【全文发布】(中文版)抗EGFR单克隆抗体引起低镁血症
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RESOURCE: Lancet Oncology 2007; 8:366-367
DOI:10.1016/S1470-2045(07)70111-0
TITLE: Anti-EGFR monoclonal antibody-induced hypomagnesaemia
AUTHOR: Marwan Fakih
第一部分:
The use of monoclonal antibodies against the epidermal growth factor receptor (EGFR) has an integral role in the management of patients with metastatic colorectal cancer. Cetuximab (Erbitux, ImClone Systems Incorporated, NY, USA, and Bristol-Myers Squibb Company, NY, USA) is incorporated commonly in the second-line or third-line treatment of metastatic colorectal cancer, based on favourable time-to-progression (TTP) and response-rate outcomes from the Bowel Oncology with Cetuximab Antibody (BOND) study.1 The incorporation of this monoclonal antibody in the first-line treatment of metastatic colorectal cancer is becoming increasingly probable because of initial favourable TTP results from a randomised study of fluorouracil (FU), leucovorin, and irinotecan, with or without cetuximab.2 Hypomagnesaemia is one of the commonly noted side-effects of this class of agents. Severe hypomagnesaemia (grade 3 to 4) has been seen in 8 of 22 (36%) and 13 of 48 (27%) patients evaluable for hypomagnesaemia who were treated with cetuximab.3,4 A review of 244 patients treated with cetuximab estimated a more conservative 10–15% incidence of severe hypomagnesaemia.5
In this issue of The Lancet Oncology, Tejpar and colleagues6 report on the first prospective clinical study to characterise magnesium wasting in patients with metastatic colorectal cancer who are treated with monoclonal antibodies that target the EGFR. The study elegantly investigated magnesium wasting by measuring the slope of magnesium concentrations over time (starting from baseline) in 98 patients treated with EGFR-targeting monoclonal antibodies. A model investigating three early time points (weeks 0, 4, and 8) to characterise the slope of magnesium concentrations was shown to be predictive for the magnesium concentration slope during the whole treatment duration. The study further characterised this hypomagnesaemia to be related to magnesium wasting at the renal distal convoluted tubule. 97% of patients had some degree of magnesium wasting during treatment with EGFR-targeting monoclonal antibodies. However, significant interpatient variability in the serum magnesium concentration slopes was noted. Despite the frequency of magnesium wasting in the studied population, the percentage of grade 3 to 4 toxicities was modest at six of 98 (6%) and at odds with all previous reports.3,4 While it is feasible that the previous retrospective studies had higher proportions of patients with a longer duration of treatment, and therefore, a higher likelihood of hypomagnesaemia, it is not clear why the numbers of patients with severe hypomagnesaemia in the study by Tejpar and co-workers were substantially less then the 10–15% noted in the meta-analysis of various cetuximab studies.5 A shorter median duration of treatment or an earlier magnesium-replacement intervention might have resulted in an underestimation of severe hypomagnesaemia in the Tejpar report.
