Clinical trials of adjuvant therapy for colorectal cancer

The MOSAIC trial

The MOSAIC trial (de Gramont 2003) randomly assigned Stage II and III patients to the FOLFOX4 regimen with oxaliplatin as opposed to the typical infusional 5-FU/ leucovorin regimen used in France.

This multinational study demonstrated almost a 25 percent reduction in the rate of metastasis in patients with Stage III disease who received the FOLFOX regimen.

We now have longer follow-up data from the MOSAIC trial (Andre 2004; de Gramont 2005; [3.1]). While the data for Stage II disease are still not statistically significant, the data in patients with Stage III are even better, and we’re beginning to approach the parameters to evaluate overall survival data. A definite improvement with FOLFOX was shown in the MOSAIC trial, and based on these data, the FDA approved this regimen as adjuvant therapy in Stage III disease.

The X-ACT trial

The other adjuvant study we should note is the X-ACT trial, which compared capecitabine 1,250 mg/m² bid versus the Mayo Clinic 5-FU/leucovorin regimen in patients with resected Dukes’ C colon cancer. This is an intriguing study because it addresses the clinical issue of using oral 5-FU for patients who are in relatively good health, have a good performance status and who oftentimes can continue to work. For them, the option of using an oral agent rather than intravenous therapy is very attractive.

Overall survival cannot be evaluated at this point, but disease-free survival was superior for patients on the capecitabine arm (Cassidy 2004; [3.2]). The p-value was approximately 0.05, bordering significance, as did the hazard ratio with the confidence intervals approaching the 1.00 mark but not crossing it. That’s important because it suggests that this is a statistically significant effect.

ASCO paper on adjuvant therapy in Stage II disease

Typically, patients with no evidence of lymph node involvement, no matter how deeply the tumor appears to extend, do not receive chemotherapy for Stage II disease. However, increasing data suggest that some patients with penetration of the intestinal wall, who would not have been treated in the past, may benefit from chemotherapy.

The ASCO committee published an aggressive position paper stating that perhaps these patients should be offered adjuvant therapy (Benson 2004). While we don’t have any convincing objective data to validate the use of adjuvant therapy in Stage II disease, subsets within that population may benefit. The ultimate proof of the benefit in such patients will come from ongoing adjuvant studies.

One reason it may be difficult to demonstrate a benefit from adjuvant therapy in Stage II disease is that fewer events occur. However, the MOSAIC trial and some of the earlier Intergroup studies have suggested certain patients can benefit from chemotherapy.

I believe we’re at the point now that with consideration of the tumor’s histologic characterization, the localization, whether it’s in the right or left side of the colon, the occurrence of methylation, microsatellite instability, TS, p53 and various other new markers being identified that we may be able to identify subsets that will benefit from adjuvant therapy.

Capecitabine/oxaliplatin in the adjuvant setting

The MOSAIC trial was reported in 2003 and led to the FDA approval of FOLFOX4 for adjuvant therapy in Stage III disease. The X-ACT trial data were reported in 2004, and we expect capecitabine will be approved in this setting also. At this time, FOLFOX appears to be superior, and that might limit the overall use of capecitabine.

However, down the road, with the availability of oxaliplatin in the practice setting, practitioners may begin to do what they did in advanced disease — use CAPOX. The CAPOX regimen is very appealing to a number of oncologists and patients, but we have no data on that combination in the adjuvant setting.

Adjuvant therapy in the nonprotocol setting

While some clinicians are still using 5-FU/leucovorin in the adjuvant setting, now that FOLFOX has been approved, I believe we’ll see a change in treatment patterns in the adjuvant setting just as we’ve seen in advanced disease. Whether adjuvant 5-FU/leucovorin without oxaliplatin is justifiable depends on the individual patient.

For example, for an elderly patient unable to take oxaliplatin, 5-FU/leucovorin could be considered. That’s also a situation in which capecitabine might have a role, based on the X-ACT study, which provides strong evidence that capecitabine is better than 5-FU/leucovorin in the adjuvant setting.

However, I believe that for the majority of patients who have reasonable performance status and are in excellent health, it’s preferable to use adjuvant FOLFOX.

Capecitabine as adjuvant therapy for patients with Stage II disease is appealing because it’s an oral agent, and given the ASCO position paper on treating Stage II disease, I foresee increased use of this. We just don’t have the clinical data at this point.

Select publications

Dr Diasio is a Professor of Medicine (Hematology/Oncology) and Pharmacology/Toxicology and Genetics, Associate Director for Basic Sciences at UAB Comprehensive Cancer Center, Chairman of the Department of Pharmacology and Toxicology and the Newman H Waters Professor and Director, Division of Clinical Pharmacology at the University of Alabama Birmingham, in Birmingham, Alabama.