ReviewElectrolyte disorders associated with the use of anticancer drugs
Introduction
Drugs used for the treatment of malignancies are increasingly prescribed (Vantard et al., 2015). However, the use of anticancer drugs is associated with many side effects; among them electrolyte disturbances are relatively frequent (Ariaans et al., 2015, Filippatos et al., 2009, Filippatos et al., 2005, Launay-Vacher et al., 2015, Miltenburg and Boogerd, 2014, Miltiadous et al., 2008, Perazella and Izzedine, 2015, Stojanovska et al., 2015, Tanvetyanon and Stiff, 2006, Teply and Lipson, 2014). In fact, electrolyte disturbances could be life-threatening if not promptly recognized and treated (Liamis et al., 2015, Miltiadous et al., 2003).
Aim of this review is to present the current evidence regarding the electrolyte abnormalities attributed to the use of anticancer drugs.
Section snippets
Methods
We searched PubMed for eligible publications (last search in January 2016) by using combinations of the following keywords: platin, cisplatin, carboplatin, oxaliplatin, nedaplatin, alkylating agents, cyclophosphamide, ifosfamide, busulfan, melphalan, glufosfamide, vinca alkaloids, vincristine, vinblastine, vinflunine, epidermal growth factor receptor monoclonal antibody inhibitors, cetuximab, panitumumab, bevacizumab, zalutumumab, tyrosine kinase inhibitors, imatinib, dasatinib, nilotinib,
Platinum-containing drugs (cisplatin, carboplatin and oxaliplatin)
Cisplatin, carboplatin and oxaliplatin are platinum-containing anticancer drugs targeting solid cancers, such as head and neck cancer, lung cancer, and cervical cancer (Ali et al., 2013). The use of these drugs has been associated with a number of electrolyte derangements (Table 1).
The most common electrolyte disorder seen with platinum drugs, especially cisplatin, is hypomagnesemia (Atsmon and Dolev, 2005). It has been reported that, without preventive measures (see section of preventing
Alkylating agents
Alkylating agents have been linked to the development of hyponatremia. These drugs can either induce the renal effect of ADH or its central release leading to hyponatremia (Gilbar et al., 2012). Another proposed mechanism is the upregulation of expression of vasopressin receptor and AQ2 due to the cyclophosphamide-induced suppression of interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α) (Park et al., 2010).
Hyponatremia is mainly developed with the administration of high intravenous doses
Vinca alkaloids
Vincristine and, less often, vinblastine are associated with the occurrence of hyponatremia (Berghmans, 1996, Raftopoulos, 2007, Ravikumar and Grage, 1983, Robertson et al., 1973). These drugs induce SIADH since they exert a direct toxic effect on the neurohypophysis and hypothalamic system leading to alteration of the normal osmoreceptor control of ADH secretion (Robertson et al., 1973). The incidence of SIADH is 1.3/100,000 treated patients with vinca alkaloids (Hammond et al., 2002).
Monoclonal antibodies
A recent meta-analysis of 25 randomized controlled trials (16,400 patients) showed that treatment with epidermal growth factor receptor (EGFR) monoclonal antibody inhibitors was associated with high incidence of hypomagnesemia (34%), hypocalcemia (16.8%) and hypokalemia (14.5%) (Wang et al., 2015). Main mechanism of hypomagnesemia is the inhibition of the EGF-mediated stimulation of the TRPM6 channels resulting to increased renal loss of magnesium (Groenestege et al., 2007, Muallem and Moe, 2007
Tyrosine kinase inhibitors
Imatinib, dasatinib, nilotinib, bosutinib and axitinib have been dose-dependently linked to hyponatremia. The main underlying mechanism is the induction of SIADH (Ha et al., 2010, Hill et al., 2015, Liapis et al., 2008, Schiller et al., 2009). Imatinib, apart from hyponatremia, can also induce hypophosphatemia through tubular damage and inappropriate phosphaturia. Another contributing factor to the occurrence of hypophosphatemia is secondary hyperparathyroidism due to diminished calcium levels (
Mammalian target of rapamycin (mTOR) inhibitor
Temsirolimus and everolimus have been associated with hyponatremia (Guo et al., 2013, Javle et al., 2010, Sanchez-Fructuoso et al., 2010, Yeo et al., 2015, Zhu et al., 2011). Aldosterone resistance is the main implicating mechanism of the decrease in sodium levels. Temsirolimus and other mTOR inhibitors also cause hypokalemia and severe hypophosphatemia (Armstrong et al., 2013, Rodriguez-Pascual et al., 2010).
Miscellaneous
Immunomodulators, such as interferon, interleukin-2, levamisole, pentostatin, cytarabine, pembrolizumab and ado-trastuzamab emtansin have been associated with hyponatremia (Berghmans, 1996, Bruno and Canada, 2007, Kolarich et al., 2014, O’Brien et al., 2012, Ribas et al., 2015). The main underlying mechanism in the majority of cases is possibly the induction of SIADH.
Methotrexate in high doses can also cause hyponatremia. Proposed mechanisms of methotrexate-induced hyponatremia include a toxic
Preventing/treating anticancer medications-related electrolyte disorders
Generally, the depletion of electrolytes should be prevented/corrected with the supplementation of intravenous administration of electrolytes. The correction of sodium, potassium, magnesium and phosphorus derangements has been extensively described in other publications and is outside of the scope of this review (Filippatos and Elisaf, 2013, Liamis et al., 2014, Liamis et al., 2015, Liamis et al., 2006, Liamis et al., 2008, Liamis et al., 2009b, Liamis et al., 2010). However, it should be
Concluding remarks
The use of anticancer drugs is beneficial for patients with malignancies but it is associated in many cases with the occurrence of electrolyte disorders. Platinum-containing drugs are frequently associated with hypomagnesemia, hypokalemia and hypocalcemia, as well as with a Gitelman syndrome-like picture with coexistent hypocalciuria and hypokalemic metabolic alkalosis. Moreover, platinum-containing drugs are associated with hyponatremia, especially when combined with large volumes of hypotonic
Conflict of interest
This Review was written independently; no company or institution supported it financially. Professor M Elisaf has received speaker honoraria, consulting fees, and research funding from AstraZeneca, Schering Plough, Merck, Pfizer, Solvay, Abbott, Boehringer Ingelheim and Fournier, and has participated in clinical trials with AstraZeneca, Merck, Sanofi-Synthelabo, Solvay, Glaxo, Novartis, Pfizer and Fournier. The authors have given talks and attended conferences sponsored by various
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