First-Line FOLFOX4 Ups Survival in Advanced Colon Cancer

ORLANDO—Compared with the standard first-line chemotherapy treatment for advanced colorectal cancer, patients treated with the FOLFOX4 regimen containing the investigational agent oxaliplatin lived longer and had fewer side effects.

The FOLFOX4 regimen, also known as the de Gramont regimen, combines oxaliplatin with an infusion of fluorouracil (5-FU)/leucovorin given over 2 days, while the standard therapy, the Saltz regimen (or IFL) consists of irinotecan (Camptosar) plus a brief injection of 5-FU/leucovorin. The study also contained a third arm consisting of oxaliplatin and irinotecan (IROX), also known as the Wasserman regimen.

Richard M. Goldberg, MD, professor of oncology, Mayo Clinic, presented the findings from the NCI-sponsored N9741 trial for the North Central Cancer Treatment Group at an oral session of the 38th Annual Meeting of the American Society of Clinical Oncology (abstract 511).

Oxaliplatin ExpandedAccess Program

Based on the interim analysis of N9741, accrual to all arms except FOLFOX4 has been discontinued. Patients already enrolled in one of the other two arms will be offered the option of switching to FOLFOX4.

Sanofi-Synthelabo, Paris, the manufacturer of oxaliplatin, has submitted data on the use of oxaliplatin for second-line treatment of colorectal cancer to the US Food and Drug Administration for review.

Until the agent is commercially available in the United States, the National Cancer Institute (NCI) is sponsoring an expanded access program known as a Treatment Referral Center (TRC) protocol.

Patients and physicians may call the NCI Cancer Information Service at 1-800-4-CANCER for information on eligibility requirements and participating sites or visit the cancer website at http://cancer.gov/clinicaltrials/developments/oxaliplatin. 

Sanofi-Synthelabo is also establishing an expanded access program for patients who have already received therapy for colorectal cancer. More information is available from the company at 1-877-435-6928 or at its website located at www.sanofi-synthelabous.com.

Doses for the three study regimens were as follows: IFL: irinotecan 125 mg/m² plus LV 20 mg/m² and 5-FU 500 mg/m²/d on days 1, 8, 15, and 22 every 6 weeks. FOLFOX4: oxaliplatin 85 mg/m² on day 1 plus LV 200 mg/m² and 5-FU 400 mg/m² bolus plus 600 mg/m² as a 22-hour infusion on days 1 and 2 every 2 weeks. IROX: oxaliplatin 85 mg/m² plus irinotecan 200 mg/m² on day 1 every 3 weeks.

After an analysis of deaths within 60 days of study entry, the starting dose of IFL was reduced. The current report, however, is based on patients enrolled before that reduction. The primary endpoint was time to progression.

A total of 795 patients were included in this phase III trial analysis (median age 61). They all had a histologic diagnosis of unresectable advanced colorectal cancer and ECOG performance status 0 to 2 with adequate organ function and life expectancy of 12 weeks or more. Minimum follow-up is 1 year.

Study Results

In the primary endpoint analysis, time to progression was 6.9 months for IFL vs 8.8 months for FOLFOX4 and 6.7 months for IROX (P = .0009 FOLFOX4 vs IFL). The time to progression curves diverged early and maintained their separation out to 2 years, Dr. Goldberg said.

Overall survival was 14.1 months for IFL, 18.6 months for FOLFOX4, and 16.5 months for IROX (P = .002 FOLFOX4 vs IFL). One-year survival was 58% for IFL, 71% for FOLFOX4, and 65% for IROX. The response rate, confirmed at 4 weeks after initial documentation, was 29% for IFL, 38% for FOLFOX4, and 28% for IROX (P = .03 FOLFOX4 vs IFL).

Adverse Events

Grade 3 or higher toxicities occurred more often in the IFL group than in FOLFOX4, with significantly more nausea (15% IFL, 6% FOLFOX4), vomiting (12% vs 4%), diarrhea (33% vs 13%), and febrile neutropenia (14% vs 4%). Paresthesias were significantly more common for FOLFOX4 (18% vs 2% for IFL). While statistical calculations for the IROX arm were not yet available, nausea, vomiting, diarrhea, and febrile neutropenia were higher than in the FOLFOX4 arm.

Dr. Goldberg commented, "The FOLFOX4 survival is the longest ever reported in an American trial in advanced colorectal cancer." He noted also that toxicity favors FOLFOX4, with the exception of late paresthesias. He concluded that oxaliplatin "deserves a place in our armamentarium of agents for treatment of colorectal cancer in the US. . . . This will change the standard of practice."

Discussant Leonard B. Saltz, MD, of Memorial Sloan-Kettering Cancer Center and the originator of the Saltz regimen, stated, "This is not a trial of drugs but of regimens."

He pointed out that the IFL and FOLFOX4 regimens are not directly comparable because in the IFL regimen, 5-FU was given as a brief bolus injection whereas in FOLFOX4, it was given as an infusion over 2 days. "There are different side effect profiles and activity levels associated with these different methods of administering fluorouracil," Dr. Saltz said. "An important take home message from this study, in my opinion, is the endorsement of the infusional fluorouracil approach."

Dr. Goldberg, in response, pointed out that no trials have shown a survival advantage for infusional 5-FU over bolus administration.

Another confounding factor, Dr. Saltz said, was variations in the availability of irinotecan and oxaliplatin for crossover second-line treatment after progression, since irinotecan is commercially available in the United States and oxaliplatin is not. Irinotecan was prescribed for 52% of patients after failure of FOLFOX4, whereas only 17% of patients received oxaliplatin after IFL failure. "How this may have affected survival is impossible to say," he commented.

‘A Positive Trial’

The "unequivocal conclusion" from the trial, Dr. Saltz continued, "is that oxaliplatin had a major favorable impact on survival ... this is a positive trial." He added: "Although these data don’t compel us to use oxaliplatin first line, they give us the option."

Drs. Goldberg and Saltz concurred that the trial confirmed the activity and importance of oxaliplatin, and that working out where and how to best use it is a future research task. Speaking at the ASCO-sponsored press conference, Dr. Goldberg called the results "one chapter in a long story."