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Published in: Targeted Oncology 4/2011

01-12-2011 | Review

Hypomagnesaemia and targeted anti-epidermal growth factor receptor (EGFR) agents

Authors: Andreia Costa, Sabine Tejpar, Hans Prenen, Eric Van Cutsem

Published in: Targeted Oncology | Issue 4/2011

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Abstract

Currently, targeted anti-epidermal growth factor receptor (EGFR) agents have an important role in the treatment of various cancers. These drugs, particularly anti-EGFR monoclonal antibodies, may induce electrolyte disorders, such as hypomagnesaemia and hypocalcaemia. Early symptoms of magnesium deficiency can easily go unrecognized. However, hypomagnesaemia can in rare cases lead to serious clinical manifestations, including cardiac arrhythmias or convulsions. The elective tubular expression of renal EGF/EGFR explains the mechanism of this class-related drug side effect. Inhibition of the EGFR induces a mutated-like transient receptor potential cation channel, subfamily M, member 6 (TRPM6) syndrome, characterized by urinary magnesium and calcium wasting. The risk of hypomagnesaemia is associated with treatment duration. It is a reversible toxicity; the recovery of magnesium serum levels is usually seen 4–6 weeks of stopping the anti-EGFR antibody. Using literature from peer-reviewed journals, this review reports the clinical trials findings and discusses the mechanisms and the treatment of hypomagnesaemia induced by anti-EGFR targeted agents.
Literature
1.
go back to reference Vivancoa I, Mellinghoff K (2010) Epidermal growth factor receptor inhibitors in oncology. Curr Op Oncol 22:573–578CrossRef Vivancoa I, Mellinghoff K (2010) Epidermal growth factor receptor inhibitors in oncology. Curr Op Oncol 22:573–578CrossRef
2.
go back to reference Izzedine H, Bahleda R, Khayat D et al (2010) Electrolyte disorders related to EGFR-targeting drugs. Crit Rev Oncol Hematol 73:213–219PubMedCrossRef Izzedine H, Bahleda R, Khayat D et al (2010) Electrolyte disorders related to EGFR-targeting drugs. Crit Rev Oncol Hematol 73:213–219PubMedCrossRef
3.
go back to reference Capdevila J, Elez E, Macarulla T, Ramos FJ, Ruiz-Echari M, Tabernero J (2009) Anti-epidermal growth factor receptor monoclonal antibodies in cancer treatment. Cancer Treat Rev 35:354–363PubMedCrossRef Capdevila J, Elez E, Macarulla T, Ramos FJ, Ruiz-Echari M, Tabernero J (2009) Anti-epidermal growth factor receptor monoclonal antibodies in cancer treatment. Cancer Treat Rev 35:354–363PubMedCrossRef
4.
go back to reference Dai LJ, Ritchie G, Kerstan D, Kang HS, Cole DE, Quamme GA (2001) Magnesium transport in the renal distal convoluted tubule. Physiol Rev 81:51–84PubMed Dai LJ, Ritchie G, Kerstan D, Kang HS, Cole DE, Quamme GA (2001) Magnesium transport in the renal distal convoluted tubule. Physiol Rev 81:51–84PubMed
5.
go back to reference Romani AM, Scarpa A (2000) Regulation of cellular magnesium. Front Bioscien 5:720–734CrossRef Romani AM, Scarpa A (2000) Regulation of cellular magnesium. Front Bioscien 5:720–734CrossRef
6.
go back to reference Ferment O, Garnier PE, Touitou Y (1987) Comparison of the feedback effect of magnesium and calcium on parathyroid hormone secretion in man. J Endocrinol 113:117–122PubMedCrossRef Ferment O, Garnier PE, Touitou Y (1987) Comparison of the feedback effect of magnesium and calcium on parathyroid hormone secretion in man. J Endocrinol 113:117–122PubMedCrossRef
7.
