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.
本人已认领该文第一部分编译，48小时后若未提交译文，请其他战友自由认领。
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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.
低镁血症常发生在癌症姑息治疗中，需要制定根据血镁浓度值大小开始药物替换治疗的指导方针。现在，在1级或2级低镁血症患者给予药物替换治疗能否提高患者生活质量或降低死亡率还缺乏循证医学证据。因为低镁血症可诱发心血管事件的风险增高，对1级或2级低镁血症患者，如无已知的心血管事件风险，例行药物替换治疗可能理由不当。因此，对有心脏病史（如心肌梗塞、充血性心衰、心律失常）患者给予此疗法要十分谨慎。当然，较严重低镁血症（3-4级）患者应实施静脉镁补充替换替换治疗，使血镁浓度达到正常标准，降低心血管事件、低钙血症发生风险、改善患者全身症状。
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.
我们目前的做法：患者接受西妥昔单抗治疗期间每2周检测血镁1次，3-4级低镁血症患者给予静脉补镁补充替换治疗。为了将3-4级低镁血症降至1-2级，这种替换治疗策略常需要静脉补充镁4–10g/次，频次在每周2次至每日1次之间。对需每周多次静脉补镁患者，我们建议采取上述的“stop-and-go”策略。
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.
制定针对抗EGFR单克隆抗体治疗引起的低镁血症的预防措施需要深入理解低镁血症潜在发病机理。虽然比利时学者Tejpar的研究在低镁血症发病机理研究上前进了一步，还需要更进一步深入的研究。假如EGFR抑制肾远曲小管对镁的重吸收是镁消耗的潜在机制，那么我们如何解释有些患者在EGFR酪氨酸激酶抑制剂治疗后并没有严重低镁血症发生？抗EGFR诱导的低镁血症看起来似乎为单克隆抗体特异的现象，单克隆抗体累积诱导的小管破坏不能完全说明镁消耗的可能机理。EGFR单克隆抗体诱导的抑制或许能对EGFR下游区靶目标更为有效的抑制，因而造成患者镁消耗。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.
当然，这些不同的假设正确与否需要在动物模型上加以验证。不管低镁血症发病病理学，抗EGFR单克隆抗体引起的严重低镁血症并非在所有的治疗患者身上发生。例如许多患者给予西妥昔单抗治疗1年以上也未发生严重低镁血症，而另一些患者在治疗的几个月后就发生。患者年龄、药物基因组异常可能是重要的易患因素。采用抗EGFR单克隆抗体治疗后可能伴发或无严重低镁血症，针对患者EGFR多态现象进行广泛研究或许能阐明这种毒副作用的发生机理。
第三部分编译：中文字数（832）
低镁血症常发生在癌症姑息治疗中，需要制定根据血镁浓度值大小开始药物替换治疗的指导方针。现在，在1级或2级低镁血症患者给予药物替换治疗能否提高患者生活质量或降低死亡率还缺乏循证医学证据。对1级或2级低镁血症患者，如无已知的心血管事件风险，例行药物替换治疗可能理由不当。因为低镁血症可诱发心血管事件的风险增高，因此，对有心脏病史（如心肌梗塞、充血性心衰、心律失常）患者给予此疗法要十分谨慎。当然，较严重低镁血症（3-4级）患者应实施静脉镁补充替换治疗，使血镁浓度达到正常标准，降低心血管事件、低钙血症发病风险、改善患者全身症状。
我们目前的做法：患者接受西妥昔单抗治疗期间每2周检测血镁浓度1次，3-4级低镁血症患者给予静脉补镁补充替换治疗。为了将3-4级低镁血症降至1-2级，这种替换治疗策略常需要静脉补充镁4–10g/次，频次在每周2次至每日1次之间。对需每周多次静脉补镁患者，我们建议采取上述的“stop-and-go”策略。
制定针对抗EGFR单克隆抗体治疗引起的低镁血症的预防措施需要深入理解低镁血症潜在发病机理。虽然比利时学者Tejpar的研究在低镁血症发病机理研究上前进了一步，还需要更进一步深入的研究。假如EGFR抑制肾远曲小管对镁的重吸收是镁消耗的潜在机制，那么我们如何解释有些患者在EGFR酪氨酸激酶抑制剂治疗后并没有严重低镁血症发生？抗EGFR诱导的低镁血症看起来似乎为单克隆抗体特异的现象，单克隆抗体累积诱导的小管破坏不能完全说明镁消耗的可能机理。EGFR单克隆抗体诱导的抑制或许能对EGFR下游区靶目标更为有效的抑制，因而造成患者镁消耗。
当然，这些不同的假设正确与否需要在动物模型上加以验证。不管低镁血症发病病理学，抗EGFR单克隆抗体引起的严重低镁血症并非在所有的治疗患者身上发生。例如许多患者给予西妥昔单抗治疗1年以上也未发生严重低镁血症，而另一些患者在治疗的几个月后就发生。患者年龄、药物基因组异常可能是重要的易患因素。采用抗EGFR单克隆抗体治疗后可能伴发或无严重低镁血症，针对患者EGFR多态现象进行广泛研究或许能阐明这种毒副作用的发生机理。
RESOURCE: Lancet Oncology 2007; 8:366-367
来源：《柳叶刀肿瘤学》 2007；8：366－367
DOI:10.1016/S1470-2045(07)70111-0
TITLE: Anti-EGFR monoclonal antibody-induced hypomagnesaemia
标题： 抗EGFR单克隆抗体导致低镁学症
AUTHOR: Marwan Fakih
作者：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
利用表皮生长因子受体(EGFR)的单克隆抗体来治疗转移性结肠直肠癌患者，有不可或缺的作用。基于从肠肿瘤学和西妥昔单抗研究(BOND)中获得的，关于治疗中疾病进展时间(TTP)和应答率的有利结果。基于这一结果，西妥昔单抗(美国纽约erbitux,imclone系统公司，美国纽约Bristol-Myers Squibb公司)，一般被在第二线或第三线治疗转移性结肠直肠癌使用。1.对氟尿嘧啶（FU），甲酰四氢叶酸，和依立替康，有无西妥昔单抗的随机化研究，得出一个初始有利TTP结果。正是因为这一结果，一线上用单克隆抗体治疗结肠直肠癌越来越成为可能。2.低镁学症是这一类药物一般的副作用之一。用西妥昔单抗治疗的病人，对低镁学症评价后发现，22个中8个(36%)和48个13个(27%)患者有重症低镁学症（3到4度)。3.4 对244名用西妥昔单抗治疗的患者进行回顾行评估得出，重症低镁学症一个保守发病率为10–15%
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.
在本期的《柳叶刀肿瘤学》，Tejpar 和其同事报告了，针对EGFR的单抗治疗结肠直肠癌患者，出现镁消耗性为特征的第一次临床前瞻性研究。这项研究通过在一段时间内(从基线)，测量98例用EGFR靶克隆单抗治疗的患者的镁浓度梯度，精致的研究了镁消耗。 建立用研究头3个时间点（0，4，8周）给出镁浓度梯度，以显示预测在整个治疗期间镁浓度梯度的模型。研究报告进一步给出低镁学症，这可能与镁在肾远曲小管的消耗有关。 97%的患者在用EGFR靶克隆单抗治疗期间，有一定程度的镁消耗。不过，病人间在血清镁离子浓度梯度上的显著差异被记录下来。 尽管消耗镁在所研究的人群中频频，但结合所有先前报告，3－4度的百分比毒性是适度的，在频率上98个中6个(6%)。3,4以往的回顾性研究显示，更长治疗持续时间的患者有较高比例的低镁学症，如果这是适宜的，那么，更长治疗持续时间可能显示与低镁学症具有较高的可能性。 目前尚不清楚为何Tejpar和其同事的研究中严重低镁学症患者数量，大大低于多方面的西妥昔单抗研究Meta分析中10–15%的记录。较短的中位持续治疗时间或较早的镁替代干预治疗，可能是Tejpar 报告中低估严重低镁血症发生率的原因。
编译后：约915个字
利用表皮生长因子受体(EGFR)的单克隆抗体来治疗转移性结肠直肠癌患者，有不可或缺的作用。基于有利的,从西妥昔单抗治疗肠肿瘤的研究得出，时间-进程(TTP)的和应答率的结果，基于这一结果，西妥昔单抗(美国纽约erbitux,imclone系统公司，美国纽约Bristol-Myers Squibb公司)，一般被在第二线或第三线治疗转移性结肠直肠癌使用。1.对氟尿嘧啶（FU），甲酰四氢叶酸，和依立替康，有无西妥昔单抗的随机化研究，得出一个初始有利TTP结果。正是因为这一结果，一线上用单克隆抗体治疗结肠直肠癌越来越成为可能。2.低镁学症是这一类药物一般的副作用之一。用西妥昔单抗治疗的病人，对低镁学症评价后发现，22个中8个(36%)和48个13个(27%)患者有重症低镁学症（3到4度)。3.4 对244名用西妥昔单抗治疗的患者进行回顾行评估得出，重症低镁学症一个保守发病率为10–15%
在本期的《柳叶刀肿瘤学》中，Tejpar 和其同事报告了，针对EGFR的单抗治疗结肠直肠癌患者，出现镁消耗性为特征的第一次临床前瞻性研究。这项研究通过在一段时间内(从基线)，测量98例用EGFR靶克隆单抗治疗的患者的镁浓度梯度，精致的研究了镁消耗。 建立用研究头3个时间点（0，4，8周）给出镁浓度梯度，以显示预测在整个治疗期间镁浓度梯度的模型。研究报告进一步给出低镁学症，这可能与镁在肾远曲小管的消耗有关。 97%的患者在用EGFR靶克隆单抗治疗期间，有一定程度的镁消耗。不过，病人间在血清镁离子浓度梯度上的显著差异被记录下来。 尽管消耗镁在所研究的人群中频频，但结合所有先前报告，3－4度的百分比毒性是适度的，在频率上98个中6个(6%)。3,4以往的回顾性研究显示，更长治疗持续时间的患者有较高比例的低镁学症，如果这是适宜的，那么，更长治疗持续时间可能显示与低镁学症具有较高的可能性。 目前尚不清楚为何Tejpar和其同事的研究中严重低镁学症患者数量，大大低于多方面的西妥昔单抗研究Meta分析中10–15%的记录。较短的中位持续治疗时间或较早的镁替代干预治疗，可能是Tejpar 报告中低估严重低镁血症发生率的原因。。
liuzeyi2002战友翻译很好，自叹莫如！
对全文第一部分有两处有不同想法，仅供参考！
based on favourable time-to-progression (TTP) and response-rate outcomes from the Bowel Oncology with Cetuximab Antibody (BOND) study.
基于有利的,从西妥昔单抗治疗肠肿瘤的研究得出，时间-进程(TTP)的和应答率的结果
基于从肠肿瘤学与西妥昔单抗研究(BOND)中获得关于治疗至疾病进展时间(TTP)和反应率的有利结果
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
一个短的持续治疗时间中位数或者一个较早的镁替代干预可能导致，在Tejpar 报告中严重的低镁血症被低估。
较短的中位持续治疗时间或较早的镁替代干预可能为Tejpar 报告低估严重低镁血症发生率的原因。
谢谢，fanqingdong2004战友，你翻译的确实比我要通顺点。具体修改如下：
based on favourable time-to-progression (TTP) and response-rate outcomes from the Bowel Oncology with Cetuximab Antibody (BOND) study.
基于从肠肿瘤学和西妥昔单抗研究(BOND)中获得的，关于治疗中疾病进展时间(TTP)和应答率的有利结果。
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
较短的中位持续治疗时间或较早的镁替代干预治疗，可能是Tejpar 报告中低估严重低镁血症发生率的原因。
本人已认领该文第二部分编译，48小时后若未提交译文，请其他战友自由认领。
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.
Martyn F Chillmaid/科学图库
据我所知，在所有正在接受EGFR靶向单克隆抗体治疗的低镁血症病人中，Tejpar的研究是第一个对该血症分度的。与先前报道相一致的是，临床重度的低镁血症（2度或2度以上的）只影响小部分接受EGFR靶向单克隆抗体治疗的病人。临床年龄特征，镁浓度基线和作为危险因素治疗的持续时间是非常重要的，这提示这类病人在治疗期间应该更详细更频繁的检查镁浓度。同时，基于治疗早期三种镁浓度的镁下降的梯度特征应该有明显的临床相关，但是只有量的早期降低才是临床显著性低镁血症发展的前兆。
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
是否有一个阈值梯度，预测在这个阈值梯度以下的病人将会发展成为2度甚至更严重的低镁血症？这个梯度是否可以决定个体患者发生临床显著性低镁血症的时间？这个预测模型的准确性如何？因为受到2度或2度以上低镁血症病例个数的限制，这些问题不能得到充分的答案。所以，一项以开展对重度低镁血症进行精确预测为目的的大规模的前瞻性研究来验证这次报道的结果是迫切需要的。只有到了那个时候，临床医生才能较早的鉴别出哪些病人在接受了EGFR靶向单克隆抗体治疗后容易发生低镁血症。这些高危险病人体内的镁浓度可以密切监视，然而对低风险发生低镁血症的病人进行低频监视也是合理的。对于这些高危险人群的选择性对策包括运用间歇性西妥昔单抗治疗来消除严重低镁血症的发展和其并发症。这种间歇性疗法在对抗其它引起累积毒性的因子（比如，奥沙利铂）方面已经被证实是成功的。7At 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.
在Roswell Park肿瘤中心，我们已实现了在3度以及3度以上低镁血症病人中西妥昔单抗停走的办法，这类病人每周需要三次以上的镁静脉输入。我们的试验证明了使低镁血症终止两个月以内是完全可以的，并且当镁浓度回到正常水平的时候，利用西妥昔单抗二次给药也是可行的。这些病人中，西妥昔单抗二次给药两个月内复发严重低镁血症的极少。
第二部分：编译后，约740汉字
Martyn F Chillmaid/科学图库
据我所知，在所有正在接受EGFR靶向单克隆抗体治疗的低镁血症病人中，Tejpar的研究是第一个对该血症分度的。与先前报道相一致的是，临床重度的低镁血症（2度或2度以上的）只影响小部分接受EGFR靶向单克隆抗体治疗的病人。临床年龄特征，镁浓度基线和作为危险因素治疗的持续时间是非常重要的，这提示这类病人在治疗期间应该更详细更频繁的检查镁浓度。同时，基于治疗早期三种镁浓度的镁下降的梯度特征应该有明显的临床相关，但是只有量的早期降低才是临床显著性低镁血症发展的前兆。是否有一个阈值梯度，预测在这个阈值梯度以下的病人将会发展成为2度甚至更严重的低镁血症？这个梯度是否可以决定个体患者发生临床显著性低镁血症的时间？这个预测模型的准确性如何？因为受到2度或2度以上低镁血症病例个数的限制，这些问题不能得到充分的答案。所以，一项以开展对重度低镁血症进行精确预测为目的的大规模的前瞻性研究来验证这次报道的结果是迫切需要的。只有到了那个时候，临床医生才能较早的鉴别出哪些病人在接受了EGFR靶向单克隆抗体治疗后容易发生低镁血症。这些高危险病人体内的镁浓度可以密切监视，然而对低风险发生低镁血症的病人进行低频监视也是合理的。对于这些高危险人群的选择性对策包括运用间歇性西妥昔单抗治疗来消除严重低镁血症的发展和其并发症。这种间歇性疗法在对抗其它引起累积毒性的因子（比如，奥沙利铂）方面已经被证实是成功的。7在Roswell Park肿瘤中心，我们已实现了在3度以及3度以上低镁血症病人中西妥昔单抗停走的办法，这类病人每周需要三次以上的镁静脉输入。我们的试验证明了使低镁血症终止两个月以内是完全可以的，并且当镁浓度回到正常水平的时候，利用西妥昔单抗二次给药也是可行的。这些病人中，西妥昔单抗二次给药两个月内复发严重低镁血症的极少。
全文第二部分的个人意见，仅供参考！
the Tejpar study is the first to show that some degree of hypomagnesaemia occurs in almost all patients receiving EGFR-targeting monoclonal antibodies
在所有正在接受EGFR靶向单克隆抗体治疗的低镁血症病人中，Tejpar的研究是第一个对该血症分度的。
Tejpar研究是第一个针对在几乎所有接受EGFR靶向单抗治疗患者中评估低镁血症发生程度的研究。
clinically significant hypomagnesaemia (grade 2 or above) affected only a small group of patients receiving EGFR-targeting monoclonal antibodies.
临床重度的低镁血症（2度或2度以上的）只影响小部分接受EGFR靶向单克隆抗体治疗的病人。
临床接受EGFR单抗靶向治疗的病人仅小部分患重度低镁血症（2度或2度以上）。
The clinical characterisation of age, baseline magnesium concentrations, and duration of treatment as risk factors is important
临床年龄特征，镁浓度基线和作为危险因素治疗的持续时间是非常重要的
临床年龄特征、基线镁浓度和治疗持续时间是患低镁血症重要危险因素。
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.
基于治疗早期三种镁浓度的镁下降的梯度特征应该有明显的临床相关，但是只有量的早期降低才是临床显著性低镁血症发展的前兆。
只有当镁浓度早期下降数值可预测严重低镁血症的发生时，基于早期治疗3个时间点的镁浓度下降梯度特征才可能有重要临床意义。
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.
在Roswell Park肿瘤中心，我们已实现了在3度以及3度以上低镁血症病人中西妥昔单抗停走的办法，这类病人每周需要三次以上的镁静脉输入。我们的试验证明了使低镁血症终止两个月以内是完全可以的，并且当镁浓度回到正常水平的时候，利用西妥昔单抗二次给药也是可行的。这些病人中，西妥昔单抗二次给药两个月内复发严重低镁血症的极少。
在Roswell Park 癌症研究所，发生3度和4度低镁血症患者给予静脉镁补充替换治疗，针对需每周3次以上静脉镁补充患者，对西妥昔单抗采取stop-and-go 策略。我们的实验证实在停用西妥昔单抗2月内，低镁血症症状完全消失；当镁浓度恢复到正常水平时，再次给药是可行的。
fanqingdong2004战友翻译得不错，句子比我翻译得也更得体、更学术化一点，谢谢您的更正、指导！
结合以上各位战友的翻译和校对，全文经过进一步校对（文中下划线部分）后的编译：
来源：《柳叶刀肿瘤学》 2007；8：366－367
利用表皮生长因子受体(EGFR)的单克隆抗体来治疗转移性结肠直肠癌患者，有不可或缺的作用。基于从肠肿瘤学和西妥昔单抗研究(BOND)中获得的，关于治疗中疾病进展时间(TTP)和应答率的有利结果，西妥昔单抗(美国纽约erbitux,imclone系统公司，美国纽约Bristol-Myers Squibb公司)通常与二线或三线方案联合治疗转移性结肠直肠癌。因为从氟尿嘧啶（FU）、甲酰四氢叶酸、依立替康联合或不联合西妥昔单抗的随机化研究中得出的初步有利TTP结果，结肠直肠癌治疗一线方案中联合单克隆抗体越来越成为可能。低镁血症是这一类药物常见的副作用之一。对西妥昔单抗治疗的患者行低镁血症评价后发现，22例中8例(36%)和48例中13例(27%)出现重症低镁血症（3到4级)。 对244名用西妥昔单抗治疗的患者进行回顾分析，保守估计重症低镁血症的发病率为10–15%。
在本期的《柳叶刀肿瘤学》，Tejpar 和其同事报告了，针对EGFR的单抗治疗结肠直肠癌患者，出现镁消耗性为特征的首次临床前瞻性研究。这项研究通过在一段时间内(从基线开始)，测量98例用EGFR靶克隆单抗治疗的患者的镁浓度梯度，详细地研究了镁消耗。 建立用研究头3个时间点（0，4，8周）给出镁浓度梯度，以显示预测在整个治疗期间镁浓度梯度的模型。研究报告进一步给出低镁血症，这可能与镁在肾远曲小管的消耗有关。 97%的患者在用EGFR靶克隆单抗治疗期间，有一定程度的镁消耗。然而患者之间血清镁离子浓度梯度存在显著差异。 不论镁消耗在所研究的人群中的发生频率，与所有先前报告相左，3至4级毒性所占百分比并不高，98例中有6例(6%)。 由于以往的回顾性研究显示持续治疗更长时间的患者中有更高比例的患者出现低镁血症，从而低镁血症可能性更高，目前尚不清楚为何Tejpar和其同事的研究中严重低镁学症患者数量，大大低于多方面的西妥昔单抗研究Meta分析中10–15%的记录。较短的中位持续治疗时间或较早的镁替代干预治疗，可能是Tejpar 报告中低估严重低镁血症发生率的原因。
