Fine tuning drug levels in neuroblastoma patients is effective

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 investigators at St. Jude Children's Research Hospital.

Neuroblastoma is a tumor of nerve tissues in the neck, chest, abdomen and pelvis. This 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 drug of topotecan might help some children; 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 work at St. Jude showed was effective and nontoxic.

Results of the study demonstrate that this technique for monitoring and adjusting drug levels, called pharmacokinetic-based (PK-based) dosing, can be a powerful tool for tailoring cancer treatment to individual children, said Clinton F. Stewart, Pharm.D., associate member of Pharmaceutical Sciences at St. Jude and senior author of a report on this work that appears in the June 20 issue of the journal Clinical Oncology.

"Fewer than half of children treated with standard therapy for neuroblastoma achieve long-term survival," Stewart said. "But PK-based dosing appears to be a way to improve those odds by letting us prolong the time a child's cancer is exposed to topotecan."

In the St. Jude study, children received topotecan before undergoing standard treatment. The aim of this initial treatment, called upfront window therapy, is to quickly reduce the size of the tumor as much as possible. "Reducing the size of the tumor first with topotecan means there will be less cancer that must be surgically removed later," he said. "And reducing the tumor size with topotecan and surgery means there is less risk that the cancer will develop resistance to the 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, M.D., 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," he added.

The PK-based dosing strategy is based on work done in the St. Jude laboratory of Peter Houghton, Ph.D., chair of Molecular Pharmacology and co- leader of the Solid Malignancies Program. Houghton, a co-author of the report, previously demonstrated in mouse models of neuroblastoma that topotecan kills more cancer cells if administered for five days a week for two weeks instead of the standard one-week course of therapy. His group also identified the optimal topotecan concentration range that should be maintained to get maximum benefit from the drug.

In the current study, the investigators administered topotecan intravenously to 28 children (median age 3.1 years) for five days a week for two consecutive weeks. To track the levels of topotecan, the investigators took plasma samples from children before and at predetermined times after completion of the topotecan infusion. If the levels were too high or low, the investigators adjusted the dosage accordingly.

Among the children in the study, one patient had a complete response, with no detectable cancer following initial treatment with topotecan; 17 children had partial responses, with at least 50 percent (but less than 100 percent) of their cancer eradicated. In addition, two children had an objective response (measurable decrease in tumor size), and the cancer stabilized (did not progress) in another eight children.

Twelve (40 percent) of the 30 patients were alive at the time the report was written. The researchers estimate that PK-based dosing will ensure that about 66 percent of patients will survive at least three years and about 44 percent will survive for at least four years.

Based on the initial success, several members of the Children's Oncology Group (COG), including St. Jude, are now conducting another study of PK-based dosing using topotecan, Santana said. COG develops and coordinates cancer clinical trials conducted at the 238 member institutions, which include cancer centers of all major universities and teaching hospitals throughout the United States and Canada, as well as sites in Europe and Australia.

Despite PK-based dosing's potential has to improve the survival rate of children with neuroblastoma, the technique is not appropriate for routine use in most institutions, Stewart said. Many hospitals do not have the resources to repeatedly monitor topotecan levels in individual children and fine tune doses to match each child's needs, he noted. Therefore, his laboratory is now trying to develop a simplified technique for achieving the right level of drug in each child. Such a simplified technique, developed using information obtained from PK-based dosing studies, would allow a doctor to calculate the dose needed by a child to maintain topotecan levels in the effective and relatively nontoxic range. The calculation would be based on age, sex, weight and standard laboratory tests that all such hospitals would routinely perform.

If successful, the simplified technique, developed through pioneering work at St. Jude in PK-based dosing, would benefit many more children throughout the world, according to Stewart.

Other authors of the study include Wayne L. Furman, Catherine A. Billups, Fredric Hoffer and Andrew M. Davidoff.

This work was supported in part by a U.S. Public Health Service Childhood Solid Tumor Program Project Grant, the National Cancer Institute and ALSAC.