Role of tolvaptan in the management of hyponatremia in patients with lung and other cancers: current data and future perspectives

Abstract

Hyponatremia is the most frequently observed electrolyte abnormality in clinical practice, and its frequency is almost double in hospitalized cancer patients. As a subset of cancer, hyponatremia is quite common in lung cancer patients, and it is often coupled with the diagnosis of syndrome of inappropriate antidiuretic hormone secretion. The presence of hyponatremia is consequential in that its presence adversely affects cancer patients’ prognosis and outcomes. Limited data suggest that correcting hyponatremia in lung cancer patients can increase response to anticancer treatment, may help reduce length of hospital stay and cost, and reduce morbidity and mortality. The type of treatment for hyponatremia depends on several factors; the key factors are the duration and severity of neurological symptoms of hyponatremia and the status of extracellular volume. When hyponatremia is caused by syndrome of inappropriate antidiuretic hormone, hypertonic saline is indicated for acute symptomatic cases, whereas fluid restriction is recommended in chronic asymptomatic hyponatremia. The latter allows a slower rate of correction, thus avoiding the dreaded complication of osmotic demyelination syndrome. Fluid restriction is, however, insufficient or impractical, and often the use of pharmacological therapy such as antidiuretic hormone receptor antagonists becomes necessary. Availability of these antagonists as an effective treatment in the management of hyponatremia has been a major breakthrough, and furthermore, its clinical or investigational use in cancer-related hyponatremia may offer a potential opportunity to gain further insights into the prognostic impact of hyponatremia correction on cancer patients’ outcomes. Tolvaptan is a prototype of ADH receptor antagonists that acts at renal tubular levels to increase free water excretion without inducing major systemic electrolyte abnormalities such as hypokalemia or alkalosis. The aim of this paper is to provide a brief review while focusing on cancer hyponatremia; (1) of the epidemiology of hyponatremia and its pathophysiology and diagnostic approaches and (2) of the pharmacokinetics of tolvaptan and its clinical efficacy, safety, and compliance.

Paraneoplastic endocrine syndromes

“…The relation between SIADH and ectopic ADH production by tumour cells has also been demonstrated in in vitro studies as high concentration of immune-reactive ADH has been found in tumour extracts of patients with SIADH (Thajudeen et al 2016). Northern blot and S 1 -nuclease analysis demonstrated the production of ADH mRNA in tumours and tumour cell lines from patients with SCLC and hyponatraemia.…”

“…In contrast, the great majority of endocrine PNS produced from non-endocrine neoplasms are found in highly malignant tumours mainly involving the lungs, breasts, prostate, ovaries, skin, colon and certain forms of haematological malignancies; however, tumours arising from virtually any tissue have been implicated, albeit rarely (Lorch et al 2007, Nimalasena et al 2008, Gilmore et al 2009, Nella et al 2014, Dimitriadis et al 2015, Thajudeen et al 2016.…”

“…The syndrome of inappropriate anti-diuretic hormone secretion (SIADH) is characterised by hypo-osmotic, euvolemic hyponatraemia in the absence of plasma hypotonicity, and it occurs in 1-2% of all patients with malignant tumours (Castillo et al 2012, Thajudeen et al 2016. SIADH is most commonly found in SCLC 24:6 although it can also result from LCLC (Raftopoulos 2007, Castillo et al 2012, Thajudeen et al 2016.…”

“…SIADH is most commonly found in SCLC 24:6 although it can also result from LCLC (Raftopoulos 2007, Castillo et al 2012, Thajudeen et al 2016. SIADH is also seen in 2-4% of non-SCLC patients, including those suffering from prostate, breast, adrenal cancer and lung carcinoids (Raftopoulos 2007, Castillo et al 2012, Thajudeen et al 2016. In SCLC, SIADH has been associated with a higher propensity for central nervous system metastases, poor response to chemotherapy and advanced stage of cancer (Thajudeen et al 2016).…”

“…SIADH is also seen in 2-4% of non-SCLC patients, including those suffering from prostate, breast, adrenal cancer and lung carcinoids (Raftopoulos 2007, Castillo et al 2012, Thajudeen et al 2016. In SCLC, SIADH has been associated with a higher propensity for central nervous system metastases, poor response to chemotherapy and advanced stage of cancer (Thajudeen et al 2016). There appears to be no clinical and/or biochemical features distinguishing the origin of the tumour although most severe symptoms are encountered in patients with highly aggressive tumours (Selmer et al 2016); hyponatraemia grade at short-term follow-up was also predictive for long-term survival (Shepshelovich et al 2015).…”