The Impact of Low Serum Sodium on Treatment Outcome of Targeted Therapy in Metastatic Renal Cell Carcinoma: Results from the International Metastatic Renal Cell Cancer Database Consortium

doi:10.1016/j.eururo.2013.10.013

European Urology

Volume 65, Issue 4, April 2014, Pages 723-730

https://doi.org/10.1016/j.eururo.2013.10.013 Get rights and content

Abstract

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.

Introduction

Renal cell cancer (RCC) is the sixth most common cancer in United States [1], accounting for an estimated 64 770 new cases and 13 570 deaths in 2012. Patients can present with metastatic disease or recur after nephrectomy. Currently, patients with advanced RCC are stratified into three different risk groups based on the two prognostic models used most [2], [3]. These prognostic models take into account several baseline clinical and laboratory values, and capture the natural history of metastatic RCC (mRCC).

Hyponatremia is one of the most common electrolyte disorders observed in hospitalized patients [4], and it is probably highly underestimated. According to the studied populations and the definition of hyponatremia, its reported frequency varies greatly, from <1% to >40% [5]. Hyponatremia can be caused by either dilution of the serum sodium by excess retained free water or by excessive sodium losses.

Hyponatremia has been associated with poor survival in several nonmalignant diseases, such as congestive heart failure, liver cirrhosis, and infectious diseases (pneumonia, childhood meningitis, necrotizing soft-tissue infection) [6], [7], [8]. Serum sodium has been analyzed in mRCC patients treated with cytokines [9], and hyponatremia was found to be associated with a worse outcome. Similar observations have been made in malignancies, such as advanced hepatocellular carcinoma [10], advanced gastric cancer [11], advanced small cell lung cancer [12], and localized RCC [13]. However, the role of hyponatremia in mRCC patients treated with targeted therapies is not well defined. One study including 87 mRCC patients treated with sunitinib or sorafenib showed that hyponatremia was significantly associated with cancer-specific survival [14]. Since serum sodium levels are routinely measured and, therefore, widely available most of the time, we sought to investigate the association of hyponatremia on treatment outcomes in mRCC patients treated with contemporary targeted therapies.

Section snippets

Patient population

The International Metastatic Renal Cell Cancer Database Consortium (IMDC) includes 20 academic cancer centers from Canada, the United States, Japan, South Korea, Singapore, and Denmark. As of October 10, 2012, a total of 2370 patients who had received first-line targeted therapy between 2003 and 2012 were included. For this study, 1661 patients from 18 centers had baseline serum sodium level information readily available.

All patients were diagnosed with mRCC of any pathologic subtype with no

Patient characteristics

Patient and disease characteristics at the initiation of targeted therapy, both of all patients (n = 1661) and separated by hyponatremia status, are presented in Table 1. Most patients were male (74%). Fifty-three percent of patients were older than 60 yr. The majority of patients had clear cell histology (89%). Patients received one of the following VEGF-targeted therapies: sunitinib (75%), sorafenib (17%), bevacizumab (4%), pazopanib (2%), tivozanib (<1%), or axitinib (<1%); or mTOR-targeted

Discussion

To our knowledge, this is the largest study to evaluate the association of hyponatremia on outcome of mRCC patients treated with targeted agents. Hyponatremia was found to be associated with a significant lower OS, TTF, and DCR at first staging evaluation in mRCC patients receiving targeted therapy. Hyponatremic patients had 57% and 51% increase in the risk of treatment failure or death, respectively. In addition, the 50% reduction in the odds of disease control according to RECIST criteria

Conclusions

In conclusion, we have shown that, in mRCC patients treated with targeted therapy, baseline hyponatremia is associated with a poorer OS, TTF, and DCR. Hyponatremia may be a quick and efficient method of stratifying patients beyond the IMDC criteria. Hyponatremia deserves to be further investigated as a prognostic factor and evaluated for inclusion in future prognostic tools.

References (26)

G.P. Patel et al.
Recognition and treatment of hyponatremia in acutely ill hospitalized patients
Clin Ther
(2007)
T.I. Huo et al.
The MELD-Na is an independent short- and long-term prognostic predictor for hepatocellular carcinoma: a prospective survey
Dig Liver Dis
(2008)
V. Arroyo et al.
Pathophysiology of ascites and functional renal failure in cirrhosis
J Hepatol
(1988)
A. Gines et al.
Incidence, predictive factors, and prognosis of the hepatorenal syndrome in cirrhosis with ascites
Gastroenterology
(1993)
F. Gankam-Kengne et al.
Mild hyponatremia is associated with an increased risk of death in an ambulatory setting
Kidney Int
(2013)
American Cancer Society. Cancer facts and figures 2012. American Cancer Society Web site....
D.Y. Heng 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)
R.J. Motzer et al.
Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma
J Clin Oncol
(1999)
T. Berghmans et al.
A prospective study on hyponatraemia in medical cancer patients: epidemiology, aetiology and differential diagnosis
Supportive Care Cancer
(2000)
A. Luca et al.
An integrated MELD model including serum sodium and age improves the prediction of early mortality in patients with cirrhosis
Liver Transpl
(2007)

