Recently Released Data Show Benefits of FOLFOX4 Extend to Adjuvant Setting

PARIS-An international study that previously demonstrated FOLFOX4 to be active and safe in first-line treatment of advanced colorectal cancer now shows it increased 3-year disease- free survival and reduced risk of recurrence by 23% in the adjuvant setting. Aimery de Gramont, MD, of Hopital Saint Antoine, Paris, reported results on the first-line treatment at the 2002 ASCO meeting (abstract 525) and data on adjuvant treatment in 2003 (ASCO abstract 1015). MOSAIC Study
In the late 1980s an intergroup study established fluorouracil(Drug information on fluorouracil) (5-FU)/levamisole as an adjuvant treatment for colorectal cancer. A few years later, 5- FU/leucovorin became the new standard and remained so for almost 10 years. "The just-completed MOSAIC (Multicenter International Study of Oxaliplatin(Drug information on oxaliplatin)/5-FU-LV in the Adjuvant Treatment of Colon Cancer) study compared LV/5-FU2 to FOLFOX4 for 6 months or 12 cycles. LV/5-FU2 is a combination of high-dose leucovorin followed by 5-FU as a bolus and a lowdose 22 hour infusion of 5-FU for 2 consecutive days; it is a semi-monthly regimen. FOLFOX4 is LV/5-FU2 plus oxaliplatin (Eloxatin). The primary endpoint was disease-free survival. Secondary endpoints were safety and overall survival," Dr. de Gramont explained. Eligibility requirements were good performance status, age between 18 and 70 years old, no prior treatment, and eligibility for treatment of stage 2 or stage 3 colon cancer after complete resection of the tumor. Followed Every 6 Months
Patients were followed every 6 months with clinical examination and imaging. Diagnosis was made on imaging confirmed by CT scan. Biopsy was required in cases of ascites or anastomotic recurrence. Included in the study were 2,246 patients, exactly the same number of patients in each arm. Mean age was 61 years. Main patient characteristics were well balanced. Furthermore, the statistical hypotheses were exactly fulfilled with the percentage of stage 2 being 40%, and stage 3 60%. Patients received a mean of 10.7 cycles in the FOLFOX4 arm and 11.3 in the LV/5-FU2 arm; 75% of patients received all the cycles of FOLFOX4. Median dose intensity for oxaliplatin was 81% in the LV/5-FU2 arm and 85% in the FOLFOX arm. Survival and Recurrence
With a little more than 3 years median follow-up, 234 events occurred in the FOLFOX arm and 288 in the LV/5-FU2 arm. The 3-year survival was 72.9% for LV/5-FU2 and 77.8% for FOLFOX. The difference was highly significant (hazard ratio 0.77). There was a 23% reduction in risk of recurrence. For stage III disease, 3- year disease-free survival with FOLFOX was 71.8% and 65.5% for LV/5- FU2. The hazard ratio was 0.76 with a 24% reduction in the risk of recurrence. For stage II disease, the 3-year disease-free survival was 86.6% for FOLFOX4 and 83.9% for LV/5-FU2. The hazard ratio was 0.82 with an 18% reduction in the risk of recurrence. FOLFOX4 improved the prognosis in all subsets of patients, including gender, age, number of lymph nodes, obstruction, perforation, carcinoembryonic antigen (CEA), and differentiation. No Mortality Increase
As noted in safety data presented in 2002, FOLFOX did not increase mortality during the treatment compared to LV/5-FU2 alone. It did not increase the number of vascular events. The most frequent grade 3/4 toxicity was neutropenia, which occurred in 41% of patients. Febrile neutropenia and sepsis occurred in less than 2% of patients. Gastrointestinal toxicity was moderate and less than 11% of patients had diarrhea. During treatment, grade 3 sensory neuropathy, involving some functional impairment, occurred in 12.4% of the patients. One year after completion of treatment with FOLFOX4, only 1% of patients still had grade 3 sensory neuropathy. An additional 4% of patients had grade 2 and 24% had grade 1 sensory neuropathy. Dr. de Gramont concluded by stating: "FOLFOX4 is a safe regimen. For the primary end point, 3-year diseasefree survival, FOLFOX4 is the first regimen to prove to be superior to leucovorin and 5-FU in the adjuvant treatment of colorectal cancer. There also was a reduction of 23% in risk of recurrence. And the benefit of FOLFOX4 was observed in all subsets of patients."