第二部分：
Martyn F Chillmaid/Science Photo Library
To my knowledge, the Tejpar study is the first to show that some degree of hypomagnesaemia occurs in almost all patients receiving EGFR-targeting monoclonal antibodies. Consistent with previous reports, clinically significant hypomagnesaemia (grade 2 or above) affected only a small group of patients receiving EGFR-targeting monoclonal antibodies. The clinical characterisation of age, baseline magnesium concentrations, and duration of treatment as risk factors is important, and suggests that this group of patients should be screened more vigorously with repeated measurements of magnesium concentrations during treatment. Also, the characterisation of a slope for magnesium decline based on three magnesium concentrations during early treatment could have significant clinical implications, but only if the amount of early decline is shown to be predictive of the development of clinically significant hypomagnesaemia. Is there a threshold slope below which one can predict which patients will develop grade 2 and above hypomagnesaemia? Can the slope for an individual patient decide the time at which clinically significant hypomagnesaemia will occur? How accurate is this predictive model? These questions cannot be answered adequately from this study because of the limited number of patients who have grade 2 or above hypomagnesaemia. Validation of the findings reported in this issue in a larger prospective study, with an aim of developing an accurate predictive model for severe hypomagnesaemia is, therefore, urgently needed. Only then will clinicians be able to identify early on which patients receiving EGFR-targeting monoclonal antibodies will probably develop severe hypomagnesaemia. The magnesium concentrations in these high-risk patients can be monitored intensively, whereas less frequent monitoring of patients at low risk for hypomagnesaemia will be possible. Alternative strategies for these high-risk populations include use of intermittent cetuximab treatment to avoid the development of severe hypomagnesaemia and its complications. Such an intermittent treatment strategy has been shown to be successful for other agents that cause cumulative toxicities, such as oxaliplatin.7 At the Roswell Park Cancer Institute, we have implemented a cetuximab stop-and-go approach in patients with grade 3 and above hypomagnesaemia needing more than three times weekly infusions of intravenous magnesium replacement. Our experience confirms the complete resolution of hypomagnesaemia within 2 months of stopping, and the feasibility of rechallenge with cetuximab when magnesium concentrations return to normal. In these patients, severe hypomagnesaemia recurs rarely within 2 months from the start of cetuximab rechallenge.
第三部分：
Hypomagnesaemia is frequently seen in the palliative treatment setting, and guidelines need to be formulated regarding the magnesium concentrations at which a replacement drug intervention should be initiated. No convincing evidence exists that replacement strategies for grade 2 or less hypomagnesaemia in this population will improve quality of life or decrease risk of mortality. While caution should be exercised in patients with cardiac history (ie, patients with history of myocardial infarction, congestive heart failure, or arrhythmia)—because hypomagnesaemia is associated with an increased risk of a cardiac event—routine replacement for grade 1 or 2 hypomagnesaemia in patients without known cardiac risks might not be warranted. Indeed, patients with more severe hypomagnesaemia (grade 3 to 4) should be offered intravenous magnesium replacement with a goal of normalising serum magnesium concentrations to decrease the risk of cardiac events, constitutional symptoms, and risk of hypocalcaemia. We currently monitor magnesium concentrations every 2 weeks in patients receiving cetuximab and implement magnesium intravenous replacement in all patients with grade 3 or above toxicity. Unfortunately, this replacement strategy usually requires anywhere between twice weekly to daily intravenous supplementation of magnesium at 4–10 g/dose to downgrade severe hypomagnesaemia to grade 2 or lower.4 In patients who need numerous weekly infusions, we have offered the stop-and-go approach described above.
Development of preventive strategies against hypomagnesaemia that is induced by anti-EGFR monoclonal antibodies will need better understanding of the underlying pathogenesis. While the Tejpar study is a step in the right direction, the mechanisms of hypomagnesaemia need further study. If EGFR inhibition in the distal convoluted tubule is the underlying mechanism behind magnesium wasting, how then can we explain the absence of severe hypomagnesaemia after treatment with EGFR tyrosine kinase inhibitors? Anti-EGFR-induced hypomagnesaemia seems to be a monoclonal antibody-specific phenomenon and monoclonal antibody precipitation-induced tubular damage cannot be completely ruled out as a possible mechanism for magnesium wasting. EGFR-monoclonal antibody-induced inhibition might result in more effective inhibition of EGFR downstream targets, which predisposes the patient to magnesium wasting.
However, these various hypotheses need to be investigated further in preclinical models. Irrespective of pathology, anti-EGFR monoclonal antibody-induced severe hypomagnesaemia does not occur in all patients. For example, many patients have been treated with cetuximab for more than 1 year without developing clinically significant hypomagnesaemia, while others did so within a few months of treatment. While age might be a predisposing factor, patient pharmacogenomics are probably an important factor in deciding the patient's susceptibility to this toxicity. Comprehensive studies of EGFR polymorphisms in patients with and without severe hypomagnesaemia after treatment with anti-EGFR monoclonal antibodies might shed further light on this toxicity.
