Skip to main content

Advertisement

SpringerLink
Log in

Efficacy and safety of oral magnesium supplementation in reducing febrile neutropenia episodes in children with solid tumors treated with cisplatin-based chemotherapy: randomized clinical trial

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Hypomagnesemia has been associated with febrile neutropenia (FN) in pediatric patients receiving cisplatin-based chemotherapy (CDDPBC). The primary aim was to determine whether oral magnesium supplementation reduces FN episodes in pediatric patients with solid tumors treated with CDDPBC.

Method

This randomized clinical trial, with open-label, single-center, parallel group and superiority design was conducted in Hospital Infantil de Mexico Federico Gomez at Mexico City. Children ≥ 9 years with solid tumors that were to receive a CDDPBC cycle were invited to participate. Each chemotherapy cycle with CDDPBC was randomly assigned to receive oral magnesium supplementation (250 mg/day) or not receive magnesium supplementation (control group). Efficacy was determined by relative risks (RR) with 95% confidence intervals (95% CI) as well as with numbers needed to treat (NNT). Active surveillance was conducted to assess safety in both groups. Analyses were carried out by intention to treat. ClinicalTrials.gov number NCT03449693.

Results

One hundred and one chemotherapy cycles with CDDPBC were analyzed (50 in the magnesium supplement arm and 51 in control group). Baseline clinical characteristics were similar comparing both groups. Oral magnesium supplementation reduces FN episodes compared to control group [RR 0.53, (95% CI 0.32–0.89), NNT = 4]. In the supplemented group, patients had fewer episodes of septic shock secondary to FN [RR 0.43, (95% CI 0.02–0.94), NNT = 6] and FN appeared on average 5 days later (p = 0.031). Hypomagnesemia episodes and adverse events were similar across both groups.

Conclusion

Oral supplementation with magnesium reduces FN episodes neutropenia in pediatric patients with solid tumors treated with CDDPBC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Availability of data and material

The database generated during the current study is not publicity available due to patient privacy laws, but is available from the corresponding author on reasonable request.

References

  1. Mueller EL, Sabbatini A, Gebremariam A, Mody R, Sung L, Macy ML (2015) Why pediatric patients with cancer visit the emergency department: United States, 2006–2010. Pediatr Blood Cancer 62(3):490–495. https://doi.org/10.1002/pbc.25288

    Article  Google Scholar 

  2. Klaassen RJ, Goodman TR, Pham B, Doyle JJ (2000) “Low-risk” prediction rule for pediatric oncology patients presenting with fever and neutropenia. J Clin Oncol 18(5):1012–1019. https://doi.org/10.1200/JCO.2000.18.5.1012

    Article  CAS  PubMed Central  Google Scholar 

  3. Zsiros J, Brugieres L, Brock P et al (2013) Dose-dense cisplatin-based chemotherapy and surgery for children with high-risk hepatoblastoma (SIOPEL-4): a prospective, single-arm, feasibility study. Lancet Oncol 14(9):834–842. https://doi.org/10.1016/S1470-2045(13)70272-9

    Article  CAS  PubMed Central  Google Scholar 

  4. Bajpai J, Chandrasekharan A, Talreja V et al (2017) Outcomes in non-metastatic extremity osteosarcoma treatment naive patients treated with a novel non-high-dose methotrexate-based, dose-dense combination chemotherapy regimen ‘OGS-12’. Eur J Cancer 85:49–58. https://doi.org/10.1016/j.ejca.2017.08.013

    Article  CAS  Google Scholar 

  5. Kooijmans EC, Bökenkamp A, Tjahjadi NS et al (2019) Early and late adverse renal effects after potentially nephrotoxic treatment for childhood cancer. Cochrane Database Syst Rev 3:CD008944. https://doi.org/10.1002/14651858.CD008944.pub3

    Article  Google Scholar 

  6. Lajer H, Daugaard G (1999) Cisplatin and hypomagnesemia. Cancer Treat Rev 25(1):47–58

    Article  CAS  Google Scholar 

  7. Lajer H, Kristensen M, Hansen HH, Christensen S, Jonassen T, Daugaard G (2005) Magnesium and potassium homeostasis during cisplatin treatment. Cancer Chemother Pharmacol 55(3):231–236. https://doi.org/10.1007/s00280-004-0899-6

