Clinton F. Stewart, PharmD

    Clinton F. Stewart, PharmD

    Fine-tuning cancer drug concentrations in neuroblastoma

    Monitoring and fine tuning the levels of the cancer drug topotecan in children with neuroblastoma holds promise for maximizing the drug’s effectiveness while reducing its toxicity, according to St. Jude investigators. Neuroblastoma is a tumor of nerve tissues in the neck, chest, abdomen and pelvis. The cancer usually arises in the tissues of the adrenal glands.

    The Phase II study addressed the problem posed by the different rates at which children eliminate or clear topotecan from their bodies. Such differences mean that the standard dose of topotecan might help some children, but in others the drug might be either too little to kill cancer cells or so high that it produces unacceptable toxicity. However, by closely monitoring and fine-tuning the drug levels in each child, investigators kept topotecan levels within a range that previous St. Jude work showed was effective and nontoxic. This technique is called pharmacokinetic-based (PK-based) dosing.

    “PK-based dosing is a promising tool that reduces variability to topotecan systemic exposure, leading to improvements in response and ultimately improving the odds of survival,” said Clinton Stewart, PharmD, of Pharmaceutical Sciences and senior author of a report on this work that appears in the Journal of Clinical Oncology.

    In the St. Jude study, children received topotecan before undergoing standard treatment. The aim of this initial treatment is to quickly reduce the size of the tumor that must be surgically removed later, said Stewart, adding that reducing tumor size with topotecan and surgery also reduces the risk that the cancer will develop resistance to standard chemotherapy drugs that are subsequently administered.

    “Our results are a proof-of-principle that children who previously would not have benefited from topotecan may now experience an early reduction of their tumor size if treated according to the PK-guided dosing strategy,” said Victor Santana, MD, director of the Solid Tumor division and co-leader of the Solid Malignancies Program. Santana is the first author of the report on this work. “Our findings also suggest this approach might improve treatment of other childhood cancers, as well.”

    The PK-based dosing strategy is based on work done in the laboratory of Peter Houghton, PhD, Molecular Pharmacology chair and co-leader of the Solid Malignancy Program.

    The other authors of the study include Wayne Furman, MD, Hematology-Oncology; Catherine Billups, Biostatistics; Fredric Hoffer, MD, Radiological Sciences; and Andrew Davidoff, MD, Surgery. 


    Last update: July 2005