Critical Reviews in Oncology/Hematology 102 (2016) 15–25

Contents lists available at ScienceDirect

Critical Reviews in Oncology/Hematology

journal homepage: www.elsevier.com/locate/critrevonc

Hyponatremia in cancer patients: Time for a new approach

Rossana Berardi a,∗ , Silvia Rinaldi a , Miriam Caramanti a , Christian Grohè b ,
Matteo Santoni a , Francesca Morgese a , Mariangela Torniai a , Agnese Savini a ,
Ilaria Fiordoliva a , Stefano Cascinu a,1
a
Medical Oncology, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti Umberto I, GM Lancisi, G Salesi, Ancona, Italy
b
Dept. of Respiratory Diseases, Ev. Lungenklinik Berlin, Lindenberger Weg 27, 13125 Berlin, Germany, Germany

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
2. Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
3. Importance of hyponatremia in cancer patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
4. Pathophysiology of hyponatremia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
4.1. Hyponatremia according to volume status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
4.1.1. Hyponatremia according to serum osmolality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
5. Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
5.1. Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
6. Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
7. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
7.1. Treatment of symptomatic hyponatremia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
7.2. Treatment of chronic asymptomatic hyponatremia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
7.3. SIADH treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
8. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

a r t i c l e i n f o a b s t r a c t

Article history: Hyponatremia is a common electrolyte disorder in cancer patients. It may be related to cancer, to anti-
Received 29 March 2015 cancer therapy or to other concomitant treatments. In this setting hyponatremia is often caused by
Received in revised form 10 February 2016 the syndrome of inappropriate anti-diuretic hormone secretion, which is due to the ectopic produc-
Accepted 8 March 2016
tion of antidiuretic hormone (vasopressin), to extracellular fluid depletion, to renal toxicity caused by
chemotherapy or to other underlying conditions.
Keywords:
Recent studies suggested that hyponatremia might be considered a negative prognostic factor for
Antidiuretic hormone
cancer patients therefore its early detection, monitoring and management might improve the patient’s
Vasopressin
Cancer
outcome.
Hyponatremia Treatment of hyponatremia depends on patient’s symptoms severity, onset timing and extracellular
SIADH volume status.
Sodium In this review we summarize the main causes of hyponatremia in cancer patients and its management,
including the available treatment options.
© 2016 Elsevier Ireland Ltd. All rights reserved.

∗ Corresponding author at: Medical Oncology Unit, Università Politecnica delle Marche − Azienda Ospedaliero-Universitaria, Ospedali Riuniti Umberto I, GM Lancisi, G
Salesi di Ancona, Via Conca 71, Ancona 60126 Italy.
E-mail address: r.berardi@univpm.it (R. Berardi).
1
Present address: Oncologia Medica, Università degli Studi di Modena e Reggio Emilia.

