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Irinotecan Easier to Give as Physicians Gain Experience

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 colorectal cancer, Dr. Leonard Saltz said at the annual meeting of the Network for Oncology Communication and Research.

"There is a definite learning curve to this drug; as you get more comfortable with it, it becomes easier to give," said Dr. Saltz, of Memorial Sloan-Kettering Cancer Center. He advised the audience that taking steps to reduce side effects, such as vomiting and diarrhea, can enhance tolerability 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, patients with a minor response or stable disease can be considered to have shown a clinical benefit. "I doubt very much if patients care if their tumor shrinks 51% or 49%," he said.

In a phase II study of irinotecan at Memorial Sloan-Kettering, the drug was given at a dosage of 125 mg/m2 × 4 weeks with a 2-week rest, to chemotherapy-naïve patients with metastatic and measurable colorectal 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-refractory colorectal cancer patients, 23% achieved a major objective response with irinotecan and 50% had a tangible clinical benefit. "With these sorts of results," Dr. Saltz said, "most patients will be happy they went on the regimen."

Irinotecan causes an acute cholinergic response, especially when given by rapid infusion. To prevent nausea and vomiting, Dr. Saltz suggests using a 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 people prefer to throw the whole antiemetic regimen in at the outset." Dr. Saltz cautioned that prochlorperazine should be avoided within 24 hours of irinotecan administration, as the drug combination has been reported to 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. "I tell my patients they're going to take a nonprescrip-tion drug in a prescription way." The instructions on over-the-counter lopera-mide say to take no more than four doses daily, but Dr. Saltz instructs his patients to take one tablet (2 mg) every two hours until they have gone 12 hours without a liquid stool.

Of the first 18 patients treated with irinotecan at Memorial Sloan-Kettering who were not on loperamide, 56% had dose-limiting diarrhea. When patients took the drug exactly as prescribed, the dose-limiting diarrhea rate fell to 9%.

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

He recommends evaluating patients early and often. If even a mild to moderate 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 weeks out of five rather than four weeks out of six. The difference in treatment time per cycle is only 60% versus 66%. He emphasized, however, that the full 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 irinotecan with 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, irinotecan alone, and the combination of all three drugs.

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

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