Tolvaptan as an alternative for treating hyponatremia secondary to cancer-related SIADH
Hyponatremia, defined as serum sodium below 135mEq/L, is the most prevalent electrolyte disorder observed in the oncology setting.1,2 It is associated with many different cancer types, from head and neck cancer to breast cancer.2 Hyponatremia is particularly prevalent in small cell lung cancer (SCLC), affecting 25% to 44% of SCLC patients.2 Hyponatremia in cancer patients is often caused by the syndrome of inappropriate antidiuretic hormone secretion (SIADH), a manifestation of paraneoplastic syndromes (PNS) which are commonly related with small cell carcinomas.3,4 In an interview with Omnihealth Practice, Dr. Angus Leung shared his view on how to optimize the treatment of hyponatremia caused by cancer-induced SIADH with the aim of achieving a better clinical outcome for cancer patients.
Cancer-induced SIADH’s prevalence and its clinical implication
Cancer-induced SIADH accounts for 67% of all SIADH cases. Among all cancer types, SCLC accounts for 70% of all cancer-induced SIADH cases, while head and neck cancers are responsible for 1.5% only.3 Cancer-related SIADH involves ectopic secretion of arginine vasopressin (AVP), also known as antidiuretic hormone (ADH), by tumor cells.2,4,5 During high osmolality, plasma AVP binding to receptors on the renal cells promotes excessive water reabsorption (that is, impaired water excretion) and reduces sodium reabsorption in renal tubules, thus subsequently reducing plasma osmolality and leading to hyponatremia.4 In one study, the presence of hyponatremia in SCLC patients was found to be correlated with poorer clinical outcomes, notably shorter survival when compared with other SCLC patients having their serum sodium level in control.2
Differential diagnosis of SIADH
Differential diagnosis is essential for selecting the appropriate treatment to resolve hyponatremia caused by tumor-related SIADH, and the SIADH diagnosis is always by exclusion. The absence of other potential causes of hypoosmolality must also be examined.1 Then next step is to determine the plasma osmolality.4 A plasma osmolality of less than 280mOsm/kg is considered as hypotonic hyponatremia.4 If hypotonic hyponatremia is confirmed, the urine osmolality and urine sodium concentration should then be assessed. Inappropriate renal dilution, i.e., an impaired water excretion, is indicated by urine osmolality of greater than 100mOsm/kg.4 Another step is to determine the extracellular fluid volume status, which can be assessed by various laboratory parameters, including urine sodium concentration.4 Patients without clinical evidence of hypovolemia or hypervolemia are considered euvolemic.4 Since euvolemic hyponatremia can be caused by SIADH or adrenocorticotropic hormone (ACTH) deficit, plasma cortisol level in patients who are not receiving pharmacological steroids should be determined.1
The European Society of Endocrinology (ESE) recommended against the measurement of vasopressin in SIADH diagnosis mainly due to the technical difficulties and its variable interpretation of results.6 Instead, the plasma osmolality, urine osmolality, and extracellular fluid volume status are recommended for more accurate diagnosis.6
Hyponatremia management and concerns
Formalized guidelines specifically for hyponatremia management in cancer patients are still unavailable.4 Yet, in general terms, hyponatremia can be managed following the Clinical Practice Guideline on Diagnosis and Treatment of Hyponatremia6. Hyponatremia treatment is determined by the presence of neurological symptoms, their severity, time of onset, and extracellular volume status of the patient (Figure 1).4,7
For patients with severely symptomatic euvolemic and hypervolemic hyponatremia, the correction is achieved by the administration of hypertonic (3%) saline through a bolus or continuous infusion tube in hospitals with close serum sodium monitoring.4,6
Euvolemic or hypervolemic hyponatremia in asymptomatic patients or patients with mild neurological symptoms is often corrected by fluid restriction with the aim of achieving a negative water balance.4,6 Oral sodium replacement with low-dose loop diuretics as the second-line treatment can also be considered.6,7 In the case of refractory hyponatremia, pharmacological intervention may be utilized. Conventional medications such as demeclocycline, lithium and urea have been used for correcting hyponatremia.4
Nevertheless, there are concerns about the abovementioned treatment options. Fluid restriction often takes several days to achieve a significant increase in serum sodium.4 As a result, cancer treatment with cisplatin might be affected as adequate hydration is required. Moreover, patient compliance with fluid restriction is poor.4
