Hyponatraemia has been reported with targeted therapies in cancer patients. Aim of the study was to perform an up-to-date meta-analysis in order to determine the incidence and relative risk (RR) in cancer patients treated with these agents.
Materials and Methods
The scientific literature regarding hyponatraemia was extensively reviewed using MEDLINE, PubMed, Embase and Cochrane databases. Eligible studies were selected according to PRISMA statement. Summary incidence, RR, and 95% Confidence Intervals were calculated using random-effects or fixed-effects models based on the heterogeneity of selected studies.
4803 potentially relevant trials were identified: of them, 13 randomized phase III studies were included in this meta-analysis. 6670 patients treated with 8 targeted agents were included: 2574 patients had hepatocellular carcinoma, whilst 4096 had other malignancies. The highest incidences of all-grade hyponatraemia were observed with the combination of brivanib and cetuximab (63.4) and pazopanib (31.7), while the lowest incidence was reported by afatinib (1.7). The highest incidence of high-grade hyponatraemia was reported by cetuximab (34.8), while the lowest incidences were reported by gefitinib (1.0). Summary RR of developing all-grade and high-grade hyponatraemia with targeted agents was 1.36 and 1.52, respectively. The highest RRs of all-grade and high-grade hyponatraemia were associated with brivanib (6.5 and 5.2, respectively). Grouping by drug category, the RR of high-grade hyponatraemia with angiogenesis inhibitors was 2.69 compared to anti-Epidermal Growth Factor Receptors agents (1.12).
Citation: Berardi R, Santoni M, Rinaldi S, Nunzi E, Smerilli A, Caramanti M, et al. (2016) Risk of Hyponatraemia in Cancer Patients Treated with Targeted Therapies: A Systematic Review and Meta-Analysis of Clinical Trials. PLoS ONE 11(5): e0152079. https://doi.org/10.1371/journal.pone.0152079
Editor: Daniele Santini, University Campus Bio-Medico, ITALY
Received: January 24, 2016; Accepted: March 8, 2016; Published: May 11, 2016
Copyright: © 2016 Berardi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper and its Supporting Information files.
Funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector. The study was realized with authors’ University funding (Università Politecnica Marche, Ancona, Italy).
Competing interests: Rossana Berardi received consulting fee or honoraria from Otsuka, Lilly, Italfarmaco; Stefano Cascinu received consulting fee or honoraria from Lilly, Amgen, Roche and they have received a research funding (paid to their Institution) from BMS for a research project. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials. The other authors declare that they have no competing interests.
Targeted therapies interfere with specific molecules involved in cancer cell growth, angiogenesis and survival, in contrast with traditional chemotherapy, drugs that mainly act against all actively dividing cells.
Such a different mechanism of action explains the absence of adverse events traditionally observed with cytotoxic chemotherapy and the occurrence of new drug-related toxicity profiles.
Among serum electrolytes disorders, hyponatraemia is probably the most frequent biochemical alterations potentially related to the use of these new agents.
Although many cases are asymptomatic, hyponatraemia may cause neurological symptoms, particularly when serum sodium declines rapidly or by a substantial extent .
Furthermore literature data suggest that hyponatraemia can be considered an unfavourable prognostic factor in this setting and it has been also hypothesized to adversely affect the response to anticancer treatment [2,3].
Moreover an effective and timely normalization of sodium levels could lead to a positive effect on prognosis of cancer patients.
The objective of the present study was to thoroughly assess incidence and relative risk of hyponatraemia in patients with solid tumors receiving targeted therapies through a revised meta-analysis of clinical trial in literature.
Materials and Methods
Selection of Studies
This systematic review and meta-analysis was achieved adhering to PRISMA guidelines for clinical trial selection . PubMed and MEDLINE (since January 1966), Embase (since 1974) and the Cochrane Central Register of Controlled Trials (since 1967) quotations were revised in order to individuate studies of interest. In particular we selected more interesting trials generated from the research finding in Pubmed.