RESOURCE: Lancet Oncology 2007; 8:366-367
DOI:10.1016/S1470-2045(07)70111-0
TITLE: Anti-EGFR monoclonal antibody-induced hypomagnesaemia
AUTHOR: Marwan Fakih
第一部分:
The use of monoclonal antibodies against the epidermal growth factor receptor (EGFR) has an integral role in the management of patients with metastatic colorectal cancer. Cetuximab (Erbitux, ImClone Systems Incorporated, NY, USA, and Bristol-Myers Squibb Company, NY, USA) is incorporated commonly in the second-line or third-line treatment of metastatic colorectal cancer, based on favourable time-to-progression (TTP) and response-rate outcomes from the Bowel Oncology with Cetuximab Antibody (BOND) study.1 The incorporation of this monoclonal antibody in the first-line treatment of metastatic colorectal cancer is becoming increasingly probable because of initial favourable TTP results from a randomised study of fluorouracil (FU), leucovorin, and irinotecan, with or without cetuximab.2 Hypomagnesaemia is one of the commonly noted side-effects of this class of agents. Severe hypomagnesaemia (grade 3 to 4) has been seen in 8 of 22 (36%) and 13 of 48 (27%) patients evaluable for hypomagnesaemia who were treated with cetuximab.3,4 A review of 244 patients treated with cetuximab estimated a more conservative 10–15% incidence of severe hypomagnesaemia.5
In this issue of The Lancet Oncology, Tejpar and colleagues6 report on the first prospective clinical study to characterise magnesium wasting in patients with metastatic colorectal cancer who are treated with monoclonal antibodies that target the EGFR. The study elegantly investigated magnesium wasting by measuring the slope of magnesium concentrations over time (starting from baseline) in 98 patients treated with EGFR-targeting monoclonal antibodies. A model investigating three early time points (weeks 0, 4, and 8) to characterise the slope of magnesium concentrations was shown to be predictive for the magnesium concentration slope during the whole treatment duration. The study further characterised this hypomagnesaemia to be related to magnesium wasting at the renal distal convoluted tubule. 97% of patients had some degree of magnesium wasting during treatment with EGFR-targeting monoclonal antibodies. However, significant interpatient variability in the serum magnesium concentration slopes was noted. Despite the frequency of magnesium wasting in the studied population, the percentage of grade 3 to 4 toxicities was modest at six of 98 (6%) and at odds with all previous reports.3,4 While it is feasible that the previous retrospective studies had higher proportions of patients with a longer duration of treatment, and therefore, a higher likelihood of hypomagnesaemia, it is not clear why the numbers of patients with severe hypomagnesaemia in the study by Tejpar and co-workers were substantially less then the 10–15% noted in the meta-analysis of various cetuximab studies.5 A shorter median duration of treatment or an earlier magnesium-replacement intervention might have resulted in an underestimation of severe hypomagnesaemia in the Tejpar report.
