ROCHESTER, Minnesota-Mature data from a phase III trial comparing three multidrug regimens against advanced colorectal cancer show that FOLFOX (infusional fluorouracil(Drug information on fluorouracil) [5-FU], leucovorin, and oxaliplatin(Drug information on oxaliplatin) [Eloxatin]) increased response rates and time to progression. Patients in the other experimental arm of the trial received irinotecan(Drug information on irinotecan) plus oxaliplatin (IROX). Patients randomized to the control arm received IFL (irinotecan [CPT-11, Camptosar] with bolus 5-FU plus leucovorin). Richard M. Goldberg, MD, of the Mayo Clinic, Rochester, Minnesota, reported the findings (ASCO abstract 1009). "Based on our results, FOLFOX should be considered a first-line standard of care over IFL or IROX," he said. Study Aims "The primary outcome was median time to tumor progression. Secondary outcomes were overall survival, response rate, quality of life, and toxicity," Dr. Goldberg explained. "Treatment with FOLFOX resulted in significantly increased time to progression and response rates when compared to IFL and IROX. Both oxaliplatin containing regimens, FOLFOX and IROX, were associated with a significantly improved overall survival compared to IFL. The toxicity profile favored FOLFOX over IFL with the exception of paresthesias. Our quality of life tools failed to discern significant overall differences between regimens." Eligibility criteria included: histologic diagnosis of incurable colorectal cancer, age 18 or over, Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, adequate organ function, and life expectancy exceeding 12 weeks. Exclusion criteria included: a second primary cancer within 5 years, prior chemotherapy for advanced disease, prior adjuvant therapy completed less than 12 months prior to the diagnosis of metastatic disease, uncontrolled intercurrent illness, brain metastases, pregnancy or lactation, more than three stools daily, symptomatic sensory neuropathy or pulmonary fibrosis. A total of 795 patients participated, divided almost evenly among the three study arms and with a median age of 61 years for each arm. Between 92% and 93% of patients had ECOG performance scores of 0 to 1. Study Results Preliminary results at 12 months follow- up were presented at the 2002 American Society of Clinical Oncology meeting (ASCO 2002 abstract S11). This year the investigators reported mature data with a follow-up of 20.4 months (ASCO abstract 1009). About 85% of patients had progressive disease and 65% had died. The 60-day mortality rates were similar: 4.5% for IFL, 2.6% for FOLFOX, and 2.7% for IROX. Febrile neutropenia, diarrhea, and nausea and vomiting were significantly more common with IROX. Paresthesias were significantly more common with FOLFOX. "There was a statistically significant survival advantage to both experimental regimens over IFL: median survival times were 14.8 months with IFL, 19.5 months with FOLFOX, and 17.4 months with IROX," Dr. Goldberg noted. "Survival proportions at 1 year were: 59% for IFL, 72% for FOLFOX, and 67% for IROX. Response rates were 31% for IFL, 45 % for FOLFOX, and 34% for IROX." Median time to progression, using the North Central Cancer Treatment Group (NCCTG) standard definition, was 6.9 months for IFL, 8.7 months for FOLFOX, and 6.5 months for IROX. Because of controversy regarding the NCCTG definition of time to progression, the study also analyzed the data using a definition employed by the US Food and Drug Administration (FDA) to isolate the effect of initial treatment. Time to progression findings were not different using the second definition. At the completion of the study specified therapy, between 67% and 75% of patients had second-line treatment. Among patients randomized to IFL, 24% later received oxaliplatin. After FOLFOX, 60% of patients received irinotecan. After IROX, 50% of patients received 5-FU.