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Page 12 of 33 Berardi et al. J Cancer Metastasis Treat 2019;5:79 I http://dx.doi.org/10.20517/2394-4722.2019.008
[73]
fact, they promote calcium deposition in the bones, reducing blood calcium concentration . Therefore,
checking calcium serum level before these treatments and implementation of calcium and vitamin D
[74]
oral intake are recommended . Furthermore, several drugs, such as chemotherapeutic agents, target
therapies, immunotherapies can induce hypocalcemia in cancer patients, through different mechanisms:
[75]
kidney injuries, iatrogenic magnesium-deficiency, gastrointestinal damage, pancreatitis . In particular,
[75]
monoclonal anti EGFR antibodies can cause hypomagnesemia with consequent hypocalcemia .
(3) Concomitant drugs: diuretics and parenteral nutrition can induce hypocalcemia .
[70]

(4) Concomitant diseases: kidney failure, autoimmune disorders causing PTH deficiency, sepsis, and
[70]
pancreatitis can induce hypocalcemia .

Management
Clinical manifestations of hypocalcemia are closely related to severity and time of onset. Symptoms and
signs are influenced by other factors such as acid-base status, hypomagnesemia, and over-activity of
sympathetic system .
[76]
Clinical disorders due to hypocalcemia depend on altered electrical potential of cell membrane, and
it appears as an imbalanced neuromuscular excitability. Chronic and mild hypocalcemia are often
asymptomatic or they can present with muscle cramps, ectopic calcifications, parkinsonism, dementia,
depression, psychosis, dry skin, and cataract.

Severe or acute hypocalcemia might cause tetanic spasms, laryngospasm until generalized convulsions, and
coma .
[76]

Severe hypocalcemia might also provoke cardiac alteration such as arrhythmias or heart block. ECG shows
typical alteration such as prolongation of the QTc and ST interval, altered repolarization, T-wave pointed
[77]
shape, or inversion .

Diagnosis of hypocalcemia is based on symptoms’ presence and it needs to be confirmed through
laboratory exam. Since serum calcium is partially bound to proteins, it is suggested to correct total serum
calcium concentrations with albumin levels [e.g., serum calcium (mg/dL) + 0.8 × (4-patient’s albumin)].
Alternatively, ionized calcium can be evaluated. For a correct differential diagnosis, serum albumin, total
protein, urinary calcium, phosphate, vitamin D, plasma PTH, and parathyroid, renal, and liver function
[78]
should be evaluated [Figure 3] .
Treatment of hypocalcemia depends on severity, clinical manifestation, and underlying causes. When
[78]
possible, it is always advisable to correct the cause of hypocalcemia .
In the case of acute and/or symptomatic hypocalcemia, patients should receive intravenous calcium.
To avoid adverse events, calcium gluconate should be infused slowly (e.g., 10 mL of a formulations of
10% calcium gluconate should be diluted in 50-100 mL of 5% dextrose and infused over 5-10 min), and
[79]
administered via a central venous catheter to prevent extravasation’s complications . In fact, a rapid
correction of hypocalcemia might increase the risk of cardiac arrhythmias, especially in patients receiving
digoxin, thus cardiac activity should be monitored with ECG and correction rate of hypocalcemia should
be checked every 1-2 h during intravenous calcium gluconate infusion .
[79]

In the case of tetanic signs due to severe and/or acute hypocalcemia, the treatment initially requires
a 10-min bolus of calcium gluconate intravenous infusion (10 mL of 10% solution) followed by the
[80]
aforementioned formulation. Moreover, concomitant hypomagnesemia or alkalosis should be corrected .