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Page 4 of 33 Berardi et al. J Cancer Metastasis Treat 2019;5:79 I http://dx.doi.org/10.20517/2394-4722.2019.008

Hyponatremia
Definition and clinical implications
Hyponatremia is defined as a serum/plasma sodium concentration lower than 135 mmol/L. It can arise
rapidly within 48 h (acute hypernatremia) or, more frequently, slowly (chronic hypernatremia). According to
its serum level, it can be classified into three severity grades: mild (130-134 mEq/L), moderate (125-129 mEq/L),
[25]
and severe (< 125 mEq/L) .
It represents the most common tumor-related electrolyte disorder. Even though its accurate incidence is
still unknown because different serum sodium cut-off levels were considered in several studies, a variable
[26]
incidence of 4%-44% was reported, depending on cancer type and clinical setting . Higher incidences are
associated with thoracic neoplasms, and, in particular, it occurs more frequently in patients with small-cell
[26]
lung cancer, with a median estimated rate of 15% .
Several studies evaluated the impact of hyponatremia on cancer patients, showing that, independently of
[27]
causes, it negatively correlates with patients’ outcome . In particular, hyponatremia seems associated to
[30]
[28]
poorer performance status and reduced survival in patients with lung cancer , renal cell carcinoma ,
[29]
[32]
[31]
[34]
[33]
malignant pleural mesothelioma , gastric cancer , colon-rectal cancer , and lymphoma . Recent
evidence shows an important negative predictive role of hyponatremia, for patients receiving both
[35]
chemotherapy and target therapy , while a prompt correction of this electrolyte disorder improves
patients’ outcome, which takes into account the correct timing to avoid neurological damage .
[36]
Furthermore, hyponatremia seems to also have a negative role in hospitalized patients, as it was
demonstrated to be associated with a longer length of hospital stay, inducing a negative impact on quality
[37]
of live and prognosis and an increase in hospitalization costs .
Causes
In cancer patients, several causes might induce hyponatremia :
[1]
(1) Cancer: paraneoplastic syndromes such as SIAD, brain metastasis, adrenal metastasis, and kidney
metastasis can cause hyponatremia.
(2) Cancer-treatment: it can cause hyponatremia as a direct effect of their mechanism of action (vinca
alkaloids might induce SIAD; platinum derivates are frequently associated to hyponatremia; and target
therapies, in particular antiangiogenetic agents, seem to induce hyponatremia, despite the underlying
mechanism being unknown) or as a result of side effects such as gastrointestinal losses (vomiting and
diarrhea caused by most of chemotherapeutic agents, target therapies, and immunotherapy), kidney loss,
and heart failure (cardiotoxic drugs such as anthracyclines and target therapies such as anti HER-2, anti-
ALK, and anti-MEK). Immunotherapeutic agents might cause direct damage to adrenal or pituitary gland,
favoring hyponatremia development.

(3) Concomitant drugs: diuretics, antibiotics, non-steroidal anti-inflammatory drugs (NSAIDs), opioids,
antidepressants, and neuroleptics can induce hyponatremia.

(4) Concomitant diseases: heart failure, kidney failure, thyroiditis, hypercortisolism, liver cirrhosis,
pneumonia, and inflammatory lung or brain diseases can induce hyponatremia.

However, in most cases, more than one of the aforementioned factors might induce hyponatremia in cancer
patients.

These causes can be traced back to two different basic mechanisms: excessive free water (for increased
intake or reduced elimination) or, rarely, sodium loss (reduced intake or increased loss). The knowledge