These data clearly suggest a cetuximab(Drug information on cetuximab) treatment duration–dependent risk for severe hypomagnesemia. It is therefore expected that the true rate of grade 3/4 hypomagnesemia might have been considerably higher in the EPIC and CRYSTAL studies had magnesium level monitoring been mandated in all patients.
Similar risks of hypomagnesemia are seen with panitumumab treatment. In a randomized study of panitumumab vs best supportive care, 36% of 229 patients receiving panitumumab had some decline in magnesium levels, but only 3% developed grade 3/4 hypomagnesemia. When combined with 5-FU, oxaliplatin(Drug information on oxaliplatin), and leucovorin, panitumumab was associated with only a 4% incidence of grade 3/4 hypomagnesemia in the first-line treatment of mCRC. The low frequency of hypomagnesemia was likely related to the lack of stringent guidelines for magnesium monitoring.It is likely that more will be learned regarding the cumulative risk of hypomagnesemia as data matures from the Cancer and Leukemia Group B (CALGB) 80405 trial, which is randomizing patients with untreated mCRC to receive combination chemotherapy with cetuximab, bevacizumab(Drug information on bevacizumab) (Avastin), or both. Based on the current data, however, it is likely that the risk of hypomagnesemia exceeds 50% but the risk of grade 3/4 hypomagnesemia ranges from 6% to 17%.
MechanismsIn a prospective study of patients receiving anti-EGFR monoclonal antibodies, Tejpar et al evaluated serial serum and urine magnesium levels. Although grade 3/4 hypomagnesemia occurred in only 6% of the overall population, a decline in serum magnesium levels occurred in almost all patients. Urine testing confirmed that magnesium wasting was the causative etiology of hypomagnesemia and that this defect was related to a direct effect of monoclonal antibodies on the distal convoluted tubule. Furthermore, the degree of magnesium wasting exhibited a high degree of interpatient variability and tended to worsen with time. There are currently no known prophylactic measures that may prevent this EGFR monoclonal antibody toxicity.
Risk FactorsThe most important risk factor for hypomagnesemia in patients receiving EGFR-targeting monoclonal antibody is the duration of treatment, with severe hypomagnesemia sometimes occurring more than 6 months after treatment initiation. Other risk factors that have been reported include a patient's age and the baseline magnesium level. Elderly patients are more susceptible to this toxicity. Interestingly, patients with higher baseline magnesium levels tended to have more pronounced magnesium wasting.
Grade 1/2 Hypomagnesemia
Most hypomagnesemia toxicities associated with cetuximab or panitumumab are grade 1/2 (0.9 mg/dL up to the lower limit of normal), with grade 3 (0.7–0.8 mg/dL) or grade 4 (≤ 0.6 mg/dL) toxicities seen in about 6% to 17% of patients. No evidence suggests that a replacement strategy is necessary for grade 1 hypomagnesemia, as these patients are typically asymptomatic.For patients with grade 2 hypomagnesemia, we have followed a strategy of weekly intravenous replacement (4 g of magnesium sulfate(Drug information on magnesium sulfate)) for patients with magnesium levels of 0.9 to 1.0 mg/dL. We have attempted oral magnesium supplementation in this population and found this practice to be ineffective and poorly tolerated due to diarrhea. The inefficiency of oral supplements has been similarly confirmed by other groups. One may also consider weekly magnesium monitoring without replacement for grade 2 hypomagnesemia in asymptomatic patients without cardiac history or cardiac risks—only after an appropriate physician-patient discussion.
Grade 3/4 Hypomagnesemia
Patients with grade 3/4 hypomagnesemia should receive appropriate replacement. These patients are often symptomatic with fatigue, cramps, or somnolence. Many patients do not complain of hypomagnesemia symptoms as they tend to attribute them to cytotoxic chemotherapy, but patients treated at our institute experienced improvement in energy level and performance status after their grade 3/4 hypomagnesemia was reversed.