Hypomagnesemia is a common side effect of platinum‐based chemotherapy. This article examines the association between hypomagnesemia and survival in patients who underwent chemotherapy regimens containing carboplatin for ovarian cancer.
Keywords: Hypomagnesemia, Carboplatin, Survival, Ovarian cancer
Abstract
Background.
Hypomagnesemia is a known side effect of several antineoplastic agents, but its impact on outcomes of patients with cancer is not well understood. We examined whether magnesium abnormalities affect survival in patients with ovarian cancer who receive chemotherapy containing carboplatin.
Materials and Methods.
We included patients with advanced ovarian cancer who had undergone surgery and chemotherapy between January 1, 2004, and December 31, 2014, at our institution. Inclusion criteria were age 18 years or older, pathology of high‐grade serous carcinoma, first treatment (surgery or chemotherapy) within 60 days of diagnosis, and chemotherapy containing carboplatin. The final cohort consisted of 229 patients. Vital signs and laboratory tests were recorded at baseline and during the treatment course. The associations between magnesium abnormalities (and other clinical characteristics) and survival were analyzed.
Results.
The median patient age was 64 years. Higher baseline heart rate (beats per minute; hazard ratio [HR] = 1.02, p = .002) and greater frequency of hypomagnesemia during the treatment course (HR = 1.05, p = .002) were significantly associated with shorter survival independent of completeness of tumor reduction (HR = 1.60, p = .02), and International Federation of Gynecology and Obstetrics stage (HR = 1.63, p = .01).
Conclusion.
Baseline heart rate and the frequency of hypomagnesemia episodes during treatment are prognostic of survival for patients with advanced ovarian cancer receiving carboplatin‐containing chemotherapy and tumor reductive surgery. Future research is needed for strategies to detect and prevent hypomagnesemia in this patient population.
Implications for Practice.
Despite standard laboratory tests and intravenous magnesium replacement prior to each cycle of chemotherapy, hypomagnesemia remains a common side effect of platinum‐based chemotherapy. This study revealed that frequent occurrence of hypomagnesemia during the course of treatment including carboplatin‐containing chemotherapy and tumor reductive surgery was strongly predictive of shorter survival in patients with advanced ovarian cancer. Strategies to effectively mitigate hypomagnesemia, such as more frequent detection, dietary recommendations, and timely replacement, should be considered in the overall cancer treatment plan for these patients.
背景。低镁血症是几种抗肿瘤药物已知所具有的一种副作用，但尚不清楚其对癌症患者预后的影响。我们对镁异常是否会影响接受卡铂化疗的卵巢癌患者的生存期进行了调查。
材料和方法。我们招募了 2004 年 1 月 1 日至 2014 年 12 月 31 日在我院进行手术和化疗的晚期卵巢癌患者。入选标准为年满 18 岁，病理表现为高级别浆液性癌，诊断后 60 天内首次接受治疗(手术或化疗)，并且化疗包含卡铂。最终队列由 229 名患者组成。我们在基线和治疗过程中记录了生命体征和实验室测试。并对镁异常(和其他临床特征)与生存期之间的关系进行了分析。
结果。患者中位年龄为 64 岁。较高的基线心率 [每分钟心跳次数；风险比 (HR)= 1.02，p = 0.002]和治疗过程中较高的低镁血症发生频率(HR = 1.05，p = 0.002)与生存期较短有显著关系，无论减瘤是否完全(HR = 1.60， p = 0.02)以及国际妇产科联盟分期(HR = 1.63，p = 0.01)如何。
结论。基线心率和治疗过程中的低镁血症发作频率会影响接受卡铂化疗和减瘤手术的晚期卵巢癌患者的生存预后。未来需要研究用于检测和预防该患者群体出现低镁血症的策略。
实践意义:尽管在每个化疗周期前都进行了标准实验室测试和静脉注射镁替代药物，低镁血症仍然是铂类化疗的常见副作用。本研究表明，在治疗过程中(包括卡铂化疗和减瘤手术)频繁出现低镁血症预计会缩短晚期卵巢癌患者的生存期。在这些患者的整体癌症治疗计划中，应考虑采取有效减轻低镁血症的策略，例如提高检测频率，提供饮食建议以及及时更换化疗药物。
Introduction