Searches were conducted entering combination of the keywords “cancer” or “solid tumor” associated to any of the following words: “abiraterone”, “afatinib”, “aflibercept”, “axitinib”, “bevacizumab”, “brivanib”, “cabozantinib”, “cediranib”, “cetuximab”, “crizotinib”, “dabrafenib”, “dovitinib”, “enzalutamide”, “erlotinib”, “everolimus”, “figitumumab”, “gefitinib”, “icotinib”, “imatinib”, “ipilimumab”, “lapatinib”, “linifanib”, “neratinib”, “nilotinib”, “nivolumab”, “orteronel”, “panitumumab”, “panobinostat”, “pazopanib”, “pembrolizumab”, “pertuzumab”, “ramucirumab”, “regorafenib”, “sorafenib”, “sunitinib”, “T-DM1”, “temsirolimus”, “tivozanib”, “trastuzumab”, “tremelimumab”, “vandetanib”, “vemurafenib”. We evaluated exclusively human studies in English literature that met the requirements listed below: (1) prospective randomized phase III trials enrolling patients affected by solid tumors; (2) patients randomly assigned to treatment arm (targeted agents) or control arm (standard of care, best supportive care or placebo) and (3) provided records regarding treatment-related and non-tumor associated hyponatraemia.
Full articles were obtained, and we checked for additional appropriate references. Where results were reported or updated in two or more publication, we selected the most recent or most thorough.
The primary objective of our study was to assess whether there is a correlation between hyponatraemia and treatment with targeted therapy.
Data Extraction and Quality Assessment
Data extraction was performed from full texts of eligible articles, by two independent evaluators (MS and EN). Data collected included author name list, year of publication, number of participants, treatment arms characteristic and targeted agent employed, number and grade (all-grade and high grade) of hyponatraemia cases reported in every arm.
National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) version 2 or 3 were applied to define adverse events (AEs). Study quality and appropriateness of randomization, double-blinding, and withdrawals was determined basing on Jadad scoring system .
We considered the following summary measurements: incidence, relative risk (RR), and their corresponding 95% confidence intervals (CIs). Incidence evaluation was performed extracting from the safety section of eligible studies the following data: (1) number of patients receiving targeted therapy and (2) number of hyponatraemia cases. RRs of hyponatraemia was analyzed basing on data extracted from comparative trials in which patients were randomly assigned to receive targeted therapy or controls.
Cochran’s Q test was applied to all variables to detect statistical heterogeneity among study outcomes; inconsistency of effects was measured using the I2 index as a parameter of inconsistency across studies attributable to heterogeneity and chance. Homogeneity of variance was violated for p values <0.1. Basing on Cochran’s Q statistic significance it was decided whether to use random effects model (in case of significant Q test) or fixed effects model (in case of not significant Q test).
For each variable, model estimate and null hypothesis of overall non-significant difference between study- and control-group were tested. Microsoft Excel 2010 was employed to collect data; data analysis has been carried out with the “MATLAB and Statistics Toolbox Release 2012b”.
Four thousand, eight hundreds and three clinical trials studying target treatments employ in neoplastic patients resulted hypothetically significant to our research; of those, 2914 studies did not meet inclusion criteria due to any of the following causes: duplicate, phase I trials, not focused on targeted agents, reviews, observational studies, meta-analyses, case reports, letters or commentaries.
Of the remaining studies, 1658 were non-randomized phase II trials while 218 lacked Drug-related hyponatraemia records in the safety profile. Eventually 13 trials [18–30] were judged suitable and relevant for our study. The selection process of studies is represented in Fig 1. Baseline features of included trials are listed in Table 1.
Quality of studies
The quality of trials selected for the meta-analysis was determined according to the Jadad assessment scale . Follow-up time was appropriate in each trial. All the studies used either Common Terminology Criteria Adverse Events (CTCAE) version 2.0 or 3.0.
Jadad scores of the 13 studies included are reported in Table 1. The average of Jadad scores was 3.7 (range 3 to 5) standing for an adequate quality of the meta-analysis.
Study population accounted for 6670 participants of whom 2574 (39% of the total) were affected by hepatocellular carcinoma (HCC) [19,20,27], and 4096 affected by other malignancies (882 patients had gastric cancer , 790 patients had melanoma , 745 had colorectal cancer , 617 had non-small cell lung cancer (NSCLC) [18,25,30], 435 had renal cell carcinoma (RCC) , 369 had head and neck tumors (HN) [22,26] and 258 had oesophageal cancer ).
An Eastern Cooperative Oncology Group performance status (ECOG-PS) not higher than 2 was required for enrolment in all 13 studies along with fair renal and hepatic functions, coagulation and haematological parameters. Baseline features of included trials are listed in Table 1. Selected target agents and their mechanism of action are listed in Table 2.
