Electrolyte disorders in cancer patients: a systematic review

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), and severe (< 125 mEq/L)^[25].

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 incidence of 4%-44% was reported, depending on cancer type and clinical setting^[26]. Higher incidences are associated with thoracic neoplasms, and, in particular, it occurs more frequently in patients with small-cell lung cancer, with a median estimated rate of 15%^[26].

Several studies evaluated the impact of hyponatremia on cancer patients, showing that, independently of causes, it negatively correlates with patients’ outcome^[27]. In particular, hyponatremia seems associated to poorer performance status^[28] and reduced survival in patients with lung cancer^[29], renal cell carcinoma^[30], malignant pleural mesothelioma^[31], gastric cancer^[32], colon-rectal cancer^[33], and lymphoma^[34]. Recent evidence shows an important negative predictive role of hyponatremia, for patients receiving both chemotherapy and target therapy^[35], 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 of live and prognosis and an increase in hospitalization costs^[37].

Causes

In cancer patients, several causes might induce hyponatremia^[1]:

• Cancer: paraneoplastic syndromes such as SIAD, brain metastasis, adrenal metastasis, and kidney metastasis can cause hyponatremia.

• 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.

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

• 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 of these two different mechanisms is fundamental for the differential diagnosis between the potential causes in order to set a correct therapeutic approach. Extracellular volume (ECV) status is fundamental to distinguishing the mechanism underlying hyponatremia.

According to ECV status, hyponatremia can be classified in [Table 1]:

• - Hypovolemic, with reduced ECV.

• - Euvolemic, with normal ECV.

• - Hypervolemic, with increased ECV.

Hypovolemic hyponatremia is often due to water loss, namely gastrointestinal loss (vomiting, diarrhea), renal losses, bleeding, and cerebral salt wasting, caused by a dysfunction of hypothalamic-renal axis.

Euvolemic hyponatremia, despite being rare, is an important and frequent condition in cancer patients. Several mechanisms induce euvolemic hyponatremia such as adrenal insufficiency, hypothyroidism, and SIAD. SIAD is the principal cause of hyponatremia in oncological and hospitalized patients, occurring in 1%-2% of all subjects and in 30% of cancer patients^[26]. It is characterized by a deregulated AVP activity, which induces a lower free water excretion. The relative free water surplus leads to serum euvolemic hypo-osmolar hyponatremia. It is often due to a paraneoplastic syndrome, related to several kinds of tumors. It is most frequently reported in patients with small-cell lung cancer, but it is also described in patients with non-small-cell lung cancer, head and neck cancer, and, rarely, other malignancies^[26].

SIAD may be caused by^[38]:

• - Inappropriate secretion of antidiuretic hormone (ADH) from cancer cells (paraneoplastic syndrome).

• - Activating mutation of ADH receptor V2.

• - Inappropriate or persistent release of AVP.

Although paraneoplastic syndrome is the most frequent cause of SIAD, it should be considered that many conditions might lead to an inappropriate release of AVP in cancer patients^[39,40]:

• - Concomitant drugs: diuretics, analgesics, chemotherapies, anticancer target agents, antidepressants, antipsychotics, antiepileptics, and antiemetics.

• - Central nervous system disease: expansive lesions such as neoplasms or hematomas, inflammatory diseases (e.g., encephalitis, meningitis, etc.), degenerative diseases (e.g., Guillain-Barré syndrome), and other rare conditions (e.g., hemorrhage, delirium tremens, hypophyseal peduncle section, transphenoidal adenectomy^[41], and hydrocephalus).

• - Pulmonary disorders: infections, respiratory failure, chronic obstructive pulmonary disease, and active pressure ventilation^[1].

• - Others: AIDS, senile atrophy, and idiopathic.

Hypervolemic hyponatremia is characterized by an excess of both total body sodium and water. It occurs in edematous conditions such as cirrhosis, chronic kidney disease, nephrotic syndrome, and congestive heart failure^[42].

According to serum osmolality status, hyponatremia can be divided into^[43,44]:

• - Hypotonic is characterized by reduced serum osmolality, due to an excess of free water compared to the sodium. This condition might be induced by an excessive water intake (e.g., primary polydipsia) or by a compromised renal water excretory capacity (SIAD).

• - Hypertonic is characterized by increased serum osmolality (e.g., in glycemic decompensation).

• - Isotonic is characterized by normal serum osmolality, often secondary to an artificially hyponatremia (pseudohyponatremia) due to elevated serum solutes concentrations (e.g., hyperlipidemia).

Management

A correct and timely diagnosis of hyponatremia is essential to setting up a rapid therapy and improving the prognosis of cancer patients. Diagnosis can occur from clinical suspicion, but it is essential for clinicians monitoring serum/plasma sodium level in all cancer patients, in order to promptly correct this electrolyte disturbance, when present, even in the case of symptoms’ absence. Hyponatremia symptoms are often absent or generic and closely related to hyponatremia grade and onset speed^[1].

Patients with mild and/or chronic hyponatremia are often asymptomatic or present blurred symptoms that can be misunderstood or imputed to other causes (e.g., dizziness, postural instability, and asthenia).

