Topotecan Doses Individualized in Neuroblastoma

MEMPHIS—In an effort to better understand the wide variation in patient response to therapy for neuroblastoma, researchers at St. Jude Children’s Research Hospital have initiated a pilot study in which chemotherapy doses will be individualized based on the patient’s personal pharmacokinetics.

St. Jude researchers are investigating pharmacogenomic variations among patients as a possible answer to the differences in patient response to chemotherapy, as well as a strategy for optimizing therapy for neuroblastoma and many other cancers.

These variations include genetic polymorphisms in drug-metabolizing enzymes, receptors, transporters, and other drug targets.

These investigations of underlying genetic and metabolic differences may someday yield answers that will allow a priori identification of patients for individualized targeted therapy.

Neuroblastoma, a solid tumor of the sympathetic nervous system that strikes very young children, has a dismal prognosis. Overall survival is only 56%. For the majority of children with disseminated disease, 80% to 85% respond, but the cancer recurs. The younger the child, the greater the chance for survival, with as many as 90% of infants surviving the disease, compared with as few as 20% to 30% of older children.

In an interview with ONI, Victor Santana, MD, a pediatric oncologist in the Department of Hematology-Oncology at St. Jude, explained that wide variations seen in drug exposure of patients treated with chemotherapy (as measured by AUC—“area under the curve”) call into question the “one-drug-one-dose-fits-all” concept.

Individual differences in drug efficacy and toxicity can be associated with the shape of an individual’s AUC. The goal, Dr. Santana said, is to balance efficacy and toxicity by aiming for the middle of the AUC.

Neuroblastoma was chosen for study because it is such a difficult disease to treat. “It’s a good model,” Dr. Santana said, “but I think the principle of pharmacokinetically guided therapy will become widely applicable for other tumors as well.”

In the current trial, 19 neuroblastoma patients, most of whom are under 5 years of age, are being treated with topotecan(Drug information on topotecan) (Hycamtin), a topoisomerase-I inhibitor. Rather than receiving the standard dose as a 30- to 60-minute infusion over 5 days, however, each patient is given a dose customized to his personal pharmacokinetics.

“We found that we needed prolonged exposure to the drug, so it is delivered in a cycle of 5 days, followed by 2 days off, and then a second 5 days,” Dr. Santana said. After 10 to 14 days off drug, the course is repeated. Antitumor response is evaluated after the second course.

Within 24 to 48 hours of beginning the first cycle, blood is drawn and pharmacokinetic studies done. The dose is quickly adjusted to achieve the ideal AUC. “Our target exposure is 100 ± 20 ng/h/mL,” Dr. Santana said.

The pilot study was begun 2 years ago and has 6 more months to run. In that time, every patient has received pharmaco-kinetically guided dosing, and all have responded to the initial treatment. “No patient has progressed, so it is quite exciting,” Dr. Santana said. He cautioned that the study is not complete, and confirmation of the results must await data analysis.

The major toxicity is myelosuppression. Dr. Santana said they were seeing it in predictable levels, neither more nor less than with standard-dose therapy.

Once the principle has been proven, future studies will compare the efficacy of pharmacokinetically guided therapy with standard-dose therapy.

The St. Jude study is based on the work of Dr. Peter Houghton, of the Department of Molecular Pharmacology, and Dr. Clinton Stewart, of the Pharmaceutical Sciences Department.