Editorial Comment from Dr Vázquez‐Alonso and Dr Puche‐Sanz to Impact of hyponatremia on survival of patients with metastatic renal cell carcinoma treated with molecular targeted therapy

Abstract

Hyponatremia has been associated with poor survival in many solid tumors (hepatocellular carcinoma, gastric cancer, small cell lung cancer) and other diseases (congestive heart failure or cirrhosis), and more recently it has been found to be of prognostic and predictive value in metastatic renal cell cancer (mRCC) patients treated with immunotherapy.1 The study by Kawashima et al. retrospectively evaluates the prognostic significance of low serum sodium concentrations in metastatic renal cell carcinoma treated with molecular targeted therapy.2 The study included 87 patients from different institutions treated with sorafenib or sunitinib as first-line therapy. The researchers used the Kumar and Berl's conservative definition of hyponatremia (≤137 mEq/L). Median cancer-specific survival time was 8.8 months in the patients with severe (≤134 mEq/L) and mild (135–137 mEq/L) hyponatremia, and 32.6 months in patients with normal natremia (P < 0.0001). The univariate and multivariate analysis of the data shows that severe and mild hyponatremia (<138 mEq/L) represents a poor prognostic factor in these patients. Furthermore, they showed that neutrophilia and high CRP levels appear to be important markers reflecting tumor aggressiveness. Despite the fact that it is retrospective and had a small number of patients, the study is well-designed and rigorous, and the results are consistent with the current knowledge reported on this issue so far. Furthermore, this is the first published study to show by univariate and multivariate analysis that severe and mild hyponatremia (<138 mEq/L) is a poor prognostic factor of mRCC treated with molecular targeted therapy as first-line therapy; and therefore, it can definitely open the door to prospective, larger-scale investigations that determine the real role that hyponatremia plays in the physiopathology and prognosis of this disease. Nevertheless, a larger international and multi-institutional, retrospective study with 855 mRCC patients treated with first-line anti-vascular endothelial growth factor therapy did show similar results.3 In this study by Schutz et al., hyponatremia (<135 mmol/L) was found in 16.7% of the patients. On univariate analysis, hyponatremia was associated with shorter overall survival (OS) (6.5 vs 18.8 months, P < 0.0001), shorter time to treatment failure (TTF; 2.8 vs 6.9 months, P < 0.0001) and lower disease control rate (DCR; as defined by complete response + partial response + stabilization; 51.2% vs 74.6%, P < 0.0001). In multivariate analysis, these effects remained significant with P < 0.001 for OS and TTF, and P = 0.01 for DCR. However, it also important to highlight that further basic research is required to better understand the mechanisms behind low serum sodium in these patients. Unlike other prognostic factors, hyponatremia is potentially correctable and there are different treatment alternatives (such as vasopressin receptor antagonists).4 Thus, the treatment and follow up of serum sodium levels, as well as their potential role in the improvement of the prognosis of these patients, might become a challenging new line of investigation, as it already is in other diseases.5, 6 Because of the lack of disease-specific prognostic markers for renal cell carcinoma and the rapid widespread use of the targeted agents, a major optimization of the current prognostic models is required and further studies should appear in this regard. Natremia and CRP levels will likely become two new factors within those prognostic models. None declared.