http://dx.doi.org/10.1016/j.critrevonc.2016.03.010
1040-8428/© 2016 Elsevier Ireland Ltd. All rights reserved.
16 R. Berardi et al. / Critical Reviews in Oncology/Hematology 102 (2016) 15–25
1. Introduction
Hyponatremia is defined as serum sodium lower than
135 mmol/l (Palmer et al., 2003). It can be classified into three lev-
els of severity: mild (130/134 mmol/l), moderate (125/129 mmol/l)
and severe (<125 mmol/l) (Ghali, 2008). According to its develop-
ment, strictly linked to the volume status and serum osmolality
of the patient, it can also be distinguish acute (if serum sodium
decreases within 48 h) and chronic hyponatremia (if sodium deple-
tion develops in more than 48 h) (Sjoblom et al., 1997).
Hyponatremia is reported as the most common electrolyte dis-
order linked to tumor-related conditions; however its incidence in
this setting is unclear because of differences in cancer type, clinical
setting, and serum sodium cut-off points (Sørensen et al., 1995).
Hyponatremia usually accompanies, but can also precede tumor
diagnosis with an incidence ranging between 1% and more than 40%
(Sørensen et al., 1995; Berghmans et al., 2000).
Cancer patients may present several risk factors for hypona-
tremia including chemotherapy itself or its toxicities. Furthermore
fluids, that are frequently administered together with chemother-
apy as well as in the palliative setting, cancer pain and opioids
may increase the risk of hyponatremia or can worsen it. More-
over nausea promotes the release of arginine vasopressin (AVP)
and vomiting also brings to gastrointestinal loss of sodium.
Lung, prostate, pancreatic, liver and renal cancers seem to be
associated to the highest frequency of moderate-severe hypona-
tremia, whilst breast cancer to the lowest (Abu Zeinah et al., 2015).
In particular small cell lung cancer (SCLC) is the most common
cancer type related to this electrolyte disorder which occurs at
diagnosis in approximately 15% of patients in retrospective studies
(Sørensen et al., 1995; Hansen et al., 2010; Gross et al., 1993).
Hyponatremia in cancer patients mainly depends to the inap-
propriate antidiuretic hormone syndrome (SIADH). SIADH may be
due to chemotherapy, especially platinum-based, opioids and non-
steroidal anti-inflammatory drugs, but it can be also related to
lung and central nervous system (CNS) diseases. Finally SIADH
may arise as a paraneoplastic syndrome in different tumor types,
with an ectopic production of antidiuretic hormone. Literature
data suggest that hyponatremia can be considered an unfavourable
prognostic factor in this setting (Berghmans et al., 2000; Abu Zeinah
et al., 2015; Hansen et al., 2010; Gross et al., 1993; Castillo et al.,
2012). Cancer-related hyponatremia has been also hypothesized to
adversely affect the response to anticancer treatment (Schutz et al.,
2014; Jeppesen et al., 2010). Furthermore there is a growing body of
evidences that effective and timely acting on the normalization of
sodium levels could lead to a positive effect on prognosis (Hansen
et al., 2010; Gross et al., 1993; Castillo et al., 2012; Schutz et al.,
2014; Jeppesen et al., 2010; Petereit et al., 2013).
In this review we analyse the role of hyponatremia in cancer
patients focusing on its main causes, its diagnosis and its manage-
ment.
2. Methods
The available scientific literature regarding hyponatremia was
extensively reviewed. We used the MEDLINE and CancerLit
databases searching studies on hyponatremia published between
1982 to February 2015 and the search was restricted to English-
language publications. The search terms included “chemotherapy,
survival, outcome, SIADH, tolvaptan, urea, saline, hypertonic saline,
demeclocycline, lithium” in association with hyponatremia and
cancer. Full articles were obtained, and we checked for additional
appropriate references. Where results were reported or updated in
more than one publication, only the most recent was used.
3. Importance of hyponatremia in cancer patients
Currently there is a growing interest on the prognostic and pre-
dictive role of hyponatremia, since it was found to be associated
with poor survival in different medical conditions as well as in
several solid tumors (Berghmans et al., 2000; Castillo et al., 2012;
Jeppesen et al., 2010).
A large body of literature is available for hyponatremia in
patients with non-cancer conditions, conversely little is known
about hyponatremia in cancer patients.
Several studies evaluated the prognostic role of hyponatremia
in this setting. Most of these studies evaluated the negative impact
of hyponatremia on SCLC patients’ survival. In fact, hyponatremia
along with lactate dehydrogenase (LDH), stage of disease, perfor-
mance status and albumin resulted as negative prognostic factors
in SCLC patients. (Cerny et al., 1987; Souhami et al., 1985).
Recently, in a retrospective study on 453 SCLC patients, Hansen
at al. showed that 44% presented hyponatremia at diagnosis
and significant lower values were observed in extensive disease
compared with limited disease. In particular patients presenting
with liver and pleural metastasis had a higher risk to develop
hyponatremia. This study showed that survival in patients with
hyponatremia was poorer than in patients with normal serum
sodium (7.7 vs. 11.2 months p = 0.0001) (Hansen et al., 2010). Fur-
thermore the authors observed that patients who did not fully
normalize serum sodium within the first two studies, had a worse
prognosis than hyponatremic patients who did.
A more recent study on 564 SCLC patients confirmed the neg-
ative prognostic role of hyponatremia for patients treated with
Topotecan as second-line chemotherapy (p = 0.0024). However a
trend of correlation between hyponatremia and response rate (RR)
and progression free survival (PFS) was observed, although it was
not statistically significant (Tiseo et al., 2014).
Hyponatremia was also confirmed as a negative prognostic fac-
tor in other types of cancer such as non-small cell lung cancer
(NSCLC) (Ray et al., 1998), pleural mesothelioma (Berardi et al.,
2015a), renal cell carcinoma (Jeppesen et al., 2010), gastrointestinal
cancer (Kim et al., 2007) and lymphoma (Dhaliwal et al., 1993).
Petereit and coll., evaluating 2100 patients with lung cancer,
confirmed the negative prognostic role of hyponatremia. In fact the
median overall survival (OS) was lower in hyponatremic compared
with eunatremic patients (10.08 vs. 12.2 months respectively) and
the 2-years OS rate was 24,4% vs. 30,8%, respectively (p = 0.08).
Moreover the authors suggested that an early and effective nor-
malization of this electrolyte disorder might improve patients’
prognosis (Petereit et al., 2011).
Furthermore low serum sodium values have been reported to
negatively correlate with performance status, which is considered
a prognostic factor in several malignancies (Sengupta et al., 2013).
Several studies investigated the prognostic role of hyponatremia
in hospitalized cancer patients. Doshi et al., analysing 3357 hospi-
talized cancer patients, found that those with hyponatremia had a
longer length of hospitalization (10.2 vs. 5.6 days) and a higher risk
of mortality (Doshi et al., 2012). Other authors confirmed these data
and also showed that in patients with moderate-severe hypona-
tremia the risk of death increased 4.28 times compared to those
with normal-mild hyponatremia (Abu Zeinah et al., 2015). In a
recent retrospective study on 295 patients who underwent inpa-
tient cancer rehabilitation Nelson et al. found that hyponatremic
patients had a prolonged rehabilitation length of stay compared to
eunatremic patients (Nelson et al., 2014). We have also recently
shown an increase in length of stay for hospitalized hyponatremic
patients with a significant increase of costs (Berardi et al., 2015b).
According to these data, a timely and effective correction of this
electrolyte disorder is important to improve patient outcomes.
 R. Berardi et al. / Critical Reviews in Oncology/Hematology 102 (2016) 15–25
Hyponatremia has been also reported to be an important predic-
tor of poor response to chemotherapy (Ray et al., 1998). However
only few studies evaluated the predictive role of hyponatremia: in
metastatic renal cell carcinoma (mRRC). Jeppesen et al. observed a
lower objective response rate (ORR) in mRRC patients with hypona-
tremia treated with IL-2 (8% vs. 16% respectively, p = 0.003) and a
lower duration of response (rate of duration of response >3 months
were respectively 17% vs. 53%) (Jeppesen et al., 2010). Schutz et al.
confirmed the association between hyponatremia and a lack of
response in mRRC patients treated with target therapy (Schutz
et al., 2014). Although it is not yet clear whether serum sodium
correction reflects exclusively the activity of anticancer drug or it
has a real role in determining an increase of survival, more and
more data are emerging about the importance of monitoring the
serum sodium levels in cancer patients for a rapid detection and
correction of any abnormalities of this electrolyte.
4. Pathophysiology of hyponatremia
Several conditions may lead to hyponatremia in cancer patients
(Table 1).
It is usually not linked to a loss of sodium, but to a relative excess
of water in relation to sodium amount (Gillum and Linas, 1984).
Therefore it is necessary to assess the extracellular volume status
and the serum osmolality, in order to identify the causes and to
select the appropriate treatment (Stuart et al., 1980).
According to these data, hyponatremia can be considered a
surrogate marker of osmolality. Then hyponatremia is commonly
classified in hypovolemic, euvolemic and hypervolemic and in
hypo-osmolar, iso-osmolar or hyper-osmolar. However the most
clinically relevant type is hypo-osmolar hyponatremia and for this
reason it usually means hypoosmolality when focusing on hypona-
tremia.
Frequently, the true nature of hyponatremia remains uncertain
due to a lot of aetiologies or to the lack of valid laboratory tests. In
these situations, it can be useful to contact experts in electrolyte
disorders (such as nephrologists or endocrinologists), in order to
treat hyponatremia with a multidisciplinary approach.
4.1. Hyponatremia according to volume status
Many conditions, such as renal fluid and solute losses, vomiting,
diarrhoea, bleeding, may contribute to hypovolemic hyponatremia.
An excess of total body water and sodium, which involves an
increased ECF, characterizes hypervolemic hyponatremia. This con-
dition occurs in several oedematous conditions and it can be caused
by cirrhosis, chronic kidney disease and congestive heart failure
(Fried and Palevsky, 1997; Oren, 2005). Euvolemic hyponatremia is
characterized by an excess of total body water content in relation
to the content of sodium.
4.1.1. Hyponatremia according to serum osmolality
Several diseases including different endocrinopathies such as
adrenal insufficiency and hypothyroidism, may cause euvolemic
hypo-osmolar hyponatremia, but the main cause in cancer patients
remains SIADH, affecting 1–2% of the entire cancer population
(Sørensen et al., 1995; Petereit et al., 2011).
SIADH is characterized by an inappropriate or persistent release
of AVP; the increased AVP secretion causes a reduced rate of
free water excretion, which leads to serum hypo-osmolality and
hyponatremia (Schwartz et al., 1957).
This syndrome represents the most common cause of hypona-
tremia in hospitalized patients. It is most common in lung, head and
neck and breast cancer patients, while it is less frequent in other
types of malignancies (Petereit et al., 2011).
17
SIADH is defined as a diagnosis of exclusion (Bartter and e
Schwartz, 1967) (Table 2).
The major criteria are the evidence of hyponatremia associated
with a serum hypo-osmolality (<275 mOsm/kg) and an inappropri-
ately increased urine osmolality (>100 mOsm/kg) in patients with
a normal extracellular volume. It is also crucial to assess urine
sodium concentration, which is usually >30 mmol/l, and plasma
urea and creatinine concentration. Hypothyroidism and adrenal
insufficiency should also be excluded as a differential diagnosis
(Bartter and e Schwartz, 1967; Osterlind et al., 1981).
Several conditions can lead to SIADH, such as CNS disorders,
pulmonary disorders, medications and a variety of other causes
(Verbalis et al., 2013) (Table 3).
SIADH may also results from ectopic production of AVP and ANP
by the tumor tissue. It can be associated with cytotoxic treatments
including vinca alkaloids, cisplatin, cyclophosphamide and mel-
phalan (Sørensen et al., 1995; Berghmans et al., 2000; Abu Zeinah
et al., 2015; Hansen et al., 2010; Gross et al., 1993; Otsuka et al.,
1996). Renal salt wasting has been described with platinum com-
pounds (Otsuka et al., 1996).
Iso-osmolar hyponatremia can occur when there is a reduction
in the serum sodium and storage of isotonic fluid to the ECF or in
case of a marked elevation in serum compounds such as proteins
and lipids that results in a pseudohyponatremia (Goh, 2004).
Hyperosmolar hyponatremia is the result of the accumulation
of osmotically active solutes in the ECF, which causes an osmotic
water efflux from the intracellular space to the extracellular space.
Hyperglycaemic states, the use of mannitol, glycerol, or sorbitol are
the most common condition related with hyperosmolar hypona-
tremia (Palevsky et al., 1993; Hillier et al., 1999).
5. Symptoms
Clinical features of hyponatremia could be heterogeneous
according to severity and time course of its development. In most
cases of mild, moderate and even severe sodium depletion, espe-
cially with chronic evolution, patients can be asymptomatic or
with few symptoms such as unspecific headache, mental impair-
ment, weakness, nausea and vomiting (Schwartz et al., 1962). In
this setting the risk of any symptom increases when hyponatremia
is combined with either hypokalemia, alcoholism, malnutrition, or
advanced liver disease (Verbalis, 2003).
In case of acute severe hyponatremia (<120 mEq/L), neuromus-
cular and neurological symptoms can worsen as hyponatremic
encephalopathy develops. Among the others, the following con-
ditions can appear: muscle cramps and rarely rhabdomyolysis,
headache, lethargy and occasionally auditory and visual halluci-
nations, severe gait disturbances up to mydriasis, seizures and
coma. Cardio-pulmonary involvement with tachypnoea, dyspnoea,
bradycardia and hypertension can also occur. Non-cardiogenic pul-
monary oedema, cardiac and respiratory arrest and death have also
been described (List et al., 1986; Ayus et al., 2000).
These severe symptoms of hyponatraemia are caused by water
entry into brain cells causing brain oedema and increased intracra-
nial pressure that usually occur when hyponatraemia develops
rapidly and the ability of the brain to adapt to its hypotonic envi-
ronment is overcome. Brain adaptation to hyponatremia takes
24–48 h: when hyponatremia develops over several days, brain
cells extrude osmotically active particles in order to avoid water
intoxication.
Hyponatremic encephalopathy, if recognized and treated in
time, is generally reversible, although sometime permanent neu-
rological damage may occur (Sterns et al., 1994). If the timing of
hyponatremia is uncertain it should be considered chronic.
18 R. Berardi et al. / Critical Reviews in Oncology/Hematology 102 (2016) 15–25