go back to reference Cholst IN, Steinberg SF, Tropper PJ, Fox HE, Segre GV, Bilezikian JP (1984) The influence of hypomagnesaemia on serum calcium and parathyroid hormone levels in human subjects. N Engl J Med 310:1221–1225PubMedCrossRef Cholst IN, Steinberg SF, Tropper PJ, Fox HE, Segre GV, Bilezikian JP (1984) The influence of hypomagnesaemia on serum calcium and parathyroid hormone levels in human subjects. N Engl J Med 310:1221–1225PubMedCrossRef
8.
go back to reference Konrad M, Schlingmann KP, Gudermann T (2004) Insights into the molecular nature of magnesium homeostasis. Am J Physiol Renal Physiol 286:599–605CrossRef Konrad M, Schlingmann KP, Gudermann T (2004) Insights into the molecular nature of magnesium homeostasis. Am J Physiol Renal Physiol 286:599–605CrossRef
9.
go back to reference Saif MW (2008) Management of Hypomagnesemia in cancer patients receiving chemotherapy. J Support Oncol 6:243–248PubMed Saif MW (2008) Management of Hypomagnesemia in cancer patients receiving chemotherapy. J Support Oncol 6:243–248PubMed
10.
11.
go back to reference Schrag D, Chung KY, Flombaum C, Saltz L (2005) Cetuximab therapy and symptomatic hypomagnesemia. J Natl Cancer Inst 97:1221–1224PubMedCrossRef Schrag D, Chung KY, Flombaum C, Saltz L (2005) Cetuximab therapy and symptomatic hypomagnesemia. J Natl Cancer Inst 97:1221–1224PubMedCrossRef
12.
go back to reference Fakih MG, Wilding G, Lombardo J (2006) Cetuximab-induced hypomagnesemia in patients with colorectal cancer. Clin Colorectal Cancer 6:152–156PubMedCrossRef Fakih MG, Wilding G, Lombardo J (2006) Cetuximab-induced hypomagnesemia in patients with colorectal cancer. Clin Colorectal Cancer 6:152–156PubMedCrossRef
13.
go back to reference Erbitux package insert. March 2006. ImClone Systems Incorporated, New York, NY 10014, USA, and Bristol-Myers Squibb Company, Princeton, NY 08543, USA Erbitux package insert. March 2006. ImClone Systems Incorporated, New York, NY 10014, USA, and Bristol-Myers Squibb Company, Princeton, NY 08543, USA
14.
go back to reference Tejpar S, Piessevaux H, Claes K et al (2007) Magnesium wasting associated with epidermal-growth-factor receptor-targeting antibodies in colorectal cancer: a prospective study. Lancet Oncol 8:387–394PubMedCrossRef Tejpar S, Piessevaux H, Claes K et al (2007) Magnesium wasting associated with epidermal-growth-factor receptor-targeting antibodies in colorectal cancer: a prospective study. Lancet Oncol 8:387–394PubMedCrossRef
15.
go back to reference Liu L, Cao Y, Tan A, Liao C, Gao F (2009) Cetuximab-based therapy versus non-cetuximab therapy for advanced cancer: a meta-analysis of 17 randomized controlled trials. Cancer Chemother Pharmacol 65:849–861PubMedCrossRef Liu L, Cao Y, Tan A, Liao C, Gao F (2009) Cetuximab-based therapy versus non-cetuximab therapy for advanced cancer: a meta-analysis of 17 randomized controlled trials. Cancer Chemother Pharmacol 65:849–861PubMedCrossRef
16.
go back to reference Jonker DJ, O’Callaghan CJ, Karapetis CS et al (2007) Cetuximab for the treatment of colorectal cancer. N Engl J Med 357:2040–2048PubMedCrossRef Jonker DJ, O’Callaghan CJ, Karapetis CS et al (2007) Cetuximab for the treatment of colorectal cancer. N Engl J Med 357:2040–2048PubMedCrossRef
17.
