In the past decades, new cancer treatments have been introduced in pediatric oncology leading to improvement in clinical outcomes and survival rates. However, due to inter-individual differences, some children experience severe chemotherapy-induced toxicities or a poor clinical outcome. An explanation for the diversity in response to chemotherapy is genetic variation, leading to differences in expression and activity of metabolizing and transport enzymes as well as drug targets. Pharmacogenetic testing has emerged as a promising tool to predict and limit acute and long-term adverse effects in patients. However, in pediatric oncology, limited number of patients and a considerable diversity in study results complicate the interpretation of test results and its clinical relevance. With this review, we provide an overview of new developments over the past four years regarding relevant polymorphisms related to toxicity in pediatric oncology. The following chemotherapeutics and associated toxicities are discussed: alkylating agents, anthracyclines, asparaginase, methotrexate, platinum compounds, steroids, thiopurines, topoisomerase inhibitors, and vinca alkaloids. Our review identifies several questions regarding the role of genetic variants in chemotherapy-induced toxicities. Ambiguities in the literature stem from small population sizes, differences in (statistical) interpretation and variations in sequencing technologies as well as different clinical outcome definitions. Standardization of clinical outcome data and toxicity definitions within electronic health records combined with the increased availability of genomic sequence techniques in clinical practice will help to validate these models in upcoming years.

In pediatric oncology, pharmacogenetic guidelines are underutilized and the potential impact of pre‐emptive pharmacogenetic screening remains largely unexplored despite this field's need for individualized approaches. While comprehensive pharmacogenetic guidelines are not yet available for all anticancer drugs, evidence‐based recommendations exist for a subset of supportive care drugs and anticancer drugs, including thiopurines, irinotecan, capecitabine, and 5‐fluorouracil. In this study, we evaluate the potential impact of pre‐emptive pharmacogenetic screening by retrospectively identifying opportunities for dose or treatment adjustments within a national pediatric oncology cohort. Our analysis focused on ten genes and 28 drugs relevant to pediatric oncology, which are included in the Clinical Pharmacogenetics Implementation Consortium and the Dutch Pharmacogenetics Working Group guidelines. In a cohort of 1,151 pediatric oncology subjects, we identified that 16% of individuals could have benefited from altered drug dosing or treatment. These include dose and treatment recommendations for allopurinol, nonsteroidal anti‐inflammatory drugs, phenytoin, amitriptyline, proton pump inhibitors, voriconazole, tramadol, codeine, paroxetine, tacrolimus, rasburicase, and 6‐mercaptopurine. As genetic data increasingly becomes available through molecular diagnostics in pediatric oncology, there is a unique opportunity to re‐utilize this data for pre‐emptive pharmacogenetic screening. Leveraging genetic profiles to guide clinicians in drug selection and dose optimization can improve patient outcomes by enhancing the safety and efficacy of treatments. We therefore recommend incorporating pharmacogenetic screening into clinical workflows to advance personalized medicine in pediatric oncology.

Over 75 kinase inhibitors (KIs) have been approved for the treatment of various cancers. KIs are orally administrated but mostly lack pediatric age-appropriate dosage forms or instructions for dose manipulation. This is highly problematic for clinical practice in pediatric oncology, as flexible oral formulations are essential to individually set dosages and to adjust it to a child’s swallowability. Most KIs are poorly soluble, categorized in Biopharmaceutics Classification System (BCS) class II or IV, and improperly manipulating the KI formulation can alter pharmacokinetics and jeopardize KI drug safety and efficacy. Therefore, the goals of this review were to provide practical recommendations for manipulating the formulation of the 15 most frequently used KIs in pediatric oncology (i.e., bosutinib, cabozantinib, cobimetinib, crizotinib, dabrafenib, dasatinib, entrectinib, imatinib, larotrectinib, nilotinib, ponatinib, ruxolitinib, selumetinib, sunitinib and trametinib) based on available literature studies and fundamental drug characteristics and to establish a decision tool that supports decisions regarding formulation manipulation of solid oral dosages of KIs that have been or will be licensed (for adult and/or pediatric cancers) but are not included in this review.

Paediatric oncology patients who develop severe chemotherapy-induced toxicity that requires dose reduction, delay or termination of treatment are at risk of decreased treatment efficacy. Previous research has provided evidence that genetic variants in TPMT, NUDT15, UGT1A1 and DPYD are associated with toxicity of anticancer drugs. This led to pharmacogenetic guidelines that are integrated into clinical practice in paediatric oncology. Recently, novel genetic variants have been associated with a higher risk of developing chemotherapy-induced toxicity. In this case series, we selected 21 novel variants and genotyped these in nine patients with excessive chemotherapy-induced toxicity using whole exome sequencing or micro-array data. We observed that six out of nine patients carried at least one variant that, according to recent studies, potentially increased the risk of developing methotrexate- or vincristine-induced toxicity. As patient-derived genetic data are becoming widely accessible in paediatric oncology, these variants could potentially enter clinical practice to mitigate chemotherapy-induced toxicity.