High-Dose Irinotecan More Likely to Spark Hematological Toxicity

Allison Gandey

July 31, 2007

July 31, 2007 (Chicago) — The risk of experiencing irinotecan-induced toxicity is a function of the dose administered in patients with genotype UGT1A1*28/*28, researchers report. The topoisomerase 1 inhibitor produced by Pfizer under the brand name Camptosar is most commonly used in the treatment of colorectal cancer. "In the spirit of maximizing patient safety, we support the use of genotype-based dosing of irinotecan for high doses but believe it may not be as useful for lower doses," lead author Janelle Hoskins, PhD, from the University of North Carolina at Chapel Hill, presented during a poster session at the recent American Society of Clinical Oncology 43rd Annual Meeting.

"We're beginning to understand the effect of different genotypes," Margaret Mooney, MD, from the National Cancer Institute's Cancer Therapy Evaluation Program, told Medscape during an interview. "And we have seen that different irinotecan schedules are better tolerated than others."

In July 2005, the US Food and Drug Administration and Pfizer Pharmaceuticals changed the package insert for irinotecan to include a patient’s UGT1A1*28 genotype as a risk factor for severe neutropenia. This change was prompted by findings from 4 pharmacogenetic studies that identified a 2.5- to 17-fold risk for toxicity in UGT1A1*28 patients receiving irinotecan.

Confusion Remains About Dosing

"Notably, a total of 34 patients in the 4 studies were homozygous for the UGT1A1*28 allele," Dr. Hoskins presented. "Subsequent studies on larger patient cohorts treated with other dosage regimens have failed to consistently replicate the UGT1A1*28 genotype-toxicity associations." The research team says this has confounded the development of dosing recommendations and has contributed to confusion on how to select a safe dose of irinotecan for a patient who is homozygous for UGT1A1*28.

"The irinotecan label is just 1 factor, but there are other issues to consider as well," Dr. Mooney emphasized to Medscape. "Comorbid factors and other health considerations all have to be taken into account when considering dosing schedules."

In this latest analysis, the investigators reviewed data presented in 10 irinotecan pharmacogenetic studies and assessed correlations between the incidences of irinotecan-induced hematological toxicities. The study included a total of 825 patients and focused on UGT1A1*28/*28 subjects, irinotecan dose, and overall toxicity.

Summary of Data Presented in 10 Irinotecan Pharmacogenetic Studies

Trial Irinotecan Dose (mg/m2) Incidence of Grade 3 or 4 Hematological Toxicity in All Patients (%) Incidence of Grade 3 or 4 Hematological Toxicity in UGT1A1*28/*28 patients (%)
Innocenti (2004) 350 18 83
Iyer (2002) 300 10 50
McLeod (2006) 200 17 55
Rouits (2004) 180 33 60
Chiara (2005) 180 28 57
Marcuello (2004) 180 25 60
Toffoli (2006) 180 15 18
Carlini (2005) 125 5 0
cLeod (2006) 100 10 18
Massacesi (2006) 80 7 14

The investigators found that the incidence of grade 3 and 4 hematological toxicities in UGT1A1*28/*28 patients in all of the studies was positively related to irinotecan dose (Spearman Rank correlation rS = 0.68, P = .04). It was also related to the overall incidence of toxicity of a regimen (rS = 0.88; P = .002). But they found that the incidence of severe hematological toxicity among all patients was not related to irinotecan dose (rS = 0.44; P = .20).

"Our results suggest that the risk of experiencing irinotecan-induced hematological toxicity for UGT1A1*28/*28 patients is a function of the dose of irinotecan administered," Dr. Hoskins said during his presentation. Answering the question posed in the title of their poster presentation, "Irinotecan-induced neutropenia and UGT1A1*28: Does dose matter?," they conclude that yes, dose matters.

American Society of Clinical Oncology 43rd Annual Meeting: Abstract 4023. Presented June 2, 2007.

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