go back to reference Sobrero AF, Maurel J, Fehrenbacher L et al (2008) EPIC: phase III trial of cetuximab plus irinotecan after Fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol 26:2311–2319PubMedCrossRef Sobrero AF, Maurel J, Fehrenbacher L et al (2008) EPIC: phase III trial of cetuximab plus irinotecan after Fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol 26:2311–2319PubMedCrossRef
18.
go back to reference Tol J, Koopman M, Rodenburg CJ et al (2008) A randomised phase III study on capecitabine, oxaliplatin and bevacizumab with or without cetuximab in first-line advanced colorectal cancer, the CAIRO2 study of the Dutch Colorectal Cancer Group (DCCG). An interim analysis of toxicity. Ann Oncol 19:734–738PubMedCrossRef Tol J, Koopman M, Rodenburg CJ et al (2008) A randomised phase III study on capecitabine, oxaliplatin and bevacizumab with or without cetuximab in first-line advanced colorectal cancer, the CAIRO2 study of the Dutch Colorectal Cancer Group (DCCG). An interim analysis of toxicity. Ann Oncol 19:734–738PubMedCrossRef
19.
go back to reference Butts CA, Bodkin D, Middleman EL et al (2007) Randomized phase II study of gemcitabine plus cisplatin or carboplatin [corrected], with or without cetuximab, as first-line therapy for patients with advanced or metastatic non small-cell lung cancer. J Clin Oncol 25(36):5777–5784, Erratum in: J Clin Oncol (2008) 26:3295PubMedCrossRef Butts CA, Bodkin D, Middleman EL et al (2007) Randomized phase II study of gemcitabine plus cisplatin or carboplatin [corrected], with or without cetuximab, as first-line therapy for patients with advanced or metastatic non small-cell lung cancer. J Clin Oncol 25(36):5777–5784, Erratum in: J Clin Oncol (2008) 26:3295PubMedCrossRef
20.
go back to reference Burtness B, Goldwasser MA, Flood W, Mattar B, Forastiere AA, Eastern Cooperative Oncology Group (2005) Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: an Eastern Cooperative Oncology Group study. J Clin Oncol 23(34):8646–8654, Erratum in: J Clin Oncol (2006) 24:724PubMedCrossRef Burtness B, Goldwasser MA, Flood W, Mattar B, Forastiere AA, Eastern Cooperative Oncology Group (2005) Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: an Eastern Cooperative Oncology Group study. J Clin Oncol 23(34):8646–8654, Erratum in: J Clin Oncol (2006) 24:724PubMedCrossRef
21.
go back to reference Vermorken JB, Mesia R, Rivera F et al (2008) Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 359:1116–1127PubMedCrossRef Vermorken JB, Mesia R, Rivera F et al (2008) Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 359:1116–1127PubMedCrossRef
22.
go back to reference Vincenzi B, Santini D, Galluzzo S et al (2008) Patients treated with cetuximab plus irinotecan as early magnesium reduction in advanced colorectal predictive factor of efficacy and outcome. Clin Cancer Res 14:4219–4224PubMedCrossRef Vincenzi B, Santini D, Galluzzo S et al (2008) Patients treated with cetuximab plus irinotecan as early magnesium reduction in advanced colorectal predictive factor of efficacy and outcome. Clin Cancer Res 14:4219–4224PubMedCrossRef
23.
go back to reference Vincenzi B, Galluzzo S, Santini D et al (2011) Early magnesium modifications as a surrogate marker of efficacy of cetuximab-based anticancer treatment in KRAS wild-type advanced colorectal cancer patients. Ann Oncol 22:1141–1146. doi:10.1093/annonc/mdq550 PubMedCrossRef Vincenzi B, Galluzzo S, Santini D et al (2011) Early magnesium modifications as a surrogate marker of efficacy of cetuximab-based anticancer treatment in KRAS wild-type advanced colorectal cancer patients. Ann Oncol 22:1141–1146. doi:10.​1093/​annonc/​mdq550 PubMedCrossRef
24.