Patients with severe and/or acute hyponatremia can present different symptoms (from gastrointestinal symptoms such as lack of appetite, nausea, and vomiting to neurological disorders such as headache, irritability, attention deficit, confusion, gait disturbances, and muscle cramps), including life-threatening conditions (bulbar paralysis, lethargy, convulsions, encephalic brain herniation, coma, and cardio-respiratory arrest).

Diagnosis of hyponatremia requires routine laboratory tests. For a correct therapeutic approach, it is crucial to identify the underlying causes, thus lab assessment should also include plasma and urine osmolality, ECV status evaluation, and urinary sodium concentration to obtain a correct differential diagnosis [Figure 1].

Figure 1. Hyponatremia management algorithm^[38,44-48]. The correct management of hyponatremia and its treatment require the detection of its cause. Plasmatic osmolarity and ECV evaluation are necessary to recognize the origin of hyponatremia. Symptomatic hyponatremia should be treated with hypertonic saline solution. Tolvaptan should be considered in hyponatremia due to SIAD. ECV: extracellular volume; SIAD: syndrome of inappropriate antidiuresis

In particular, due to different therapeutic options, it is fundamental to exclude SIAD. SIAD diagnosis is diagnosis of exclusion, for which the main criteria are:

• - Presence of hyponatremia (< 135 mEq/L).

• - Normal ECV.

• - Lower serum osmolality (< 275 mOsm/kg).

• - Altered urine osmolality (> 100 mOsm/kg).

• - Elevated urine sodium concentration (> 30 mmol/L).

• - Normal renal function.

• - Normal adrenal and thyroid function.

• - No use of diuretics.

The therapeutic approach depends on etiology, presence of symptoms, and grade of hyponatremia [Figure 1]. Regardless of hyponatremia’s cause, it is important to remember that an effective and prompt correction of serum sodium concentration improves the outcome of cancer patients^[45].

Treatment options include fluid restriction, diuretics, saline solution administration, and vaptans (selective vasopressin receptor antagonists).

Fluid restriction is a difficult therapeutic choice since it is associated with poor compliance because cancer patients often need abundant hydration for oncological therapies. Furthermore, several days are required to correct serum sodium concentrations. In the case of ECV, isotonic saline infusion should be preferred.

In the case of hyponatremia secondary to SIAD, the use of Tolvaptan, a selective V2 receptor antagonist, should be considered^[46]. In fact, has shown an important efficacy to correct and stabilize serum sodium concentration, favoring the beginning and prosecution of anticancer treatments without delay. Furthermore, it seems to reduce the risk of hyponatremia development as chemotherapy adverse event^[47]. Tolvaptan schedule requires starting dose of 15 mg once daily and it should be administrated first in a hospital department to monitor the therapeutic response and any adverse event. It could be increased at 24-h intervals, when serum/plasma sodium levels are not improved, to a maximum of 60 mg once a day^[46].

Other approved therapeutic agents are urea and Demeclocycline. However, due to their toxicity and poor patient compliance, they are no longer employed in clinical practice.

In the case of presence of severe neurological symptoms or life-threatening conditions, serum sodium levels should be corrected rapidly and the appropriate therapy is the administration of 3% hypertonic saline^[48].

It is important to monitor the rate of correction of hyponatremia since an excessive speed of rising sodium levels might cause the development of central pontine myelinolysis, an irreversible condition that leads to death. The correction rate should not exceed 12 mmol/L/24 h. Therefore, it is recommended to monitor plasma sodium levels in the first 24 h at regular intervals of 4-6 h, in order to control the correction speed^[49].

Definition and clinical implication

Hypernatremia is defined as an elevated serum sodium level over 145 mmol/L. It is a frequent electrolyte disturbance occurring in 1%-5% of hospitalized patients. It represents a negative prognostic factor, related to an elevated mortality rate (40%-75%) compared to eunatremic patients^[50].

Causes

In cancer patients, several causes might induce hypernatremia [Table 2]^[51,52]:

• Cancer: anorexia and cancer cachexia, kidney damage, brain metastasis inducing diabetes insipidus, and gastrointestinal disorders due to cancer infiltration (e.g., fistulae and nasogastric drainage due to bowel obstruction) can induce hypernatremia.

• Cancer treatment: adverse events such as vomiting and diarrhea common to most anti-cancer agents (chemotherapy, TKIs, and immunotherapies) associated with reduced thirst stimulation might cause hypernatremia. Elevated serum sodium concentration might be induced also by bowel direct damage due to antiangiogenetic agents or immunotherapy. Furthermore, some chemotherapeutic agents such as ifosfamide might induce an iatrogenic diabetes insipidus.

• Concomitant drugs: osmotic diuretics, corticosteroids, enteral or parenteral nutrition, and hypertonic saline infusion can induce hypernatremia.

• Concomitant diseases: cushing syndrome might induce hypernatremia.

Two different basic mechanisms might be involved in hypernatremia development: water loss (for reduced introduction (euvolemic hypernatremia) or increased elimination (hypovolemic hypernatremia), or, rarely, accumulation of sodium (often on iatrogenic basis, hypervolemic hypernatremia). Understanding these mechanisms is crucial for a correct differential diagnosis among potential causes of hypernatremia.

The most frequent mechanism underlying hypernatremia is total body water loss due to impaired thirst stimulation. It is often associated with altered mental status conditions, such as older age, brain tumors, damage, or surgery, causing a deficit in thirst and osmoregulation^[51]. Water loss can also be due to renal or extra renal disorders^[52].