Table 1
Causes of hyponatremia.

Type of hyponatremia Causes

Euvolemic SIADH
Polydipsia
Hypothyroidism
Beer abuse

Hypervolemic Edematous syndromes

Cirrhosis
Ascites
Congestive Heart Failure
Nephrotic syndrome
Renal failure

Hypovolemic Depletion of water and salts

Gastrointestinal losses (vomiting)
Diuretics
Mannitol
Adrenal insufficiency
Nephropathy sodium-dispersing
Cerebral salt wasting

Pseudohyponatraemia (hyperosmolar hyponatremia) Hyperglycaemia

Pseudohyponatraemia (laboratory artefact) Hypertriglyceridemia
Multiple Myeloma

Table 2
Diagnostic criteria for the diagnosis of SIADH (Classic Bartter Schwartz Criteria).

Essential diagnostic criteria Additional diagnostic criteria

Reduced plasma osmolality (<275 mOsm/kg) No use of diuretics

Increased urine osmolality (>100 mOsm/kg) Reduced Blood uric acid (<4 mg/dl)
Euvolemic status Reduced BUN1 (<10 mg/dl)
Increased Urinary sodium (>30 mmol/L) Increased Na2 renal excretion fraction (>1%)
Normal kidney, thyroid and adrenal function Increased urea excretion fraction (>55%)

BUN: Blood Urea Nitrogen; Na: sodium.

Table 3
Causes of SIADH in cancer patients.

Cancer • Lung cancer

• Gastro-intestinal carcinoma
• Renal cancer
• Head and neck cancer
• Sarcomas
• Lymphomas

Pulmonary diseases • Infection

• Asthma
• COPD
• Acute respiratory failure
• Positive-pressure ventilation

CNS disorder • Infection

• Bleeding
• Trauma
• Masses as brain tumors or brain metastasis

Drugs Stimulation of vasopressin release:

• Chlorpropamide,
• SSRIs
• carbamazepine,
• anti-psychotic drugs
• opioids
• chemotherapic drugs (vinca alkaloids, platinum derivatives, methotrexate. . .)

Increasing renal sensitivity:

• NAIDs1
• Hypoglycaemic

NAIDs: Non-steroidal anti-inflammatory drugs.

 R. Berardi et al. / Critical Reviews in Oncology/Hematology 102 (2016) 15–25
5.1. Complications
Chronic hyponatremia, even when mild, is often considered as
an asymptomatic condition as it allows the nervous system to
adapt. However, recent studies reported that is associated with
long-term adverse effects such as deficits in gait and attention, falls,
bone losses and fractures [43-44-45].
Renneboog et al. analysed 122 patients with asymp-
tomatic chronic hyponatremia (serum sodium = 126 on
average +/− 5 mmol/L), compared with 244 eunatremic patients.
They found that patients with moderate chronic hyponatremia
fall more frequently than controls. Furthermore a higher rate of
attention impairments and cognitive deficits were observed in the
group of hyponatremic patients. The authors also reported that
patients with mild chronic hyponatremia had marked gait insta-
bility and higher incidence of falls (21.3% vs. 5.3%). The correction
of hyponatremia improved the instability (Renneboog et al., 2006).
The increased risk of falls in hyponatremic patients represents
a risk factor for fractures and this risk can be amplified in this set-
ting because hyponatremia has been reported to be associated with
osteoporosis (Verbalis et al., 2010; Hannon and Verbalis, 2014).
6. Diagnosis
Routine laboratory tests can identify hyponatremia and help
physicians in classifying subtypes of sodium depletion. We sug-
gest testing each patient for electrolyte disorders, especially in case
of cancer patient with neurological or gastrointestinal suggestive
symptoms.
However, in most cases hyponatremia is an incidental finding
within laboratory tests performed before or during chemotherapy
(Adrogué and Madias, 2000).
The differential diagnosis is based on clinical data, on patholog-
ical and pharmacological history and laboratory tests (Fig. 1).
The most important laboratory investigations are plasma and
urine osmolality, extracellular fluid volume status and urine
sodium levels.
These tests should be performed simultaneously after the find-
ing of hyponatremia, before starting any treatment, however to
perform an effective differential diagnosis the results should be
analysed sequentially.
The first test to evaluate is plasma osmolality. Normal or high
values of plasma osmolality are suggestive for a pseudohypona-
tremia or for the presence of osmotically active substances (glucose,
mannitol etc.).
If serum osmolality is lower than normal, it is necessary to con-
sider urine osmolality.
If urine are inappropriately concentrated (>100 mOsm/L) is nec-
essary to assess the volume status.
The extracellular fluid volume status may be indirectly evalu-
ated examining the patient (oedematous states, heart failure. . .).
Further information can be obtained from urea, creatinine and uric
acid; in addition serum albumin and haematocrit could be con-
sidered even if they are rarely useful for diagnosis (Verbalis et al.,
2013, 2010; Otsuka et al., 1996; Goh, 2004; Palevsky et al., 1993;
Hillier et al., 1999; Schwartz et al., 1962; List et al., 1986; Ayus et al.,
2000; Sterns et al., 1994; Renneboog et al., 2006; Gankam et al.,
2008; Barsony et al., 2011; Hannon and Verbalis, 2014; Adrogué
and Madias, 2000; Hyponatremia, 2006).
Hypovolaemic hyponatremia is suggestive of increased loss of
sodium. Urinary sodium concentration with clinical features (use of
drugs such diuretics, vomiting, diarrhoea) can help to understand
whether there are renal or extra-renal losses (Graber and Corish,
1991).
19
In the absence of clinical signs of hypovolemia or hypervolemia
patients may be considered euvolaemic (Oren, 2005).
Hypo-osmolar and euvolemic hyponatremia in cancer patients
are strongly suggestive of SIADH, even if it represents only a
third of euvolemic hyponatremia cases. Furthermore the Bartter-
criteria should be met for the diagnosis of SIADH (Table 2). The
aforementioned biochemical parameters are fundamental for dif-
ferential diagnosis whilst AVP and copeptin assessment is not
useful (Verbalis et al., 2007).
7. Treatment
Hyponatremia management is incompletely understood.
Greenberg et al., conducted a recent registry study on hypona-
tremia, including 3087 hyponatremic patients from 225 sites in
the United States and European Union. The hyponatremia Registry
recorded diagnostic measures, utilization, efficacy, and outcomes
of therapy for eu- or hypervolemic hyponatremia.
Fluid restriction resulted the most frequently used treatment
approach (35%) at first, resulting in a median increase of 2 mEq/L
during the first 24 h. Isotonic saline was administer in 15% of cases
and determined a median 3 mEq/L increase from baseline. Isotonic
or normal saline is commonly used for volume repletion in hypov-
olemic individuals and may not be appropriate for individuals who
are hypervolemic. Hypertonic saline used in 2% of cases determined
a median increase of serum sodium of 5 mEq/l. Tolvaptan was then
administered in a minority of cases (5%) producing more robust
increase in serum sodium (4 mEq/L); 17% received no active agent
and median serum sodium increase was 1 mEq/l during the first
day. Studies to assess short- and long-term benefits of hypona-
tremia correction with effective therapies are needed (Greenberg
et al., 2015).
In 2007 a panel of expert reviewed the current therapies for
hyponatremia in order to evaluate the role of vasopressin receptor
antagonists and they developed hyponatremia treatment guide-
lines (Verbalis et al., 2007). Later, in 2013, the same panel of
experts reported an update of recommended approaches for dif-
ferent aetiologies of hyponatremia based on consensus opinion and
on published data (Verbalis et al., 2013).
Subsequently Clinical Practice Guideline on the diagnostic
approach and treatment of hyponatraemia have been published in
2014 by the European Society of Intensive Care Medicine (ESICM),
the European Society of Endocrinology (ESE) and the European
Renal Association—European Dialysis and Transplant Association
(ERA-EDTA) represented by European Renal Best Practice (ERBP)
(Spasovski et al., 2014).
Recently a multidisciplinary group of Spanish experts published
algorithms addressing the acute correction of hyponatremia as well
as the management of mild and moderate hyponatremia due to
SIADH (Runkle et al., 2014).
Furthermore a position paper by the Italian Association of
Medical Oncology (AIOM) about the clinical recommendations for
diagnosis and management of electrolytes disorder in oncology was
published (Santini et al., 2016).
Within clinical practice, the rate of correction of serum sodium
depends on the aetiology, the time of onset, the severity of clinical
presentation and the extracellular volume status of patients. Acting
effectively and timely on the normalization of sodium levels could
have a positive effect on prognosis of cancer patients [1-7-20].
Treatment options include: fluid restriction, sodium adminis-
tration, or the use of selective vasopressin receptor antagonists
(Fig. 2). Other drugs such as lithium, urea and demeclocycline can
be used for the treatment of euvolemic hyponatremia due to SIADH
(Verbalis et al., 2007; Runkle et al., 2014).
20 R. Berardi et al. / Critical Reviews in Oncology/Hematology 102 (2016) 15–25

