How to Improve the Safe and Effective Use of Doxorubicin in Children with Cancer

Doxorubicin, one of the anthracyclines, is a chemotherapeutic agent widely used to treat several pediatric cancers such as acute lymphocytic leukemia, acute myeloid leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, softtissue sarcoma, bone sarcoma, Ewing sarcoma, neuroblastoma, and Wilms tumor. As such, this drug has contributed substantially to the dramatic improvement of the 5-year survival rates for many of these childhood cancers [1]. However, a major potential adverse event of the use of doxorubicin is its cardiotoxicity. More than 50 % of patients will develop asymptomatic cardiac dysfunction, whereas one in six will result in clinical heart failure due to cardiomyopathy [2]. The exact causative mechanism of this devastating adverse event is, despite the fact that doxorubicin has been used for decades in many patients, not fully elucidated. There is more or less consensus about the important role of reactive oxygen species causing cardiac cell damage, progressive myocyte loss that ultimately will result in a decreased cardiac contractility [3]. To date, several clinical risk factors have been linked to the development of doxorubicin-induced cardiotoxicity and these are a higher single as well as total cumulative dose, cardiac irradiation, short infusion time duration, younger age, longer time since the treatment, and female sex [4]. In addition, much more recently, the potentially important role of genetic factors as predictors of doxorubicin-induced cardiotoxicity has been brought to our attention [5]. Multiple genetic variants in several genes associated with this cardiotoxicity have been identified [6]. However, until now, the currently available knowledge about both the clinical as well as the genetic risk factors has never resulted in sufficient discriminatory power to divide patients into groups with a high or low risk of developing cardiotoxicity. In this issue of the journal, Voller and colleagues have described a population pharmacokinetic model of doxorubicin in children in which they have used a power function to describe the relation between doxorubicin clearance and age [7]. They were able to show, for the first time, that the pharmacokinetics (PK) of doxorubicin in infants and children with cancer are age dependent. Clearly, this finding might eventually assist in designing a more tailored, safe, and effective dosing regimen for the use of doxorubicin in children with cancer. However, before this demonstrated lower clearance of doxorubicin in infants and children younger than 3 years of age will be able to change the currently used dosing regimens in pediatric patients with cancer, there is an absolute need to not only consider developmental PK but also, and probably more importantly, developmental pharmacodynamics (PD). At first glance, based on the demonstrated lower total body clearance, it seems that we need less doxorubicin in this group of young patients to reach the same amount of doxorubicin exposure as compared with older children and adolescents. However, what do we really know about the dose-concentration-effect relationship in children with cancer between 1 and 18 years of age? In other words, there is an urgent need to better This commentary refers to the article available at doi:10.1007/s40262-015-0272-4.