    Article  CAS  Google Scholar 

  8. Castelán-Martinez OD, Rodriguez-Islas F, Vargas-Neri JL et al (2016) Risk factors for febrile neutropenia in children with solid tumors treated with cisplatin-based chemotherapy. J Pediatr Hematol Oncol 38(3):191–196. https://doi.org/10.1097/mph.0000000000000515

    Article  Google Scholar 

  9. Galland L (1988) Magnesium and immune function: an overview. Magnesium 7(5–6):290–299

    CAS  Google Scholar 

  10. Zimowska W, Girardeau JP, Kuryszko J, Bayle D, Rayssiguier Y, Mazur A (2002) Morphological and immune response alterations in the intestinal mucosa of the mouse after short periods on a low-magnesium diet. Br J Nutr 88(5):515–522

    Article  CAS  PubMed Central  Google Scholar 

  11. Martin M, Diaz-Rubio E, Casado A, López Vega JM, Sastre J, Almenarez J (1992) Intravenous and oral magnesium supplementations in the prophylaxis of cisplatin-induced hypomagnesemia: results of a controlled trial. Am J Clin Oncol 15(4):348–351. https://doi.org/10.1097/00000421-199208000-00016

    Article  CAS  PubMed Central  Google Scholar 

  12. National Cancer Institute (2017) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x11.pdf. Accessed 05 Dec 2019

  13. Bodey GP, Buckley M, Sathe YS, Freireich EJ (1966) Quantitative relationships between circulating leukocytes and infection in patients with acute leukemia. Ann Intern Med 64(2):328–340

    Article  CAS  PubMed Central  Google Scholar 

  14. American College of Chest Physician/Society of Critical Care Medicine Consensus Conference: definition for sepsis and organ failure guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992; 20(6):864–874.

  15. Musso CG (2009) Magnesium metabolism in health and disease. Int Urol Nephrol 41(2):357–362

    Article  CAS  PubMed Central  Google Scholar 

  16. Institute of Medicine (US) Standing Committee on the Scientific Evaluation of Dietary Reference Intakes (1997) Magnesium. In: Dietary reference intakes for calcium, phosphorus, magnesium, vitamin d, and fluoride. National Academies Press (US), Washington (DC), pp 190–248

  17. Willox JC, McAllister EJ, Sangster G, Kaye SB (1986) Effects of magnesium supplementation in testicular cancer patients receiving cis-platin: a randomised trial. Br J Cancer 54(1):19–23

    Article  CAS  PubMed Central  Google Scholar 

  18. Cojocaru IM, Cojocaru M, Tanasescu R, Iacob SA, Iliescu I (2009) Changes of magnesium serum levels in patients with acute ischemic stroke and acute infections. Rom J Intern Med 47(2):169–171

    PubMed Central  Google Scholar 

  19. Ravell J, Otim I, Nabalende H (2018) Plasma magnesium is inversely associated with Epstein–Barr virus load in peripheral blood and Burkitt lymphoma in Uganda. Cancer Epidemiol 52:70–74. https://doi.org/10.1016/j.canep.2017.12.004

    Article  PubMed Central  Google Scholar 

  20. Van Laecke S, Vermeiren P, Nagler EV et al (2016) Magnesium and infection risk after kidney transplantation: an observational cohort study. J Infect 73(1):8–17. https://doi.org/10.1016/j.jinf.2016.04.007

    Article  Google Scholar 

  21. Meisel P, Schwahn C, Luedemann J, John U, Kroemer HK, Kocher T (2005) Magnesium deficiency is associated with periodontal disease. J Dent Res 84(10):937–941. https://doi.org/10.1177/154405910508401012

    Article  CAS  Google Scholar 

  22. Limaye CS, Londhey VA, Nadkar MY, Borges NE (2011) Hypomagnesemia in critically ill medical patients. J Assoc Physicians India 59:19–22

    CAS  Google Scholar 

  23. Thongprayoon C, Cheungpasitporn W, Erickson SB (2015) Admission hypomagnesemia linked to septic shock in patients with systemic inflammatory response syndrome. Ren Fail 37(9):1518–1521. https://doi.org/10.3109/0886022X.2015.1074519

    Article  Google Scholar 

  24. Jiang P, Lv Q, Lai T, Xu F (2017) Does hypomagnesemia impact on the outcome of patients admitted to the intensive care unit? A systematic review and meta-analysis. Shock 47(3):288–295

