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    Low doses of drug help kids avoid genetic test

    Clinton F. Stewart, PharmD

    St. Jude investigators have shown that when the cancer drug irinotecan is given in low doses for multiple days, it eliminates the need to perform costly genetic testing that would delay treatment. In the past, such testing has been recommended by the U.S. Food and Drug Administration to determine if the patient is at risk for serious treatment side effects, such as neutropenia. Neutropenia is an abnormal reduction in the numbers of immune cells, called neutrophils; the disorder leaves individuals more vulnerable to infections.

    The finding means that clinicians can begin treatment sooner and eliminate the cost of this specialized test, which determines if the child carries a variation in the gene UGT1A1, which is linked to this side effect of neutropenia.

    By giving the drug in small doses for two weeks instead of the standard single, large dose once a month, children can begin treatment with irinotecan immediately. Irinotecan is used to treat childhood solid tumors such as neuroblastoma, sarcomas and kidney tumors.

    A report on this study is in the June 20 issue of Journal of Clinical Oncology.

    UGT1A1 makes an enzyme that modifies the activated form of irinotecan, a molecule called SN-38, so the body can easily remove it. Variations of this enzyme, especially one called UGT1A1*28, do not work as well and allow SN-38 to remain in the body at high levels for an extended period of time, causing side effects.

    Like many genes, UGT1A1 has a series of DNA building blocks called thymidine and adenine (TA) repeating several times just in front of the gene itself. This area, called the promoter region, acts as an “on” switch that triggers the reading of the gene. The normal UGT1A1 has six copies of TA in front of it, while UGT1A1*28 has seven.

    Previous studies had shown that when adults who carry two copies of the UGT1A1*28 gene variation received a single, high dose of irinotecan, they suffered severe diarrhea or neutropenia, said the report’s first author, Clinton Stewart, PharmD, Pharmaceutical Sciences. “The U.S. Food and Drug Administration requires the irinotecan package labeling to indicate that patients with UGT1A1*28 are at increased risk for neutropenia and that clinicians should consider using a reduced dosage for these individuals,” Stewart said. “Based on this warning, we wanted to determine if children with the UGT1A1*28 gene variation were likely to suffer the same toxicity even if they received irinotecan in 10 small doses over two weeks instead of one large dose.”

    The St. Jude team conducted a retrospective study of 74 children who had received this low-dose treatment for a variety of solid tumors. A total of 27 children had both copies of the normal gene UGT1A1 with six copies of TA in the promoter region; 36 had one normal and one UGT1A1*28 gene with seven copies of TA; and nine had two copies of UGT1A1*28.

    The researchers found no association between UGT1A1*28 and either diarrhea or neutropenia—even if the patient had two copies of this gene when irinotecan was given at the reduced dose. Therefore, the researchers concluded that it was not useful to test patients to determine if they had UGT1A1*28.

    “This is a negative finding in the sense that the UGT1A1*28 variation does not seem to predict toxic responses in patients treated with low-dose irinotecan,” said the report’s senior author Lisa McGregor, MD, PhD, Oncology. “But it should help clinicians design effective and safe irinotecan treatments for individual children.”

    Other authors of this study include Melinda O’Shaughnessy, PharmD, Thandranese Owens, John Panetta, PhD, and Stacy Throm, PhD, all of Pharmaceutical Sciences; Charles Fraga, Pathology; Catherine Billups, Biostatistics; Wayne Furman, MD, and Carlos Rodriguez-Galindo, MD, Oncology; Amar Gajjar, MD, Oncology co-chair; and former Biostatistics employee Tiebin Liu.