Hyponatremia normalization as an independent prognostic factor in patients with advanced non-small cell lung cancer treated with first-line therapy

The aim of the study was to assess, for the first time, the prognostic role of hyponatremia and sodium normalization in patients receiving first-line chemo- or targeted therapy for advanced non-small cell lung cancer. Four hundred thirty-three patients with advanced non small cell lung cancer were treated with first line chemo- or targeted therapy between 2006 and 2015 at our institutions. Patients were stratified in two groups, with or without hyponatremia (group A and B, respectively). Progression free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier method. A Cox regression model was carried out for univariate and multivariate analyses. Sixty-nine patients (16%) presented with hyponatremia at the start of first-line therapy. The median OS was 8.78 months in Group A and 15.5 months in Group B (p < 0.001), while the median PFS was 4.1 months and 6.3 months respectively (p = 0.24). In Group A, median OS was significantly higher in patients who normalized their sodium levels (11.6 vs. 4.7 months, p = 0.0435). Similarly, the median PFS was significantly higher in patients who normalized their sodium levels (6.7 vs. 3.3 months, p = 0.011). At multivariate analysis, sodium normalization was an independent prognostic factor for both OS and PFS. Sodium normalization during first-line therapy is an independent prognostic factor for OS and PFS in patients with advanced lung cancer treated with first-line therapies. Frequent clinical monitoring and prompt treatment of hyponatremia should be emphasized to optimize the outcome of these patients.


INTRODUCTION
Hyponatremia is a common electrolyte disorder in cancer patients, particularly in those who are hospitalized [1]. Although patients with hyponatremia are often asymptomatic, when symptoms do occur they are mainly neurological and include headaches, lethargy, poor concentration, confusion, vomiting, hallucinations and even coma [2]. Mild chronic hyponatremia can lead to marked gait instability, falls, fractures and a higher incidence and duration of hospitalization [3].
The incidence and prevalence of hyponatremia vary depending on the tumor type, clinical setting, and serum sodium cut-off level [4]. The frequency of hyponatremia was estimated at up to 40% in hospitalized patients and 15% in patients with small cell lung cancer (SCLC) [5, Clinical Research Paper www.impactjournals.com/oncotarget 6]. The syndrome of inappropriate anti-diuretic hormone secretion (SIADH) is the main cause of hyponatremia in malignancy [7], with other causes including heart failure, nephritic syndrome, extracellular volume depletion, chemotherapy [5] and target therapies [8]. The onset of hyponatremia has been associated with worst prognosis in several cancers including SCLC, mesothelioma, renal cell carcinoma, gastrointestinal cancer and lymphoma [9,10,11,12,13,14,15,16]. Furthermore hyponatremia represents a prognostic factor in terminal cancer patients [17], although a prompt correction of serum sodium level is associated to a longer survival and an improvement of clinical condition [18]. Non-small-cell lung cancer (NSCLC) is a poor-prognosis malignancy, which is the leading cause of cancer related death. Often asymptomatic in the early stages, more than half of patients have metastatic disease at time of first diagnosis [19]. The incidence of hyponatremia in NSCLC varies from 1% to 50% [20]. Early recognition and a prompt treatment of this electrolytic imbalance could prevent clinical complications and improve survival [21].
In this study, we aimed to investigate for the first time the prognostic significance of hyponatremia normalization in patients with advanced NSCLC treated with first line therapy.

Patient characteristics
Five hundred and twenty-one patients were treated with first-line therapies at our institutions. Of these, 433 patients (299 males and 134 female) were included in this analysis, whilst 88 were excluded due to lack of complete data.

Overall Survival (OS)
Median OS from first-line therapy was 13.4 months (95% CI 11.4 to 15.9) in the overall population. Two hundred and eighty one patients (64.9%) died during their follow-up.
For patients with hyponatremia (group A), median OS was significantly higher in patients who normalized their sodium levels (11.6 vs. 4.7 months, p =0.0435) ( Figure 2A).

Univariate and Multivariate analyses in the overall study population
Univariate analysis demonstrated that male gender, PS ≥2, tumor stage IV, non-adenocarcinoma      (Table 2A). At multivariate analysis, PS, tumor stage, and hyponatremia were predictors of OS (Table 2A). With respect to PFS, univariate analysis showed that male gender, PS ≥ 2, tumor stage IV and wild-type EGFR status were significantly associated with worse PFS (Table 2B). Multivariate Cox regression analysis revealed that tumor stage IV and wild-type EGFR status were independent prognostic factors for worse PFS (Table 2B).

