Irinotecan Easier to Give as Physicians Gain Experience

BOCA RATON, Fla--Recent data on the topoisomerase I inhibitor irinote-can(Camptosar) are quite encouraging for its use in refractory colorectalcancer, Dr. Leonard Saltz said at the annual meeting of the Network forOncology Communication and Research.

"There is a definite learning curve to this drug; as you get morecomfortable with it, it becomes easier to give," said Dr. Saltz, ofMemorial Sloan-Kettering Cancer Center. He advised the audience that takingsteps to reduce side effects, such as vomiting and diarrhea, can enhancetolerability of the drug.

Trials of irinotecan used strict criteria for determining partial response(greater than 50% reduction in tumor size), he said, but in reality, patientswith a minor response or stable disease can be considered to have showna clinical benefit. "I doubt very much if patients care if their tumorshrinks 51% or 49%," he said.

In a phase II study of irinotecan at Memorial Sloan-Kettering, the drugwas given at a dosage of 125 mg/m² × 4 weeks with a 2-weekrest, to chemotherapy-naïve patients with metastatic and measurablecolorectal cancer. More than 75% of patients had a tangible clinical benefit(32% partial remission, 20% minor remission, and 25% disease stabilization).

In a phase II trial at the University of Texas, San Antonio, of 48 fluorouracil-refractorycolorectal cancer patients, 23% achieved a major objective response withirinotecan and 50% had a tangible clinical benefit. "With these sortsof results," Dr. Saltz said, "most patients will be happy theywent on the regimen."

Irinotecan causes an acute cholinergic response, especially when givenby rapid infusion. To prevent nausea and vomiting, Dr. Saltz suggests usinga 90-minute infusion time and routinely giving a pretreatment dose of dexamethasone.

The serotonin antagonists such as ondansetron (Zofran) and granisetron(Kytril) can be used later if needed, he said, "although some peopleprefer to throw the whole antiemetic regimen in at the outset." Dr.Saltz cautioned that prochlorperazine should be avoided within 24 hoursof irinotecan administration, as the drug combination has been reportedto cause agitation.

Managing Diarrhea

Since diarrhea is the major dose-limiting toxicity of irinotecan, Dr.Saltz recommends using loperamide (Imodium) at the onset of diarrhea. "Itell my patients they're going to take a nonprescrip-tion drug in a prescriptionway." The instructions on over-the-counter lopera-mide say to takeno more than four doses daily, but Dr. Saltz instructs his patients totake one tablet (2 mg) every two hours until they have gone 12 hours withouta liquid stool.

Of the first 18 patients treated with irinotecan at Memorial Sloan-Ketteringwho were not on loperamide, 56% had dose-limiting diarrhea. When patientstook the drug exactly as prescribed, the dose-limiting diarrhea rate fellto 9%.

He also noted that there is no clear indication that dose intensificationis needed with irinotecan. "You'll be much more likely to be ableto continue a therapeutic trial if you don't hit the patient too hard ortoo early," he said.

He recommends evaluating patients early and often. If even a mild tomoderate toxicity is noticed, it is okay to drop the dose back by 25 mg/m².And, he said, results can be achieved treating patients for three weeksout of five rather than four weeks out of six. The difference in treatmenttime per cycle is only 60% versus 66%. He emphasized, however, that thefull two-week rest between cycles should be maintained.

Irinotecan is now being studied as initial treatment of colorectal cancer.Dr. Saltz published results last year of a phase I trial combining irinotecanwith fluorouracil and leucovorin. He is currently heading a phase III trial,being conducted at centers in the United States, Canada, and Australia,that has three treatment arms: standard fluorouracil and leucovorin, irinotecanalone, and the combination of all three drugs.

Eligible patients are those who have newly diagnosed metastatic diseaseand have received no chemotherapy, or who have received adjuvant chemotherapyand have been disease free for at least one year. About 660 patients willbe enrolled in the trial.