Hypomagnesemia is a common side effect of platinum‐based chemotherapy. The incidence of hypomagnesemia was observed to be 20% after the first cycle and 100% after the sixth cycle of cisplatin‐based chemotherapy [1]. The mechanism of hypomagnesemia is most likely platinum‐induced renal tubular necrosis at the site of magnesium reabsorption [2]. The clinical relevance of hypomagnesemia in the population of patients with cancer is not well understood. Common clinical manifestations of hypomagnesemia, such as fatigue, irritation, muscle weakness, and constipation, are nonspecific and frequently seen in patients with cancer. Hypomagnesemia is linked to risks of diabetes, hypertension, coronary heart disease, ischemic stroke, and cardiac arrhythmias [3], [4]. It is also associated with rapid disease progression, more complications, and poor survival in patients with diabetes mellitus [5]. The evidence about the impact of hypomagnesemia on cancer progression and survival has been scant and conflicting. One study observed that cetuximab‐induced hypomagnesemia was associated with poor overall survival among patients with advanced colorectal cancer, and the severity of hypomagnesemia adversely correlated with overall survival [6]. However, in another report, among patients with advanced colorectal cancer treated with cetuximab plus irinotecan, those with hypomagnesemia were found to have a higher treatment response rate and longer overall survival than those with normal magnesium levels [7]. A recent meta‐analysis echoed the same beneficial association of hypomagnesemia with survival among 1,723 patients with metastatic colorectal cancer receiving cetuximab‐ or panitumumab‐based chemotherapy [8].
Our study examined the association of hypomagnesemia with survival among patients with ovarian cancer who underwent chemotherapy regimens containing carboplatin.
Materials and Methods
Study Design and Patients
This retrospective study was approved by The University of Texas MD Anderson Cancer Center's Institutional Review Board in accordance with an assurance filed with, and approved by, the Department of Health and Human Services. Using the tumor registry database of MD Anderson Cancer Center and pathology reports, we identified patients with ovarian cancer who underwent chemotherapy with carboplatin and tumor reduction surgery between January 1, 2004, and December 31, 2014, and who (a) were 18 years of age or older, (b) had pathology consistent with high‐grade serous carcinoma and high‐grade mixed serous and endometroid carcinoma, (c) received the first treatment (surgery or chemotherapy) at MD Anderson within 60 days of diagnosis, and (d) had an interval between treatments (chemotherapy and surgery) of less than 3 months.
The patients’ demographic data, including age, race, International Federation of Gynecology and Obstetrics (FIGO) stage, basal Eastern Cooperative Oncology Group (ECOG) scale, vital status, and date of death or date of last follow‐up, were obtained from the tumor registry, pathology report, and chart review. Data (December 1, 2003, to January 1, 2015) about International Classification of Diseases, Ninth Revision (ICD‐9) codes, vital signs, laboratory tests, and pharmacy dispensing records, including chemotherapy drug names and date of administration and intravenous magnesium sulfate dose and date of administration, were obtained from the MD Anderson Data Warehouse. Information about area under the concentration versus time curve (AUC) for carboplatin and the completeness of tumor reduction were obtained through chart review.
Baseline was defined as the period from 30 days before to the day of first chemotherapy administration or tumor reductive surgery, and treatment course was defined as the period from 1 day after the first administration of chemotherapy or surgery to 30 days after the last administration of chemotherapy. Body mass index was calculated using the formula weight in kg/(height in m)2. Charlson Comorbidity Index (CCI) was calculated using ICD‐9 codes [9]. Hypomagnesemia was defined as serum magnesium level <1.8 mg/dl, hyponatremia as serum sodium level <135 mEq/L, and hypokalemia as serum potassium level <3.5 mEq/L. Grade I hypomagnesemia was defined as a serum magnesium level less than normal to 1.2 mg/dL, grade II as <1.2 to 0.9 mg/dL, grade III as <0.9 to 0.7 mg/dL, and grade IV as <0.7 mg/dL, based on National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [10]. Frequency of hypomagnesemia was the number of occurrences of hypomagnesemia.
