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For infants and very young children with brain tumors, chemotherapy after surgical resection is the main treatment due to neurologic and neuroendocrine adverse effects from whole brain irradiation. Topotecan, an anticancer drug with antitumor activity against pediatric brain tumors, can be given intravenous or orally. However, high interpatient variability in oral drug bioavailability is common in children less than 3 years old. Therefore, this study aimed to determine the population pharmacokinetics of oral topotecan in infants and very young children, specifically evaluating the effects of age and ABCG2and ABCB1on the absorption rate constant (Ka), as well as other covariate effects on all pharmacokinetic parameters. A nonlinear mixed effects model was implemented in Monolix 4.3.2 (Lixoft, Orsay, France). A one-compartment model with first-order input and first-order elimination was found to adequately characterize topotecan lactone concentrations with population estimates as [mean (S.E.)]; Ka= 0.61 (0.11) h−1, apparent volume of distribution (V/F) = 40.2 (7.0) l, and apparent clearance (CL/F) = 40.0 (2.9) l/h. After including the body surface area in the V/F and CL/F as a power model centered on the population median, the ABCG2rs4148157 allele was found to play a significant role in the value of Ka. Patients homozygous or heterozygous for G>A demonstrated a Kavalue 2-fold higher than their GG counterparts, complemented with a 2-fold higher maximal concentration as well. These results demonstrate a possible role for the ABCG2rs4148157 allele in the pharmacokinetics of oral topotecan in infants and very young children, and warrants further investigation.

Medulloblastoma is a malignant brain tumour that occurs predominantly in childhood, but is also seen in infancy and throughout adulthoodAlthough the prognosis of medulloblastoma is favourable with current therapeutic regimens, the heterogeneous nature of this cancer has confounded efforts to substantially improve survival and reduce therapy-related toxicityAdvancements in technology and its accessibility have led, through molecular interrogation, to the recognition that medulloblastoma heterogeneity is broadly explained by the existence of four main molecular tumour subtypesEach molecular medulloblastoma subtype, termed Wnt, SHH, group 3, and group 4 medulloblastoma, has unique clinical and molecular characteristics, which influence nearly every facet of the disease, including survivalArmed with this knowledge, paediatric oncologists find themselves at an opportune moment to capitalize on these newly elucidated characteristics to improve survival and reduce morbidity by tailoring therapy towards the individual subtypes

The survival rate of patients with pediatric cancer has increased considerably due to improved understanding of the biology of cancer subtypes, and the development of targeted therapies. This Review analyzes the recent findings that link pharmacogenomic variations with drug exposure, adverse effects, and efficacy of the emerging new treatments in pediatric oncology.

A retrospective study evaluated the clinical characteristics, prognostic factors, and outcome of patients with newly diagnosed supratentorial malignant gliomas treated with preirradiation chemotherapy. Of 41 patients with supratentorial malignant gliomas accrued between 1984-1994, all had neuroimaging documentation of the extent of resection and 37 had complete neuraxis staging prior to treatment; 80% were treated with one of a variety of neoadjuvant chemotherapy regimens. Thirteen patients had anaplastic astrocytoma (AA), 25 had glioblastoma multiforme (GBM), and 3 had anaplastic oligodendroglioma. Gross total resection (GTR) was performed in 10 patients, subtotal resection (STR) in 22 patients, and biopsy (Bx) alone in 9 patients. For the entire group the 3-year overall and progression free survivals were 35 ± 8% and 18 ± 6%, respectively. Tumor recurrence was dominantly local. However, 9 patients with initially local disease failed at a distant neuraxis site, giving a 26 ± 7% actuarial risk of dissemination at 3 years. The only significant prognostic factor was extent of tumor resection: patients who underwent GTR survived longer than those who underwent STR or Bx (P = 0.004). Histology (GBM vs. AA), age, and the use of enhanced local dose radiation therapy (brachytherapy or stereotactic irradiation) did not affect survival. Neoadjuvant chemotherapy was not associated with a survival rate significantly different from that observed in adjuvant chemotherapy studies. Systematic neuraxis staging at diagnosis and recurrence revealed a rate of neuraxis dissemination as a component of recurrence that was higher than previously reported; the utility of craniospinal irradiation in preventing isolated dissemination remains uncertain. Cancer 1997; 80:497-504. © 1997 American Cancer Society.