Traditional pharmacological agents also have some limitations. Demeclocycline is reported to be nephrotoxic and only works in about 60% of the patients with an unpredictable onset.4 Lithium is toxic to multiple organs and works in an even smaller proportion of patients than demeclocycline.4 Urea is an osmotic diuretic which works by increasing water excretion and sodium retention.4 Although urea is generally effective, it might cause hypersensitivity, liver failure and azotemia.4 Besides, it also comes with an unpleasant taste. 4
Tolvaptan as an alternative treatment option
Considering the limitations of the existing treatment options, a better and safer alternative is warranted. Tolvaptan, a selective vasopressin V2 receptor (V2R) antagonist that specifically blocks the binding of arginine vasopressin (AVP) at the V2 receptor of the distal portions of nephron, has demonstrated superior efficacy in increasing the serum sodium levels in patients with euvolemic or hypervolemic hyponatremia from 2 pivotal, double-blind, placebo-controlled clinical trials.4,8 It is indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia secondary to SIADH based on the promising results of Study of Ascending Levels of Tolvaptan in Hyponatremia 1 (SALT 1) and SALT 2 trials.8
A post hoc exploratory sub-analysis of the SALT-1 and SALT-2 trials was performed to examine the effectiveness of tolvaptan on the participants with a primary etiology of SIADH and a diagnosis of cancer.2 There were a total of 28 subjects identified with cancer and SIADH, 12 of whom were randomized to the study arm and 16 to the control arm.2 The most common cancers in this subgroup were lung cancer (29%), head and neck cancer (25%) and breast cancer (11%). Study assessments occurred at baseline, 8 hours after the first administration of tolvaptan, and 2, 3, 4, 11, 18, 25, and 30 days.2
The primary endpoint in the SALT trials was the change in average daily serum sodium area under the curve (AUC) from baseline to day 4 and from baseline to day 30. The cancer or SIADH subjects on tolvaptan exhibited a highly significant improvement in this parameter (p<0.0001) compared with placebo to day 4 (5.0 vs. -0.3mEq/mL) and to day 30 (6.9 vs. 1.0mEq/L).2 The responses in the SIADH or cancer subgroup were similar to those in the overall SIADH population without cancer (Figure 2).2
Proven safety profile
In SIADH/cancer subjects, tolvaptan was generally well-tolerated, except for one reported case of severe nausea observed during the clinical trials, all adverse events (AEs) reported were mild to moderate.2 In the complete SALT-1 and SALT-2 study population, the most common AEs included thirst (14%), dry mouth (13%) and increased urination (7%).2,4 All AEs were medically manageable.2
Tolvaptan might not be appropriate for certain types of patients. It is contraindicated in patients with hypovolemic hyponatremia, volume depletion, anuria, inappropriate response to thirst (e.g., in unconscious patients), and breastfeeding women.8 The use of tolvaptan in patients who need an urgent rise in serum sodium levels should also be avoided.8
An overly rapid correction of serum sodium levels is often a major concern during hyponatremia management.2 Rapid rise in serum sodium could lead to osmotic demyelination syndrome (ODS) and results in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma, and even death.2 These risks can be managed by initiating tolvaptan therapy at a low dose of 15mg per day, then slowly increasing the dose according to the serum sodium levels of the patients.2 If patients develop a rise in serum sodium too rapidly (e.g. >12mEq/L/24 hours), it is advised to discontinue or interrupt the treatment with tolvaptan and consider administration of hypotonic fluid.8
Re-initiating tolvaptan and its efficacy
In an open-label extension of the SALT trials, the re-initiation of tolvaptan demonstrated comparable efficacy in raising serum sodium levels to those seen in initial therapy.4 Furthermore, these levels were maintained by continued daily tolvaptan therapy for 1 or more than 1 year.4
Case report and discussion shared by Dr. Leung
A 50-year-old man diagnosed with SCLC with pleural effusion and bone metastasis developed paraneoplastic syndrome, feeling fatigued and loss of appetite. His serum sodium concentration was found to be at an inappropriately low level of 118mEq/L. After excluding other causes, a diagnosis of SIADH was confirmed. The patient was initially treated with fluid restriction and sodium replacement. However, the rise in serum sodium level was not significant after 4 to 5 days of the initial treatment. Therefore, fluid restriction was discontinued, and the patient was put on oral tolvaptan therapy with a low starting dose of 15mg per day, and was monitored closely for the changes of serum sodium level when tolvaptan was given in the first couple of days so as to avoid osmotic demyelination syndrome (ODS) due to too rapid correction of serum sodium. After 10 days of tolvaptan therapy, the serum sodium level rose to around 130mEq/L, and reportedly his symptoms of fatigue and loss of appetite subsided (Figure 3). During the 1-month tolvaptan therapy, the serum sodium level increased steadily and was maintained at the normal range between 135mEq/L and 145mEq/L.
