Hypercalcemia: a dose-limiting toxicity associated with 13-cis-retinoic acid

13-cis-Retinoic acid (cis-RA) has efficacy in the treatment and prevention of certain malignancies. In vitro effects against neuroblastoma include induction of differentiation, inhibition of proliferation, and decreased N-myc expression. We hypothesized that cis-RA may be effective against minimal residual disease in neuroblastoma patients. A phase I trial to determine the maximal tolerated dosage and toxicity of cis-RA in pediatric patients with neuroblastoma after bone marrow transplantation was initiated.

Forty-nine pediatric patients (status post-bone marrow transplant for neuroblastoma) were treated for 14 days with oral cis-RA in escalating doses from 100 to 200 mg/m2/day followed by a 14-day rest period for up to 12 months.

In three of 39 patients (7.7%) evaluable for calcium levels, hypercalcemia (12.6-18.7 mg/dl) was the dose-limiting toxicity. Grade 1-3 hypercalcemia occurred in nine of 39 patients (23%). The overall incidence of hypercalcemia was 31% (12 of 39). Only one patient was symptomatic due to the hypercalcemia, with arthralgias and myalgias. The hypercalcemia resolved with temporary discontinuation of the drug and a 25% dose reduction for subsequent courses.

Hypercalcemia is a novel dose-limiting toxicity for cis-RA. Patients receiving high doses of cis-RA should have monitoring of serum calcium levels.