Statistical Analysis
The primary outcome was overall survival (OS). OS was defined as the number of days between the date of diagnosis of ovarian cancer and the date of death. If a patient was not known to be dead, survival time was censored at their last confirmed contact date with the health care system. We used descriptive statistics to analyze the frequencies, medians, means, and standard deviations of the study variables for the study cohort. Student's t test and the Mann‐Whitney rank sum test assessed statistical significance of continuous variables, and the chi‐squared test was used for categorical variables.
Univariate analysis of the association between individual clinical or laboratory characteristics and OS was performed using the Kaplan‐Meier method followed by the log‐rank test to compare the survival distributions within the group. Factors with p < .2 from the univariate analysis were considered for inclusion in multivariate models of survival data based on Cox proportional hazards regression, with variable selection using Akaike information criterion, and their hazard ratios were calculated along with the 95% confidence intervals. Correlation between clinical factors was evaluated using the Pearson product moment correlation or Wilcoxon signed‐rank test. After exploratory analyses, a final regression model was chosen, and results were considered significant if the p value was below .05. All statistical analyses were performed using R software (version 3.3.3, The R Foundation, http://www.r-project.org).
Results
Patient Characteristics
Figure 1 depicts the process of patient selection. The final cohort included 229 patients.
Figure 1.
Flow chart of patient selection.
*Patients excluded: previous treatments before presenting to our institution, changed from carboplatin to cisplatin, received intraperitoneal cisplatin.
†Histology excluded except high‐grade serous carcinoma, mixed high‐grade carcinoma with a major component of high‐grade serous carcinoma.
Abbreviation: AUC, area under the concentration versus time curve.
Patients’ demographics and characteristics of potential study confounders are illustrated in Table 1. The overall mortality rate was 75%. Most patients (75%) had optimal tumor reduction surgery. Eighty‐four percent (192) of patients had at least one incident of hypomagnesemia during the treatment course. Sixty‐three (28%) patients had hypomagnesemia at baseline. Grade I hypomagnesemia accounted for most of the occurrences (97%), with grade III occurring once among the study cohort. The median frequency of hypomagnesemia was four occurrences. Seventy‐six percent had early occurrence of hypomagnesemia (before the third cycle of carboplatin). The median cumulative intravenous magnesium sulfate dose was 1.97 g. The median heart rate at baseline was 86 beats per minute. ECOG score was available in 84 (37%) patients. Of these, 68 (81%) had a score of 0, and 11 (13%) had 1.
Table 1. Patient demographics and clinical characteristics.
Value during treatment course of chemotherapy and surgery.
Abbreviations: BMI, body mass index; CCI, Charlson Comorbidity Index; FIGO, International Federation of Gynecology and Obstetrics; IQR, interquartile range.
Univariate and Multivariate Analysis
The univariate of associations between demographic, clinical, and laboratory factors and OS is reported in Table 2.
Table 2. Univariate analysis of the clinical factors and survival.
Value during treatment course of chemotherapy and surgery.
Abbreviations: AUC, area under the concentration versus time curve; BMI, body mass index; CCI, Charlson Comorbidity Index; CI, confidence interval; FIGO, International Federation of Gynecology and Obstetrics; HR, hazard ratio.
In the univariate analysis, baseline heart rate, completeness of tumor reduction, CCI, and frequencies of hypomagnesemia and hypokalemia during the treatment course were all significantly associated with OS, whereas other factors such as age, AUC of carboplatin, systolic blood pressure at baseline, frequency of hyponatremia, and levels of hemoglobin, blood glucose, and creatinine during the treatment course were not. Presence of hypomagnesemia at baseline and early occurrence of hypomagnesemia were not predictive of survival.
Exploratory multivariate analysis (Table 3) started with nine factors that had p < .2 from the univariate analyses, whereas the number of carboplatin cycles and cumulative dose of intravenous magnesium sulfate were not included in the multivariate analysis because of their significant correlations with the frequency of hypomagnesemia during the treatment course. High baseline heart rate and frequent occurrence of hypomagnesemia remained significant factors predictive of adverse OS independent of the completeness of tumor reduction and FIGO stage.