Incidence of all-grade and high-grade hyponatraemia
Occurrences of hyponatraemia (all-grade and high-grade) accounted for a total of 1402 cases; of those 575 all-grade events occurred among the 3036 patients belonging to treatment groups versus 284 among controls. Considering only patients assigned to receive targeted therapy, the incidences of all-grade and high-grade hyponatraemia were 25.6% (95% CI 23.8 to 27.4) and 10.0% (95% CI 9.1 to 11.0), respectively.
All-grade hyponatraemia reached its maximum incidence with the combination of brivanib and cetuximab  (63.4%, 95% CI 58.5 to 68.3) and with pazopanib  (31.7%, 95% CI 26.3 to 37.1), whereas afatinib  (1.7%, 95% CI 0.0 to 3.0) showed the lowest incidence of hyponatraemia. However, several studies did report only high-grade events [22,24–26,29].
Three hundred and fifty six high-grade hyponatraemia occurrences were reported in patients assigned to treatment arms and 187 in the controls. The highest and lowest incidences of high-grade hyponatraemia were observed with cetuximab  (44.8%, 95% CI 32.0 to 57.6), and gefitinib  (1.0%, 95% CI 0 to 2.3), respectively. The incidences of all-grade and high-grade hyponatraemia are reported in Table 3.
RR of all-grade and high-grade hyponatraemia in the overall population and by single study
RR analysis was conducted considering 4 studies for the analyses of all-grade events [19,23,27,29] and 9 for high-grade events [19, 22–29]. In three studies placebo was administered in the control arm [19, 25,28], while patients in the other studies were assigned to active control arms [20,22–24,26,29,30].
In the overall study population, RR of all-grade and high-grade hyponatraemia was 1.36 (95% CI 1.06 to 1.75) for patients receiving targeted treatments compared to 1.52 (95% CI 1.06 to 2.20) in control arms. The RRs of all-grade hyponatraemia across selected trials are reported in Figs 2 and 3.
Eight different agents were available for this analysis. In patients stratified by single studies, the highest RR of all-grade hyponatraemia was associated with brivanib  (6.5, 95% CI 2.1 to 21.0). On the other hand, the lowest RR was associated with cetuximab  (1.1, 95% CI 0.73 to 1.70).
High-grade hyponatraemia highest RRs occurred with brivanib  (5.2; 95% CI 1.6 to 17.0), sorafenib  (2.4; 95% CI 1.1 to 5.1) and vorinostat  (2.1; 95% CI 0.63 to 0.81), while the lowest RR of high-grade hyponatraemia was observed with cetuximab  (0.93; 95% CI 0.63 to 1.42) and gefinitib  (0.26; 95% CI 0.03 to 2.33]. The RRs of all-grade hyponatraemia across selected trials are reported in Figs 2 and 3.
RR of high-grade hyponatraemia by drug category
For an experimental examination, 5 out of the 6 targeted therapies studied in the RR analysis of high-grade hyponatraemia [19,22–28] were grouped into 2 categories: (1) inhibitors of angiogenesis (brivanib, pazopanib, sorafenib); (2) anti-Epithelial growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) or monoclonal antibodies (mAbs) (gefitinib, cetuximab). The same analysis was not performed for all-grade events due to the smaller number of studies available. Afatinib was omitted in reason of an active control arm . Vorinostat was excluded due to the number of patients in this study , which was too small to constitute a single group.
A total of 946 patients received inhibitors of angiogenesis [19,28,29], whereas 442 received anti-EGFR TKIs or mAbs [22–26]. The incidence of high-grade hyponatraemia was 7.2 [95% CI 5.5 to 8.8] with the inhibitors of angiogenesis and 8.8 [95% CI 6.9 11.0] with anti-EGFR TKIs or mAbs. Moreover, the RR of high-grade hyponatraemia with inhibitors of angiogenesis was 2.69 (95% CI 1.62 to 4.48) compared to anti-EGFR TKIs or mAbs (1.12 95% CI 0.81 to 1.53) (Fig 4).
Publication biases were quantified by Egger and Begg tests for both the incidence and RR. Egger test showed z = 1·62 p = 0·11, while Begg test showed Kendall's tau = 0.1111 p = 0.7614. Funnel plots are showed in S1 Fig.
Hyponatraemia represents an increasingly important issue in oncology clinical practice since it negatively correlates with performance status and with prognosis of cancer patients . Patients with hyponatraemia have a higher risk of mortality and present a longer time of hospitalization with consequent cost increases . An early detection and a prompt treatment of this disorder could prevent serious neurologic complication and improve overall survival (OS) . For this reasons, it is pivotal for both physicians and patients to be aware about the risk of drug-induced hyponatraemia so as to promptly take the appropriate measures to face these events.