    Article  CAS  Google Scholar 

  25. Simental-Mendía LE, Simental-Mendía M, Sahebkar A, Rodríguez-Morán M, Guerrero-Romero F (2017) Effect of magnesium supplementation on lipid profile: a systematic review and meta-analysis of randomized controlled trials. Eur J Clin Pharmacol 73(5):525–536. https://doi.org/10.1007/s00228-017-2212-8

    Article  CAS  Google Scholar 

  26. Simental-Mendia LE, Sahebkar A, Rodriguez-Moran M, Zambrano-Galvan G, Guerrero-Romero F (2017) Effect of magnesium supplementation on plasma C-reactive protein concentrations: a systematic review and meta-analysis of randomized controlled trials. Curr Pharm Des 23(31):4678–4686

    Article  CAS  Google Scholar 

  27. Zarif Yeganeh M, Vakili M, Shahriari-Ahmadi A, Nojomi M (2016) Effect of oral magnesium oxide supplementation on cisplatin-induced hypomagnesemia in cancer patients: a randomized controlled trial. Iran J Public Health 45(1):54–62

    PubMed Central  Google Scholar 

  28. Wood L, Egger M, Gluud LL et al (2008) Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta-epidemiological study. BMJ 336(7644):601–605

    Article  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank all patients and their families for participating in the study. This clinical trial was supported by the National Autonomous University of Mexico (Grant PAPIIT-IA207417). Victoria E. Barrios-López would like to thank CONACYT for supporting her postgraduate studies trough the scholarship no. 827608.

Funding

This clinical trial was supported by the National Autonomous University of Mexico (Grant PAPIIT-IA207417).

Author information

Authors and Affiliations

  1. Clinical Pharmacology Laboratory, UMIEZ, Facultad de Estudios Superiores Zaragoza, UNAM, Batalla 5 de mayo s/n esquina Fuerte de Loreto, Col. Ejército de Oriente, Iztapalapa, CP 09230, Mexico City, Mexico

    Osvaldo D. Castelán-Martínez & Karla M. Silva-Jivaja

  2. Onco-Hematology Department, Hospital Infantil de México Federico Gómez, Mexico City, Mexico

    Miguel A. Palomo-Colli, Victoria E. Barrios-López & Luis E. Juárez-Villegas

  3. Pharmacology Department, Centro de Investigación y Estudios Avanzados del Instituto Politécnico Nacional, Mexico City, Mexico

    Victoria E. Barrios-López & Gilberto Castañeda-Hernández

  4. Research Uniton Gerontology, Facultad de Estudios Superiores Zaragoza, UNAM, Mexico City, Mexico

    Martha A. Sánchez-Rodríguez

Authors
  1. Osvaldo D. Castelán-Martínez
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Miguel A. Palomo-Colli
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Victoria E. Barrios-López
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Karla M. Silva-Jivaja
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Luis E. Juárez-Villegas
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gilberto Castañeda-Hernández
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Martha A. Sánchez-Rodríguez
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

ODCM carried out conceptualization, funding acquisition, methodology formal analysis, data interpretation and project administration and wrote the original draft. MAP-C performed conceptualization, funding acquisition, investigation and formal analysis and wrote the original draft. VEB-L contributed to investigation, formal analysis, project administration and data curation and wrote the original draft. KMS-J conducted formal analysis and data curation and wrote the original draft. LEJ-V and GC-H were involved in investigation and data interpretation and wrote the original draft. MAS-R took part in investigation and wrote the original draft.

Corresponding author

Correspondence to Osvaldo D. Castelán-Martínez.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethics approval

The study was approved by Hospital Infantil de México Federico Gómez Institutional Review Board (HIM 2017–85).

Consent to participate

Written informed consent and written assent were obtained from the parents and children, respectively.

Consent for publication

All patients and parents provided written informed consent prior to initiation of study procedures. No identifying patients’ details, images or videos are used in this manuscript.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Castelán-Martínez, O.D., Palomo-Colli, M.A., Barrios-López, V.E. et al. Efficacy and safety of oral magnesium supplementation in reducing febrile neutropenia episodes in children with solid tumors treated with cisplatin-based chemotherapy: randomized clinical trial. Cancer Chemother Pharmacol 86, 673–679 (2020). https://doi.org/10.1007/s00280-020-04155-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-020-04155-4

Keywords

Search

Navigation