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MOSAIC: Adjuvant FOLFOX4 increased survival in stage II/III colon cancer
In the PETACC-3 trial, adjuvant irinotecan plus leucovorin/5-FU did not improve DFS or OS.
Despite the benefit of adding irinotecan to infusional FU/leucovorin in first-line treatment of patients with advanced colorectal cancer, the topoisomerase 1 inhibitor did not improve survival in the adjuvant treatment of patients with stage III colon cancer, according to data from the PETACC-3 trial. However, data from another phase-3 trial, the MOSAIC trial, demonstrated a 20% reduction in the risk for recurrence when oxaliplatin was added to FU/leucovorin in this setting.
Results of both studies were published in The Journal of Clinical Oncology.
“Doctors should not assume that a new therapy will be effective in the adjuvant setting until a properly conducted adjuvant therapy study has been done with adequate follow-up,” Michael J. O’Connell, MD, of the National Surgical Breast and Bowel Project and author of an accompanying editorial, told HemOnc Today.
PETACC-3
Researchers from PETACC-3 conducted a randomized, multicenter, phase-3 trial to determine whether irinotecan plus LV5FU2 improved DFS in patients with stage II or stage III colon cancer after surgical resection. At the investigator’s choice patients could be randomly assigned to either LV5FU2 with or without irinotecan (n=3,018) or an alternative high-dose FU/leucovorin regimen with or without irinotecan (n=260).
The efficacy analysis was based on 2,094 patients with stage III cancer assigned to LV5FU2 with or without irinotecan.
After a median 66.3 months follow-up, the five-year DFS rate was 56.7% for patients assigned to irinotecan compared with 54.3% for those assigned to LV5FU2 alone. Compared with patients assigned to LV5FU2 alone, patients in the irinotecan group had a higher probability of being free of disease at any given time; however, the difference was not statistically significant (HR=0.90).
A multivariate analysis also revealed no statistically significant difference in DFS between groups.
The researchers reported no improvement in five-year OS in the irinotecan group compared with patients assigned to LV5FU2 alone (73.6% vs. 71.3%; P=.094). Similarly, there was no improvement in five-year OS among patients with stage II disease assigned to irinotecan vs. those assigned to LV5FU2 alone (90.0% vs. 88.8%; P=.344).
Patients in the irinotecan group experienced more nonhematologic adverse events compared with those assigned to LV5FU2 alone (37.7% vs. 24.3%).
“Physicians should be aware that they should not be using irinotecan in combination with other drugs in the surgical adjuvant setting for patients with colon cancer,” O’Connell said.
Oxaliplatin increased survival
Like the PETACC-3 trial, researchers from MOSAIC examined the efficacy of oxaliplatin in combination with LV5FU2 for adjuvant therapy in patients with stage II or III colon cancer.
The study included 2,246 patients aged 18 to 75 who were randomly assigned to LV5FU2 (n=1,123) or FOLFOX4 for six months. The primary and secondary endpoints were DFS and OS. The researchers conducted follow-up every two weeks during treatment and every six months up to five years after study completion.
According to the researchers, after a median follow-up of 81.9 months, FOLFOX4 was associated with a 16% reduction in the risk for death compared with LV5FU2 alone (95% CI, 0.71-1.00). The main prognostic factor of OS was disease stage (HR=1.85; 95% CI, 1.47-2.34). Therefore, the researchers conducted additional independent OS analyses for patients with stage II and III tumors; however, there was no statistical significance for the relationship between disease stage and treatment.
Fewer deaths occurred in the FOLFOX4 group compared with LV5FU2 (21.8% vs. 25.2%); most deaths occurred as a result of relapse or recurrence, but adverse events accounted for six deaths in each group. At six years, FOLFOX4 was associated with a 20% reduction in the risk for death among patients with stage III disease. Similarly, FOLFOX4 was associated with a 20% reduction in the risk for relapse in all patients.
Grade-3 peripheral sensory neuropathy occurred in 12.5% of patients in the FOLFOX4 arm vs. 0.2% of those in the LV5FU2 arm. However, the frequency of peripheral sensory neuropathy declined during the follow-up period in patients assigned to FOLFOX4. Additionally, patients in the FOLFOX4 group experienced fewer second cancers compared with those in the LV5FU2 group.
According to O’Connell, the future of colon cancer adjuvant therapy might include targeted monoclonal antibodies, individualized therapy and stratification of colon cancer subtypes based on emerging genetic and epigenetic factors.
“The future [of colon cancer therapy in the adjuvant setting] is based on predictive and prognostic molecular markers to improve the therapeutic ratio,” he said. “In addition, there are many interesting new targeted therapies being developed based upon our improved knowledge of how the cancer cells work. There are also many that specifically interrupt various pathways in the cancer cell so that we can hope in the future combining these targeted therapies with chemotherapy may result in further benefits to patients.” – by Stacey L. Adams
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