Oxaliplatin/5FU/LV in adjuvant colon cancer: Updated efficacy results of the MOSAIC trial, including survival, with a median follow-up of six years

Reviewer: Christopher Dolinsky, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 5, 2007

Presenter: Aimery De Gramont
Presenter's Affiliation: Hopital St. Antoine, Paris, France
Type of Session: Scientific

Background

Oxaliplatin is a chemotherapeutic agent with demonstrated activity in colorectal cancer.
This abstract presents a 6 year update to previously published results from a large phase III randomized trial (MOSAIC).
MOSAIC demonstrated superiority of a regimen containing oxaliplatin/5- fluorouracil/leukovorin (FOLFOX4) to one containing 5-fluorouracil and leukovorin (LV5FU2) as adjuvant therapy for stage II and III colon cancer (Andre et al., NEJM 2004).

Materials and Methods

A multi-institution phase III prospective trial randomized 2246 patients with stage II/III colon cancer to either FOLFOX4 or LV5FU2 given as adjuvant therapy.
Both regimens were given every 2 weeks for 6 cycles.
40% of patients were stage II and 60% of patients were stage III.
Primary endpoint was 3 year disease free survival.
This abstract presents 5 year disease free survival data and 6 year overall survival data.
Median follow-up is now 73 months.

Results

The FOLFOX4 arm had improved disease free survival compared to the LV5FU2 arm at 5 years median follow-up (hazard ratio 0.80, p=0.003).
This improvement in disease free survival remains if stage III patients are analyzed separately (hazard ratio 0.78, p=0.005); however, when stage II patients are analyzed, the hazard ratio is no longer statistically significantly improved (hazard ratio 0.84, p=0.258).
Grade 3 or 4 neutropenia was seen in 41% of the FOLFOX4 patients, and 4.7% of the LV5FU2 patients.
Treatment related death was the same in both arms (0.5%).
At 4 years of follow-up, 15.7% of the FOLFOX4 patients continued to have peripheral neuropathy (12% grade 1, 2.8% grade 2, and 0.7% grade 3).
At 6 years, the FOLFOX4 arm had improved overall survival (HR 0.85, p=0.057).
In stage III patients, there is an improvement in overall survival in the FOLFOX4 arm (HR 0.8, p=0.029).
In stage II patients, there is no difference seen in overall survival between the two arms (HR 1.00, p=0.80).

Author's Conclusions

The DFS benefit at 3 years was maintained at 5 years.
A significant benefit in overall survival was seen in stage III patients.
No increase was seen in the rate of secondary cancers.
Late recovery from sensory neuropathy is present and common.

Clinical/Scientific Implications

This was a well designed and well executed large phase III trial. The results of this trial confirm oxaliplatin's safety and efficacy as adjuvant therapy for stage III colon cancer. The biggest debate that will arise following this presentation is what to do with the stage II patients. The FOLFOX4 regimen has become the standard of care in many communities for stage II and III patients, and old habits die hard. However, it seems that oxaliplatin should be abandoned in stage II patients based on this mature analysis. The success of this regimen has sparked a large body of research, and ongoing work using FOLFOX4 in combination with targeted therapies may continue to improve outcomes in this disease.