Renal water loss usually is caused by osmotic diuresis (e.g., hyperglycemia, increased serum urea concentration, or administration of mannitol or hypertonic solutions) and by a treatment with diuretics^[53].

Rarely, renal water loss can be induced by insipidus diabetes, a deficit of the vasopressin-ADH-receptor system, which can have a central or a nephrogenic origin. Central insipidus diabetes is characterized by a reduced secretion of AVP, often related to a central nervous system damage (e.g., pituitary or hypothalamus neoplasms, brain surgery, or irradiation)^[54]. Nephrogenic insipidus diabetes instead depends on renal resistance to the action of AVP. It is a rarely congenic condition, more frequently related to iatrogenic effect of amphotericin B, lithium, ifosfamide, foscarnet, and streptozocin on tubular reabsorption of water^[53]. Extra-renal water loss is often related to gastrointestinal diseases (vomiting, nasogastric drainage, and diarrhea).

Rarely, hypernatremia can be caused by excessive salt intake. This condition is often iatrogenic and induced by parenteral administering of hypertonic solutions or chronic nutrition support with hyperosmolar or high protein feeds^[55].

Management

Hypernatremia causes neurological symptoms, for which severity is correlated with both grade and onset speed. In most cases, patients refer non-specific symptoms such as thirst, anorexia, restlessness, nausea, muscle weakness, and confusion. In the case of rapid onset or severe hypernatremia, patients might present lethargy, hyperreflexia, until convulsions, and coma^[56].

Clinical suspicion of hypernatremia should be confirmed by laboratory exam. The correct diagnosis and the detection of specific causes or predisposing factors are crucial for a correct management [Figure 2].

Figure 2. Algorithm of hypernatremia’s management^[48,51-60]. The treatment of hypernatremia in cancer patients is based on the correction of the cause. For the differential diagnosis, the evaluation of volume and urinary sodium are fundamental. DI: diabetes insipidus; EVC: extracellular volume

For a correct differential diagnosis between hyponatremia caused by excess of sodium intake and hyponatremia caused by loss of free water, the assessment of urine osmolality, urine sodium concentration, and urine volume should be obtained^[57]. Concentrated urine is usually related to insufficient water intake or extra-renal losses.

Conversely, hypernatremia is associated to elevated serum osmolality and low urine osmolality renal damage with deficient capacity of urinary concentration^[56].

Hypernatremia associated to polyuria (e.g., 24 h urine volume exceeding 2.5 L), low urine osmolality, and urinary sodium are criteria for central insipidus diabetes diagnosis^[58].

Once hypernatremia diagnosis is confirmed, the optimal management requires the removal of the cause and the correction of the electrolyte disorder based on the total ECV, restoring intravascular volume and free water.

In collaborating and asymptomatic patients without gastrointestinal dysfunction, oral hydration is effective, and should be preferred. In patients with severe hypernatremia or unable to intake fluid orally (due to vomiting or neurological changes), intravenous hydration should be considered.

The infusion of free water (5% dextrose solution) should be considered in the case of loss of free water alone. Loop diuretics should be considered in the case of pure sodium gain natriuresis.

In patients with acute hypernatremia (within 24 h) or severe symptoms, treatment with isotonic or hypotonic solutions should be started immediately, since it was demonstrated that a prompt correction (up to 8-12 mmol/L per day) improves patients’ prognosis without risk of convulsions or cerebral edema. A correction of 1 mEq/L/h should be considered safe^[59].

In patients with chronic hypernatremia or when time of onset is unknown, the correction should be obtained within 48 h, with a reduction of serum osmolality of no more than 0.5 mOsm/L/h to avoid cerebral edema onset. A reduction of serum sodium concentration of 8-10 mmol/L per day should be considered safe. Monitoring serum sodium levels at regular intervals of 4 h is highly recommended to control the correction speed^[59].

Patients experiencing central insipidus diabetes should receive nasal or oral desmopressin. Nephrogenic insipidus diabetes should be treated with a combination of thiazide diuretics and low sodium-low protein, removing potential precipitation factors^[60].

Definition

Hypocalcemia is defined as a lower serum calcium concentration (total serum calcium of < 2.1 mmol/L or < 8.5 mg/dL or ionized form of < 1.1 mmol/L or > 4.5 mg/dL)^[70].

Causes

Several causes can induce hypocalcemia in cancer patients [Table 3]:

1. Cancer: malnutrition due to anorexia, cancer cachexia or bowel obstruction, malabsorption related to bowel tumor infiltration or previous intestinal surgery, abnormal liver function due to liver metastasis might promote the development of hypoalbuminemia and subsequent hypocalcemia^[70]. Furthermore, malabsorption and malnutrition might frequently cause vitamin D deficiency and then hypocalcemia in cancer patients^[70]. Another condition leading to hypocalcemia is PTH deficiency. It is a common condition of patients undergoing total thyroidectomy with subtotal or total parathyroidectomy for cancer^[71]. Paraneoplastic disorders are also involved in hypocalcemia in cancer syndrome. Such as tumor lysis syndrome or the hungry bone syndrome. The “hungry bone syndrome” is frequent in metastatic parathyroid and prostate cancer and it is characterized by osteoblastic metastases causing an increased deposition of calcium and phosphate in bone and decreased serum calcium and phosphate concentrations^[72].

