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Getting the right dosage of a drug is important for treatment of any disease. Researchers at St. Jude Children’s Research Hospital know that finding the best dosage of the drug topotecan offers hope to children with neuroblastoma. This tumor usually arises in the tissues of the adrenal glands but is also seen in the nerve tissues of the neck, chest, abdomen and pelvis. Pinpointing the optimum dosage to treat neuroblastoma can be tricky.
“Topotecan is a fascinating drug,” says Clinton Stewart, PharmD, of St. Jude Pharmaceutical Sciences. “It interacts with a critical enzyme in the body called topoisomerase. This enzyme helps DNA unwind so it can replicate, and topotecan inhibits its function, leading to cell death.”
From the results of a number of earlier studies, St. Jude researchers found that giving a low topotecan dosage on an extended schedule was the best way to kill tumors. More recently scientists found that if they closely monitored and fine tuned topotecan drug levels for each child—a technique called pharmacokinetic-based (PK-based) dosing—children with neuroblastoma responded very well.
“PK-based dosing is a promising tool that reduces variability in the amount of topotecan in the body, leading to improvements in response and ultimately improving the odds of survival,” Stewart says. “Basically, what we’re trying to do is get the right dosage of topotecan in the kids to get a good anti-tumor effect and to minimize toxicity.”
One of those studies was in collaboration with Victor Santana, MD, director of the Solid Tumor division and co-leader of the Solid Malignancies Program.
“The study with Dr. Santana showed that by obtaining plasma samples from children with neuroblastoma, then adjusting the topotecan dosage, we could attain the concentrations in the blood we needed,” Stewart says. “It showed that we could do this and that it would be safe in children.”
A recent 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 topotecan dosage might help some children, but in others the drug levels might be either too low to kill cancer cells or so high that it produces unacceptable side effects.
According to researchers, this study was critical. “Those children were newly diagnosed; they received topotecan as one agent, and they got two courses on the dosage individualization schedule,” Stewart explains.
In the study, children received topotecan before undergoing standard treatment. The aim of this initial treatment was to quickly reduce the size of the tumor that must be surgically removed. Reducing tumor size with topotecan and surgery also reduces the risk that the cancer will develop resistance to standard chemotherapy drugs that are administered afterward. The children did exceedingly well and tolerated the therapy with few ill effects.
“Topotecan was the first drug Bryce got,” says Kristi Cherry, whose son was found to have stage IV neuroblastoma when he was 10 months old. “After only two rounds of chemotherapy, his softball-sized primary tumor shrank 25 percent. The doctors were very pleased at how well it worked.”
Bryce also had mild side effects that were on par with other drugs he was taking. “But I didn’t realize how great topotecan was until I started speaking to other families who had children on the same drug,” Kristi says. “They were raving.”
Those rave reviews are what doctors like to hear.
“Our results are a proof-of-principle that children who receive topotecan may have an earlier reduction of their tumor size if treated according to the PK-guided dosing strategy,” says Santana. “Our findings also suggest that children who receive topotecan according to a PK-guided dosing strategy may have a better initial response and reduction in the size of the tumor.”
St. Jude researchers have also used PK-based topotecan dosing for the brain tumor medulloblastoma and are starting the same type of studies with the eye cancer retinoblastoma. Results of the neuroblastoma study are being sent to the Children’s Oncology Group (COG) for another PK-based dosing pilot study. COG is a National Cancer Institute-supported clinical trials cooperative group devoted to childhood and adolescent cancer research.
“If there is success in the pilot study, we hope to propose some form of dosage individualization for topotecan in a Phase III study for the entire Children’s Oncology Group,” Stewart says. “In addition, we are working on a method where we could tell pediatric oncologists that if their patient has certain characteristics they could adjust the topotecan dosage to get a better anti-tumor effect and not even need to check blood levels.”
Six-year-old Bryce is thriving, says his mother.
“He reacted so well to topotecan,” she says. “He plays T-ball and is an active child. You would never know he had cancer.”
Reprinted from Promise magazine, winter 2006
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