IFL Regimen Dosages and Schedules Adjusted to Decrease Toxicity

NEW YORK—By tinkering with both dosage and scheduling, researchers are hoping to shift the balance of benefits over toxicity in patients treated with 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 (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.

In an attempt to minimize toxicity the schedule was changed from a 4-week on, 2-week off sequence to a day 1, day 8 schedule given every 21 days, with day 15 as a rest day, and starting doses were reduced.

Concerns About Toxicity

"Concerns over toxicity came into particular focus when national trials using the Saltz IFL regimen as the experimental arm were reported to have inordinate amounts of toxicity," Dr. Ilson said. Intergroup trial C89803 compared the Saltz IFL regimen to the Roswell Park 5-FU/leucovorin regimen as adjuvant therapy in stage III colon cancer. The trial was suspended in April 2001 because there were significantly more sepsis, thrombosis, and diarrhea on the experimental arm and because 60-day all-cause mortality was 2.5% for the IFL arm vs 0.8% for the 5-FU/leucovorin arm.

Intergroup trial NCCTG N9741 was also suspended in April 2001 due to increased therapy-related deaths on IFL, which was being compared to oxaliplatin (Eloxatin) plus irinotecan and to oxaliplatin plus continuous-infusion 5-FU/leucovorin. Sixty-day all-cause mortality was 4.5% on the IFL arm vs 1.8% on the other arms.

Dr. Ilson said that further analysis of data from the original IFL study published by Saltz and colleagues showed that in terms of deaths that could be directly attributed to treatment, 60-day mortality for the Saltz IFL regimen was 0.9% vs 1.4% for the 5-FU/leucovorin regimen. "This suggests that concerns about toxicity of the Saltz IFL regimen may be open to question," he said. "To put this in perspective, data from historical trials of 5-FU/leucovorin, from the registration trials, and from postmarketing surveillance in the community, showed minimal and acceptable 60-day mortality rates for IFL ranging from 1.3% to 3.8%, compared to 5.5% to 7.6% for 5-FU/leucovorin."

New Recommendations

The toxicity analyses led to new recommendations for monitoring of patients who are receiving irinotecan plus 5-FU/leucovorin. These include:

• close monitoring during weekly visits;

• aggressive use of loperamide (Imodium, Kaopectate II), and the empiric use of fluoroquinolone antibiotics, in patients having diarrhea for more than 24 hours or neutropenia even in the absence of fever;

• hospitalizing patients who have diarrhea for more than 48 hours;

• treating cramping as equivalent to diarrhea;

• weekly monitoring of neutrophil counts and use of empiric fluoroquinolones when absolute neutrophil count (ANC) drops below 500/mL.

Reducing Starting Dose

"Another proposal is to consider reducing the starting dose of drugs," Dr. Ilson said. This includes:

• holding therapy for patients who develop diarrhea within 24 hours prior to treatment with IFL;

• reducing doses by one level (to 100 mg/m² irinotecan and 400 mg/m² 5-FU) for grade 2 diarrhea or neutropenia the day of treatment; and

• reducing doses by two levels (to 75 mg/m² irinotecan and 320 mg/m² 5-FU) for grade 3/4 diarrhea or neutropenia.

"Performance status 2 patients are at increased risk for adverse events, and the decision to treat with IFL should be made with patient knowledge, careful follow-up, and reduced starting doses," Dr. Ilson said. He also noted that recent studies (reported in this supplement) have shown that 5-FU administered by continuous infusion can reduce toxicity.