2. Cancer treatment: hypocalcemia is also reported in cancer patients receiving bisphosphonates or denosumab, an anti-RANKL (receptor activator of nuclear factor kappa B ligand) monoclonal antibody, employed in cancer patients with bone metastasis in order to delay or prevent skeletal-related events. In fact, they promote calcium deposition in the bones, reducing blood calcium concentration^[73]. Therefore, checking calcium serum level before these treatments and implementation of calcium and vitamin D oral intake are recommended^[74]. Furthermore, several drugs, such as chemotherapeutic agents, target therapies, immunotherapies can induce hypocalcemia in cancer patients, through different mechanisms: kidney injuries, iatrogenic magnesium-deficiency, gastrointestinal damage, pancreatitis^[75]. In particular, monoclonal anti EGFR antibodies can cause hypomagnesemia with consequent hypocalcemia^[75].

3. Concomitant drugs: diuretics and parenteral nutrition can induce hypocalcemia^[70].

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

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 shape, or inversion^[77].

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 should be evaluated [Figure 3]^[78].

Figure 3. Algorithm of hypocalcemia management^[48,78-86]. For a correct diagnostic classification of hypocalcemia, it is essential to distinguish between hypoparathyroidism and other causes through the dosage of blood parathyroid hormone. In the case of high parathormone concentrations, dosage of vitamin D is useful to exclude deficiency. PTH: parathyroid hormone

Treatment of hypocalcemia depends on severity, clinical manifestation, and underlying causes. When possible, it is always advisable to correct the cause of hypocalcemia^[78].

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 administered via a central venous catheter to prevent extravasation’s complications^[79]. 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 aforementioned formulation. Moreover, concomitant hypomagnesemia or alkalosis should be corrected^[80].

In the case of hypoparathyroidism, the treatment aims to control symptoms, maintaining adequate serum calcium levels (2.00-2.12 mmol/L), and a calcium-phosphate ratio below 4.4 mmol/L, in order to prevent hypercalciuria and precipitation of calcium salts in soft tissues^[81]. Calcitriol, a vitamin D analog, is usually used with a starting dose of 0.5 mcg/day, which might be increased until adequate serum calcium concentrations are reached. Thiazide diuretics associated with a low phosphate diet could be considered^[82].

It is recommended to monitor weekly serum calcium, phosphorus concentration, and creatinine during initial administration to obtain a correct stabilization of the dose^[83].

In the case of chronic hypocalcemia, oral supplementation of calcium (calcium carbonate or calcium citrate) and vitamin D is recommended. In the case of hypomagnesemia, it should be corrected^[84].

Vitamin D insufficiency requires supplementation with oral or intramuscular ergocalciferol (vitamin D2) or oral cholecalciferol (vitamin D3). When hypocalcemia is secondary to vitamin D malabsorption, it is important to correct the underlying cause (e.g., celiac patients should receive a gluten-free diet)^[85].

Patients receiving bisphosphonates or anti-RANKL should receive oral calcium and vitamin D supplementation to prevent hypocalcemia^[86].

Definition and clinical implication

Hypercalcemia is defined as a higher serum calcium concentration (total serum calcium over than 10.5 mg/dL)^[87]. It is a common electrolyte disorder in patients with advanced malignancies and it correlates with poor prognosis^[88].

Causes

Several causes might contribute to the development of hypercalcemia in cancer patients [Table 4]:

1. Cancer: the main cause of hypercalcemia in cancer patients is hyperparathyroidism. It can be divided into primary and secondary hyperparathyroidism. Primary hyperparathyroidism, the most common cause of hypercalcemia in the general population, is characterized by inappropriate secretion of PTH provoking elevated serum calcium concentrations. Single parathyroid carcinoma is a frequent cause of primary hyperparathyroidism, sometimes inducing a rare but life-threatening condition, hyperparathyroidism-induced hypercalcemic crisis characterized by elevated PTH concentrations (3-10 times higher than normal values) and serum calcium-levels^[89]. Secondary hyperparathyroidism, instead, is characterized by elevated quantities of PTH, secreted by parathyroids. Several causes might contribute to this mechanism^[90], in particular malnutrition and cancer anorexia are the most common cancer related causes. Malignancies are an important cause of hypercalcemia. It was described as occurring in 20%-30% of cancer patients, especially those hospitalized, and it represents one of the most common life-threatening metabolic disorders^[91]. Even though several mechanisms underlay hypercalcemia in cancer patients, it seems to be correlated, especially in some kinds of tumors (head and neck, lung, renal cell, ovarian, thyroid, endometrial, colorectal, breast cancer, hepatocarcinoma, cholangiocarcinoma, thymomas, neuroendocrine tumors, gastrointestinal stromal tumor, and leukemias), with the ectopic production of PTH or parathormone-related peptide (PTHrP). These factors seem responsible for osteoclastic activation, through an increased synthesis of RANKL, provoking bone destruction and calcium release. Furthermore, they determine an increased renal calcium reabsorption, favoring the development of metastatic calcification involving multiple organs, especially lungs, potentially resulting in pulmonary edema^[92]. Moreover, bone metastases, in particular osteolytic ones, are often associated to hypercalcemia due to calcium release from bone. It represents a common cause of hypercalcemia, occurring in approximately 20% of patients with malignancy-related hypercalcemia. Bone metastasis releases several local factors, e.g., transforming growth factor β, RANKL, lymphotoxin, interleukin-1, interleukin-6, hepatocyte growth factor, and macrophage inflammatory protein (MIP-1alfa), that favor the release of PTHrP and bone remodeling resulting in hypercalcemia^[93]. Rarely, hypercalcemia might be due to ectopic activity of 1-alpha-hydroxylase resulting in calcitriol production that promotes increased bone resorption with calcium release and intestinal calcium absorption. This mechanism is described in some kinds of tumors such as lymphomas (lymphoma-associated calcitriol production) and ovarian germ cell tumors^[88]. Finally, immobilization due to bedridden patients, a common condition of advanced cancer, can favor an acceleration of bone resorption resulting in hypercalcemia^[94].

