Originally, this randomized phase III trial was designed to compare time to progression of disease using various schedules of oxaliplatin/5FU/LV or CPT-11/5FU/LV compared with the two-drug combination 5FU/LV. Patients enrolled in the study had a history of unresectable, advanced colorectal cancer.

Dosage levels in the three regimens reported here were (in mg/m2): CPT-11 275 d1 and LV 20 followed by 5FU 400 d2-5; OXAL 130 d1, LV 20 followed by 5FU 320 d1-5; and LV 20 followed by 5FU 425 d1-5. The CPT-11 arm was based on a Mayo Clinic phase I trial; the OXAL regimen was based on a European phase II trial.

The 5FU/LV arm was closed after the U.S. Food and Drug Administration found that the Saltz CPT-11 + 5FU/LV regimen demonstrated survival advantage over 5FU/LV alone. The Saltz regimen then became the control arm of the larger study. The other two arms closed due to excessive toxicity.

"In trials of this kind, a 1% fatal toxicity is typical, and this served as an important toxicity benchmark for us," said Dr. Morton. The investigators used a real time toxicity monitoring system. Centers were required to report any hospitalization or grade III/IV event within 24 hours.

The sequential CPT-11 + 5FU/LV arm was closed following five treatment-related deaths among the first 61 patients, a rate of 8%. Their deaths were attributed to hypovolemic shock (3), aspiration pneumonia (1), respiratory failure (1), and cause unknown (1).

Three deaths were reported in the OXAL + 5FU/LV arm among the first 16 patients, a rate of 19%. OXAL dosage was reduced to100 and 5FU to 240 after 15 patients, but an additional death in the next 31 patients caused closure of the arm. Deaths in this arm were attributed to nausea, vomiting, and dehydration (3) and weakness and neutropenia (1).

In addition to closing these arms, the investigators reduced the dose levels of CPT-11 to 100 and of 5FU to 400 for continuing patients.

After noting that the fatal toxicities had occurred during the first cycle of treatment, several questioners asked Dr. Morton if there were some way to predict which patients might be susceptible to such toxic reactions. "These toxicities were unexpected and we had real time monitoring in place so we were able to stop it," he replied.

The entire Intergroup N9741 trial is currently closed to additional patients pending a monitoring committee decision regarding whether to continue.