A phase III trial comparing FULV to FULV + oxaliplatin in stage II or III carcinoma of the colon: Results of the NSABP Protocol C-07.

Reviewer: Christopher Dolinsky, MD
University of Pennsylvania School of Medicine
Last Modified: May 16, 2005

Presenter: N. Wolmark
Presenter's Affiliation: Allegheny General Hospital, Pittsburgh, Pennsylvania
Type of Session: Scientific

Background

Oxaliplatin is a new chemotherapeutic agent with demonstrated activity in colorectal cancer.
A previously reported large phase III randomized trial (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.
The 5-fluorouracil in MOSAIC was given as 24 hour continuous infusion.
After results of MOSAIC were presented, oncologists wondered if a regimen containing oxaliplatin and bolus 5-fluorouracil would be equally effective.

Materials and Methods

A multi-institution phase III prospective trial randomized 2492 stage II or III colon cancer patients to either 5-fluorouracil/leukovorin (FULV) or oxaliplatin/5-fluorouracil/leukovorin (FLOX).
The FULV was given as three, 8 week cycles of 500mg/m²of 5-FU IV bolus weekly x 6 and 500mg/m² leukovorin weekly x 6.
The FLOX was given as oxaliplatin 85mg/m² on weeks 1, 3 and 5 of each 8 week cycle in addition to the same FULV dosing schedule.
Patients were stratified by number of positive nodes.
Primary endpoint was disease free survival.
The arms were well balanced in terms of age, gender, tumor location and number of nodes.
29% of patients were node negative.
Median follow-up was 34 months.

Results

3 year disease free survival was 76.5% in the FLOX arm and 71.6% in the FULV arm.
The translates into a hazard ratio for the FLOX arm of 0.79, p<0.004 and a 21% risk reduction for this arm.
Toxicities were well balanced between the arms, with 50% of the FLOX patients developing any grade III/IV toxicity compared to 41% of the FULV patients.
The worst toxicity in the FLOX arm was neurotoxicity.
85% of FLOX patients developed any neurotoxicity during treatment, and 29% of them had any neurotoxicity at 1 year of follow-up.
8% of FLOX patients developed grade 3 neurotoxicity during treatment, and 0.5% of them had grade 3 neurotoxicity at 1 year of follow-up.
73% of patients received their full planned chemotherapy dose.
Diarrhea was common in the FLOX arm (40% of patients), although neutropenia was uncommon (4%).

Author's Conclusions

The addition of oxaliplatin to bolus 5-FU/leukovorin as adjuvant therapy produces a significant improvement in disease free survival for patients with stage II/III colon cancer.
This trial continues and expands the knowledge about oxaliplatin that was produced from the MOSAIC trial.
This trial supports the use of oxaliplatin with bolus 5FU/leukovorin.

Clinical/Scientific Implications

This was a well designed and executed large phase III trial. The results of this trial confirm oxaliplatin's efficacy as adjuvant therapy for stage II/III colon cancer. However, it also raises some difficult questions about clinical practice. For instance, should patients now be treated with bolus based regimens to spare them a port placement and risk of neutropenia? The data from MOSAIC are more mature, and were updated at this ASCO meeting, so the cautious answer would seem to support the continued use of infusional 5-FU. However, given what appears to be a higher risk of neutropenia with infusional 5-FU, one could argue for bolus therapy in selected patients based on these data. As follow-up continues, further analyses may demonstrate some more significant differences between the two delivery systems.