Background Hyponatremia has been associated with poor survival in many solid tumors and more recently found to be of prognostic and predictive value in metastatic renal cell cancer (mRCC) patients treated with immunotherapy. Objective To investigate the influence of baseline hyponatremia in mRCC patients treated with targeted therapy in the International Metastatic Renal Cell Carcinoma Database Consortium. Design, setting, and participants Data on 1661 patients treated with first-line vascular endothelial growth factor (VEGF) or mammalian target of rapamycin (mTOR) targeted therapy for mRCC were available from 18 cancer centers to study the impact of hyponatremia (serum sodium level <135 mmol/l) on clinical outcomes. Outcome measurements and statistical analysis The primary objective was overall survival (OS) and secondary end points included time to treatment failure (TTF) and the disease control rate (DCR). The chi-square test was used to compare the DCR in patients with and without hyponatremia. OS and TTF were estimated with the Kaplan-Meier method and differences between groups were examined by the log-rank test. Multivariable logistic regression (for DCR) and Cox regression (for OS and TTF) were undertaken adjusted for prognostic risk factors. Results and limitations Median OS after treatment initiation was 18.5 mo (95% confidence interval [CI], 17.5-19.8 mo), with 552 (33.2%) of patients remaining alive on a median follow-up of 22.1 mo. Median baseline serum sodium was 138 mmol/l (range: 122-159 mmol/l), and hyponatremia was found in 14.6% of patients. On univariate analysis, hyponatremia was associated with shorter OS (7.0 vs 20.9 mo), shorter TTF (2.9 vs 7.4 mo), and lower DCR rate (54.9% vs 78.8%) (p < 0.0001 for all comparisons). In multivariate analysis, these effects remain significant (hazard ratios: 1.51 [95% CI, 1.26-1.80] for OS, and 1.57 [95% CI, 1.34-1.83] for TTF; odds ratio: 0.50 [95% CI, 34-0.72] for DCR; adjusted p < 0.001). Results were similar if sodium was analyzed as a continuous variable (adjusted p < 0.0001 for OS, TTF, and DCR). Conclusions This is the largest multi-institutional report to show that hyponatremia is independently associated with a worse outcome in mRCC patients treated with VEGF- and mTOR-targeted agents.
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Financial disclosures: Toni K. Choueiri certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Daniel Y.C. Heng has advisory roles at Aveo, Pfizer, Novartis, and Bayer. Mary J. Mackenzie has advisory roles at Novartis and Pfizer, and has received research funding from both. Lori A. Wood has advisory roles at Pfizer and Novartis, and has received research funding from Pfizer, Novartis, and GlaxoSmithKline. Ulka Vaishampayan has received honoraria and research funding from Pfizer, Novartis, and GlaxoSmithKline. Sun-Young Rha has advisory roles at Novartis, Pfizer, and GlaxoSmithKline, and has received research funding from Novartis and Bayer Korea. Frede Donskov has received research funding from Novartis. Christian Kollmannsberger has advisory roles at Pfizer, Novartis, and GlaxoSmithKline, and has received honoraria and research funding from Pfizer, Novartis, and GlaxoSmithKline. Brian I. Rini has advisory role at Pfizer, GlaxoSmithKline, Aveo, Bayer, Onyx, and has received research funding from GlaxoSmithKline and Pfizer. Sandy Srinivas has advisory roles at Pfizer, Novartis, and Genentech. Scott A. North has an advisory role Pfizer, Novartis, Bayer, and GlaxoSmithKline. Toni K. Choueiri has received research funding from Pfizer and has advisory roles at Aveo, Pfizer, Novartis, GlaxoSmithKline, Genentech, Bayer, and Onyx. The other authors declare that they have no conflicts of interest.
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