Abstract
Aim: We aimed to assess whether the efficacy of pre-hydration with 15 mEq magnesium prevents cisplatin-induced nephrotoxicity in cisplatin regimens (dosage: 50 mg/m2 or more) for gynecological cancer. Patients and Methods: This historical, prospective cohort study compared nephrotoxicity in patients who received pre-hydration with or without magnesium sulfate (Mg-hydration group, n=37; non-Mg-hydration group, n=37). We used serum creatinine (Scr), creatinine clearance (Ccr) and Risk, Injury, Failure, Loss of kidney function and End-stage kidney disease (RIFLE) criteria. Results: A change of Scr and Ccr in the Mg-hydration group was higher than in the non-Mg-hydration group. Based on the RIFLE criteria, the number of moderate renal dysfunction patients classified as “Risk” in the Mg-hydration group was significantly lower than in the non-Mg-hydration group (Mg-hydration group=21.6%; non-Mg-hydration group=51.4%; p<0.01). Serum magnesium levels in the Mg-hydration group significantly declined during chemotherapy (p<0.01). Conclusion: We found that a 15 mEq magnesium as pre-hydration provided nephroprotective effects in patients receiving this cisplatin regimen. Future research should involve finding appropriate magnesium doses.
- Gynecological cancer
- cisplatin
- pre-hydration
- magnesium
- nephrotoxicity
Platinum anticancer drugs, including cisplatin, are key drugs for chemotherapy used to treat gynecological cancer. Nephrotoxicity is a major dose-limiting factor in almost all cisplatin containing regimens (1, 2).
Magnesium is one substance that has a nephroprotective effect against cisplatin toxicity (3-6). It is assumed that supplementing magnesium decreases the risk of cisplatin-induced nephrotoxicity due to expression of the renal organic cation transporter 2 (OCT2), which controls cisplatin transport into kidney cells and is up-regulated in hypomagnesemia (7, 8).
The adequate magnesium dose to provide a nephroprotective effect against cisplatin is unclear and reports differ (3-6, 9-10). We previously reported that the incidence of cisplatin-induced nephrotoxicity significantly decreased when a dose of 15 mEq magnesium was administered during pre-hydration in patients with cervical cancer receiving cisplatin alone (dosage: 40 mg/m2, administration interval: per week) (6). In cisplatin regimens used extensively against many cancers, dosage is often 50 mg/m2 or more, with administration intervals of 3-4 weeks. The risk of nephrotoxicity in this cisplatin regimen is probably higher than in cisplatin alone. It has been reported that an increased risk of cisplatin-induced nephrotoxicity is associated with a higher dosage of cisplatin, resulting in high plasma-free platinum concentrations (11). Additionally, it has been reported that serum magnesium levels significantly decreased with higher dosage of cisplatin (12). Until now, no clinical trial has examined the protective effects of 15 mEq magnesium as pre-hydration against cisplatin-induced nephrotoxicity and changes in serum magnesium levels during this regimen.
We prospectively examined whether pre-hydration supplemented with 15 mEq magnesium has a protective effect against cisplatin-induced nephrotoxicity in patients with gynecological cancer receiving cisplatin-containing regimens (dosage: 50 mg/m2 or more, administration interval: 3-4 weeks). Additionally, we investigated the association between serum magnesium levels and cisplatin-induced nephrotoxicity.
Patients and Methods
Study participants. This study was a single-center, prospective, open-label, non-randomized, historically-controlled study conducted at Aichi Medical University School of Medicine. We targeted an experimental cohort (Mg-hydration group) and a retrospective control group (non-Mg-hydration group). Patients were selected for this study according to the following criteria: (i) diagnosis of gynecological cancer; (ii) Eastern Cooperative Oncology Group performance status of 0-2; (iii) chemotherapy regimens that included 50 mg/m2 or more of cisplatin; (iv) receiving treatment as an inpatient at our Institution between January 2010 and December 2014. The following variables were recorded for each patient: age, body surface area, body mass index, performance status according to the Eastern Cooperative Oncology Group scale, tumor type, disease stage, cisplatin dosage, number of chemotherapy cycles and baseline renal function. We began to measure serum magnesium levels before the administration of cisplatin when the magnesium hydration protocol was started in 2012.