Table 3. Multivariate Cox proportional hazard analysis of clinical factors and survival.
Value during treatment course of chemotherapy and surgery.
Abbreviations: CI, confidence interval; FIGO, International Federation of Gynecology and Obstetrics.
Correlation Between Variables
The occurrence of hypomagnesemia during the treatment course significantly correlated with that of hyponatremia (r = 0.22, p < .001) and hypokalemia (r = 0.39, p < .001). There was no significant difference in baseline creatinine level (p = .802) or CCI (p = .084) between patients with or without baseline hypomagnesemia. Both presence of hypomagnesemia at baseline (p < .001) and early occurrence of hypomagnesemia (p = .007) were associated with higher frequency of hypomagnesemia during treatment. The cumulative dose of intravenous magnesium sulfate correlated with chemotherapy cycles (r = 0.42, p < .001). Seventy‐nine percent of the intravenous magnesium infusions were given within 24 hours of a carboplatin cycle. Baseline heart rate did not correlate with baseline systolic blood pressure (r = −0.03, p = .651).
Discussion
Occurrence of hypomagnesemia is well reported among patients with ovarian cancer receiving platinum‐based chemotherapy. However, its impact on survival has not been reported in patients with ovarian cancer. Our study examined the association of hypomagnesemia and survival of patients with advanced ovarian cancer in a homogenous cohort in staging, pathology, and initial treatment strategies. The study revealed that the frequency of hypomagnesemia occurrence during the treatment course of carboplatin‐containing chemotherapy and tumor reductive surgery was a strong predictor of OS independent of many known confounding factors, including age and completeness of tumor reduction, as well as other electrolyte disturbances, despite its significant correlation with them. However, unlike the frequency of hypomagnesemia occurrence, both basal hypomagnesemia and early occurrence of hypomagnesemia during chemotherapy were not significantly associated with OS. Magnesium level was routinely measured at the time of each chemotherapy infusion; frequent occurrence of hypomagnesemia represents more of a persistence of this disturbance, rather than its severity. On the other hand, basal and early occurrence of hypomagnesemia may not be long lasting. It may be that persistent, rather than transient, hypomagnesemia has more of a significant impact on OS. Future study is needed to confirm this hypothesis.
Severe hypomagnesemia was not observed frequently in our study. Almost all of the hypomagnesemia in our study was grade I. This may be due to magnesium measurements being taken at the time of chemotherapy and not earlier in the weeks between chemotherapy administrations. Thus, the peak impact of carboplatin on magnesium metabolism, potentially occurring earlier in the cycle, may not have been captured. Our study was not able to observe the impact of the severity of hypomagnesemia on OS.
Our finding of hypomagnesemia as a negative predictor of survival conflicts with the role of hypomagnesemia in patients with advanced colorectal cancer treated with cetuximab; in those patients, early occurrence of hypomagnesemia is a predictor of survival advantage and considered a surrogate marker of treatment efficacy [11]. The renal effect of platinum agents is pathophysiologically different from that of cetuximab. Cisplatin, the most researched platinum agent, causes morphologically evident nephrotoxicity that may result in long‐term or even permanent damage to renal functions. Cetuximab, on the other hand, reduces renal magnesium reabsorption through a reversible effect of epidermal growth factor receptor inhibition in the renal distal convoluted tubule without causing extensive cell injury [12], [13]. Hypomagnesemia after cisplatin is more a biochemical index of nephrotoxicity than a marker of treatment efficacy [1]. Future studies are needed to examine the survival benefit of prevention of hypomagnesemia and nephrotoxicity in patients with malignancies that are primarily treated with platinum‐based chemotherapy.
