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Page 2 of 33 Berardi et al. J Cancer Metastasis Treat 2019;5:79 I http://dx.doi.org/10.20517/2394-4722.2019.008

INTRODUCTION
Electrolyte disorders are very common conditions in cancer patients. They mainly concern changes
in serum sodium, potassium, calcium, and magnesium levels. In most cases, these alterations are
asymptomatic and therefore not always taken into consideration in clinical practice. However, they can
sometimes be associated with clinical manifestations that can worsen patient’s clinical condition up to
more serious life-threatening events. Furthermore, several clinical studies showed an important impact of
electrolyte disorders on cancer patients’ journey. Firstly, they seem to correlate with a worsening quality of
life and performance status, reduced probability of tumor response to anti-cancer treatment and treatment
[1]
delays, and cause poorer outcomes and reduced survival . Electrolyte disorders in cancer patients might
depend on several causes: cancer physiopathology, anti-tumor treatments, concomitant clinical conditions,
or therapies. However, they often have a multifactorial origin and they might be both secondary and
responsible for multiple organ systems’ dysfunction. A prompt correction of electrolyte disorders
is commonly associated with a better prognosis. Therefore, increasing attention towards electrolyte
[3]
[2]
disturbances is emerging in the literature and clinical trials . Ingles Garces et al. published a review
on phase I trials performed between 2011 and 2015. They showed elevated rates of hyponatremia (62%),
hypokalemia (40%), hypomagnesemia (17%), and hypocalcemia (12%) in cancer patients treated with new
anticancer-agents and that patients who developed adverse events in terms of electrolyte disturbances
during follow-up had a poorer median overall survival (26 weeks vs. 37 weeks, hazard ratio = 1.61; P <
0.001). These data suggest the importance of monitoring and correcting electrolyte disorders in cancer
patients. The relationship between electrolyte disorders and poor prognostic impact on cancer patients
might depend on the fact that several ion channels and transporters are over- or under-expressed in cancer
[4]
cells and implicated in phenomena of cell proliferation, apoptosis, migration, and invasiveness . Recently,
it has been demonstrated that several channel genes are expressed in several cancer types, suggesting
an important role in tumor development and progression. For example, a recent study proposed an ion
channel gene signature for breast cancer as a prognostic and diagnostic biomarker, showing an association
[5]
between different ion gene expression and p53 mutation status, estrogen receptor status, and grading .

Our review aims to focus on electrolyte disorders in cancer patients, providing information for correct and
prompt diagnosis, therapy, and monitoring, in order to improve the outcome of the patients.

SODIUM
Sodium is the major cation of extracellular fluid (ECF) and the main constituent of serum osmolality.
Its concentration in ECF is essential for maintaining the circulating blood volume and it is strictly
interdependent of water presence. Normal serum sodium level is 135-145 mmol/L and its imbalance may
[6]
be caused by alteration of both solute and water intake, depletion, and dilution .
Several integrated systems are involved in maintaining normal serum sodium concentration, such as
regulation of water intake by thirst, control of free water renal excretion by antidiuretic hormone secretion,
renal sodium excretion by glomerular filtration, peritubular conditions, and adrenal aldosterone secretion.

In particular, the angiotensin II arginine vasopressin (AVP) - atrial natriuretic peptide pathway is the most
[7]
[8]
important mechanism of sodium balance , and it is strictly associated to serum osmolality .
Alterations in serum sodium concentration include hyponatremia and hypernatremia. Sodium channels
[4]
have been described in cancer cells and associated with a more aggressive behavior . Voltage-gated
sodium channels (VGSC) are a large group of trans-membrane proteins that allow the flow of sodium
ions down the electrochemical gradient through cell membranes. In particular, overexpression of Nav 1.5,
a VGSC, seems to promote cell proliferation, migration, invasion, and metastasis of oral squamous cell