go back to reference Vickers MM, Karapetis CS, Tu D et al (2011) The influence of hypomagnesemia (hMg) on overall survival (OS) in phase III randomized study of cetuximab (CET) plus best supportive care (BSC) versus BSC: NCIC CTG/AGITG CO. 17. J Clin Oncology 29(suppl):abstr. 3601 Vickers MM, Karapetis CS, Tu D et al (2011) The influence of hypomagnesemia (hMg) on overall survival (OS) in phase III randomized study of cetuximab (CET) plus best supportive care (BSC) versus BSC: NCIC CTG/AGITG CO. 17. J Clin Oncology 29(suppl):abstr. 3601
26.
go back to reference Van Cutsem E, Peeters M, Siena S et al (2007) Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 25:1658–1664PubMedCrossRef Van Cutsem E, Peeters M, Siena S et al (2007) Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 25:1658–1664PubMedCrossRef
27.
go back to reference Hecht JR, Mitchell E, Chidiac T et al (2008) A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol 27:672–680PubMedCrossRef Hecht JR, Mitchell E, Chidiac T et al (2008) A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol 27:672–680PubMedCrossRef
28.
go back to reference Dimke H, van der Wijst J, Alexander TR et al (2010) Effects of the EGFR inhibitor erlotinib on magnesium handling. J Am Soc Nephrol 21:1309–1316PubMedCrossRef Dimke H, van der Wijst J, Alexander TR et al (2010) Effects of the EGFR inhibitor erlotinib on magnesium handling. J Am Soc Nephrol 21:1309–1316PubMedCrossRef
29.
go back to reference Hoenderop JG, Bindels RJ (2005) Epithelial Ca2+ and Mg2+ channels in health and disease. J Am Soc Nephrol 16:15–26PubMedCrossRef Hoenderop JG, Bindels RJ (2005) Epithelial Ca2+ and Mg2+ channels in health and disease. J Am Soc Nephrol 16:15–26PubMedCrossRef
30.
go back to reference Quamme GA (1997) Renal magnesium handling: new insights in understanding old problems. Kidney Int 52:1180–1195PubMedCrossRef Quamme GA (1997) Renal magnesium handling: new insights in understanding old problems. Kidney Int 52:1180–1195PubMedCrossRef
31.
go back to reference Voets T, Nilius B, Hoefs S et al (2004) TRPM6 forms the Mg2+ influx channel involved in intestinal and renal Mg2+ absorption. J Biol Chem 279:19–25PubMedCrossRef Voets T, Nilius B, Hoefs S et al (2004) TRPM6 forms the Mg2+ influx channel involved in intestinal and renal Mg2+ absorption. J Biol Chem 279:19–25PubMedCrossRef
32.
go back to reference Simon DB, Lu Y, Choate KA et al (1999) Paracellin-1, a renal tight junction protein required for paracellular Mg2+ resorption. Science 285(5424):103–106PubMedCrossRef Simon DB, Lu Y, Choate KA et al (1999) Paracellin-1, a renal tight junction protein required for paracellular Mg2+ resorption. Science 285(5424):103–106PubMedCrossRef
33.
go back to reference Schlingmann KP, Weber S, Peters M et al (2002) Hypomagnesemia with secondary hypocalcemia is caused by mutations in TRPM6, a new member of the TRPM gene family. Nat Genet 31:166–170PubMedCrossRef Schlingmann KP, Weber S, Peters M et al (2002) Hypomagnesemia with secondary hypocalcemia is caused by mutations in TRPM6, a new member of the TRPM gene family. Nat Genet 31:166–170PubMedCrossRef
34.
go back to reference Walder RY, Landau D, Meyer P et al (2002) Mutation of TRPM6 causes familial hypomagnesemia with secondary hypocalcemia. Nat Genet 31:171–174PubMedCrossRef Walder RY, Landau D, Meyer P et al (2002) Mutation of TRPM6 causes familial hypomagnesemia with secondary hypocalcemia. Nat Genet 31:171–174PubMedCrossRef
35.
