Hyponatremia Associated With Poor Prognosis in mRCC

Hyponatremia is significantly associated with worse outcomes in patients with metastatic renal cell carcinoma (mRCC) who received treatment with VEGF- and mTOR-targeted agents, according to a retrospective analysis published in European Urology.

In the largest-ever analysis to examine this topic, researchers found that baseline hyponatremia was significantly associated with worse prognosis, shorter overall survival (OS), shorter time to treatment failure (TTF), and lower disease control rate (DCR) for patients with mRCC treated with targeted therapies. The study was conducted using data from the International Metastatic RCC Database Consortium (IMDC).

“This study extends the IMDC’s prior work and currently represents the largest known series, with 1661 mRCC patients from 18 academic centers worldwide,” Joaquim Bellmunt, MD, PhD, and Jeffrey Leow, MD MPH, from the Dana-Farber/Brigham and Women's Cancer Center, wrote in an accompanying article. “The authors are to be congratulated for their continued work in improving prognostication for mRCC patients.”

The study, led by Fabio A.B. Schutz, MD, from the Dana-Farber Cancer Institute, evaluated the association of hyponatremia (serum sodium level <135 mmol/l) with OS in 1661 patients with mRCC who received treatment with first-line VEGF- or mTOR-targeted therapy. The secondary endpoints of the study included TTF and DCR. The data were adjusted using IMDC risk factors, which include anemia, thrombocytosis, neutrophilia, hypercalcemia, Karnofsky performance status <80%, and <1 yr from diagnosis to treatment.

The median OS after treatment initiation was 18.5 months (95% CI, 17.5—19.8), with 552 patients (33.2%) remaining alive at a median follow-up of 22.1 months. Overall, hyponatremia was found in 243 patients (14.6%) in the database analysis.

Hyponatremia was associated with a median univariate OS of 7.0 months versus 20.9 months in patients with normal sodium levels (multivariate hazard ratio [HR] = 1.51; 95% CI, 1.26-1.80; P <0.0001). For patients with and without hyponatremia, respectively, TTF was 2.9 months versus 7.4 months (multivariate HR = 1.57; 95% CI, 1.34-1.83; P <0.0001) and the DCR rate was 54.9% versus 78.8% (multivariate odds ratio = 0.50; 95% CI, 34-0.72; P <0.001). The results remained similar if sodium was analyzed as a continuous variable.

“Unlike other relatively unmodifiable prognostic factors such as the Karnofsky performance status, time from diagnosis to treatment, and number of metastatic sites, low serum sodium may be amenable to correction,” Bellmunt and Leow noted in their editorial. “However, it is not known if correction to eunatremia will affect outcomes; this area has potential for further research in mRCC.”

The association between hyponatremia and poor outcomes has been established in many solid tumors. Additionally, smaller trials have demonstrated a connection between sodium levels and prognosis in localized and metastatic RCC.

The collection of retrospective analyses suggests that hyponatremia and related neutrophilia, and high C-reactive protein levels represent significant predictive factors in mRCC. However, despite the growing number of retrospective trials, the prognostic and predictive value of hyponatremia has yet to be validated in a prospective setting.

“Future studies will need to confirm whether the addition of hyponatremia improves the current prognostic indices substantially to enhance our understanding of prognostication for mRCC patients treated with targeted therapies and determine whether we can improve outcomes by correcting hyponatremia,” wrote Bellmunt and Leow.