CPT-11 Recommended as Standard in 5-FU Resistant Colorectal Cancer

LOS ANGELES--Irinotecan (Camptosar), also known as CPT-11, should be standard therapy for patients whose metastatic colorectal cancer has become resistant to fluorouracil (5-FU), David Cunningham, MD, said at the plenary session of the American Society of Clinical Oncology (ASCO) annual meeting. Dr. Cunningham is head of the Gastrointestinal Cancer Unit, Royal Marsden Hospital, London, UK.

In a multicenter phase III trial, patients randomized to irinotecan were 2.6 times more likely to be alive at 1 year following treatment and lived significantly longer than those who received only best supportive care.

"We found that the quality of life of patients on the CPT-11 arm of the trial was significantly better and also that they had fewer symptoms related to the underlying cancer," Dr. Cunningham said. "The findings are so impressive that we would no longer consider best supportive care to be an acceptable treatment option for this population."

Irinotecan, a topoisomerase I inhibitor, is licensed by the FDA for use as second-line therapy in metastatic colorectal cancer, based on a 15% objective response rate seen in pretreated metastatic colorectal cancer patients in a phase II trial.

There has been concern that this improvement might not be sufficient to make the agent a worthwhile option in these patients, in view of the agent’s significant problems with diarrhea.

Thus, Dr. Cunningham and his colleagues initiated this randomized phase III trial to confirm the clinical benefit of irinotecan vs no active anticancer therapy in terms of overall survival in resistant metastatic colorectal cancer.

Inclusion criteria included tumor progression within 6 months of prior 5-FU, no more than two prior 5-FU palliative regimens, and no bulky disease. Patients with poor performance status (PS of 2 or less) were also excluded because studies had shown that irinotecan is not effective in that population.

The trial randomized 279 patients in a 2:1 ratio to either irinotecan, 350 mg/m² every 3 weeks (300 mg/m² if age 70 or more, or PS = 2) plus optimal supportive care, or optimal supportive care alone.

Better Survival

Overall survival rates were significantly better in the patients treated with irino-tecan (see Figure), and the curves began to separate within 2 months of beginning treatment (P =.0001). At 12 months, the odds of death were 2.6 times higher with best supportive care than with irinotecan (36.2% survival for irinotecan vs 13.8% for supportive care).

Multivariate analysis found that the five most important prognostic variables were performance status, weight loss, hemoglobin level, alkaline phosphatase level, and number of involved organs.

"After correcting for all of the major prognostic factors, treatment with CPT-11 continues to have a major, significant impact on the risk of death for this patient population," Dr. Cunningham commented.

More patients in the treatment arm survived without deterioration in performance status, and more had pain-free survival.

"CPT-11 prolongs survival, improves quality of life, and improves control of tumor-related symptoms," Dr. Cun-ningham said. "The results are sufficiently important for us to believe that this represents a new standard of care for second-line treatment of patients with colorectal cancer. When the disease has become resistant to treatment with 5-fluorouracil, patients should be offered CPT-11."

Nearly All Become Resistant

Virtually all patients with metastatic disease eventually become resistant to 5-FU. The effect of irinotecan occurred regardless of prior response to 5-FU.

"Median survival of patients with metastatic colorectal disease is about 12 months. CPT-11 adds an additional 3 months to that," Dr. Cunningham said. "Patients were able to carry on a normal life for much longer."

Irinotecan has a well-known tendency to cause sometimes serious diarrhea and did cause severe diarrhea in about 22% of patients, but Dr. Cunningham said that the diarrhea was readily managed by conventional antidiarrheal agents in this study.

In discussing the study, Michael O’Connell, MD, of the Mayo Clinic, agreed that irinotecan had a highly significant short-term survival effect but pointed out that median survival was prolonged by only 2.7 months and that there was no long-term survival benefit associated with treatment.

However, Dr. O’Connell also noted that the cost of irinotecan is similar to that for other agents used to treat advanced cancer and that the drug is widely available and can be given as outpatient treatment.

He suggested that the dose should perhaps be reduced to 300 mg/m² for patients over age 70 and that the drug might not be appropriate for patients with bulky disease, especially hepatic tumors, or for those who have had prior pelvic radiation and are therefore more susceptible to severe diarrhea.