NEW YORKBy tinkering with both dosage and scheduling, researchers are hoping to shift the balance of benefits over toxicity in patients treated with irinotecan(Drug information on irinotecan)/fluorouracil/leucovorin (IFL). Variations being tried include moving to a day 1, day 8 schedule every 21 days with day 15 as a rest day, and reducing starting doses for particular patient groups, David H. Ilson, MD, PhD, reported. Dr. Ilson is associate attending physician at Memorial Sloan-Kettering Cancer Center and assistant professor of medicine at Weill Medical College of Cornell University in New York.
"One of the seminal studies that established efficacy of this regimen was a Pharmacia-sponsored trial in which IFL with bolus fluorouracil(Drug information on fluorouracil) (5-FU) was compared to 5-FU/leucovorin (allowing salvage irinotecan [CPT-11, Camptosar]) and to irinotecan alone (allowing salvage 5-FU/leucovorin). The other was a European Aventis-sponsored trial in which an infusional 5-FU/leucovorin schedule was compared to the same regimen plus irinotecan," Dr. Ilson said.
"Dosing of the irinotecan/bolus 5-FU regimen in the first trial (see Table 1) was a relatively simple regimen that required minimal patient and practitioner time and avoided the need for central venous access. The European infusional regimen (see Table 2) was more complex, required greater patient and practitioner time, and required a central catheter and infusion pump, with all the potential problems associated with such catheters," Dr. Ilson said.
Response Rate Doubled
The "take-home message" from both studies is that adding irinotecan to the combination doubled the response rate (from about 20% to about 40%) and added 2 to 3 months to progression-free survival. "These studies established combination therapy as standard-of-care in advanced colorectal cancer," Dr. Ilson said.
This improvement came at a cost in toxicity. With the bolus 5-FU regimen, grade 3 or 4 diarrhea and grade 2 to 4 neutropenia were major problems and dose reduction was generally needed, Dr. Ilson said. "By the third week, 50% of patients required reduction by at least one dose level."
Toxicity was not age-related, but there was more grade 2 toxicity for patients over age 65. During the first cycle of IFL, patients younger than 65 had an average one level dose reduction and those over 65 had an average two level dose reduction. These dose reductions were maintained for cycle two.