Irinotecan dose, patient genotype influence neutropenia risk

September 21, 2007

NEW YORK (Reuters Health) - Both irinotecan dose and the patient's UGT1A1*28 genotype modulate the risk of irinotecan-induced neutropenia, according to a report in the Journal of the National Cancer Institute for September 5th.

"The key point from this work was that there needs to be context to all therapeutic recommendations," Dr. Howard L. McLeod told Reuters Health. "In this case, testing for UGT1A1*28 genotype will only identify an important risk of toxicity in the patients receiving the higher dosage irinotecan regimens."

In light of prior evidence linking UGT1A1*28 genotype and irinotecan-induced hematologic toxicity, Dr. McLeod from the University of North Carolina, Chapel Hill, and colleagues assessed the relationships between the incidence of irinotecan-induced hematologic toxicity and irinotecan dose among patients with the UGT1A1*28/*28 genotype.

The relative risk of hematologic toxicity in patients with UGT1A1*28/*28 compared to those with either UGT1A1*1/*1 or UGT1A1*1/*28 increased significantly as irinotecan dose increased, the authors report.

At irinotecan doses below 150 mg/m², the risk of toxicity was not significantly different between the genotypes. However, the investigators found, the risk of toxicity was 3.22-fold higher among patients with UGT1A1*28/*28 than among patients with the other genotypes at doses between 150 and 250 mg/m² and 27.8-fold higher at doses above 250 mg/m².

In contrast, UGT1A1*28 genotype was not associated with diarrhea, but the rate of diarrhea was inversely associated with dose among patients with one or two wild-type (UGT1A1*1) alleles.

"Studies are ongoing to better define the safe and effective dose of irinotecan for each UGT1A1 genotype," Dr. McLeod explained. "At the moment we have a lot of data on toxicity, but we also need to confirm the impact of dosage changes on tumor response. It appears that the 'good risk' patients can tolerate much higher doses of irinotecan, and studies are evaluating whether that will translate into even better responses to irinotecan."

"The cost of genotyping is approximately $250 per patient, so it is a very small percentage of the cost of chemotherapy and almost immeasurable alongside the cost of severe toxicity," Dr. McLeod commented.