2. Cancer treatment: antineoplastic drugs can indirectly cause hypercalcemia, for example through kidney damage^[88].

3. Concomitant drugs: several drugs might cause hypercalcemia. Thiazide diuretics, vitamin D intoxication, and parenteral nutrition are the most common agents involved in this electrolyte disorder in cancer patients.

4. Concomitant diseases: several pathological conditions might cause hypercalcemia. It may depend on excess of PTH (primary hyperparathyroidism due to parathyroid adenoma, familial hypocalciuric hypercalcemia, isolated familial hyperparathyroidism, or most commonly secondary hyperparathyroidism due to renal failure or drugs such as lithium) or arise due to mechanisms independent of PTH (chronic granulomatous disorders, hyperthyroidism, acromegaly, pheochromocytoma, and adrenal insufficiency)^[88-90].

Management

To improve patients’ outcome, a periodic monitoring of calcium serum levels and prompt correction of potential hypercalcemia should be performed. To define an effective hypercalcemia, it is important to avoid the presence of concomitant factors that can influence the share of bound and free calcium (e.g., hyperglobulinemia might increase total calcium levels without modifying ionized concentrations; acidemia and reducing albumin-calcium affinity might increase the level of the ionized form, without altering total calcium levels)^[87]. Diagnosis is often incidentally during routine laboratory investigations, as most patients with mild hypercalcemia are asymptomatic^[88]. Chronic hypercalcemia, due to hyperparathyroidism, is often asymptomatic; however, in some cases, this long-lasting electrolyte disorder might cause nephrolithiasis. Instead, chronic hyperparathyroidism secondary to renal failure and dialysis might cause bone pain related to bone remodeling process, fibrous degeneration, and formation of cysts and nodules of fibrosis.

Clinical presentation depends on grade and time of onset. Most common symptoms are general malaise, thirst, lethargy, and constipation often associated with abdominal pain. Renal symptoms and signs such as polyuria, polydipsia, nycturia, nephrolithiasis, and rarely renal failure and nephrocalcinosis should be also considered.

Neuromuscular disorders, starting from muscles weakness, emotional instability, and confusion, until development of delirium, psychosis, stupor, and coma, could be observed in acute or severe hypercalcemia (serum calcium levels > 12 mg/dL). Furthermore, hypercalcemia might cause cardiac arrhythmias. The most common electrocardiographic changes are absent or shortened ST segment, shortened QT interval, widened QRS complex, enlarged T wave, and prolonged PR interval. Rarely, it might cause branch block and arrhythmias until to cardiac arrest in the case of serum calcium levels over 15 mg/dL^[88].

Renal function and immunoreactive parathyroid hormone analysis are recommended for a complete diagnostic classification that allows making differential diagnosis and to consider potential serious conditions (cardiac arrhythmias).

Electrocardiography should also be performed in order to avoid presence of cardiac alterations^[95].

Generally, primary hyperparathyroidism is usually characterized by hypercalcemia (with high ionized free serum calcium levels), hypophosphatemia, PTH being inappropriately high (e.g., no hypocalcemia), and excessive bone turnover.

Differential diagnosis between primary and secondary hyperparathyroidism could be difficult in the case of renal failure, although hyperphosphatemia is often linked to secondary hyperparathyroidism and normal or low phosphorus levels are indicative of primary hyperparathyroidism^[96].

Furthermore, in the presence of secondary hyperparathyroidism, radiographic examination should be useful to detect bone cysts presence and bone reabsorption.

When hyperparathyroidism has been excluded, a serum calcium level above 12 mg/dL is suspicious of malignancies, mostly when associated with hypophosphatemia, hypoalbuminemia, and lower or undetectable PTH level. PTHrP is a peptide that shows homology with the N-terminal portion of PTH, mimicking the action. It can be produced from breast, lung, and kidney cancer cells. When possible, the individuation of PTHrP is useful for reach diagnosis of paraneoplastic hypercalcemia^[88].

Treatment depends on clinical manifestation, grade of hypercalcemia, and underlying cause, which should be correct whenever possible [Figure 4]. In the case of mild symptoms, serum calcium levels are below 11.5 mg/dL, which could sufficiently remove the cause of hypercalcemia.