We defined patients receiving cisplatin-containing regimens between January 2010 and June 2012 as the non-Mg-hydration group and between July 2012 and December 2014 as the Mg-hydration group. We compared nephrotoxicity between these two groups.
The Institutional Review Board decided to exempt this study from the usual review process. Study approval was obtained from the president of the Aichi Medical University Hospital, Aichi, Japan (approval number: 13-102).
Administration of pre-hydration. A program of forced diuresis of 2,500 ml of fluids (lactate Ringer's solution) infused with cisplatin dissolved in 500 ml of normal saline was administered as pre-hydration. Urine flow was established at rates of at least 100 ml/h for 2 days following cisplatin administration. If urine flow rate dropped below 100 ml/h, an additional infusion solution was administered. If the additional solution failed to increase urine flow rate, 20 mg furosemide was administered. Mannitol was not administered.
After chemotherapy treatment, 500 ml, 1,000 ml and 1,000 ml of intravenous infusion fluid (lactate Ringer's solution) were administered as post-hydration on days 1, 2, and 3, respectively. Beginning in July 2012, a modified hydration protocol including magnesium sulfate was used. Fifteen mEq of magnesium sulfate was used as pre-hydration and a daily dose of 5 mEq of magnesium sulfate was used as post-hydration on days 2 and 3.
Nephrotoxicity evaluation. In line with a previous report (6), we used serum creatinine (Scr) and creatinine clearance (Ccr) to divide patients into categories based on the Risk, Injury, Failure, Loss of kidney function and End-stage kidney disease (RIFLE) criteria. RIFLE criteria are used widely in cases involving acute nephrotoxicity (13). Scr was measured enzymatically, while Ccr was calculated using the Cockroft-Gault formula. The Common Terminology Criteria for Adverse Events classify renal dysfunction only as an elevation of Scr and do not refer to Ccr values. However, we chose to use the RIFLE criteria, which define nephrotoxicity according to Ccr and Scr values. RIFLE criteria define “risk” (Class R) as a proportional increase in Scr of more than 50% or a decrease in Ccr of less than 25% relative to baseline after cisplatin administration. In addition, “injury” (Class I) is defined as a proportional increase in Scr of more than 100% or a decrease in Ccr of less than 50% relative to baseline after cisplatin administration. We also used the difference between the baseline values of Scr and the maximum increment of Scr (ΔScr), as well as the difference between baseline value of Ccr and maximum decrement of Ccr (ΔCcr) to evaluate cisplatin-induced nephrotoxicity. When there was no change over a particular time period, we recorded this as 0.
Statistical analyses. All statistical analyses were performed with EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria). More precisely, it is a modified version of R commander designed to add statistical functions frequently used in biostatistics. Tumor type, disease stage, pathological stage, chemotherapy regimen, number of chemotherapy cycles and RIFLE criteria were compared using Fisher's exact test. Other patient demographic data, ΔScr and ΔCcr were compared using the Mann–Whitney U-test. A comparison of serum magnesium levels before and after treatment was performed using a one-way ANOVA. All reported p-values are two-sided, with a value of p<0.05 considered statistically significant.
Results
Data for 74 patients with gynecological cancer (Mg-hydration group, n=37; non-Mg-hydration group, n=37) were included in the analysis. Patients' characteristics are shown in Table I. Characteristics other than tumor type and chemotherapy regimen were not significantly different between the Mg-hydration and non-Mg-hydration groups. The cisplatin dosages for chemotherapy in gynecology registered at Aichi Medical University School of Medicine were 50 mg/m2 with the exception of irinotecan plus cisplatin combination chemotherapy (CPT-11+CDDP) (60 mg/m2) and cisplatin alone (40 mg/m2). The rate of CPT-11+CDDP administered was similar between the two groups, thus avoiding any bias in chemotherapy regimen. Although the dosage of cisplatin was not significantly different between the groups, the dosage showed a trend to be higher in the Mg-hydration group compared with the non-Mg-hydration group, while the planned dose intensity was significantly higher in the Mg-hydration group.
