Elsevier

European Journal of Cancer

Volume 44, Issue 17, November 2008, Pages 2608-2614
European Journal of Cancer

Renal protection with magnesium subcarbonate and magnesium sulphate in patients with epithelial ovarian cancer after cisplatin and paclitaxel chemotherapy: A randomised phase II study

https://doi.org/10.1016/j.ejca.2008.08.005Get rights and content

Abstract

Background

The aim of this study was to examine the effect of magnesium supplementation on nephrotoxicity accompanying standard cisplatin-based chemotherapy in patients with epithelial ovarian cancer (EOC).

Patients and methods

A double-blind, placebo-controlled, randomised study was conducted in which study arm magnesium sulphate (5 g) was administered before each course of standard chemotherapy with paclitaxel (135 mg/m2/24 h) plus cisplatin (75 mg/m2) every 3 weeks in patients with EOC. Magnesium subcarbonate (500 mg), three times per day orally, was administered during the treatment intervals. The control arm was administered a placebo instead of both magnesium salts. Magnesium serum levels (sMg) and GFR markers: serum levels of creatinine (sCr), Cockroft–Gault (ClCG) and Modification Diet of Renal Disease (MDRD) formulae were recorded before each cycle, and 3 weeks after the sixth course.

Results

41 EOC patients were randomised and 40 were eligible. sMg varied significantly between the supplemented and placebo groups (p<0.0001). The control group showed a significantly greater decrease of GFR assessed by: sCr (p = 0.0069), ClCG (p = 0.0077) and MDRD (p = 0.032) formulae compared with the magnesium supplemented group.

Conclusions

These results demonstrate the nephroprotective effect of magnesium supplementation during chemotherapy with cisplatin.

Introduction

Ovarian cancer is the most common cause of death among women with gynaecologic malignancies. Poor treatment results (i.e. 5-year survival approximately 50%) are mainly caused by the advanced stage noted at the time of diagnosis. In most instances, treatment for ovarian cancer includes primary surgery followed by systemic chemotherapy. The standard chemotherapy consists of a platinum analogue (carboplatin or cisplatin) combined with paclitaxel.1, 2 The efficacy of combined chemotherapy is highly related to the amount of residual tumour left after surgery.

Nephrotoxicity is a well-known side effect of cisplatin treatment. Though not necessarily dose limiting, renal toxicity still affects the majority of patients and a significant decrease in glomerular filtration rate is observed during treatment.3 Logistic regression analyses have shown that the risk factors for nephrotoxicity development include older age, female gender, smoking, hypoalbuminaemia and paclitaxel coadministration. The nephrotoxic damage appears to be a clinical problem in 28–42% of patients applied cisplatin.4, 5 The principal site of damage is the proximal tubule in the outer renal medulla, particularly in the S3 segment and in the thick ascending limb of the loop of Henle or in the distal parts of the nephron segments.6 Several mechanisms contribute to dose-dependent and cumulative cisplatin-induced nephrotoxicity: DNA damage, oxidative stress, inhibition of protein synthesis, mitochondrial dysfunction, and involvement of receptors of the tumour necrosis factor (TNF) family and apoptosis of the renal epithelial cells.7, 8, 9

Great electrolyte abnormalities are often emerged from tubular reabsorption defects. One of them is hypomagnesaemia, initially described by Schilsky and Anderson in 1979.10 Renal tubular toxicity provides a mechanistic explanation. Sobrero and colleagues11 suggested that the active transport mechanism may become saturated, leading to an overconcentration of cisplatin in tubular cells with subsequent cellular necrosis. Magnesium and calcium are involved in the active cisplatin transport system, and decreasing their concentrations may contribute to the intensification of cisplatin toxicity effects toward the tubular cell in the kidney. One recent study has suggested that magnesium salt supplementation is a crucial factor in protection against the nephrotoxic actions of Cyclosporin A (CsA) in cell lines isolated from rat proximal tubules.12 It was demonstrated that low serum magnesium levels are associated with a faster rate of decline in kidney allograft function and increased rates of graft loss in renal transplant recipients with chronic CsA nephropathy.13 An experimental rat model study has indicated a substantial additive effect of magnesium-depletion on cisplatin induced renal toxicity as evidenced by significant changes in plasma creatinine and urea, renal failure induced mortality and loss of renal transporters. This should shed light on the nephrotoxicity observed during cisplatin treatment which might be substantiated by the known magnesium-loss associated with cisplatin treatment, particularly in patients affected by severe gastrointestinal side effects.14

The aim of this study was to examine the effect of magnesium supplementation on nephrotoxicity accompanying standard cisplatin-based chemotherapy in patients with ovarian cancer, and to assess the impact of this strategy on the outcome and toxicity of treatment.

Section snippets

Patients and methods

This prospective study included consecutive patients with ovarian cancer, after primary surgery, who qualified for first-line chemotherapy. The study protocol was approved by the local Ethics Committee, and written informed consent was obtained from all participants of the study.

Patients were assigned to receive six courses of the standard, first line chemotherapy consisting of 135 mg/m2 of intravenous infusion paclitaxel over a 24-h period on day 1 followed by 75 mg/m2 of intravenous infusion

Study population

Between January 2003 and January 2006, 41 women were randomly assigned: 20 and 21 women to the supplemented (study) and placebo (control) groups, respectively. One patient from the placebo group was ineligible for analysis because she withdrew the consent of participation in this study during the first cycle of chemotherapy. Table 1 shows the characteristics of the 40 eligible patients whose data form the basis of this report. There were no significant differences between both groups in

Discussion

Cisplatin appears to be a very important cytostatic agent but has numerous side-effects including a paramount one, nephrotoxicity, which has attracted much attention as the major dose-limiting factor. The mechanism by which cisplatin selectively does harm to renal tubular cells has not yet been fully elucidated. Similar to several nephrotoxic heavy metals, cisplatin may accumulate in the kidney to interact with sulfhydryl groups, following the increased membrane fragility and depletion of

Conflict of interest statement

None declared.

Acknowledgement

Support from the Military Institute of The Health Services, Warsaw, Poland, Grant No. WIM-1231/2004.

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      In a rat model, magnesium (Mg) supplementation showed a kidney-protective effect against CIN by regulating renal platinum accumulation via changes in cisplatin efflux transporter expression in the tubular epithelial cells [7]. In humans, the efficacy of Mg supplementation for CIN prevention was evaluated in several clinical trials in adults and showed promising results [8–12], but its efficacy in pediatric patients has not been thoroughly evaluated. Prior to designing the current study, we performed a retrospective study which suggested that Mg supplementation had a kidney-protective effect in a pediatric cancer cohort [13].

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