Figure 4. Algorithm of hypercalcemia management^{[48,88,94-104]}. To treat hypercalcemia, a correct diagnostic framework is essential, which is based on the parathyroid dosage to distinguish between hyperparathyroidism and other causes. In the case of low blood PTH concentrations, the dosage of PTHrP is useful to exclude paraneoplastic hypercalcemia and vitamin D intoxication. PTH: parathyroid hormone; PTHrP: parathyroid hormone-related protein; MEN: multiple endocrine neoplasia; FHH: familial hypocalciuric hypercalcaemia; FIHP: familial isolated hyperparathyroidism

In the case of severe hypercalcemia (total serum calcium over 15 mg/dL) or severe symptoms or signs, a treatment aimed to reduce serum calcium levels is recommended, in order to restore adequate intravascular volume and to improve glomerular filtration rate^[96]. Since hypercalcemia induces polyuria, most patients are dehydrated. Therefore, intravenous isotonic saline solution (NaCl 0.9%) should be administered with an infusion rate of 100/120 mL/h, in order to obtain a urine output of 100-150 mL/h and a reduction of serum calcium concentration^[97]. Two to three liters of isotonic saline solution/day with a close monitoring of serum electrolyte levels and urinary volume is recommended^[98]. In patients with edematogenic syndromes (e.g., congestive heart failure) or anuria isotonic solution should be administered with caution in order to avoid fluid overload. However, only 30% of patients reach normocalcemia with fluids alone. Loop diuretics (e.g., furosemide) might be considered mostly in patients with edematogenic syndromes, in whom it is required to improve diuresis. The use of furosemide should be limited in dehydrated patients or in patients presenting other electrolyte abnormalities (magnesium and, potassium)^[99].

In patients with malignant hypercalcemia, salmon calcitonin administration (4-8 IU/kg s.c. or i.m. every 12 h) was demonstrated to control serum calcium levels (estimated a maximal serum calcium drop of 2 mg/dL in 4 h after administration), and it can be used also in patents with renal injuries, in which intravenous saline is not recommended^[100]. Furthermore, calcitonin is more efficacious and quicker than bisphosphonates in normalizing calcemia and it can be used with bisphosphonates or in the case of bisphosphonates’ resistance. However, due to the risk of tachyphylaxis, the duration of treatment with calcitonin should not exceed 48 h^[101].

The addition of corticosteroids (e.g., 20-40 mg of prednisone/day) is useful to control malignant hypercalcemia especially due to hematological tumors, through an increased renal calcium excretion and inhibition of bone reabsorption. However, since fewer than 50% of patients with malignant hypercalcemia respond to glucocorticoids after several days, in clinical practice. an alternative treatment is usually preferred. Corticosteroids are also use for the treatment of vitamin D intoxication, idiopathic hypercalcemia, and sarcoidosis^[102].

Finally, bisphosphonates, such as ibandronate, pamidronate, and mostly zoledronic acid, have been shown to be effective in reducing serum calcium in approximately 12 h^[103].

Recent evidence demonstrates the activity of denosumab in control malignant hypercalcemia, especially in patients with persistent hypercalcemia despite bisphosphonates. Furthermore, it could also be used in patients with reduced renal function^[104].

Definition and clinical implications

Hypokalemia is defined as a low serum potassium concentration (< 3.5 mEq/L). Severe hypokalemia is defined as a potassium level lower than 2.5 mEq/L, representing a potential life-threatening disorder^[118].

Causes

Hypokalemia is a common electrolyte disorder in cancer patients. Several causes might induce hypokalemia in cancer patients^[108]:

• Cancer: several conditions related to cancer might induce a reduced potassium intake (malnutrition, anorexia, and malabsorption due to cancer bowel infiltration or bowel obstruction). Some neuroendocrine tumors might cause hypokalemia through secretive diarrhea, favoring potassium losses. Other tumors induce renal potassium losses through the production of hormones such as adrenocorticotropic hormone (ACTH), cortisol, and mineralocorticoids, or through kidney damage, such as multiple myeloma.

• Cancer treatment: chemotherapeutic agents, target therapies and immunotherapies might cause hypokalemia secondary to diarrhea or vomiting.

• Concomitant drugs: thiazide diuretics, insulin, granulocyte growth factors, beta-2 agonists, and glucocorticoids might cause hypokalemia.

• Concomitant diseases: endocrine dysfunctions causing excess glucocorticoids or mineralocorticoids, toxic epidermal necrolysis, and inflammatory bowel diseases might cause hypokalemia.

Causes of hypokalemia might be resumed substantially in three mechanisms: an inadequate potassium intake, redistribution of potassium among intra- and extracellular compartments, and potassium losses [Table 5].

In cancer patients, inadequate intake is often related to malnutrition and anorexia due to drugs and/or tumor condition.

The passage of potassium into the intracellular compartment might depend on many mechanisms: uptake of potassium by tumor cells, alkalosis, hypothermia, and drugs. For example, granulocyte growth factors, often employed in cancer patients, provoke an acute hematopoietic cell formation, favoring rapid potassium intake by the new cells^[119]. Hypokalemia is similarly induced by rapid cell proliferation in acute leukemia^[120].