We used the RIFLE criteria to classify the severity of renal dysfunction among patients (Table II). The percentage of moderate renal failure in patients classified as Class R in the Mg-hydration group was significantly lower than in the non-Mg-hydration group (Mg-hydration group=21.6%; non-Mg-hydration group=51.4%; p<0.01). The percentage of severe renal failure in patients classified as Class I did not differ significantly by group (Mg-hydration group=8.1%; non-Mg-hydration group=16.2%; p=0.29). ΔScr in the Mg-hydration group was significantly lower than in the non-Mg-hydration group (p=0.04) and ΔCcr was also similar to ΔScr (p=0.03). Six patients were excluded because of insufficient data and, therefore, the serum magnesium levels of 31 patients were recorded. Serum magnesium levels in the Mg-hydration group significantly declined during chemotherapy (p<0.01; Figure 1). Seven patients (22.6%) became hypomagnesemic (Mg<1.8 mg/dl) because of cisplatin administration. Two of these seven patients (28.6%) were classified as having renal dysfunction according to the RIFLE criteria. We divided the patients in the Mg-hydration group into two groups based on their median decrease from initial serum magnesium levels (median=0.3). Class R renal patients in whom serum magnesium levels decreased by a value of 0.3 or more from their initial serum magnesium levels significantly outnumbered the other group (p=0.03; Table III).
Discussion
In this study, the number of renal dysfunction patients (according to the RIFLE criteria) in the Mg-hydration group was lower than in the non-Mg-hydration group. The number of patients classified as Class R, moderate renal failure, significantly differed between the groups. ΔScr and ΔCcr in the Mg-hydration group were also significantly lower than in the non-Mg-hydration group. Consequently, we found that a pre-hydration protocol with 15 mEq magnesium had nephroprotective effects in patients with gynecological cancer undergoing chemotherapy involving cisplatin (dosage: 50 mg/m2 or more, administration interval: per 3-4 weeks). The percentage of renal dysfunction patients classified according to the RIFLE criteria R and I in the Mg-hydration group (21.6% and 8.1%, respectively) was higher in this study compared to our previous study (7.1% and 0%) (6). The percentage of hypomagnesemic patients administered magnesium in this study (22.6%) was also higher than that in our previous study (7.1%). We speculate that these results were due to the high-dosage cisplatin regimen used in the present work.
We did not find a relationship between hypomagnesemia and cisplatin-induced nephrotoxicity; and there was a low rate of hypomagnesemia in this study. Among patients classified as Class R, a significantly greater number experienced a decrease in serum magnesium levels from an initial value of 0.3 or higher compared with those who did not experience such a decrease. Therefore, we suggest that patients whose serum magnesium levels substantially decrease from their initial level should be carefully monitored for cisplatin-induced nephrotoxicity even when their serum magnesium levels stay within the normal range. This study is the first report that focuses on the relationship between changes in serum magnesium levels and cisplatin-induced nephrotoxicity.
Serum magnesium levels in the Mg-hydration group declined despite the administration of 15 mEq magnesium. Bonder et al. reported that administering 40 mEq of magnesium did not alter the initial serum magnesium values in patients receiving paclitaxel (135 mg/m2) plus cisplatin (75 mg/m2) every 3 weeks (4). For this reason, we speculate that patients receiving a cisplatin regimen of 50 mg/m2 or more and with 3-4 weeks administration interval should be administered a higher magnesium dose than those receiving dosages of cisplatin under 50 mg/m2. We conclude that patients receiving cisplatin regimens should receive a uniform magnesium dose and should receive adjustments to their magnesium dose in order to change serum magnesium levels, especially as treatment progresses. Future research should involve finding appropriate magnesium doses, paying careful attention to the risk of hypermagnesemia (>2.5 mg/dl).
There were some limitations to our study. First, this was a non-randomized, non-double-blind, historically-controlled study. Second, we used Scr and Ccr to indicate cisplatin-induced nephrotoxicity without assessing N-acetyl-beta-glucosaminidase and beta 2-microglobulin, which are susceptible to cisplatin-induced nephrotoxicity. Finally, serum magnesium levels were measured in only a small sample of patients.
In this study, we found that a 15 mEq magnesium dose given as pre-hydration provided nephroprotective effects in patients with gynecological cancer receiving cisplatin chemotherapy. Additionally, we revealed that patients receiving cisplatin are at increased risk for nephrotoxicity when their serum magnesium levels dramatically decrease from their initial values.
Acknowledgements
This study received no foundational support.
Footnotes
Conflicts of Interest
No conflicts of interest exist.
- Received February 12, 2016.
- Revision received March 19, 2016.
- Accepted March 21, 2016.
- Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved