Affiliations of authors: Department of Medicine, Division of Gastrointestinal Oncology (DS, KYC, LS) and Renal Service (CF), Memorials Sloan-Kettering Cancer Center, New York, NY
Correspondence to: Deborah Schrag, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., Box 221, New York, NY 10011 (e-mail: schragd{at}mskcc.org).
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ABSTRACT |
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Shortly after cetuximab became commercially available, we treated a 34-year-old male patient with metastatic colorectal cancer who developed profound symptomatic hypomagnesemia (Mg2+ level of <0.5 mg/dL) during cetuximab-based therapy. Hypomagnesemia had not been reported as a consequence of the clinical trials that led to cetuximab registration, to our knowledge; however, serum magnesium levels were not systematically evaluated as part of these studies. We therefore now report on our index case in detail and review the incidence of electrolyte abnormalities among a consecutive case series of 154 patients treated with cetuximab at our institution.
Our index patient was a 34-year-old man with no past medical history who presented with extensive metastatic colorectal cancer to liver and lungs in December 2003. Before initiating combined therapy with fluorouracil, leucovorin, and oxaliplatin, according to the FOLFOX regimen, the patient had normal levels of electrolytes, including potassium, calcium, and magnesium, that had been measured twice. He received FOLFOX therapy from December 2003 through February 2004. Restaging subsequently revealed substantial disease progression in the liver that prompted a change of therapy to single-agent irinotecan. Measurement of electrolytes during irinotecan monotherapy revealed normal levels of serum potassium, calcium, and magnesium. Increasing levels of carcinoembryonic antigen 6 weeks after initiation of irinotecan therapy and evidence of clinical progression prompted a repeat computed tomography scan to document progression. Cetuximab with a loading dose of 400 mg/m2 followed by a weekly dose of 250 mg/m2 was added to the irinotecan regimen. Evaluation on the day that cetuximab was started revealed normal levels of serum calcium and potassium, no fatigue, and no other neurologic complaints. After 2 weeks of cetuximab therapy, the patient developed a grade 2 acneiform rash and profound fatigue. The serum calcium level, corrected for albumin, was low but not repleted. After 4 weeks of combined cetuximab-plus-irinotecan therapy, the patient had grade 2 diarrhea, grade 2 acneiform rash, worsening fatigue, and paresthesia in the hands. A low level of potassium (3.2 milliequivalents [meq]/L) was attributed to diarrhea and was repleted at the time of chemotherapy infusion. After 8 weeks of cetuximab, the patient was brought to the emergency department when he became too weak to walk. A repeat computed tomography scan showed no evidence of disease progression, compared with the scan performed just before initiation of cetuximab therapy. After a routine blood chemistry examination found a corrected serum calcium of 6.8 mg/dL (reference range = 8.510.5 mg/dL) and muscle fasciculation, Chovstek's and Trousseau's signs were noted on physical examination, and the level of serum magnesium was found to be 0.6 mg/dL (grade 3 hypomagnesemia is <0.90.7 mg/dL, and grade 4 is <0.7 mg/dL). The serum potassium level was 3.0 meq/L, but other parameters, including blood urea nitrogen (BUN) and creatinine were within their reference ranges. The patient received intravenous repletion of magnesium and calcium with a rapid increase in energy and disappearance of paresthesias. In the workup, we also measured vitamin D, thyroid stimulating hormone, and parathyroid hormone (PTH) levels, which were normal, thus eliminating endocrine causes as the source of the metabolic disorder.
The patient was discharged from the emergency department on oral supplementation with calcium carbonate and magnesium oxide twice daily. He felt well for 24 hours, but fatigue and paresthesias then recurred; and after 48 hours, he returned to the emergency department with recurrent grade 4 hypomagnesemia (0.5 mg/dL) and grade 3 hypocalcemia (6.2 mg/dL). Urinary electrolytes revealed inappropriately high levels of magnesium in the setting of low serum levels, thereby establishing renal wastage as the source of the hypomagnesemia and effectively eliminating malabsorption or excessive gastrointestinal losses as the primary explanations for this disorder. The patient had no history of alcohol abuse, use of alternative medicine supplements, or use of any drugs known to cause renal magnesium wasting. Hospitalization required administration of intravenous magnesium sulfate (36 g/day) to prevent hypomagnesemia, hypocalcemia, profound fatigue, and muscle fasciculations. The patient was discharged on oral magnesium supplements (6 g/day) with 34 g of intravenous magnesium sulfate administered by a home nursing company three times per week. Because the patient was responding to combined treatment with cetuximab plus irinotecan, therapy was continued. For the duration of cetuximab therapy, he required intravenous magnesium sulfate supplementation (up to 10 g daily) infused overnight. When cetuximab was discontinued secondary to progression of liver disease, magnesium repletion was gradually tapered and stopped 5 weeks after the last dose of cetuximab. The patient's laboratory parameters before, during, and after cetuximab therapy are shown in Table 1. The onset of this disorder shortly after the initiation of cetuximab, the resolution of hypomagnesemia in response to cessation of cetuximab, and the absence of an alternative drug or disorder to explain this toxicity led us to suspect that this phenomenon was indeed associated with cetuximab therapy. Review of published clinical trials of cetuximab did not identify any studies that included systematic assessment of calcium or magnesium.
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We suggest that, like several other important oncology drugs, such as cisplatin (6,7), cetuximab impairs magnesium reabsorption in the kidney and may cause clinically significant hypomagnesemia. Recognition of this phenomenon is important for several reasons. The relationship between EGFR blockade and magnesium transport may help elucidate important cellular pathways. Magnesium transport has long been poorly understood (8), but recently, the protein TRPM6, a member of the transient receptor potential family of cation channels, has been shown to mediate active transport (9,10). Patients with a germline mutation in the TRPM6 gene have severe congenital hypomagnesemia. TRPM6 is localized along the apical membrane of the loop of Henle and the distal convoluted tubule, as well as the brush border of the small intestine. EGFR is also highly expressed in these regions.
Free extracellular magnesium is filtered at the glomerulus, and 70% is reabsorbed in the thick ascending limb of the loop of Henle, although typically 15% may be resorbed in the proximal tubule and 15% in the distal tubule (8). Analysis of data from our case series and our index case with documented inappropriate elevation of urinary magnesium in the setting of hypomagnesemia suggests the hypothesis that blockade of EGFR in the nephron reversibly impairs function of the proteins involved in active transport of extracellular magnesium. We cannot exclude the possibility of effects of EGFR blockade on magnesium absorption from the gut; however, we have no direct evidence to support or refute such a hypothesis at this time.
Because our case series was assembled retrospectively, the levels of serum and urinary magnesium were not routinely measured, and we therefore cannot offer a precise estimate of the extent of hypomagnesemia in patients receiving cetuximab. Another limitation is that we cannot precisely quantify the strength of the association among fatigue, cetuximab therapy, and electrolyte disorders because the level of fatigue was not systematically recorded during routine clinical care.
This report has important implications for the practicing oncologist, for clinical trialists, and for informaticians charged with designing systems to maximize patient safety. When clinical trials are designed, it is not possible to anticipate all possibly relevant clinical information, and thus it is inevitable that some toxic effects will be recognized only after regulatory approval. Thus, rapid reporting systems that encourage clinicians to voluntarily report unusual treatment complications encountered after regulatory approval are essential. Information systems that maximize the ability to rapidly review the incidence of both common and rare side effects among observational cohorts of patients are essential. Proposed enhanced collaboration between the Center for Medicare and Medicaid Services (CMS) and the FDA may be one strategy to facilitate the identification of drug toxic effects that arise after FDA approval.
For clinical trialists, we suggest that assessments of baseline serum magnesium be incorporated into existing EGFR protocols with periodic repeat evaluations especially in the setting of fatigue. Because this phenomenon is potentially a class effect, this precaution should also apply to other EGFR antibodies in development. The Gastrointestinal Oncology Intergroup is opening a phase III clinical trial to compare the FOLFOX or FOLFIRI regimens (biweekly 5-fluorouracil, leucovorin, and irinotecan) by randomly assigning patients to treatment with cetuximab, bevacizumab, or both in the summer of 2005. Serum magnesium levels will be monitored enabling better determination of the magnitude of the association between cetuximab therapy and clinically significant electrolyte disorders. Trials that combine antibodies against EGFR with cisplatin, such as those in head and neck cancer, may need to consider more frequent assessment of magnesium levels.
For practicing oncologists, we emphasize that the symptoms of hypomagnesemia can be very nonspecific. The irritability, paresthesias, and severe fatigue that some patients in our cohort noted could easily have been attributed to the underlying tumor or to previous chemotherapy regimens. Indeed, for our index patient and several other patients in our case series, symptomatic electrolyte disorders were not immediately appreciated.
None of the patients in our series had known cardiac manifestations of hypomagnesemia; however, such problems were also not explicitly assessed. In the setting of hypomagnesemia, PTH release and the ability of PTH to mobilize calcium from the bone are impaired. For this reason, correction of serum magnesium is usually sufficient to normalize serum calcium levels. We suggest that fatigue, paresthesias, and hypocalcemia in patients treated with cetuximab should prompt physicians to measure levels of serum magnesium. The test for serum magnesium is inexpensive and can easily be added to routine chemistry profiles, and thus the threshold for measurement should be low. Magnesium wasting is associated with symptoms that may be profound but are also readily reversible with magnesium supplementation.
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Dr. Flombaum has served as a consultant for Bristol Myers Squibb. Dr. Saltz is currently conducting research funded by Bristol-Myers Squibb, ImClone, Taiho Roche, and Pfizer; he has served as a paid consultant for Genentech, Sanofi, and Pfizer.
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Manuscript received March 10, 2005; revised June 14, 2005; accepted June 23, 2005.
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