Potassium losses can be classified into renal and non-renal losses. The most common extra-renal losses are gastrointestinal losses due to drugs or cancer-induced diarrhea and vomiting, infections, radiation enteritis, and type of tumors (villous adenoma and neuroendocrine neoplasms)^[121]. In particular, neuroendocrine neoplasms, although rare, are represented with the carcinoid syndrome characterized by serotonin and kallikrein hypersecretion inducing flushing, severe secretory diarrhea with cramps and hypokalemia, tachycardia, hypotension until heart failure, and bronchial constriction^[122]. Another rare syndrome due to tumor hypersecretion of vasoactive intestinal polypeptide induces important watery diarrhea with hypokalemia and achlorhydria^[123].

Renal losses have several potential causes. Endocrine disorders should be considered in cancer patients. For example, Cushing syndrome can be due in rare cases to ACTH-producing tumors, especially in patients with small-cell lung cancer, medullary thyroid carcinoma, islet cell adenoma or carcinoma, pheochromocytoma, and ganglioneuroma, inducing an excessive production of cortisol able to blind mineralocorticoid receptors inducing hypokalemia^[124]. Another rare cause is primary aldosteronism, due to the excessive and autonomous secretion of aldosterone by adrenal adenomas or carcinoma. This syndrome is characterized by polydipsia, polyuria, resistant hypertension, and severe hypokalemia^[125].

Furthermore, a common cause of potassium renal losses in cancer patients is drug-related tubular toxicity. Several chemotherapeutic agents, target therapies, and immunotherapeutic drugs [Table 5] might induce renal injury associated to hypokalemia. Renal function should be evaluated before drug administration to avoid further renal damage^[126]. Concomitant therapies such as thiazide diuretics and glucocorticoids can favor potassium renal losses.

Finally, some kinds of tumor induce renal damage. For example, patients with multiple myeloma producing Bence-Jones proteins develop a progressive renal injury leading to hypomagnesemia and hypokalemia. Acute myeloid leukemia, through secretion of lysozyme, induces renal tubular damage^[127].

In hematological patients, especially in those with marked leukocytosis (e.g., in acute myeloid leukemia), hypokalemia can be confused with pseudo-hypokalemia, due to potassium intake in the stored blood sample before the laboratory analysis^[128].

Definition and clinical implications

Hyperkalemia is defined as an increased serum potassium concentration (> 5.5 mEq/L). According to potassium level, three different grades of severity are described: mild hyperkalemia (5.1-6.0 mEq/L), moderate hyperkalemia (6.1-7.0 mEq/L), and severe hyperkalemia (> 7.0 mEq/L), which represents a life-threatening condition^[140].

Causes

Several causes might induce hypokalemia in cancer patients^[108]:

• Cancer: several conditions related to cancer might induce hyperkalemia. Tumors with high proliferative index such as leukemia and small-cell lung carcinomas can result in lysis syndrome after specific anticancer treatment, inducing hyperkalemia.

• Cancer treatment: chemotherapeutic agents, such as platinum derivatives, might cause renal injury, which can lead to hyperkalemia.

• Concomitant drugs: diuretics, potassium-sparing diuretics, angiotensin-converting enzyme, inhibitors, and NSAIDs might induce hypokalemia.

• Concomitant diseases: renal failure, diabetes mellitus, sepsis, and parenteral nutrition might induce hypokalemia.

However, causes of hyperkalemia might be resumed in different mechanisms, such as excessive intake, redistribution into extracellular compartment, or abnormal renal elimination, that might depend on aldosterone deficiency or on renal parenchyma damage [Table 6].

Rarely, hyperkalemia depends only on increased potassium intake, and it is often associated with other risk factors: renal failure, diabetes mellitus, and concomitant medications that inhibit potassium excretion (e.g., potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, and NSAIDs). Furthermore, in cancer patients, parenteral nutrition rich in potassium might induce to life-threatening hyperkalemia^[141].

Tumor lysis syndrome (TLS) represents an important cause of acute hyperkalemia in cancer patients. It is a rare but serious oncological emergency characterized by hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, and azotemia. It usually appears 48-72 h after the commencement of anticancer-therapy (chemotherapy, radiotherapy, and radiofrequency ablation) as a consequence of massive cell necrosis and acute release of intracellular factors into the systemic circulation^[142]. In particular, elevated uric acid and calcium phosphate release tend to precipitate into renal tubules, causing local damage with glomerular filtration rate reduction until acute kidney injury (AKI). AKI worsens metabolic disorders and hyperkalemia, which might induce severe cardiac arrhythmias until death; low serum calcium levels and acidosis may exacerbate this risk^[143]. In high-grade hematologic malignancies and childhood cancers, it might also occur spontaneously^[144].

Several predisposing factors to tumor lysis syndrome were detected, such as elevated tumor burden, rapid-growing neoplasms, high tumor sensibility to anti-cancer treatment, concomitant renal failure, elevated lactate dehydrogenase serum level, hyperuricemia, and hyperazotemia. These factors should be investigated before starting treatment, in order to set up a preventive therapy^[145].

Adrenal insufficiency secondary to metastasis involving both adrenal glands might cause hyperkalemia in cancer patients, especially with advanced lung and breast cancer or lymphomas. However, despite the high frequency of adrenal metastasis (40%-60% of patients), adrenal insufficiency is rarely described, thanks to concomitant administration of corticosteroids^[146]. Finally, in the case of elevated leukocytosis or thrombocytosis, hyperkalemia should be distinguished from pseudo-hyperkalemia, due cellular potassium escape after the blood sample is taken^[147].

Definition and clinical implications

Hypomagnesemia is an electrolyte disorder characterized by reduced magnesium serum level (< 1.5 mEq/L). Serum magnesium concentration lower than 1 mg/dL is defined as severe hypomagnesemia. It occurs frequently (7%-12%) in hospitalized patients, and it is correlated to increased risk of death^[156].

Causes

Hypomagnesemia in cancer patients might result from different causes:

1. Cancer: several conditions related to cancer might induce hypomagnesemia. Anorexia, malnutrition, vomiting, intestinal injury, intestinal drainage/fistulae, diarrhea, and malabsorption syndrome are frequent conditions in cancer patients inducing reduced magnesium intake.

2. Cancer treatment: several drugs commonly used in cancer patients induce kidney damage and secondary hypomagnesemia. Cisplatin might induce hypomagnesemia through distal renal tubular damage, and it persists after treatment discontinuation. Therefore, intravenous supplementation of magnesium is indicated to prevent hypomagnesemia and decrease risk of nephrotoxicity^[157]. Hypomagnesemia was also described in patients receiving EGFR inhibitors with an incidence of 34% in patients treated with monoclonal anti-EGFR antibodies. In fact, EGFR activation is crucial for magnesium renal reabsorption through TRPM-6 channel^[158].

3. Concomitant drugs: diuretics, antibiotics beta-adrenergic agonists, foscarnet, and amphotericin B might induce hypomagnesemia.

4. Concomitant diseases: hyperparathyroidism, hyperthyroidism, diabetes mellitus, dialysis, renal failure, and hereditary disorders (e.g., Bartter’s syndrome and Gitelman’s syndrome) might induce hypomagnesemia.

Three main mechanisms are involved: reduced intake, redistribution into intracellular compartment, and increased renal losses [Table 7].

The most common mechanism inducing hypomagnesemia is renal losses. However, reduced magnesium intake is also frequent in cancer patients, mainly due to altered absorption secondary to diarrhea, malabsorption syndromes, and extensive bowel resection, while rarely due to severe malnutrition.

Management

Treatment of hypomagnesemia depends on clinical manifestation and severity, and it should be focused on hypomagnesemia correction and causes removal.

Patients with hypomagnesemia are usually asymptomatic, until magnesium concentration falls below 1.2 mg/dL, although symptoms usually do not correlate with serum magnesium levels^[159].

The earliest manifestations of magnesium deficiency are usually non-specific neuromuscular and neuropsychiatric alterations such as weakness and muscle cramps. Severe hypomagnesemia might cause cardiac arrhythmia, disorientation, irritability, tremors, tetany, athetosis, jerking, and confusion, as well as eventually hallucinations, depression, and epileptic crisis. Furthermore, hypomagnesemia is often associated with multiple biochemical alterations, such as hypokalemia, hypocalcemia, and metabolic acidosis that might confuse clinical manifestations^[160].

Hypomagnesemia might manifest with electrocardiographic alterations such as prolonged PR and QT intervals, T wave inversion, and ST elevation^[161].

The diagnosis is based on the detection of lower serum magnesium levels. For a correct differential diagnosis, data on potential gastrointestinal or renal losses and concomitant drugs should be collected. To distinguish between renal and extra-renal losses, magnesium fractional excretion, and urinary calcium and creatinine should be assessed [Figure 7]. Urine magnesium concentration > 2 mmol/day is due to renal wasting.

Figure 7. Algorithm of hypomagnesemia management^[48,159-162]. The treatment of hypomagnesemia is based on the correction of the underlying cause and the integration of magnesium, which can be oral or intravenous based on the degree and symptoms reported. The differential diagnosis of hypomagnesemia is based on fractional excretion of magnesium: if it is > 2%, it might indicate renal loss, while, if it is < 2%, hypomagnesemia might depend on gastrointestinal losses or reduced intake . FE Mg: fractional excretion of magnesium; U Ca/Cr: urinary calcium/creatinine ratio

Treatment for hypomagnesemia depends on severity and clinical presentations. Underlying disorders causing hypomagnesemia should be corrected^[162]. Patients with anamnestic risk magnesium deficiency; laboratory tests and clinical symptoms should be monitored and, when indicated, a prophylactic treatment should be considered. For example, in patients receiving cisplatin-based chemotherapy, intravenous supplementation of magnesium on the day of cisplatin administration and 2-3 days after therapy is indicated.

In asymptomatic patients, oral supplementation of magnesium salts should be preferred (40-60 mEq/day); however, diarrhea might represent a dose-limiting adverse event.

In symptomatic patients, infusion of intravenous magnesium sulfate should be preferred. A total of 1-4 g should be administered with low infusion in 12-24 h (1 g/h), until magnesium levels rise to 1.2 mg/dL.

In the case of severe hypomagnesemia, patients should receive a prompt replacement therapy, in order to prevent cardiac arrhythmias and death^[161]. A total dose of 4-6 g of magnesium sulfate is usually required in these cases.

The maximum infusion rate should be 8 mEq/h in asymptomatic patients, since rapid intravenous administration of magnesium sulfate induces elevated serum magnesium levels, which favor magnesium renal excretion. Therefore, a slow infusion is crucial to obtain an adequate correction of hypomagnesemia^[163]. Concomitant electrolyte disorder and vitamin D deficiency should be corrected^[164].