Our results show that the highest RR of all-grade hyponatraemia was associated with brivanib (RR = 6.5), whilst the highest RRs of high-grade hyponatraemia were reported by brivanib (RR = 5.2), sorafenib (RR = 2.4) and vorinostat (RR = 2.1). Moreover, grouping the selected agents into drug categories even strengthens these data. Indeed, the RR of developing high-grade hyponatraemia with anti-angiogenic agents was 2.69 compared to anti-EGFR TKIs or mAbs.
Recent studies demonstrated the activity of vascular endothelial growth factor (VEGF) in renal sodium metabolism, thus suggesting an activity of anti-VEGF/VEGF receptor agents in the homeostasis of sodium. Gu et al. evaluated the correlation between VEGF inhibition and hypertension. They found that rats receiving semaxanib (SU5416), a small-molecule inhibiting VEGF downstream signaling, showed increased mean arterial pressure and natriuresis. They also described a right shift with a slightly higher intercept of the pressure-natriuresis curve in rats with dietary salt-induced hypertension . In addition, Grisk and colleagues reported that early hypertension induced by anti-VEGFR-TKI sunitinib is probably related to the direct action of this agent on the collecting ducts, suggesting a role for VEGFR-TKI in regulating renal sodium reabsorption .
Although the exact mechanisms underlying the increased incidence of hyponatraemia in patients exposed to targeted agents is still unclear, these evidences suggest an important role of VEGF/VEGFR pathway in sodium homeostasis. Most of the studies included in this analysis concerned hepatocellular carcinoma. In this condition, risk of developing hyponatremia is increased due also to concomitant liver cirrhosis that stimulates arginine vasopressin (AVP) secretion .
This study has several limitations. First of all it is a meta-analysis achieved starting from clinical trials and not from individual patients’ data. This implies also the potential presence of confounding factors that were not considered, for instance patient comorbidities, previous administration of cytotoxic chemotherapy, and simultaneous treatments. In particular, in some of aforementioned trials, target agents were administrated with cisplatin. In this respect, literature data reported evidences about hyponatremia due to cisplatin-based chemotherapy, suggesting two possible mechanisms: stimulation of hypothalamic AVP production and damage of renal tubules with development of salt wasting syndrome [1,38]. Available data are insufficient to exclude a synergic effect between chemotherapy and target agents.
Furthermore, it should be consider that patients eligible for clinical trials mostly show fair organ functions, for this reason the incidence and severity of hyponatraemia may appear underrated in our meta-analysis comparing to clinical practice. Another limitation is the lack of data regarding delays, interruptions and discontinuations because of hyponatraemia, to correlate to our results.
In face of the limitations described, this meta-analysis, for the first time in literature, pointed out a correlation between targeted agents, in particular anti-angiogenetic ones, and hyponatraemia of all- and high-grade in patients with solid tumors. Moreover this study was the first to analyze RR of hyponatraemia in different groups of targeted agents, showing that maximum incidence of hyponatraemia was observed in patients treated with anti-VEGFR agents. Considering the negative prognostic and predictive role of hyponatraemia in cancer patients, a careful and prompt recognition of this event is preferred so as to limit negative consequences on patient outcome and to prevent possible treatment delays or interruptions.
Physicians and patients should be informed of such risks and an appropriate laboratory monitoring should be suggested to early detect hyponatraemia and optimize the management of these agents.
Hyponatraemia represents a negative prognostic factor for cancer patients. Increasing evidences showed a significant increased risk of developing hyponatraemia in patients treated with biological therapy. Therefore an accurate and frequent monitoring of serum sodium should be evaluated in patients treated with new-targeted agents, in particular with antiangiogenetic drugs, both in clinical practise and in prospective studies, for a rapid diagnosis and correction of this electrolyte disturbance.
Funnel graphs for the assessment of potential publication bias among selected studies for all-grade (A) and high-grade (B) hyponatraemia.
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector. The study was realized with Authors’ University Funding (Università Politecnica Marche, Ancona, Italy).
Conceived and designed the experiments: RB MS SR SC. Performed the experiments: EN A. Smerilli MC FM MT A. Savini IF AO MP AT. Analyzed the data: EN A. Smerilli MC FM MT A. Savini IF AO MP AT. Contributed reagents/materials/analysis tools: RB MS SR. Wrote the paper: EN A. Smerilli MC FM MT A. Savini IF AO MP AT.
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