The International Metastatic Renal-Cell Carcinoma Database Consortium (IMDC) criteria are largely adopted in clinical practice to estimate a patients ‘prognosis. Of note, IMDC score has been validated in the target therapy era and heterogeneity may exist among each risk category.1,2 In addition, none of the variables included in IMDC score is directly related to the biological assessment of tumours. Nonetheless, IMDC categories are a key element to consider before the choice of first line treatment. Indeed, cabozantinib and ipilimumab-nivolumab combination have shown clear efficacy on patients with intermediate/poor risk.3,4
Inclusion of the primary site of metastases as independent variables in IMDC score could reflect an important biological rationale.
Previous large studies showed that patients with brain, bone and/or liver metastasis are related to worst prognosis in patients with metastatic renal cell carcinoma.5
Our hypothesis is that early development of metastases in these three organs may be strictly related to the development of more aggressive cancer cell clones. Renal cell carcinoma biological evolution is a dynamic and very complex issue that has been only partially elucidated. In particular, there are three different evolution mechanisms theorized: the linear, the branched and the punctuated tumour evolution models. The last evolution model is related to more clinically aggressive tumours able to give a large metastatic volume in several organs.6 Early development of liver metastases could reveal a punctuated evolution.
In our study, we added a new variable to the pre-existing six IMDC variables. By this methods we integrated a pre-existing model with the inclusion of another variable thus the predictive value of initial IMDC score is not reduced but at least the same or higher.
The presence of primary bone, brain and/or liver metastases could differentiate patients’ prognosis in both intermediate and good risk categories. In the poor risk category, the distinction of patients with/without primary brain, bone and/or liver metastases did not reflect a different survival however the small number of patients with poor risk could have affected this observation.
In conclusion, our study suggests that integration of primary site of metastases to the other IMDC variables may improve prognosis prediction and maybe also patients categorization among IMDC risk groups.
Our data should be validated in an independent cohort. Considering that the treatment algorithm of metastatic disease in first and subsequent lines is going to change the assessment of IMDC criteria in this novel population is a critical issue. In this optic, the assessment of primary metastatic sites as an independent variable included in IMDC score should be considered.
Written by: Vincenzo Di Nunno, Veronica Mollica, Riccardo Schiavina, Elisabetta Nobili, Michelangelo Fiorentino, Eugenio Brunocilla, Andrea Ardizzoni, Francesco Massari
Division of Oncology, S-Orsola-Malpighi Hospital, Bologna, Italy., Department of Urology, University of Bologna, S-Orsola-Malpighi Hospital, Bologna, Italy., Pathology Service, Addarii Institute of Oncology, S-Orsola-Malpighi Hospital, Bologna, Italy., Division of Oncology, S-Orsola-Malpighi Hospital, Bologna, Italy.References:
- 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 Dec 1;27(34):5794-9. doi: 10.1200/JCO.2008.21.4809.
- Iacovelli R, De Giorgi U, Galli L et al. Is It Possible to Improve Prognostic Classification in Patients Affected by Metastatic Renal Cell Carcinoma With an Intermediate or Poor Prognosis? Clin Genitourin Cancer. 2018 Oct;16(5):355-359.e1. doi: 10.1016/j.clgc.2018.04.007.
- Choueiri TK, Halabi S, Sanford BL et al. Cabozantinib Versus Sunitinib As Initial Targeted Therapy for Patients With Metastatic Renal Cell Carcinoma of Poor or Intermediate Risk: The Alliance A031203 CABOSUN Trial. J Clin Oncol. 2017 Feb 20;35(6):591-597. doi: 10.1200/JCO.2016.70.7398. Epub 2016 Nov 14. Erratum in: J Clin Oncol. 2017 Nov 10;35(32):3736. J Clin Oncol. 2018 Feb 10;36(5):521.
- Motzer RJ, Rini BI, McDermott DF et al. Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial. Lancet Oncol. 2019 Oct;20(10):1370-1385. doi: 10.1016/S1470-2045(19)30413-9.
- Sonpavde G, Sudarshan S, Escudier B. Do the sites of metastases provide additional information regarding prognosis and biology in renal cell carcinoma? Eur Urol 2014;65(3):585-586. doi: 10.1016/j.eururo.2013.09.001.
- Turajlic S, Xu H, Litchfield K et al. Tracking Cancer Evolution Reveals Constrained Routes to Metastases: TRACERx Renal. Cell. 2018;173(3):581-594.e12. doi: 10.1016/j.cell.2018.03.057.