Serum magnesium level is routinely monitored in patients receiving platinum‐based chemotherapy, and magnesium supplementation is recommended at each treatment cycle [1]. Consistently, our study showed a significant positive correlation between intravenous magnesium sulfate dose and number of chemotherapy cycles. Nearly 80% of the intravenous magnesium was given on the same day of carboplatin treatment. Hypomagnesemia and inhibition of renal magnesium uptake are observed to have an additive effect on cisplatin‐induced renal toxicity in animal models, whereas magnesium infusion significantly reduces renal cisplatin accumulation and cisplatin‐induced nephrotoxicity in a dose‐dependent manner [14], [15]. In a study of mice bearing colon tumors, magnesium supplementation was shown to protect against cisplatin cytotoxicity without compromising cisplatin's antitumor efficacy in vivo [16]. Our study adds critical clinical evidence that appeals for research effort to study the impact of magnesium supplementation on survival in patients with ovarian cancer receiving platinum‐based chemotherapy.
Magnesium is crucial to a wide range of biochemical reactions required for cell proliferation, differentiation, angiogenesis, and apoptosis. The benefit of magnesium supplementation is likely beyond reducing hypomagnesemia‐related symptoms. Because high‐dose intravenous magnesium replacement is not adequate to maintain the magnesium level beyond 72 hours [17], routine intravenous replacement of magnesium at each cycle will not effectively prevent the occurrence of hypomagnesemia. Oral magnesium supplementation is often poorly tolerated by patients because of its common side effect of diarrhea [17]. Our future studies will focus on developing optimum methods of magnesium supplementation to effectively prevent hypomagnesemia and on investigating its clinical relevance to renal protection and antitumor efficacy.
Although no specific correlations were identified between the presence of baseline hypomagnesemia and baseline systolic blood pressure or heart rate within our study cohort, higher baseline heart rate prior to the initial treatment, chemotherapy or surgery, was independently associated with shorter survival. Resting heart rate has been shown to be a strong predictor of cardiovascular mortality and morbidity in the general population as well as in patients with chronic heart failure, with higher heart rate associated with worse combined outcomes [18], [19], [20]. However, no threshold heart rates have been established. The relationship between rapid heart rate and cardiovascular mortality has been shown previously to be independent of systolic blood pressure [21]. In our study, the baseline heart rate did not have a negative correlation with systolic blood pressure, as one would predict in the setting of dehydration or orthostatic hypotension. The pathogenesis of the connection between high heart rates and cardiovascular death is not completely clear. The underlying mechanisms have been postulated to be poor physical fitness, subclinical loss of cardiac reserve, and imbalance of the autonomic nerve system [18], [22], [23]. Unhealthy lifestyle behaviors and psychological stress are also associated with rapid heart rate [24], [25]. Our study observation supports that integration of evaluating and optimizing patients’ cardiovascular and psychological conditions prior to and throughout the treatment course may help achieve optimal outcomes for patients with cancer.
The strengths of our study are its homogenous cohort (advanced ovarian cancer of high‐grade serous pathology, treated with carboplatin‐containing chemotherapy and tumor reductive surgery), data set of extensive confounding factors, and novel study findings. However, owing to its retrospective nature, our study has limitations. First, the causes of death were not available for analysis. Our outcome study was limited to OS without cause specific analysis. Laboratory tests may not have been collected during the same time frames relative to chemotherapy administrations and/or surgery. Screening for laboratory abnormalities could also have been limited by test frequency. The true severity and frequency of laboratory abnormalities may be underrepresented in our study. Levels of calcium and phosphorus were largely absent from our data set, so we were not able to include hypocalcemia and hypophosphatemia as factors in our analyses, even though these conditions can be present in patients with cancer receiving platinum‐based treatments, albeit less frequently than hypomagnesemia. Magnesium is an essential cofactor for vitamin D biosynthesis, activation, and transportation to target tissue [26]. In addition, nutritional calcium and magnesium ratio has significant influence on health outcomes [26]. Future prospective studies should include serum 25‐hydroxy‐vitamin D and parathyroid hormone levels (in addition to serum calcium and phosphate levels) to improve our understanding of the mechanism for hypomagnesemia after chemotherapy and strategies in the prevention. Data about oral magnesium replacement were also inadequate for analysis, as information about prescriptions filled outside our institution and patients’ compliance with or tolerance of the replacement was not available. But the current method of magnesium supplementation is nonetheless inadequate, as evidenced by the frequent occurrence of hypomagnesemia. The limited availability of data, such as baseline performance status and beta‐blocker use, also restricted our analysis from including all confounding factors.