go back to reference Müller D, Kausalya PJ, Meij IC, Hunziker W (2006) Familial hypomagnesemia with hypercalciuria and nephrocalcinosis: blocking endocytosis restores surface expression of a novel claudin-16 mutant that lacks the entire C-terminal cytosolic tail. Hum Mol Genet 15:1049–1058PubMedCrossRef Müller D, Kausalya PJ, Meij IC, Hunziker W (2006) Familial hypomagnesemia with hypercalciuria and nephrocalcinosis: blocking endocytosis restores surface expression of a novel claudin-16 mutant that lacks the entire C-terminal cytosolic tail. Hum Mol Genet 15:1049–1058PubMedCrossRef
36.
go back to reference Konrad M, Schaller A, Seelow D et al (2006) Mutations in the tight-junction gene claudin 19 (CLDN19) are associated with renal magnesium wasting, renal failure, and severe ocular involvement. Am J Hum Genet 79:949–957PubMedCrossRef Konrad M, Schaller A, Seelow D et al (2006) Mutations in the tight-junction gene claudin 19 (CLDN19) are associated with renal magnesium wasting, renal failure, and severe ocular involvement. Am J Hum Genet 79:949–957PubMedCrossRef
37.
go back to reference Groenestege WM, Thébault S, van der Wijst J et al (2007) Impaired basolateral sorting of pro-EGF causes isolated recessive renal hypomagnesemia. J Clin Invest 117:2260–2267PubMedCrossRef Groenestege WM, Thébault S, van der Wijst J et al (2007) Impaired basolateral sorting of pro-EGF causes isolated recessive renal hypomagnesemia. J Clin Invest 117:2260–2267PubMedCrossRef
38.
go back to reference Salido EC, Barajas L, Lechago J, Laborde NP, Fisher DA (1986) Immunocytochemical localization of epidermal growth factor in mouse kidney. J Histochem Cytochem 34:1155–1160PubMedCrossRef Salido EC, Barajas L, Lechago J, Laborde NP, Fisher DA (1986) Immunocytochemical localization of epidermal growth factor in mouse kidney. J Histochem Cytochem 34:1155–1160PubMedCrossRef
39.
go back to reference Gesualdo L, Di Paolo S, Calabró A et al (1996) Expression of epidermal growth factor and its receptor in normal and diseased human kidney: an immunohistochemical and in situ hybridization study. Kidney Int 49:656–665PubMedCrossRef Gesualdo L, Di Paolo S, Calabró A et al (1996) Expression of epidermal growth factor and its receptor in normal and diseased human kidney: an immunohistochemical and in situ hybridization study. Kidney Int 49:656–665PubMedCrossRef
40.
go back to reference Rall LB, Scott J, Bell GI et al (1985) Mouse prepro-epidermal growth factor synthesis by the kidney and other tissues. Nature 313:228–231PubMedCrossRef Rall LB, Scott J, Bell GI et al (1985) Mouse prepro-epidermal growth factor synthesis by the kidney and other tissues. Nature 313:228–231PubMedCrossRef
41.
go back to reference Bell GI, Fong NM, Stempien MM et al (1986) Human epidermal growth factor precursor: cDNA sequence, expression in vitro and gene organization. Nucl Acids Res 14:8427–8446PubMedCrossRef Bell GI, Fong NM, Stempien MM et al (1986) Human epidermal growth factor precursor: cDNA sequence, expression in vitro and gene organization. Nucl Acids Res 14:8427–8446PubMedCrossRef
Metadata
Title
Hypomagnesaemia and targeted anti-epidermal growth factor receptor (EGFR) agents
Authors
Andreia Costa
Sabine Tejpar
Hans Prenen
Eric Van Cutsem
Publication date
01-12-2011
Publisher
Springer-Verlag
Published in
Targeted Oncology / Issue 4/2011
Print ISSN: 1776-2596
Electronic ISSN: 1776-260X
DOI
https://doi.org/10.1007/s11523-011-0200-y

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