V. Nair et al.

Hyponatremia in community-acquired pneumonia

Am J Nephrol

(2007)

J. Rossi et al.

Improvement in hyponatremia during hospitalization for worsening heart failure is associated with improved outcomes: insights from the Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist in Chronic Heart Failure (ACTIV in CHF) trial

Acute Card Care

(2007)

A.N. Jeppesen et al.

Hyponatremia as a prognostic and predictive factor in metastatic renal cell carcinoma

Br J Cancer

(2010)

Cited by (68)

RENO Study: Clinical characteristics, treatment patterns and survival results in patients with metastatic renal cell carcinoma in Northern Spain
2024, Seminars in Oncology
The current available evidence on the management of metastatic renal cell cancer (mRCC) in real life is scarce in our environment. We present a summary of the existing real-world data and the results of an analysis describing the clinical characteristics, treatments, and health outcomes of patients with mRCC in northern Spain.
Retrospective observational study. Adult patients diagnosed with mRCC between Jan 2007 and Dec 2019 were included. Epidemiological, efficacy and toxicity data were collected. Median overall survival (OS) and progression-free survival (PFS) were determined using the Kaplan-Meier method.
A total of 829 patients were included (median age at diagnosis:63 years;73% men). Median follow-up was 180 months. The preponderant histology was clear cell (85%). In 50% the initial diagnosis was advanced disease. The distribution according to IMDC prognosis was good (24%), intermediate (50%) and poor (26%). The most frequent metastatic locations were lung (68.3%) and lymph node (41.0%). Most patients (95%) received a first line (1L) systemic treatment, 60% were treated with a second line (2L) of therapy and 37% received third line (3L). A VEGFR-TKIs was the most common treatment (1L: 90%, n = 507; 2L: 49%, n = 233; 3L: 54%, n = 156) followed by mTOR inhibitors (1L: 2%, n = 4; 2L: 27%, n = 126; 3L: 23%, n = 68) and immunotherapy (1L: 3.7%, n = 25; 2L: 27%, n = 126). Median OS was 24.5 months in the general population. According to IMDC prognostic groups, OS was 52.5, 25.7 and 9 months respectively. From the start of the 1L, 2L, and 3L treatment, median PFS was: 1L: 7.8 (6.8–9.0); 2L: 4.9 (4.3–5.5); 3L: 4.3 (3.8–4.8) months. No unexpected toxicity was reported.
The Real-World Data on the management of mRCC in Northern Spain are comparable in epidemiology, efficacy, and safety to studies conducted in other areas of the world. The significant reduction in the number of patients receiving second and subsequent lines of therapy hampers the access to new therapies developed in this context.
Clinical laboratory tests associated with survival in patients with metastatic renal cell carcinoma: A Laboratory Wide Association Study (LWAS)
2022, Urologic Oncology: Seminars and Original Investigations
Citation Excerpt :
This analysis further supports prior findings that low serum sodium levels are associated with survival for patients with mRCC [26,27]. Schutz et al. demonstrated that hyponatremia (serum sodium concentration <135 mmol/L) was associated with disease progression and poor survival in 1,661 patients in the International Metastatic Renal Cell Cancer Database Consortium [26]. Hyponatremia has been further linked with outcomes for patients receiving tyrosine kinase therapy in hepatocellular carcinoma [28], non-small cell lung cancer, ovarian carcinoma, and glioblastoma [29,30].
Prognostic models for patients with metastatic renal cell carcinoma (mRCC) include select laboratory values. These models have important limitations, including reliance on a limited array of laboratory tests, and use of dichotomous (“high-low”) cutoffs. We applied a Laboratory-Wide Association Study (LWAS) framework to systematically evaluate common clinical laboratory results associated with survival for patients diagnosed with mRCC.
We used laboratory data for 3,385 patients diagnosed with mRCC from 2002 to 2017. We developed a LWAS framework, to examine the association with 53 common clinical laboratory tests results (641,712 measurements) and overall survival. We employed false-discovery rate to test the association of multiple laboratory tests with survival, and validated these results using 3 separate cohorts to generate a standardized hazard ratio (sHR), reported for a 1 standard deviation unit change in each laboratory test.
The LWAS approach confirmed the association of laboratory values currently used in prognostic models with survival, including calcium (HR 1.35, 95%CI 1.24–1.48), leukocyte count (HR 1.40, 95%CI 1.30–1.51), platelet count (HR 1.36, 95%CI 1.27–1.51), and hemoglobin (HR 0.79, 95%CI 0.72–0.86). Use of these tests as continuous variables improved model performance. LWAS also identified acute phase reactants associated with survival not typically included in prognostic models, including serum albumin (HR 0.66, 95%CI 0.61–0.72), ferritin (HR 1.25, 95%CI 1.08–1.45), alkaline phosphatase (HR 1.31, 95%CI 1.23–1.40), and C-reactive protein (HR 1.70, 95%CI 1.14–2.53).
