in RCC (14). However, there may be a positive effect of metformin use in metastatic patients treated with sunitinib (15). Thus, the prognostic effect of metformin also remains unclear and seems not to have an independent prognostic effect.

To conclude, in clinical routine diabetic patients should be treated the same as non-diabetic patients concerning radicality and time of treatment.


Acknowledgments

None.


Footnote

Conflicts of Interest: The author has no conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.


References

  1. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394-424. [Crossref] [PubMed]
  2. Chow WH, Devesa SS. Contemporary epidemiology of renal cell cancer. Cancer J 2008;14:288-301. [Crossref] [PubMed]
  3. Chow WH, Dong LM, Devesa SS. Epidemiology and risk factors for kidney cancer. Nat Rev Urol 2010;7:245-57. [Crossref] [PubMed]
  4. Ljungberg B, Campbell SC, Choi HY, et al. The epidemiology of renal cell carcinoma. Eur Urol 2011;60:615-21. [Crossref] [PubMed]
  5. Ribback S, Cigliano A, Kroeger N, et al. PI3K/AKT/mTOR pathway plays a major pathogenetic role in glycogen accumulation and tumor development in renal distal tubules of rats and men. Oncotarget 2015;6:13036-48. [Crossref] [PubMed]
  6. Bao C, Yang X, Xu W, et al. Diabetes mellitus and incidence and mortality of kidney cancer: a meta-analysis. J Diabetes Complications 2013;27:357-64. [Crossref] [PubMed]
  7. Nayan M, Finelli A, Jewett MA, et al. Diabetes and kidney cancer outcomes: a propensity score analysis. Endocrine 2017;55:470-7. [Crossref] [PubMed]
  8. Kriegmair MC, Mandel P, Porubsky S, et al. Metabolic syndrome negatively impacts the outcome of localized renal cell carcinoma. Horm Cancer 2017;8:127-34. [Crossref] [PubMed]
  9. Chen L, Li H, Gu L, et al. The impact of diabetes mellitus on renal cell carcinoma prognosis: a meta-analysis of cohort studies. Medicine (Baltimore) 2015;94:e1055. [Crossref] [PubMed]
  10. Patel HD, Kates M, Pierorazio PM, et al. Comorbidities and causes of death in the management of localized T1a kidney cancer. Int J Urol 2014;21:1086-92. [Crossref] [PubMed]
  11. Breyer J, Otto W, Lausenmeyer EM, et al. Clinical and pathological prognostic factors for the long-term survival of patients with pT1 renal cell carcinoma. Aktuelle Urol 2017;48:230-7. [PubMed]
  12. Nayan M, Jalali S, Kapoor A, et al. Diabetes and kidney cancer survival in patients undergoing nephrectomy: A Canadian multi-center, propensity score analysis. Urol Oncol 2019;37:576.e11-576.e16. [Crossref] [PubMed]
  13. Hakimi AA, Chen L, Kim PH, et al. The impact of metformin use on recurrence and cancer-specific survival in clinically localized high-risk renal cell carcinoma. Can Urol Assoc J 2013;7:E687-91. [Crossref] [PubMed]
  14. Hamieh L, McKay RR, Lin X, et al. Effect of metformin use on survival outcomes in patients with metastatic renal cell carcinoma. Clin Genitourin Cancer 2017;15:221-9. [Crossref] [PubMed]
  15. Keizman D, Ish-Shalom M, Sella A, et al. Metformin use and outcome of sunitinib treatment in patients with diabetes and metastatic renal cell carcinoma. Clin Genitourin Cancer 2016;14:420-5. [Crossref] [PubMed]
  16. Liu J, Li M, Song B, et al. Metformin inhibits renal cell carcinoma in vitro and in vivo xenograft. Urol Oncol 2013;31:264-70. [Crossref] [PubMed]
Cite this article as: Breyer J. Does diabetes mellitus play an independent prognostic role in kidney cancer? Ann Transl Med 2019;7(Suppl 8):S382. doi: 10.21037/atm.2019.12.85