MOSAIC adjuvant trial

Rationale

Two clinical trials, one in the advanced disease setting and the other in the adjuvant setting, provided the rationale for the MOSAIC adjuvant trial. The trial in patients with advanced disease, published in the Journal of Clinical Oncologyin 2000, compared a bimonthly regimen of 5-FU/leucovorin (leucovorin plus bolus and infusional 5-FU administered for two days) with or without oxaliplatin.

Patients treated with oxaliplatin plus bimonthly 5-FU/leucovorin (FOLFOX) had a response rate of 50 percent, which was more than double the response rate for the patients treated with bimonthly 5-FU/leucovorin alone. Patients receiving FOLFOX had a progression-free survival of almost nine months, again very different from the patients treated with bimonthly 5-FU/leucovorin alone.

The adjuvant trial compared a monthly five-day bolus 5-FU/leucovorin regimen to the bimonthly bolus and infusional 5-FU/leucovorin regimen. The results from that adjuvant trial, published in the Journal of Clinical Oncology in 2003, demonstrated similar efficacy, but less toxicity for the bimonthly 5-FU/leucovorin regimen.

Efficacy

The MOSAIC adjuvant trial was conducted worldwide and involved 2,246 patients with Stage II or III disease who were less than 75 years of age. Because it was too early to analyze overall survival, a difference was not found at three years. We have published the three-year disease-free survival results demonstrating a significant five percent improvement for patients treated with adjuvant FOLFOX (3.1).

When the subsets of the population (ie, patients with Stage II or III disease and all other prognostic factors) were analyzed, all groups of patients benefited from adjuvant FOLFOX. In the patients with Stage III disease, the absolute difference in disease-free survival was approximately seven percent, which equated to a 23 percent reduction in the risk of recurrence. In patients with Stage II disease, the absolute difference in disease-free survival was 2.7 percent, which equated to a 20 percent reduction in the risk of recurrence. Clearly, patients with higher-risk disease benefit more from adjuvant FOLFOX, but we cannot say that patients with Stage II disease do not benefit.

At ASCO 2004, we presented data from the patients with Stage II disease enrolled in the MOSAIC adjuvant trial. In an analysis of the patients with high-risk Stage II disease (eg, T4, bowel obstruction, tumor perforation, venous invasion or less than 10 lymph nodes analyzed), the difference in disease-free survival in favor of FOLFOX was more than five percent. In patients with high-risk Stage II disease, adjuvant FOLFOX should be considered.

The first update to the MOSAIC trial, with almost four years of follow-up, will be presented at the 2004 European Society for Medical Oncology (ESMO) meeting. I am not sure why, but we have observed that the results appear to be improving. In one or two years, we may have the first results of overall survival.

Toxicity

The overall safety in the MOSAIC adjuvant trial was good. No excess deaths occurred with FOLFOX compared to 5-FU/leucovorin alone. We did observe more GI toxicity with FOLFOX, but the differences in the incidence of the toxicities remained low. The two main toxicities associated with oxaliplatin were neutropenia and sensory peripheral neuropathy. Grade III or IV neutropenia occurred in 41 percent of the patients treated with FOLFOX. Because it is a bimonthly regimen, the patients’ blood counts were always at their nadir; however, only about two percent of the patients treated with FOLFOX had febrile neutropenia.

Grade III sensory peripheral neuropathy, which indicates some degree of functional impairment, occurred in 12 percent of the patients receiving FOLFOX. With follow-up, this neuropathy was reversible. Grade II or III neuropathy remained in only six percent of the patients after one-year of follow-up and in 3.9 percent of the patients at 18 months of follow-up.

Three-year disease-free survival as an endpoint for adjuvant colon cancer trials

At ASCO 2004, Dan Sargent presented data demonstrating that a very strong correlation exists between three-year disease-free survival and five-year overall survival. Hence, we don’t need to wait an additional two years to determine whether one adjuvant treatment is better than another if the differences in the three-year disease-free survival are large, like in the MOSAIC study. Waiting for five-year overall survival means not treating some patients who could potentially avoid relapse.

Clearly, it’s important to have an early endpoint. The FDA has also decided to recognize three-year disease-free survival as an endpoint for adjuvant studies, not only because of the correlation between three-year disease-free survival and five-year overall survival, but also because not relapsing is a good quality-of-life endpoint.

Adjuvant therapy for patients not enrolled in a clinical trial

I would certainly offer adjuvant FOLFOX to patients with Stage III or high-risk Stage II disease, and I would discuss it with the other patients. In patients with a very good prognosis, the potential risks and benefits of an adjuvant regimen must be weighed in a discussion that should occur between the patient and physician.

In patients with low-risk Stage II disease, the benefit of an adjuvant regimen without oxaliplatin (eg, 5-FU/leucovorin) is about two percent. If an additional two percent benefit can be obtained with the addition of oxaliplatin, then a four percent benefit can be considered. A well-informed patient can decide whether an increase in survival of a few percent is worth the risk of developing neuropathy.

OPTIMOX trials

Oxaliplatin is usually discontinued in therapy of metastatic disease because of neuropathy, not tumor progression. It’s important to maintain sensitivity to oxaliplatin to optimize its use. We have experience with the reintroduction of oxaliplatin in the OPTIMOX trials.

The OPTIMOX-I trial compared FOLFOX4 administered until disease progression to six cycles of FOLFOX7, with a higher dose of oxaliplatin, followed by maintenance therapy with 5-FU/leucovorin alone for six months and later reintroduction of FOLFOX7. Median overall survival was 20.7 months for the patients receiving FOLFOX4 and 21.4 months for the patients receiving FOLFOX7, which was not a significant difference.

Dose-intense oxaliplatin did not improve the response rate or resection rate, but patients receiving only six cycles had fewer side effects. A strategy that allows the reintroduction of oxaliplatin (eg, second-line therapy with the same regimen used as first-line therapy) and the subsequent utilization of an irinotecan-based regimen may increase survival.

In the OPTIMOX-II trial, we evaluated a strategy involving FOLFOX7 for six cycles, stopping all chemotherapy and then reintroducing FOLFOX7 before the tumor reached its baseline measure. The OPTIMOX-III trial will compare capecitabine and oxaliplatin (XELOX) plus FOLFOX for three months with or without erlotinib during the break in chemotherapy.

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Dr de Gramont is a Professor of Oncology (Professeur des Universités-Praticien Hospitalier) and the Department Head of Internal Medicine in Oncology at the Hôpital Saint-Antoine in Paris, France.