Routinely measured laboratory tests can refine current prognostic models, facilitate comparisons across clinical trial cohorts, and match patients with specific systemic therapies.
Hyponatremia is a Prognostic Factor in Patients Receiving Nutrition Support
2021, American Journal of the Medical Sciences
Hyponatremia, the most common electrolyte disorder, has been reported to be related to increased mortality. However, the association between hyponatremia and prognoses remains unclear in patients with nutrition support team (NST) intervention. This study aimed to determine the prevalence of abnormal serum sodium levels, its relation to patient data, and the impact of hyponatremia on prognosis.
Patients who received nutrition support at Tokushima University Hospital for the first time and whose serum sodium levels were measured at the start of NST intervention were enrolled. Patients were classified into three groups according to their serum Na levels at the start of NST intervention: hyponatremia group, normonatremia group, and hypernatremia group.
In the hyponatremia group compared to the normonatremia group, body weight and body mass index were significantly lower. C-reactive protein levels and urea nitrogen/creatinine ratios were significantly higher. Meanwhile, there was no significant difference in the estimated glomerular filtration rate among the groups. The prevalence of malnutrition and anemia were the highest in the hyponatremia group. The 3-year survival rate was approximately 45% in the hyponatremia group, which was the lowest of all three groups. The mortality risk ratio of the hyponatremia group to the normonatremia group was 2.29.
Hyponatremia in NST intervention patients is an independent prognostic predictor. Therefore, adding an assessment of serum sodium at the beginning of NST intervention can identify patients at high risk at an early stage and may improve the quality of NST activity.
Electrolyte disorders in advanced non-small cell lung cancer patients treated with immune check-point inhibitors: A systematic review and meta-analysis
2020, Critical Reviews in Oncology/Hematology
Aim of this meta-analysis was to determine the relative risk (RR) of electrolyte disorders (EDs) in advanced non-small cell lung cancer (aNSCLC) patients treated with immune check-point inhibitors (ICIs).
We searched for phase II/III randomized controlled trials (RCTs) comparing ICIs (alone or combined with chemotherapy) with standard chemotherapy in aNSCLC. Summary incidence and RR were calculated.
Six RCTs with data on all-grade hyponatremia were identified (n = 3257). The incidence was 8.7 % in the study group and 4.9 % in the control group (RR 1.78, 95 %CI 1.12–2.80). Looking at all-grade hypokalemia, 7 RCTs were included (n = 4119). Incidence was 10.4 % in ICIs-treated patients and 5.9 % in the control arms (RR 1.62, 95 % CI 1.30–2.02).
Treatment with ICIs in aNSCLC is associated with a significant increased risk of hyponatremia and hypokalemia compared to chemotherapy. Monitoring of electrolyte levels should be emphasized in this setting.
Causes and Results of Nephrology Consultation in Oncological Diseases: A Single-Center Experience
2023, Turkish Journal of Nephrology
Hyponatremia and Cancer: From Bedside to Benchside
2023, Cancers

View all citing articles on Scopus

^†: Co-senior authors.

View full text

Abstract

Background

Objective

Design, setting, and participants

Outcome measurements and statistical analysis

Results and limitations

Conclusions

Introduction

Section snippets

Patient population

Patient characteristics

Discussion

Conclusions

Clin Ther

Dig Liver Dis

J Hepatol

Gastroenterology

Kidney Int

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

Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma

J Clin Oncol

A prospective study on hyponatraemia in medical cancer patients: epidemiology, aetiology and differential diagnosis

Supportive Care Cancer

An integrated MELD model including serum sodium and age improves the prediction of early mortality in patients with cirrhosis

Liver Transpl

Hyponatremia in community-acquired pneumonia

Am J Nephrol

Improvement in hyponatremia during hospitalization for worsening heart failure is associated with improved outcomes: insights from the Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist in Chronic Heart Failure (ACTIV in CHF) trial

Acute Card Care

Hyponatremia as a prognostic and predictive factor in metastatic renal cell carcinoma

Br J Cancer