Plasma osmolarity

>290 mOsm/l0 275/290 mOsm/l <275 mOsm/l

Hyperproteinemia
Hyperglicemia Multiple Mieloma Urinary osmolality
Mannitol Hyperlipidimia
Positive osmol gap Post-TURP

<100 mOsm/l
>100 mOsm/l

Primary polydipsia
low solute intake
ECF volume
Beer potomania

Hypervolemia Euvolemia Hypovolemia

Urinary Urinary Urinary

NA+ NA+ >20 Urinary NA+ NA+
<10mEq/l mEq/l Urinary >20 mEq/l <10
NA+ mEq/l
>20mEq/l

Renal Diuretic therapy

failure Osmotic diuresis
Hypoaldosteronism
Cerebral salt wasting

Edematous SIADH Gastrointestinal

syndromes Cortisol deficit loses
Heart failure Hypothyroidism Bowel obstruction
Ascites Drugs with ADH Pancreatitis
Cirrhosis increased action Muscle trauma
Nephrotic syndrome Reset osmostat

Fig. 1. Algorithm for the Diagnostic approach to hyponatremia. This possible diagnostic algorithm was created based on the evidences of studies reported in the text. Starting
from plasmatic osmolarity, this algorithm allows to identify the diagnosis of hyponatremia, based on blood and urinary laboratory tests. TURP: transurethral resection of the
prostate; ECF: Extracellular fluid; SIADH: syndrome of inappropriate antidiuretic hormone; ADH: antidiuretic hormone.

However the use of these drugs is limited due to their availability
in different Countries and to their tolerability (Verbalis et al., 2007).
It is also important to prevent and to remove those conditions,
which might cause hyponatremia (Runkle et al., 2014).
In order to effectively manage hyponatremia, the physician has
to consider whether the condition is acute (defined as a duration
of less than 48 h) or chronic, first of all the presence of symptoms
and finally the degree of hyponatremia.
7.1. Treatment of symptomatic hyponatremia
Severely symptomatic hyponatremia might conduct to perma-
nent neurological deficits and death. Literature data suggest that
a rapid increase of serum sodium concentration in the first hour
might reduce the risk of serious brain damages.
When severe neurological symptoms are present, serum sodium
should be corrected more rapidly in order to avoid neurological
complications due to onset of CNS oedema, independently from
hyponatremia duration and degree (Berghmans et al., 2000).
Hypertonic saline is the recommended option in these cases, as
it will produce a rapid improvement in the patient’s serum sodium
level. It can be prepared adding 60 ml of 20% saline solution to
500 ml of isotonic saline (0,9%) (Runkle et al., 2014). Furthermore
it is particularly useful for raising the serum sodium by a small
amount whilst waiting for laboratory results to confirm the diag-
nosis of SIADH.
The joint European Best Practice Guidelines recommend the
use of i.v. infusion of 150 ml hypertonic solution (3%) over 20 min
(Spasovski et al., 2014). The serum sodium concentration should be
checked after 20 min; the infusion of 150 ml hypertonic saline (3%)
 R. Berardi et al. / Critical Reviews in Oncology/Hematology 102 (2016) 15–25 21

HYPONATREMIA

Reduced: Normal : Increased:

Total body water Total body water Total body water
Total body Na+ Total body Na+ Total body Na+

Asymptomatic: Fluid
Asymptomatic: Isotonic
restriction + furosemide
saline solution (0.9% NaCl)
Hyponatremia secondary
to SIADH Symptomatic: Hypertonic
Symptomatic: Hypertonic
solution (3% NaCl) +
solution (3% NaCl)
furosemide

Asymptomatic or mild
Moderate Symptoms Severe symptomps
symptoms

• Fluid restriction
•.Hypertonic solution (3%
• If fluid restriction fails • Hypertonic solution (3%
NaCl)
consider Tolvaptan NaCl)
•Tolvaptan

Fig. 2. Algorithm for treatment of hyponatremia. This possible treatment algorithm was created based on the results of the most important trial and guidelines reported
in the text. Starting from the diagnosis of hyponatremia and the evaluation of circulating volume, this algorithm allows identifying the best therapeutic approach for each
patient, considering mainly type of hyponatremia and symptoms’ presence. SIADH: syndrome of inappropriate antidiuretic hormone.

Pa!ent not candidate for Chemotherapy

Mild Hyponatremia Moderate / Severe Hyponatremia

Na+ = 135-130 mEq/l Na+ < 130 mEq/l

Support No
Symptoma!c Asymptoma!c
Treatment treatment

Na+ < 120 mEq/l Na+ > 120 mEq/l

Consider
Suppor!ve
Treatment
Hypertonic Tolvaptan
saline solu!on
(HSS) 3%

Monitoring
Clinical and
Response No Na+
24h: Na+ > response
120 mEq/l 24h

Assess other
treatment (Tolvaptan
or suppor" reatment)

