The first systematic review of epidermal growth factor receptor (EGFR) inhibitor induced hypomagnesemia has concluded no optimal magnesium supplement strategy currently exists to reverse the depletion effects.

Overexpression of EGFR has been identified in many tumor sites, most commonly in colorectal, lung, and head and neck cancer. EGFR-targeting monoclonal antibodies (mAbs), such as cetuximab and panitumumab, are commonly used to treat this, as they lead to tumor apoptosis and stimulated immunologic response. However, there is a significant related risk of grade 3 or 4 hypomagnesemia with common mAbs; cetuximab and panitumumab (3.9%–27% and 5.4% risk, respectively).

The review, conducted by researchers in Canada, consisted of 6 studies that reported EGFRIs as possible hypomagnesemia causes. There were a total of 486 patients included, most had advanced colorectal cancer (n=426) or squamous cell carcinoma of the head and neck (n=46). Of the 486 patients, 289 were treated with cetuximab and 197 with panitumumab.

Forty-four percent of patients experienced some degree of hypomagnesemia, which was severe for 7%. However, the studies only discussed incidences of EGFRI-induced hypomagnesemia when magnesium replacement strategies were analyzed, therefore these figures likely don’t reflect true rates. In a recent meta-analyses of prospective clinical trials, cetuximab was associated with a 34.9% incidence of all grade hypomagnesemia and 4.4% for grade 3/4, while panitumumab had a 31.8% overall incidence of hypomagnesemia (all grades) and 5.4% for grade 3/4 (Tumour Biol 2015; 36:3471-82).

Hypomagnesemia severity was associated with length of treatment, concomitant platinum chemotherapy, increasing age, and higher baseline serum magnesium concentrations. Saliently, almost all patients with severe hypomagnesemia failed to fully correct their serum magnesium levels despite multiple high-dose magnesium infusions per week. Additionally, improvement in serum magnesium levels from intravenous magnesium supplementation did not extend beyond 48–72 hours.

Recommendations based on expert opinion suggest severe hypomagnesemia induced by EGFRIs should be replaced intravenously, though this method can have negative impacts on a patient’s quality of life, and intravenous magnesium may also exacerbate renal magnesium leak. Researchers found no randomized controlled trials (RCTs) that compared intravenous versus oral magnesium replacement in patients treated with EGFRIs.

The authors found that magnesium concentration levels returned to normal within 90 days after cessation of EGFRI therapy, but they could not make any recommendations based on this regarding dose reductions to improve possible hypomagnesemia due to a lack of evidence in research.

Although the authors observed that higher dosages of magnesium replacement were ineffective in cases of severe hypomagnesemia caused by EGFRI, the limitations of the studies they reviewed mean that no definitive conclusion can be drawn at the optimal management of EGFRI-induced hypomagnesemia. Because of this, the authors call for further prospective studies “in order to define a best replacement strategy”.

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