Univariate and Multivariate analyses in patients with hyponatremia (Group A)
Univariate and multivariate analysis showed that tumor IV disease and failure to normalize sodium neutralization were significantly associated with worse OS (Table 3A).
Univariate analysis showed that adenocarcinoma histotype and sodium normalization were significantly associated with longer PFS (Table 3B). Multivariate Cox regression analysis confirmed the prognostic value of sodium normalization (Table 3B).
Hyponatremia has been identified as a negative prognostic factor in a number of different malignancies [5,9,26,27,28,29,30,31,32]. In the lung cancer population hyponatraemia is a negative prognostic factor in hospitalized patients and those with advanced-stage disease treated with erlotinib [33,34]. Furthermore it has been shown to negatively correlate with the performance status [20] as well as tumour status and inflammation in completely resected NSCLC [35]. It is important for physicians to determine and validate prognostic factors in order to optimize and personalize the management of NSCLC. Therefore we evaluated the prognostic value of hyponatremia in 433 NSCLC patients treated with first-line chemotherapy or targeted therapy. We observed a significant difference between eunatremic and hyponatremic patients in OS (15.5 vs. 8.8 months, respectively) but not PFS (6.3 vs. 4.1 months p = 0.24). Futhermore, for the first time, we showed the prognostic significance of hyponatremia normalization in patients with advanced NSCLC treated with first line therapy.
Our results are consistent with those reported in SCLC by Hansen et al. that showed that hyponatremia was associated with a lower median OS in a retrospective study of 453 SCLC patients undergoing chemotherapy. The study showed also that patients who did not fully correct serum sodium values within the first two cycles of chemotherapy had a worse outcome [25]. Hence, our results showed that the correction of sodium levels was associated with significantly higher OS (11.6 vs. 4.7 months) and PFS (6.7 vs. 3.3 months) in patients with NSCLC treated with first-line therapy. Lack of hyponatremia normalization was associated with worse OS and PFS at univariate and multivariate analyses. Thus suggesting that an early detection, a careful monitoring and supportive therapy of hyponatremia can help to improve the medical case and prognosis.
It is therefore important to achieve international consensus about the optimal investigation, diagnosis and management of hyponatraemia in order to optimize the outcome of NSCLC patients.
There are limitations to this study. First, it is a retrospective analysis, which is therefore susceptible to bias in data selection and analysis. A prospective study would be useful to validate these results.
Secondly, the management of hyponatremia was not standardized in all patients and therefore it is not possible to certain whether failure to normalize serum sodium was a reflection of the overall clinical scenario or sub-optimal medical management. Finally, concurrent drugs cannot be fully accounted for could influence the cause and course of hyponatremia.
Our results confirm the prognostic value of low serum sodium in NSCLC patients treated with firstline therapy and underline the importance of a prompt and effective correction of hyponatremia in lung cancer patients.

Study population and data collection
The study population included adult patients with histologically or cytologically confirmed diagnosis of locally advanced or metastatic NSCLC treated with firstline chemotherapy or targeted therapy at two institutions (Università Politecnica Marche, Italy and Chelsea & Westminster Hospital, UK) between 1 st May 2006 and 31th January 2015. Tumor stage was assessed according to the tumor-node-metastasis (TNM) system and included patients with stage IIIB, IV and IIIA not suitable for surgery, as defined in AJCC version 7. Data were retrospectively collected from patients' medical records.
Treatment with first-line chemotherapy or targeted therapy was continued until evidence of disease progression, unacceptable adverse events, or death. Follow-up generally consisted of regular physical examination and laboratory assessment (haematology and serum biochemistry), and imaging using computed tomography (CT) or magnetic resonance imaging (MRI) according to local procedures every 8-12 weeks.
Overall survival (OS) was defined as the time from beginning of first-line treatment to death, irrespective of cause. Progression free survival (PFS) was defined as the time from beginning of treatment to progression or to death from any cause, whichever occurred first. Patients without tumour progression or death at the time of the data cut-off for the analysis or at the time of receiving an additional anticancer therapy were censored at their last date of tumour evaluation.

Statistical Analysis
PFS and OS were estimated using Kaplan-Meier method with Rothman's 95% confidence intervals (CI) and compared across the groups using the log-rank test. Patients with a stable disease (SD), partial remission, and a complete remission were considered as responders.
Hyponatremia was assessed within one week prior to starting first-line therapy, and after each treatment cycle.
Potential factors associated with outcome were evaluated, including patients' age (≥ 70y vs. < 70y), gender, tumor stage, histology, EGFR mutational status, Eastern Cooperative Oncology Group performance status (PS) and smoking history. Data about concomitant medications were not available.
Cox proportional hazards models were applied to explore patients' characteristics predictors of survival in univariate-and multivariable analysis. Variables not fitting at univariate analysis were excluded from the multivariate model. No-multicollinearity of the grouped co-variates was checked. Significance level in the univariate model for inclusion in the multivariate final model was more liberally set at a 0.2 level [36,37]. The likelihood ratio test was conducted to evaluate the improvement in prediction performance gained by backward elimination of variables from the prognostic model [38]. All other significance levels were set at a 0.05 value and all P values were twosided. Statistical analyses were performed using MedCalc version 11.4.4.0 (MedCalc Software, Broekstraat 52, 9030 Mariakerke, Belgium). The research was carried out in accordance with the ethical committee of our institution. All patients gave their written consent to all the diagnostictherapeutic procedures.