据我所知，Tejpar研究是第一个针对在几乎所有接受EGFR靶向单抗治疗患者中评估低镁血症发生程度的研究。与先前报道相一致的是，临床接受EGFR单抗靶向治疗的病人仅小部分患重度低镁血症（2级及以上）。临床年龄特征、基线镁浓度和治疗持续时间是患低镁血症重要危险因素，这提示这类病人在治疗期间应该更详细更频繁的检查镁浓度。同时，只有当镁浓度早期下降数值可预测严重低镁血症的发生时，基于早期治疗3个时间点的镁浓度下降梯度特征才可能有重要临床意义。
是否有一个阈值梯度，预测在这个阈值梯度以下的病人将会发展成为2级甚至更严重的低镁血症？这个梯度是否可以决定个体患者发生临床显著性低镁血症的时间？这个预测模型的准确性如何？因为受到2级或2级以上低镁血症病例个数的限制，这些问题不能得到充分的答案。所以，一项以开展对重度低镁血症进行精确预测为目的的大规模的前瞻性研究来验证这次报道的结果是迫切需要的。只有到了那个时候，临床医生才能较早的鉴别出哪些病人在接受了EGFR靶向单克隆抗体治疗后容易发生低镁血症。这些高危险病人体内的镁浓度可以密切监视，然而对低风险发生低镁血症的病人进行低频监视也是合理的。对于这些高危险人群的选择性对策包括运用间歇性西妥昔单抗治疗来消除严重低镁血症的发展和其并发症。这种间歇性疗法在对抗其它引起累积毒性的因子（比如，奥沙利铂）方面已经被证实是成功的。
在Roswell Park 癌症研究所，给予3级和4级低镁血症患者每周3次以上静脉镁补充治疗，并采用西妥昔单抗间断治疗策略。我们的试验证实在停用西妥昔单抗2月内，低镁血症症状完全消失；当镁浓度恢复到正常水平时，再次给药是可行的。这些病人中，西妥昔单抗二次给药两个月内复发严重低镁血症的极少。
低镁血症常发生在癌症姑息治疗中，需要制定根据血镁浓度值大小开始药物替换治疗的指导方针。现在，在1级或2级低镁血症患者给予药物替换治疗能否提高患者生活质量或降低死亡率还缺乏循证医学证据。因为低镁血症可诱发心血管事件的风险增高，对1级或2级低镁血症患者，如无已知的心血管事件风险，例行药物替换治疗可能理由不当。因此，对有心脏病史（如心肌梗塞、充血性心衰、心律失常）患者给予此疗法要十分谨慎。当然，较严重低镁血症（3-4级）患者应实施静脉镁补充替换替换治疗，使血镁浓度达到正常标准，降低心血管事件、低钙血症发生风险、改善患者全身症状。
我们目前的做法：患者接受西妥昔单抗治疗期间每2周检测血镁1次，3-4级低镁血症患者给予静脉补镁补充替换治疗。为了将3-4级低镁血症降至1-2级，这种替换治疗策略常需要静脉补充镁4–10g/次，频次在每周2次至每日1次之间。对需每周多次静脉补镁患者，我们建议采取上述的间断治疗策略。
制定针对抗EGFR单克隆抗体治疗引起的低镁血症的预防措施需要深入理解低镁血症潜在发病机理。虽然比利时学者Tejpar的研究在低镁血症发病机理研究上前进了一步，还需要更进一步深入的研究。假如EGFR抑制肾远曲小管对镁的重吸收是镁消耗的潜在机制，那么我们如何解释有些患者在EGFR酪氨酸激酶抑制剂治疗后并没有严重低镁血症发生？抗EGFR诱导的低镁血症看起来似乎为单克隆抗体特异的现象，单克隆抗体累积诱导的小管破坏不能完全说明镁消耗的可能机理。EGFR单克隆抗体诱导的抑制或许能对EGFR下游区靶目标更为有效的抑制，因而造成患者镁消耗。
当然，这些不同的假设正确与否需要在动物模型上加以验证。不管低镁血症发病病理学，抗EGFR单克隆抗体引起的严重低镁血症并非在所有的治疗患者身上发生。例如许多患者给予西妥昔单抗治疗1年以上也未发生严重低镁血症，而另一些患者在治疗的几个月后就发生。患者年龄、药物基因组异常可能是重要的易患因素。采用抗EGFR单克隆抗体治疗后可能伴发或无严重低镁血症，针对患者EGFR多态现象进行广泛研究或许能阐明这种毒副作用的发生机理。