Tolvaptan was well-tolerated, and no AE was reported in this patient. Chemotherapy of etoposide and cisplatin for tumor control could then resume. Pleural effusion was reduced, and the patient’s quality-of-life (QoL) was improved.
Hyponatremia management in the oncology setting can be challenging. Fluid restriction and sodium replacement are sometimes insufficient to bring the serum sodium back to normal within a desired period of time. Patient compliance with the first-line treatment is also a concern. Patients often complain about the inconvenience of fluid restriction and the palatability of sodium replacement tablets. Furthermore, fluid restriction can limit the use of cisplatin for tumor control because patients must be adequately hydrated for cisplatin treatment.4 Considering these limitations, tolvaptan, an oral therapy which does not require fluid restriction, can be a suitable treatment option to address the challenges.
A message to oncologists
Hyponatremia in the oncology setting is usually caused by SIADH, especially in SCLC.3 Proactive differential diagnosis is crucial for choosing the appropriate treatment to correct the electrolyte imbalance disorder.1,4 While fluid restriction and sodium replacement are the standard first-line treatment in managing hyponatremia, they can be inappropriate and inefficacious in some scenarios.4,6,7 Patient compliance is also an issue for the traditional treatment options.4 Alternatively, tolvaptan can be used to manage clinically significant hypervolemic and euvolemic hyponatremia in cancer patients, with proven effectiveness in correcting hyponatremia secondary to SIADH.4,8 In the case shared, the oral formulation, once-daily dosing regimen, and needlessness to restrict fluid intake of tolvaptan improved patient compliance and QoL, and allowed chemotherapy with cisplatin to achieve optimal tumor control. Of note, precautions should be taken to prevent an overly rapid rise in serum sodium.8 All in all, tolvaptan can be a suitable and safe alternative to traditional treatment options for hyponatremia management caused by SIADH in cancer patients.
This is an advertorial article, published and distributed through unrestricted support from Otsuka Pharmaceutical (H.K.) Ltd., for the purpose of continuing medical education only. The views expressed in this publication reflect the experience and/or opinion of the author(s) and are not necessarily those of editors and publisher. Because of rapid advances in medicine, independent verification of clinical diagnoses, medical suitability and dosage should be made before treatment prescription.
- Marquina G et al. The management of hyponatremia in cancer patients: a practical view in Spain. J Cancer Metastasis Treat. 2020;6:6.
- Gralla RJ et al. Tolvaptan use in cancer patients with hyponatremia due to the syndrome of inappropriate antidiuretic hormone: a post hoc analysis of the SALT-1 and SALT-2 trials. Cancer Med. 2017;6(4):723-729.
- Yoo M et al. Syndrome of inappropriate antidiuretic hormone (SIADH) secretion caused by squamous cell carcinoma of the nasopharynx: case report. Clin Exp Otorhinolaryngol. 2008;1(2):110-112.
- Castillo JJ et al. Diagnosis and management of hyponatremia in cancer patients. Oncologist. 2012;17(6):756-765.
- Koichi M et al. Successful treatment by tolvaptan of the syndrome of inappropriate antidiuretic hormone secretion that may be associated with chemotherapy-induced tumour lysis in a patient with small-cell lung carcinoma. Respirol Case Rep. 2018;6(3):e00296.
- Goce S et al. Clinical practice guideline on diagnosis and treatment of hyponatremia. Eur J Endocrinol. 2014; 170(3):G1-47.
- Adrogué HJ, Madias NE. Diagnosis and treatment of hyponatremia. Am J Kidney Dis. 2014;64(5):681-684.
- SAMSCA® (tolvaptan) Hong Kong Prescribing Information revised Mar 2019.
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