Evaluation of Toxicity and Effect on Growth and Sexual Development in
Children with MAPK Pathway Driven Tumors Treated with BRAF and MEK
Inhibitors -- A Single Center Experience
Abstract
Background The MAPK pathway, is a signal transduction pathway involved
in the oncogenesis of a variety of pediatric tumors. The clinical use of
BRAF inhibitors and MEK inhibitors is increasingly used in oncology
practice. The toxicity profile of these drugs in the pediatric
population, particularly in relation to development, growth and sexual
maturation remains insufficiently studied. Procedure This study includes
22 pediatric patients with molecularly confirmed MAPK pathway driven
tumors treated with MEK or BRAF between August 2014 and March 2020.
Throughout treatment they underwent regular laboratory, endocrine,
cardiac, ophthalmic and dermatologic evaluation. Toxicity was recorded
and evaluated according to CTCA v4. Results Overall an adverse event
frequency of 86% was encountered. Dermatological disorders accounted
for 68% of the adverse events. Overall 8 patients suffered from severe
adverse events including Erythema Nodosum, PLEVA-like rash,
osteoporosis, Sarcoid-like massive lymphadenopathy, retinal toxicity and
elevated liver enzymes & CPK. Four patients discontinued treatment as a
result of adverse events. In this cohort we did not encounter any
treatment-related abnormalities of sexual maturation or gonadal function
nor statistically significant growth retardation, however a slower than
expected growth rate was observed in one patient. In addition
dose-dependent, non-symptomatic and within normal range for age
decreased cardiac SF% was noted in two patients treated with MEK
inhibitor. Conclusion Treatment with BRAF and MEK inhibitors was shown
to be generally safe, we report drug tolerability of 82%. However,
further prospective studies should be preformed to are characterize the
full scope of side effects in the pediatric population.