Platinum‐based chemotherapy regimens are widely used in treating a variety of cancers. Our study observation provides important clinical evidence for future interventional trials on the impact of magnesium therapy on outcomes of patients with ovarian cancer.
Conclusion
Frequent occurrence of hypomagnesemia significantly predicts shorter overall survival in patients with advanced ovarian cancer undergoing chemotherapy containing carboplatin and tumor reductive surgery. Prevention of hypomagnesemia through more frequent monitoring and timely replacement is recommended. Fast heart rate prior to treatment is adversely associated with overall survival. Prevention of hypomagnesemia and optimizing cardiovascular condition may be important strategies in overall treatment planning to improve clinical outcomes for these patients. Future prospective studies are needed to confirm the benefits of these strategic interventions.
Contributed equally.
Author Contributions
Conception/design: Wenli Liu, Aiham Qdaisat, Lois Ramondetta, Eduardo Bruera, Sai‐Ching J. Yeung
Collection and/or assembly of data: Wenli Liu, Aiham Qdaisat
Data analysis and interpretation: Wenli Liu, Aiham Qdaisat, Sai‐Ching J. Yeung
Manuscript writing: Wenli Liu, Aiham Qdaisat, Pamela T. Soliman, Lois Ramondetta, Gabriel Lopez, Santhosshi Narayanan, Lorenzo Cohen, Eduardo Bruera, Sai‐Ching J. Yeung
Final approval of manuscript: Wenli Liu, Aiham Qdaisat, Sai‐Ching J. Yeung
Disclosures
The authors indicated no financial relationships.
References
- 1.Hodgkinson E, Neville‐Webbe HL, Coleman RE. Magnesium depletion in patients receiving cisplatin‐based chemotherapy. Clin Oncol 2006;18:710–718. [DOI] [PubMed] [Google Scholar]
- 2.Lajer H, Daugaard G. Cisplatin and hypomagnesemia. Cancer Treat Rev 1999;25:47–58. [DOI] [PubMed] [Google Scholar]
- 3.Bertinato J, Wang KC, Hayward S. Serum magnesium concentrations in the Canadian population and associations with diabetes, glycemic regulation, and insulin resistance. Nutrients 2017;9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Houston M. The role of magnesium in hypertension and cardiovascular disease. J Clin Hypertens 2011;13:843–847. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Sakaguchi Y, Shoji T, Hayashi T et al. Hypomagnesemia in type 2 diabetic nephropathy: A novel predictor of end‐stage renal disease. Diabet Care 2012;35:1591–1597. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Vickers MM, Karapetis CS, Tu D et al. Association of hypomagnesemia with inferior survival in a phase III, randomized study of cetuximab plus best supportive care versus best supportive care alone: NCIC CTG/AGITG CO.17. Ann Oncol 2013;24:953–960. [DOI] [PubMed] [Google Scholar]
- 7.Vincenzi B, Santini D, Galluzzo S et al. Early magnesium reduction in advanced colorectal cancer patients treated with cetuximab plus irinotecan as predictive factor of efficacy and outcome. Clin Cancer Res 2008;14:4219–4224. [DOI] [PubMed] [Google Scholar]
- 8.Hsieh MC, Wu CF, Chen CW et al. Hypomagnesemia and clinical benefits of anti‐EGFR monoclonal antibodies in wild‐type KRAS metastatic colorectal cancer: A systematic review and meta‐analysis. Sci Rep 2018;8:2047. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Charlson ME, Pompei P, Ales KL et al. A new method of classifying prognostic comorbidity in longitudinal studies: Development and validation. J Chron Dis 1987;40:373–383. [DOI] [PubMed] [Google Scholar]
- 10.National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, 2010. https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm. Accessed May 16, 2018.
