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Page 2 of 12 Khan et al. J Cancer Metastasis Treat 2019;5:71 I http://dx.doi.org/10.20517/2394-4722.2019.017

INTRODUCTION
[1]
Dysnatremias are common electrolyte imbalances in cancer patients . Hyponatremia (serum
sodium < 135 mEq/L) is the most common electrolyte abnormality encountered in clinical practice.
Oncology patients are particularly at risk of developing hyponatremia due to their underlying cancer
(including associated paraneoplastic syndromes), predisposition to infections, antibiotic use, concurrent
chemotherapy, and nausea and pain. Hyponatremia in cancer patients is a predictor of outcome, hospital
[2-5]
length and cost of stay, and an independent predictor of mortality in the intensive care unit . The
[6]
syndrome of inappropriate antidiuresis (SIAD) is a frequent cause of cancer related hyponatremia .
Hyponatremia due to ectopic arginine vasopressin (AVP; also known as antidiuretic hormone or ADH)
production has been identified in 24.6% of small cell lung cancer patients and is associated with shorter
[7]
survival . After brain metastasis, hyponatremia is the second leading cause of neurologic disorders in
[8]
patients with small cell lung cancer . Other malignancies with a high prevalence of hyponatremia include
[9]
gastrointestinal, hematological, breast and urological malignancies . Many chemotherapeutic agents
[10]
coupled with hydration protocols can cause hyponatremia. Concomitant use of thiazide diuretics and
opioid derivatives used for the management of cancer-related pain increase AVP release and contribute
[5]
to hyponatremia . Vincristine and vinblastine have neurotoxic effects on the hypothalamic-pituitary-
thyroid axis and cause hyponatremia while cyclophosphamide enhances the effect of AVP on the kidneys.
Furthermore, cisplatin and carboplatin stimulate production of AVP and inhibit absorption of sodium
by renal tubules. Treatment strategies with targeted therapies (inhibitors of angiogenesis, anti-epithelial
growth factor tyrosine kinase receptor inhibitors and monoclonal antibodies) in cancer patients increases
the incidence of hyponatremia (25.5%) in the treatment group. Higher incidence of hyponatremia is
observed with a treatment combination of cetuximab and brivanib (63.4%) as well as with pazopanib
[11]
(31.7%) . Patients receiving chemotherapy generally increase their free water intake. In small cell lung
cancer patients receiving chemotherapy, tumor lysis syndrome increases the risk of hyponatremia due to
increased release of AVP. In this clinical situation hyponatremia could be prevented by water restriction
before the start of chemotherapy.

In cases of symptomatic hyponatremia, pharmacologic intervention may be necessary to increase serum
[8]
sodium levels . The management of hyponatremia is becoming increasingly important in oncology due
to the negative correlation of hyponatremia with performance status and the prognosis of cancer [7,11] .
[12]
Treatment of hyponatremia in small cell lung cancer patients is associated with improved survival .
Sodium normalization is an independent prognostic factor for improved overall survival and progression
free survival in patients with advanced non-small cell cancer with hyponatremia treated with first line
[11]
chemotherapy or targeted therapy . Failure to identify the potential cause of hyponatremia and delay in
appropriate treatment plan places the patient at risk of an adverse outcome. In this review, we discuss the
initial evaluation, diagnostic algorithm and treatment of hyponatremia in cancer patients.

CLINICAL PRESENTATION
Symptoms of hyponatremia have variable clinical presentations, can be nonspecific and confounded by
other comorbidities, and can range from mild cognitive deficits to severe neurologic symptoms. Symptoms
of mild hyponatremia are nonspecific and may manifest as malaise, anorexia, muscle cramps, nausea,
confusion, lethargy, and headache. More severe neurologic manifestations such as vomiting, somnolence,
seizures, respiratory arrest, coma, and death are due to cerebral edema. Symptoms are often subtle, if
present at all, in patients with chronic hyponatremia in which the brain has had time to adapt to the
[13]
hypotonic state. Chronic hyponatremia is associated with falls and increased risk of fracture . A rapid
decrease in serum sodium induces symptoms at a higher sodium level and the severity of symptoms reflect
the degree of brain edema and guide the urgency of management. Patients with acute hyponatremia are at
risk of permanent neurologic impairment.