Fig. 3. Treatment algorithm of hyponatremia in patients not candidate to chemotherapy. This possible treatment algorithm was created based on the results of the most
important trial and guidelines reported in the text. Starting from the diagnosis of hyponatremia, this algorithm allows identifying the best therapeutic approach for patients
not candidates to chemotherapy.
22 R. Berardi et al. / Critical Reviews in Oncology/Hematology 102 (2016) 15–25
every 20 min should be repeated twice or until a target of 5 mmol/l
increase in serum sodium concentration.
If symptoms improve after a 5 mmol/l increase in serum
sodium concentration, the guidelines development group suggests
stopping hypertonic saline infusion and beginning cause-specific
treatment in order to stabilize serum sodium concentration
(Spasovski et al., 2014).
A 4–6 mmol/l increase in serum sodium seems to be sufficient
to improve serious symptoms of hyponatremia: for severely symp-
tomatic patients the treatment goal can be reached in the first six
hours, postponing subsequent efforts to increase serum sodium
level until the next day (Sterns et al., 2009).
Moreover there is no evidence that a greater rate of correction
could improve outcomes in patients with acute or chronic hypona-
tremia (Verbalis et al., 2007).
No other treatments should be given concomitantly with hyper-
tonic saline to raise serum sodium levels.
If symptoms do not improve after a 5 mmol/l increase in serum
sodium concentration during the first hour, Spasovski and col-
leagues suggest investigating the presence of other causes for
clinical signs than hyponatremia. Hypokalaemia, if present, should
be corrected. They also recommend continuing an i.v. infusion of 3%
hypertonic saline or equivalent aiming for an additional 1 mmol/l
per hour increase in serum sodium concentration. The administra-
tion should be stopped when symptoms improve or there is an
increase in a total serum sodium concentration of 10 mmol/l or
when natremia reaches 130 mmol/l (Spasovski et al., 2014). In order
to induce a correction of 1 mmol/l per hour, some authors advised
the administration of many millilitres per hour of 3% hypertonic
solution as Kg of patient weight (for example, for a patient weight-
ing 70 kg, 70 ml/h of hypertonic solution should be administered
for a few hours) (Verbalis et al., 2007; Runkle et al., 2014; Santini
et al., 2016).
Furthermore Androguè—Madias’ formula may be used to correct
serum sodium disorder. However the increase might be underes-
timated (Spasovski et al., 2014; Santini et al., 2016; Adrogue and
Madias, 2000).
The infusion of 3% hypertonic saline requires a careful monitor-
ing of serum sodium level to avoid hyponatremia overcorrection.
The neurologic manifestations associated with a rapid overcor-
rection can constitute the osmotic demyelination syndrome (ODS,
formerly called central pontine myelinolysis).
Some authors suggested repeating serum sodium concentration
2 h after initiating hypertonic saline solution infusion, adapting the
rate of infusion on the basis of serum sodium values and clinical
signs (Runkle et al., 2014).
Also moderately severe hyponatremia is considered a serious
condition: however rapid diagnostic assessments are recom-
mended in this condition in order to detect cause-specific
treatment. A single i.v. infusion of 150 ml 3% hypertonic saline or
equivalent over 20 min may be used to prevent further decrease in
serum sodium concentration.
A similar approach is suggested for acute hyponatremia without
severe or moderately severe symptoms (Spasovski et al., 2014).
7.2. Treatment of chronic asymptomatic hyponatremia
In most cases of chronic asymptomatic hyponatremia, removing
the underlying causes of hyponatremia can be decisive.
Treatment of asymptomatic patient is closely linked to volume
status and underlying cause of hyponatremia.
Correction of hypovolemic hyponatremia is based on the rein-
troduction of fluids and sodium. In asymptomatic or mildly
symptomatic patients, isotonic saline solutions i.v. (0.9%) or a
balanced crystalloid solution at 0,5–1 ml/Kg per hour can be rec-
ommended to correct volume status and it is usually sufficient to
correct the electrolyte disturbance (Verbalis et al., 2007; Spasovski
et al., 2014).
Water restriction is the mainstay of hypervolemic and
euvolemic hyponatremia treatment in asymptomatic patient.
However, it takes several days to correct serum sodium levels and it
is often associated with poor patient compliance; moreover in some
cases it can lead to hypovolemia and worsening of renal function
(Onitilo et al., 2007).
If the patient is asymptomatic or hyponatremia onset
occurs chronically, the correction may take place more slowly
(0.5 mmol/L/h) (Verbalis et al., 2007; Runkle et al., 2014; Santini
et al., 2016).
Spasowsky et al. recommend cause-specific treatment and sug-
gest against treatment in mild hyponatremia; in moderate or severe
hyponatraemia experts advise not to increase serum sodium con-
centration more than 10 mmol/l during the first 24 h and 18 mmol/l
in the first 48 h (Spasovski et al., 2014).
Serum sodium concentration should be checked every 6 h until
achievement of stable values.
In chronic hyponatremia Verbalis et al. suggest a minimum
correction of 4–8 mmol/l/day with a lower goal of therapy of
4–6 mmol/l/day if the ODS risk is high; the recommended limit
should not exceed 8 mmol/l/24 h for patients with high risk of ODS
and 10–12 mmol/l/24 h for those with normal risk of ODS (Verbalis
et al., 2013).
Underlying risk factors and not only the rate of correc-
tion may predispose to ODS: patients with severe hyponatremia
(<105 mmol/L), hypokalemia, malnutrition, alcoholism, and liver
dysfunction are more likely to develop ODS (Verbalis et al., 2013;
Spasovski et al., 2014; Santini et al., 2016).
Corrective measures are recommended if serum sodium val-
ues are overcorrected. They include discontinuation of ongoing
active treatment, oral liquids and i.v. dextrose solution 5%
(4–6 ml/Kg/hour for 2 h with subsequent re-evaluation of serum
sodium concentration). Some authors also suggest the association
of desmopressin (Verbalis et al., 2013; Spasovski et al., 2014; Runkle
et al., 2014).
7.3. SIADH treatment
Treatment options for SIADH include: fluid restriction, increased
intake of osmotic solutes to enhance clearance of water or the use
of selective vasopressin receptor antagonists. In some Countries
also demeclocycline, urea and lithium can be used for treatment
of SIADH. However, due to the unpredictable response and poten-
tial liver and kidney toxicities, their use is limited (Spasovski et al.,
2014).
Some evidences about the benefit from demeclocycline and
lithium are described (Spasovski et al., 2014).
Demeclocycline is a tetracycline derivative inducing nephro-
genic diabetes insipidus in approximately 60% of treated patients.
The effect appears only after few days and it is burdened by high
incidence of liver and kidney toxicity and photosensitivity (Forrest
et al., 1978). Furthermore, it lacks a robust evidence base to support
its use.
In cases of moderately elevated urine osmolality, urea is a
potential treatment option, and is also relatively inexpensive. Urea
induces an osmotic diuresis by promoting the water excretion. Oral
urea might be a practical method to achieve increased solute intake.
Again, urea lacks a solid evidence base to support its use, too,
and it can cause liver toxicity. In addition, because of its bad taste
is poorly tolerated by patients, especially by those presenting nau-
sea (Decaux and Soupart, 2001; Sherlock and Thompson, 2010).
To combine urea with sweet-tasting substances could potentially
solve this inconvenient.
 R. Berardi et al. / Critical Reviews in Oncology/Hematology 102 (2016) 15–25
Symptomatic patients with hyponatremia due to SIADH could
be treated with hypertonic (3%) saline via a continuous infusion or
bolus (Verbalis et al., 2007; Runkle et al., 2014; Santini et al., 2016)
which will improve hyponatremia and related clinical signs even if
only temporarily.
In asymptomatic patients, the first therapeutic approach can
also be fluid restriction with the purpose of achieving a negative
water balance and a gradual increase in serum sodium concen-
tration (Verbalis et al., 2013; Spasovski et al., 2014; Santini et al.,
2016).
It is important to consider all fluids in the restriction; besides
the necessary degree of restriction the urine output plus insensible
fluid loss should be taken into account. Fluids should be 500 ml less
than daily urine output (Verbalis et al., 2013; Spasovski et al., 2014;
Santini et al., 2016).
However, this approach requires a few days before the onset of
the effect and the patient’s compliance is often poor. In addition,
fluid restriction may not be the most suitable approach in cancer
patients, for the necessity to perform infusive therapies (Verbalis,
2006; Gross et al., 1988; Smith et al., 2004).
Some authors suggested the urine/plasma electrolyte ratio
(Na + urine + K + urine/Na + serum) to guide any water restriction.
This formula (the Furst Formula) is also useful in predicting patients
who will respond to fluids restriction (Furst et al., 2000).
If the ratio is less than 0,5, water intake can be limited to 1000 ml,
whereas patients with a result between 0,5 and 1 need to be limited
to 500 ml of liquid a day.
If urinary electrolytes are relatively high and the ratio is found
to be at least 1 or more patients will not respond to fluid restriction.
In moderate or profound hyponatraemia some authors suggest
increasing solute intake with 0.25–0.50 g/kg per day of urea or a
combination of low-dose loop diuretics and oral sodium chloride
as second lines treatment (Spasovski et al., 2014).
AVP-receptor antagonists, that are selective for the V2 receptor
in the renal collecting ducts, represent a new therapeutic option for
hyponatremia due to SIADH.
Tolvaptan is approved in Europe for the treatment of hypona-
tremia secondary to SIADH (Verbalis et al., 2007; Greenberg et al.,
2015; Spasovski et al., 2014; Runkle et al., 2014; Santini et al., 2016;
Flombaum, 2000; Sterns et al., 2009; Adrogue and Madias, 2000;
Onitilo et al., 2007; Verbalis, 2006; Forrest et al., 1978; Decaux and
Soupart, 2001; Sherlock and Thompson, 2010; Gross et al., 1988;
Smith et al., 2004; Furst et al., 2000; SamscaTM , 2009).
In the SALT1 and 2 (Study of Ascending Levels of Tolvaptan
in hyponatremia) randomized, double-blind, placebo-controlled,
multicenter studies 424 patients with euvolemic or hypervolemic
hyponatremia (serum sodium <135 mEq/L) were enrolled and
treated for 30 days with tolvaptan or oral placebo. A follow-up of
7 days after withdrawal was performed. These trials demonstrated
that Tolvaptan significantly increase serum sodium from baseline
to 8 h (tolvaptan, 2.5 mEq/L; placebo, −0.5 mEq/L, P < 0.0001), to
Day 4 (tolvaptan, 4.0 mEq/L; placebo, 0.4 mEq/L, P < 0.0001) and
to Day 30 (tolvaptan, 6.2 mEq/L; placebo, 1.8 mEq/L, P < 0.0001)
(Schrier et al., 2006),
A post-hoc analysis of SALT-1 and SALT-2 trials confirmed the
efficacy of Tolvaptan (Verbalis et al., 2011).
Treatment with tolvaptan should be initiated in hospital, to
allow close monitoring of serum sodium. Too rapid correction of
hyponatremia (e.g., >12 mEq/L/24 h), as aforementioned, can occur
in 10% of patients and can cause osmotic demyelination resulting
in dysarthria, mutism, dysphagia, lethargy, affective changes, spas-
tic quadriparesis, seizures, coma and death. In susceptible patients,
including those with severe malnutrition, alcoholism or advanced
liver disease, slower rates of correction may be advisable. Whether
serum sodium levels rises too quickly, the treatment should be dis-
continued. The initial dose is 15 mg per day and it can be doubled
23
after at least 24 h if necessary, until reaching a maximum of 60 mg
per day (Verbalis et al., 2013).
Patients receiving tolvaptan should discontinue any previous
fluid restriction and drinking should be encouraged.
The most common reported adverse event are thirst, dry mouth
and urinary frequency.
When tolvaptan is used, authors recommend monitoring serum
sodium levels at baseline, 4–6 h after the initial dose, after 24 and
48 h of treatment. (Runkle et al., 2014)
In 2013 Salahudeen published a double-blind randomized
placebo-control clinical trial that showed the efficacy of tolvap-
tan in correcting hyponatremia due to SIADH in cancer patients
(SamscaTM , 2009). The study also confirmed the safety and tolera-
bility of the drug.
A recent small study on ten patients with SCLC and severe SIADH
has shown an efficient correction with tolvaptan of both clinical
symptom and hyponatremia. However Petereit and colleagues sug-
gested that treatment with tolvaptan supported the treatment of
underlying SCLC disease in leading to an improvement in perfor-
mance status (Petereit et al., 2013).
When the hyponatremia is caused by the tumor, antineoplas-
tic treatment can also be an active treatment of SIADH. However,
given the prognostic and predictive role of hyponatremia in cancer
patients, some authors have suggested correcting the electrolyte
disturbance before starting chemotherapy (Hansen et al., 2010;
Gross et al., 1993; Castillo et al., 2012; Schutz et al., 2014; Jeppesen
et al., 2010; Petereit et al., 2013, 2011; Cerny et al., 1987; Souhami
et al., 1985; Tiseo et al., 2014; Ray et al., 1998; Berardi et al.,
2015a, 2015b; Kim et al., 2007; Dhaliwal et al., 1993; Sengupta
et al., 2013; Doshi et al., 2012; Nelson et al., 2014; Knepper, 1997;
Verbalis, 2003; Gillum and Linas, 1984; Stuart et al., 1980; Fried
and Palevsky, 1997; Oren, 2005; Schwartz et al., 1957, 1962; Bartter
and e Schwartz, 1967; Osterlind et al., 1981; Verbalis et al., 2013,
2010, 2007; Otsuka et al., 1996; Goh, 2004; Palevsky et al., 1993;
Hillier et al., 1999; List et al., 1986; Ayus et al., 2000; Sterns et al.,
1994; Renneboog et al., 2006; Gankam et al., 2008; Barsony et al.,
2011; Hannon and Verbalis, 2014; Adrogué and Madias, 2000;
Hyponatremia, 2006; Graber and Corish, 1991).
Furthermore, early palliative care has a significant impact on
prognosis in lung cancer patients and normalizing hyponatremia
can improve symptoms as well as outcome. In this setting tolvaptan
can be used in case of moderate/severe symptomatic hypona-
tremia:
• If Na+ >120 mEq/l: consider to start with Tolvaptan (closely mon-
itoring)
• If Na+ <120 mEq/l: consider to keep Tolvaptan after failure of
hypertonic saline solution (Fig. 3)(De las Pen˜as et al., 2014; Grohé
et al., 2015).
Other factors such as co-medications should be checked as
SIADH causes and considered to optimize the treatment (Hansen
et al., 2010).
8. Conclusions
Hyponatremia has been reported as a negative prognostic
factor in cancer patients. SIADH is the most common cause of
hyponatremia in this setting. An early and prompt management of
hyponatremia could improve cancer patients’ prognosis. In order
to correct hyponatremia, it is important to determine the causes
and the onset time of hyponatremia, as well as the presence of
symptoms and the extracellular volume status of patients.
Treatment options include fluid restriction, saline solutions and
hypertonic saline solutions, or the use of selective vasopressin
24 R. Berardi et al. / Critical Reviews in Oncology/Hematology 102 (2016) 15–25
receptor antagonists. Tolvaptan, a selective V2 antagonist that acts
by blocking the action of AVP, is approved in Europe for the treat-
ment of hyponatremia secondary to SIADH.
Several studies have demonstrated the efficacy and good toler-
ability of this drug for treatment of hyponatremia SIADH-related,
even in cancer patients.
Further studies are needed to identify the effect of normalizing
hyponatremia on cancer patients’ prognosis and to improve the
management of this electrolyte disorder in this setting.
Conflict of interest
Berardi Rossana and Christian Grohè received consulting fees
from Otsuka. The other authors declare that they have no com-
peting interests. All authors contributed to the study, read and
approved the final manuscript.
Acknowledgements
This research did not receive any specific grant from any fund-
ing agency in the public, commercial or not-for-profit sector. The
study was realized with Authors’ University Funding (Università
Politecnica Marche, Ancona, Italy).
References
Abu Zeinah, G.F., Al-Kindi, S.G., Hassan, A.A., Allam, A., 2015. Hyponatraemia in
cancer: association with type of cancer and mortality. Eur. J. Cancer Care (Engl)
24 (2), 224–231.
Adrogué, H.J., Madias, N.E., 2000. Hyponatremia. N. Engl. J. Med. 342, 1581–1589.
Adrogue, H.J., Madias, N.E., 2000. Hyponatremia N. Engl. J. Med. 342, 1581–1589.
Ayus, J.C., Varon, J., Arieff, A.I., 2000. Hyponatremia, cerebral edema, and
noncardiogenic pulmonary edema in marathon runners. Ann. Intern. Med. 132,
711–714.
Barsony, J., Sugimura, Y., Verbalis, J.G., 2011. Osteoclast response to low
extracellular sodium and the mechanism of hyponatremia-induced bone loss.
J. Biol. Chem. 286, 10864–10875.
Bartter, F.C., e Schwartz, W.B., 1967. The syndrome of inappropriate secretion of
antidiuretic hormone. Am. J. Med. 42, 790–806.
Berardi, R., Caramanti, M., Fiordoliva, I., Morgese, F., Savini, A., Rinaldi, S., et al.,
2015a. Hyponatraemia is a predictor of clinical outcome for malignant pleural
mesothelioma. Support. Care Cancer 23, 621–626.
Berardi, R., Caramanti, M., Castagnani, M., Guglielmi, S., Marcucci, F., Savini, A.,
et al., 2015b. Hyponatremia is a predictor of hospital length and cost of stay
and outcome in cancer patients. Support. Care Cancer (Epub ahead of print.).
Berghmans, T., Paesmans, M., Body, J.J., 2000. A prospective study on
hyponatraemia in medical cancer patients: epidemiology, aetiology and
differential diagnosis. Support. Care Cancer 8, 192–197.
Castillo, J.J., Vincent, M., Justice, E., 2012. Diagnosis and management of
hyponatremia in cancer patients. Oncologist 17, 756–765.
Cerny, T., Blair, V., Anderson, H., Bramwell, V., Thatcher, N., 1987. Pretreatment
prognostic factors and scoring system in 407 small-cell lung cancer patients.
Int. J. Cancer 39, 146–149.
De las Pen˜as, R., Escobar, Y., Henao, F., Blasco, A., Rodrıı́guez, C.A., 2014. SEOM
guidelines on hydroelectrolytic disorders. Clin. Transl. Oncol. 16, 1051–1059.
Decaux, G., Soupart, A., 2001. Rehyponatremia. Clin. Endocrinol. (Oxf) 54, 843.
Dhaliwal, H.S., Rohatiner, A.Z., Gregory, W., et al., 1993. Combination
chemotherapy for intermediate and high grade non-Hodgkin’s lymphoma. Br.
J. Cancer 68, 767–774.
Doshi, S.M., Shah, P., Lei, X., Lahoti, A., Salahudeen, A.K., 2012. Hyponatremia in
hospitalized cancer patients and its impact on clinical outcomes. Am. J. Kidney
Dis. 59, 222–228.
Flombaum, C.D., 2000. Metabolic emergencies in the cancer patient. Semin. Oncol.
27, 322–334.
Forrest Jr., J.N., Cox, M., Hong, C., Morrison, G., Bia, M., Singer, I., 1978. Superiority
of demeclocycline over lithium in the treatment of chronic syndrome of
inappropriate secretion of antidiuretic hormone. N. Engl. J. Med. 298, 173–177.
Fried, L.F., Palevsky, P.M., 1997. Hyponatremia and hypernatremia. Med. Clin.
North Am. 81, 585–609.
Furst, H., Hallows, K.R., Post, J., Chen, S., Kotzer, W., Goldfarb, S., et al., 2000. the
urine/plasma electrolyte ratio: a predictive guide to water restriction. Am. J.
Med. Sci. 319, 240–244.
Gankam, K.F., Andres, C., Sattar, L., Melot, C., Decaux, G., 2008. Mild hyponatremia
and risk of fracture in the ambulatory elderly. Q. J. Med. 101, 583–588.
Ghali, J.K., 2008. Mechanisms, risks, and new treatment options for hyponatremia.
Cardiology 111, 147–157.
Gillum, D.M., Linas, S.L., 1984. Water intoxication in a psychotic patient with
normal renal water excretion. Am. J. Med. 77, 773–774.
Goh, K.P., 2004. Management of hyponatremia. Am. Fam. Phys. 69, 2387–2394.
Graber, M., Corish, D., 1991. The electrolytes in hyponatremia. Am. J. Kidney Dis.
18, 527–545.
Greenberg, A., Verbalis, J.G., Amin, A.N., et al., 2015. Current treatment practice and
outcomes: report of the hyponatremia registry. Kidney Int. 88 (1), 167–177.
Grohé, C., Berardi, R., Burst, V., 2015. Hyponatraemia—SIADH in lung cancer
diagnostic and treatmentalgorithms. Crit. Rev. Oncol. Hematol. 96, 1–8.
Gross, P., Ketteler, M., Hausmann, C., Reinhard, C., Schömig, A., Hackenthal, E., et al.,
1988. Role of diuretics, hormonal derangements, and clinical setting of
hyponatremia in medical patients. Klin. Wochenschr. 66, 662–669.
Gross, A.J., Steinberg, S.M., Reilly, J.G., et al., 1993. Atrial natriuretic factor and
arginine vasopressin production in tumor cell lines from patients with lung
cancer and their relationship to serum sodium. Cancer Res. 53, 67–74.
Hannon, M.J., Verbalis, J.G., 2014. Sodium homeostasis and bone. Curr. Opin.
Nephrol. Hypertens. 23, 370–376.
Hansen, O., Sørensen, P., Hansen, K.H., 2010. The occurrence of hyponatremia in
SCLC and the influence on prognosis: a retrospective study of 453 patients
treated in a single institution in a 10-year period. Lung Cancer 68, 111–114.
Hillier, T.A., Abbott, R.D., Hyponatremia, Berrett E.J., 1999. evaluating the
correction factor for hyperglycemia. Am. J. Med. 106, 399–403.
Hyponatremia, Douglas I., 2006. why it matters, how it presents, how we can
manage it. Clevel. Clin. J. Med. 73, S4–12.
Jeppesen, A.N., Jensen, H.K., Donskov, F., Marcussen, N., von der Maase, H., 2010.
Hyponatremia as a prognostic and predictive factor in metastatic renal cell
carcinoma. Br. J. Cancer 102, 867–872.
Kim, H.S., Yi, S.Y., Jun, H.J., et al., 2007. Clinical outcome of gastric cancer patients
with bone marrow metastases. Oncology 73, 192–197.
Knepper, M.A., 1997. Molecular physiology of urinary concentrating mechanism:
regulation of aquaporin water channels by vasopressin. Am. J. Physiol. 272,
F3–F12.
List, A.F., Hainsworth, J.D., Davis, B.W., Hande, K.R., Greco, F.A., Johnson, D.H., 1986.
The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in
small-cell lung cancer. J. Clin. Oncol. 4, 1191–1198.
Nelson, M., Palmer, J.L., Fu, J., Williams, J.L., Williams, J.L., Yadav, R., Guo, Y., 2014.
Hyponatraemia in cancer patients on an inpatient rehabilitation unit. Eur. J.
Cancer Care 23, 363–369.
Onitilo, A.A., Kio, E., Doi, S.A., 2007. Tumor-related hyponatremia. Clin. Med. Res. 5,
228–237.
Oren, R.M., 2005. Hyponatremia in congestive heart failure. Am. J. Cardiol. 95,
2B–7B.
Osterlind, K., Hansen, M., Dombernowsky, P., 1981. Hypouricaemia and
inappropriate secretion of antidiuretic hormone in small-cell bronchogenic
carcinoma. Acta Med. Scand. 209, 289–291.
Otsuka, F., Hayashi, Y., Ogura, T., Hayakawa, N., Ikeda, S., Makino, H., et al., 1996.
Syndrome of inappropriate secretion of antidiuretic hormone following
intrathoracic cisplatin. Intern. Med. 35, 290–294.
Palevsky, P.M., Rendulic, D., Diven, W.F., 1993. Maltose-induced hyponatremia.
Ann. Intern. Med. 118, 526–528.
Palmer, B.F., Gates, J.R., Lader, M., 2003. Causes and management of hyponatremia.
Ann. Pharmacother. 37, 1694–1702.
Petereit, C., Zaba, O., Teber, I., Grohé, C., 2011. Is hyponatremia a prognostic marker
of survival for lung cancer. Pneumologie 65, 565–571.
Petereit, C., Zaba, O., Teber, I., Lüders, H., Grohé, C., 2013. A rapid and efficient way
to manage hyponatremia in patients with SIADH and small cell lung cancer:
treatment with tolvaptan. BMC Pulm. Med. 13, 55.
Ray, P., Quantin, X., Grenìer, J., Pujol, J.L., 1998. Predictive factors of tumor response
and prognostic factors of survival during lung cancer chemotherapy. Cancer
Detect. Prev. 22, 293–304.
Renneboog, B., Musch, W., Vandemergel, X., Manto, M.U., Decaux, G., 2006. Mild
chronic hyponatremia is associated with falls, unsteadiness, and attention
deficits. Am. J. Med. 119, 71–78.
Runkle, I., Villabona, C., Navarro, A., Pose, A., Formiga, F., Tejedor, A., Poch, E., 2014.
Treatment of hyponatremia induced by the syndrome of Inappropriate
antidiuretic hormone secretion: a multidisciplinary Spanish algorithm.
Nefrologia 34 (4), 439–450, http://dx.doi.org/10.3265/Nefrologia.pre2014.Apr.
12220 (English,Spanish).
Sørensen, J.B., Andersen, M.K., Hansen, H.H., 1995. Syndrome of inappropriate
secretion of antidiuretic hormone (SIADH) in malignant disease. J. Intern. Med.
238, 97–110.
SamscaTM , 2009. (Tolvaptan) Tablets for Oral Use [Prescribing Information]. Otsuka
America Pharmaceutical, Inc., Rockville, MD.
Santini, D., Berardi, R., Caramanti, M., Peri, A., Armento, G., Barni, S., On behalf of
the Italian Association of Medical Oncology (AIOM), Electrolytes disorder:
recommendations for diagnosis and treatment in cancer patients, Position
paper. www.aiom.it.
Schrier, R.W., Gross, P., Gheorghiade, M., Berl, T., Verbalis, G., Czerwiec, F.S.,
Orlandi, C., 2006. SALT Investigators. Tolvaptan, a selective oral vasopressin
V2-receptor antagonist, for hyponatremia. N. Engl. J. Med. 355 (20),
2099–2112.
Schutz, F.A., Xie, W., Donskov, F., et al., 2014. The impact of low serum sodium on
treatment outcome of targeted therapy in metastatic renal cell carcinoma:
results from the international metastatic renal cell cancer database
consortium. Eur. Urol. 65, 723–730.
Schwartz, W.B., Bennet, W., Curelop, S., Bartter, F.C., 1957. A syndrome of renal
sodium loss and hyponatremia probably resulting from inappropriate
secretion of antidiuretic hormone. Am. J. Med. 23, 529–542.
 R. Berardi et al. / Critical Reviews in Oncology/Hematology 102 (2016) 15–25
Schwartz, E., Fogel, R.L., Chokas, W.V., Panariello, V.A., 1962. Unstable osmolar
homeostasis with and without renal sodium wastage. Am. J. Med. 33, 39–53.
Sengupta, A., Banerjee, S.N., Biswas, N.M., Jash, D., Saha, K., Maji, A.,
Bandyopadhyaya, A., et al., 2013. The incidence of hyponatraemia and its effect
on the ECOG performance status among lung cancer patients. J. Clin. Diagn.
Res. 7, 1678–1682.
Sherlock, M., Thompson, C.J., 2010. The syndrome of inappropriate antidiuretic
hormone: current and future management options. Eur. J. Endocrinol. 162
(Suppl. 1), S13–8.
Sjoblom, E., Hojer, J., Ludwigs, U., Pirskanen, R., 1997. Fatal hyponatraemic brain
oedema due to common gastroenteritis with accidental water intoxication.
Intensive Care Med. 23, 348–350.
Smith, D., Moore, K., Tormey, W., Baylis, P.H., Thompson, C.J., 2004. Downward
resetting of the osmotic threshold for thirst in patients with SIADH. Am. J.
Physiol. Endocrinol. Metab. 287, E1019–E1023.
Souhami, R.L., Bradbury, I., Geddes, D.M., Spiro, S.G., Harper, P.G., Tobias, J.S., 1985.
Prognostic significance of laboratory parameters measured at diagnosis in
small cell carcinoma of the lung. Cancer Res. 45, 2878–2878.
Spasovski, G., Vanholder, R., Allolio, B., Annane, D., Ball, S., Bichet, D., et al., 2014.
Clinical practice guideline on diagnosis and treatment of hyponatraemia. Eur. J.
Endocrinol. 170, G1–G47.
Sterns, R.H., Cappuccio, J.D., Silver, S.M., Cohen, E.P., 1994. Neurologic sequelae
after treatment of severe hyponatremia: a multicenter perspective. J. Am. Soc.
Nephrol. 4, 1522–1530.
Sterns, R.H., Nigwekar, S.U., Hix, J.K., 2009. The treatment of hyponatremia. Semin.
Nephrol. 29, 282–299.
Stuart, C.A., Neelon, F.A., Lebovitz, H.E., 1980. Disordered control of thirst in
hypothalamic-pituitary sarcoidosis. N. Engl. J. Med. 303, 1078–1082.
Tiseo, M., Buti, S., Boni Mattioni, R., Ardizzoni, A., 2014. Prognostic role of
hyponatremia in 564 small cell lung cancer patients treated with topotecan.
Lung Cancer 86, 91–95.
Verbalis, J.G., Goldsmith, S.R., Greenberg, A., Schrier, R.W., Sterns, R.H., 2007.
Hyponatremia treatment guidelines 2007: expert panel recommendations.
Am. J. Med. 120, S1–21.
Verbalis, J.G., Barsony, J., Sugimura, Y., Tian, Y., Adams, D.J., Carter, E.A., et al., 2010.
Hyponatremia-induced osteoporosis. J. Bone Miner. Res. 25, 554–563.
25
Verbalis, J.G., Adler, S., Schrier, R.W., Berl, T., Zhao, Q., Czerwiec, F.S., 2011. SALT
Investigators. Efficacy and safety of oral tolvaptan therapy in patients with the
syndrome of inappropriate antidiuretic hormone secretion. Eur. J. Endocrinol.
164 (5), 725–732.
Verbalis, J.G., Goldsmith, S.R., Greenberg, A., et al., 2013. Diagnosis, evaluation, and
treatment of hyponatremia: expert panel recommendations. Am. J. Med. 126,
S1–4.
Verbalis, J.G., 2003. Disorders of body water homeostasis. Best Pract. Res. Clin.
Endocrinol. Metab. 17, 471–503.
Verbalis, J.G., 2006. AVP receptor antagonists as aquaretics: review and assessment
of clinical data. Cleve. Clin. J. Med. 73, S24–S33.
Biography
Rossana Berardi, is Professor in Medical Oncology at Università Politecnica
Marche, Ancona, Italy. She is Head of Department of Medical Oncology, Directorof
the Postgraduate School of Oncology, Director of the “Genetic Cancer” Labora-
tory,Deputy Director of Department of Clinical and Molecular Science, at Università
PolitecnicaMarche, Ancona, Italy.She is Member of the Academic Medical Oncology
Committee, Member of the “Educationand Training” Working Group of the Italian
Association of Medical Oncology and memberof the “Core Curriculum” Task Force of
the European Society for Medical Oncology(ESMO). She is also member of the Euro-
pean Hyponatremia network.Dr. Berardi has been awarded many grants and prizes
(among the others, several ASCOand ESMO travel grants and merit awards and, more
recently, an Italian Oscar Prize forbest researcher in oncology). She has authored
more than 170 manuscripts in peerreviewedjournals, she has been a speaker at
national and international meetings and shehas been involved in advisory boards
on GI, lung cancer, SIADH and on clinical andtranslational research. Dr. Berardi was
a Research Fellow in the Department of Oncologyat Middlesex Hospital, University
College London Hospitals.Dr Berardi has been selected as an expert evaluator in
several boards of examiners (i.e.European Community, Italian University Ministry).