- 11.Vincenzi B, Galluzzo S, Santini D et al. Early magnesium modifications as a surrogate marker of efficacy of cetuximab‐based anticancer treatment in KRAS wild‐type advanced colorectal cancer patients. Ann Oncol 2011;22:1141–1146. [DOI] [PubMed] [Google Scholar]
- 12.Muallem S and Moe OW. When EGF is offside, magnesium is wasted. J Clin Invest 2007;117:2086–2089. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Tejpar S, Piessevaux H, Claes K et al. Magnesium wasting associated with epidermal‐growth‐factor receptor‐targeting antibodies in colorectal cancer: A prospective study. Lancet Oncol 2007;8:387–394. [DOI] [PubMed] [Google Scholar]
- 14.Lajer H, Kristensen M, Hansen HH et al. Magnesium depletion enhances cisplatin‐induced nephrotoxicity. Cancer Chemother Pharmacol 2005;56:535–542. [DOI] [PubMed] [Google Scholar]
- 15.Saito Y, Okamoto K, Kobayashi M et al. Magnesium attenuates cisplatin‐induced nephrotoxicity by regulating the expression of renal transporters. Eur J Pharmac 2017;811:191–198. [DOI] [PubMed] [Google Scholar]
- 16.Kumar G, Solanki MH, Xue X et al. Magnesium improves cisplatin‐mediated tumor killing while protecting against cisplatin‐induced nephrotoxicity. Am J Physiol Renal Physiol 2017;313:F339–f350. [DOI] [PubMed] [Google Scholar]
- 17.Jiang DM, Dennis K, Steinmetz A et al. Management of epidermal growth factor receptor inhibitor‐induced hypomagnesemia: A systematic review. Clin Colorect Cancer 2016;15:e117–e123. [DOI] [PubMed] [Google Scholar]
- 18.Kannel WB, Kannel C, Paffenbarger RS Jr et al. Heart rate and cardiovascular mortality: The Framingham study. Am Heart J 1987;113:1489–1494. [DOI] [PubMed] [Google Scholar]
- 19.Lancellotti P, Ancion A, Magne J et al. Elevated heart rate at 24–36h after admission and in‐hospital mortality in acute in non‐arrhythmic heart failure. Int J Cardiol 2015;182:426–430. [DOI] [PubMed] [Google Scholar]
- 20.Böhm M, Swedberg K, Komajda M et al. Heart rate as a risk factor in chronic heart failure (SHIFT): The association between heart rate and outcomes in a randomised placebo‐controlled trial. Lancet 2010;376:886–894. [DOI] [PubMed] [Google Scholar]
- 21.Cooney MT, Vartiainen E, Laakitainen T et al. Elevated resting heart rate is an independent risk factor for cardiovascular disease in healthy men and women. Am Heart J 2010;159:612–619.e613. [DOI] [PubMed] [Google Scholar]
- 22.Thayer JF, Yamamoto SS, Brosschot JF. The relationship of autonomic imbalance, heart rate variability and cardiovascular disease risk factors. Int J Cardiol 2010;141:122–131. [DOI] [PubMed] [Google Scholar]
- 23.Guo Y, Palmer JL, Strasser F et al. Heart rate variability as a measure of autonomic dysfunction in men with advanced cancer. Eur J Cancer Care 2013;22:612–616. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Felber Dietrich D, Schwartz J, Schindler C et al. Effects of passive smoking on heart rate variability, heart rate and blood pressure: An observational study. Int J Epidemiol 2007;36:834–840. [DOI] [PubMed] [Google Scholar]
- 25.Ohira T, Diez Roux AV, Prineas RJ et al. Associations of psychosocial factors with heart rate and its short‐term variability: Multi‐ethnic study of atherosclerosis. Psychosomat Med 2008;70:141–146. [DOI] [PubMed] [Google Scholar]
- 26.Rosanoff A, Dai Q, Shapses SA. Essential nutrient interactions: Does low or suboptimal magnesium status interact with vitamin d and/or calcium status? Adv Nutr 2016;7:25–43. [DOI] [PMC free article] [PubMed] [Google Scholar]