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Page 4 of 7 Peri. J Cancer Metastasis Treat 2019;5:40 I http://dx.doi.org/10.20517/2394-4722.2019.14

recruited in a study aiming to examine the prognostic value of hematologic and biochemical parameters,
+
and other tumor-related factors. Multivariate analyses showed that preoperative serum [Na ] was an
independent predictor of OS and disease-free survival, when considered either as a continuous variable or
+
when patients were grouped based on a cut-off of serum [Na ] of 139 mmol/L (median value). The estimates
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of 5-year OS were 67.6% (95%CI: 54.2-80.9) and 44.3% (95%CI: 32.8-55.8) for patients with serum [Na ] above
[29]
or below 139 mmol/L respectively . A Danish study addressed patients with metastatic RCC, divided into
two independent cohorts of 120 patients/each. In each cohort 20% and 14% of patients had hyponatremia.
Patients with hyponatremia at baseline had a median OS of 5.5 and 4.8 months in the two cohorts, whereas
[30]
patients with normonatremia at baseline had a median OS of 18.6 and 16.9 months, respectively . In
multivariate analysis, hyponatremia proved to be an independent prognostic factor (HR 1.90, 95%CI: 1.1-3.2,
P = 0.014), together with increased neutrophils (HR 1.75, CI: 1.1-2.8, P = 0.018), lactate dehydrogenase > 1.5
ULN (HR 2.09, 95%CI: 1.3-3.3, P = 0.002), and number of metastatic sites (+3) (HR 1.92, 95%CI: 1.3-2.9, P =
0.003). Finally, hyponatremia was significantly associated with lack of response to treatment in both cohorts.
A more recent Japanese study confirmed that hyponatremia appears to be a powerful prognostic predictor
[31]
in patients with metastatic RCC treated with tyrosine-kinase inhibitors following radical nephrectomy .
In this study both progression-free survival (PFS) and OS were significantly lower in hyponatremic patients
(median 10.0 and 20.9 months, respectively) than in normonatremic patients (median 28.4 and 38.5 months,
respectively).

Reduced serum [Na ] was indicated as a negative prognostic marker also in patients with gastric cancer
+
[32]
and bone marrow metastases [HR 4.57; 95%CI: 1.99-10.52; P < 0.001] and in patients with hepatocellular
[33]
carcinoma .
WHY IS HYPONATREMIA ASSOCIATED WITH A WORSE OUTCOME IN CANCER PATIENTS?
Clinical data clearly indicate that hyponatremia may be viewed as a predictor of a negative outcome in
cancer patients. Admittedly, one open question is whether the reduced PFS and OS, described by a number
of publications, is directly attributable to the electrolyte disorder itself or might be a sign of the severity of
the underlying disease. With regard to this point, a Belgian prospective study on hyponatremia in cancer
patients, published almost 20 years ago, suggested that the increase mortality rate observed in cancer
patients with hyponatremia (19.5% vs 6.3% in normonatremic partients) was not apparently due to reduced
+
serum [Na ], thus indicating that hyponatremia was to be considered as a marker of general debility in
[34]
advanced disease . A retrospective review (entitled “Mortality and serum sodium: do patients die from
or with hyponatremia?”) of the medical records of patients admitted to a teaching hospital in Rochester,
NY, for different pathologies and who died after developing hyponatremia, also suggested that the main
determinant of the observed deaths was likely the severity of the underlying illness rather than the degree
[35]
of hyponatremia . Similarly, a retrospective study that included patients diagnosed with SIAD in a
community hospital in Israel showed that long-term survival was determined by SIAD etiology rather than
[36]
by hyponatremia severity .

Recently, a study performed at two teaching hospitals in Italy and one teaching hospital in England demonstrated
+
that serum [Na ] normalization during first-line therapy is an independent prognostic factor for OS and PFS in
[37]
patients with non-small cell lung cancer . Similarly, normalization of serum [Na ] was associated with a better
+
[38]
prognosis in patients with metastatic RCC treated with everolimus . These findings are in agreement with the
results of a meta-analysis that analyzed articles reporting the outcome of patients with different diseases in which
hyponatremia had been corrected. The meta-analysis indicated that any improvement of hyponatremia was
[39]
associated with a reduced risk of overall mortality [HR = 0.57 (0.40-0.81)] .
Anyway, this issue is still a matter of debate and prospective randomized studies in cancer patients with
hyponatremia, aiming to evaluate whether correction of hyponatremia can counteract the progression of the
disease, are necessary.