Irinotecan is a first-line treatment for colorectal cancer that, along with other therapies, has helped increase the median survival among colorectal cancer patients from 12 months to about 18 to 21 months over the 10 years.
However, some patients do not respond to treatment with irinotecan and so other therapies are required for such patients.
A research team from hospitals across Europe has therefore investigated the use of cetuximab, a monoclonal antibody that binds with high specificity to the epidermal growth factor receptor (EGFR).
This receptor is of relevance in colorectal cancer because in up to 80% of patients with colorectal cancer, there is up-regulation and expression of the EGFR gene. Furthermore, expression of the gene has been shown to be associated with poor survival.
Through binding of its ligand (epidermal growth factor, or transforming growth factor-) EGFR is involved in signaling pathways that become deregulated in cancer cells, including cell differentiation, proliferation, migration, angiogenesis and apoptosis.
| Cetuximab has clinically significant activity in patients with irinotecan-refractory colorectal cancer|
|New England Journal of Medicine|
By binding to EGFR, cetuximab blocks activation of these signaling pathways, thus helping to control the cancerous activities of the cells on which EGFR is expressed. In addition, cetuximab has also been shown in experimental systems to enhance the effects of irinotecan and radiotherapy.
Led by Dr David Cunningham, from the Royal Marsden Hospital, in Surrey, England, the research team compared the efficacy of cetuximab alone with that of cetuximab in combination with irinotecan in patients with metastatic colorectal cancer that was refractory to treatment with irinotecan.
329 patients whose disease had progressed during or within 3 months after treatment with an irinotecan-based regimen were randomly assigned to receive either cetuximab and irinotecan (218 patients) or cetuximab monotherapy (111 patients).
Cetuximab was administered at an initial dose of 400 mg/m2, followed by weekly infusions of 250 mg/m2, while patients receiving the combination therapy received their irinotecan at the same dose and schedule as that given during their most recent prestudy therapy.
In cases of disease progression, the addition of irinotecan to cetuximab monotherapy was permitted.
Tumor response was evaluated every 6 weeks for the first 24 weeks and then at 3 month intervals, using either CT or MRI scans.
Each patient was evaluated radiologically for tumor response and was also evaluated for the time to tumor progression, survival and side-effects of treatment.
Patients receiving the combination therapy were found to respond at a significantly higher rate than those in the monotherapy cohort (22.9% compared to 10.8%).
The median time to progression was also significantly greater in the combination therapy group (4.1 compared to 1.5 months in the monotherapy group).
The median survival time was 8.6 months in the combination therapy group and 6.9 months in the monotherapy group.
However, toxic effects were more frequent in the combination-therapy group, but their severity and incidence were similar to those that would be expected with irinotecan alone.
Commenting on their findings, Dr Cunningham said that the observed tumor-response rate of 22.9% in the combination therapy group was clinically important, since after the standard drugs (including irinotecan) have failed, there are no accepted treatment options.
"Cetuximab has clinically significant activity when given alone or in combination with irinotecan in patients with irinotecan-refractory colorectal cancer," he concluded.