第二部分：
Martyn F Chillmaid/Science Photo Library
To my knowledge, the Tejpar study is the first to show that some degree of hypomagnesaemia occurs in almost all patients receiving EGFR-targeting monoclonal antibodies. Consistent with previous reports, clinically significant hypomagnesaemia (grade 2 or above) affected only a small group of patients receiving EGFR-targeting monoclonal antibodies. The clinical characterisation of age, baseline magnesium concentrations, and duration of treatment as risk factors is important, and suggests that this group of patients should be screened more vigorously with repeated measurements of magnesium concentrations during treatment. Also, the characterisation of a slope for magnesium decline based on three magnesium concentrations during early treatment could have significant clinical implications, but only if the amount of early decline is shown to be predictive of the development of clinically significant hypomagnesaemia. Is there a threshold slope below which one can predict which patients will develop grade 2 and above hypomagnesaemia? Can the slope for an individual patient decide the time at which clinically significant hypomagnesaemia will occur? How accurate is this predictive model? These questions cannot be answered adequately from this study because of the limited number of patients who have grade 2 or above hypomagnesaemia. Validation of the findings reported in this issue in a larger prospective study, with an aim of developing an accurate predictive model for severe hypomagnesaemia is, therefore, urgently needed. Only then will clinicians be able to identify early on which patients receiving EGFR-targeting monoclonal antibodies will probably develop severe hypomagnesaemia. The magnesium concentrations in these high-risk patients can be monitored intensively, whereas less frequent monitoring of patients at low risk for hypomagnesaemia will be possible. Alternative strategies for these high-risk populations include use of intermittent cetuximab treatment to avoid the development of severe hypomagnesaemia and its complications. Such an intermittent treatment strategy has been shown to be successful for other agents that cause cumulative toxicities, such as oxaliplatin.7 At the Roswell Park Cancer Institute, we have implemented a cetuximab stop-and-go approach in patients with grade 3 and above hypomagnesaemia needing more than three times weekly infusions of intravenous magnesium replacement. Our experience confirms the complete resolution of hypomagnesaemia within 2 months of stopping, and the feasibility of rechallenge with cetuximab when magnesium concentrations return to normal. In these patients, severe hypomagnesaemia recurs rarely within 2 months from the start of cetuximab rechallenge.
第三部分：
Hypomagnesaemia is frequently seen in the palliative treatment setting, and guidelines need to be formulated regarding the magnesium concentrations at which a replacement drug intervention should be initiated. No convincing evidence exists that replacement strategies for grade 2 or less hypomagnesaemia in this population will improve quality of life or decrease risk of mortality. While caution should be exercised in patients with cardiac history (ie, patients with history of myocardial infarction, congestive heart failure, or arrhythmia)—because hypomagnesaemia is associated with an increased risk of a cardiac event—routine replacement for grade 1 or 2 hypomagnesaemia in patients without known cardiac risks might not be warranted. Indeed, patients with more severe hypomagnesaemia (grade 3 to 4) should be offered intravenous magnesium replacement with a goal of normalising serum magnesium concentrations to decrease the risk of cardiac events, constitutional symptoms, and risk of hypocalcaemia. We currently monitor magnesium concentrations every 2 weeks in patients receiving cetuximab and implement magnesium intravenous replacement in all patients with grade 3 or above toxicity. Unfortunately, this replacement strategy usually requires anywhere between twice weekly to daily intravenous supplementation of magnesium at 4–10 g/dose to downgrade severe hypomagnesaemia to grade 2 or lower.4 In patients who need numerous weekly infusions, we have offered the stop-and-go approach described above.
Development of preventive strategies against hypomagnesaemia that is induced by anti-EGFR monoclonal antibodies will need better understanding of the underlying pathogenesis. While the Tejpar study is a step in the right direction, the mechanisms of hypomagnesaemia need further study. If EGFR inhibition in the distal convoluted tubule is the underlying mechanism behind magnesium wasting, how then can we explain the absence of severe hypomagnesaemia after treatment with EGFR tyrosine kinase inhibitors? Anti-EGFR-induced hypomagnesaemia seems to be a monoclonal antibody-specific phenomenon and monoclonal antibody precipitation-induced tubular damage cannot be completely ruled out as a possible mechanism for magnesium wasting. EGFR-monoclonal antibody-induced inhibition might result in more effective inhibition of EGFR downstream targets, which predisposes the patient to magnesium wasting.
However, these various hypotheses need to be investigated further in preclinical models. Irrespective of pathology, anti-EGFR monoclonal antibody-induced severe hypomagnesaemia does not occur in all patients. For example, many patients have been treated with cetuximab for more than 1 year without developing clinically significant hypomagnesaemia, while others did so within a few months of treatment. While age might be a predisposing factor, patient pharmacogenomics are probably an important factor in deciding the patient's susceptibility to this toxicity. Comprehensive studies of EGFR polymorphisms in patients with and without severe hypomagnesaemia after treatment with anti-EGFR monoclonal antibodies might shed further light on this toxicity.
