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Adapted from the NCI Cancer Bulletin, vol. 6/no. 3, Feb. 10, 2009 (see the current issue ³).

A randomized clinical trial testing chemotherapy combined with bevacizumab ⁴ (Avastin) and cetuximab ⁵ (Erbitux), and comparing this with chemotherapy and bevacizumab alone, found that the addition of cetuximab actually shortened patients’ recurrence-free and median survival.

This runs counter to some studies using animal models of cancer, which suggest that combining a drug that targets vascular endothelial growth factor (VEGF) with a drug that targets epidermal growth factor receptor (EGFR) may be more effective than either drug alone. The trial results appeared in the February 5, 2009, New England Journal of Medicine (see the journal abstract ⁶).

Investigators from the Netherlands enrolled 755 patients with metastatic, inoperable colon or rectal cancer into the trial, continuing treatment until disease progression, death, or unacceptable side effects. Overall, “the addition of cetuximab significantly decreased the median progression-free survival” from 10.7 months to 9.4 months, they reported. Median overall survival was 20.3 months for patients receiving chemotherapy and bevacizumab and 19.4 months for patients receiving chemotherapy, bevacizumab, and cetuximab. Patients who received cetuximab reported less improvement in overall quality of life and health during treatment.

The researchers analyzed these results in the context of whether patients had tumors with the normal or mutated form of a gene called KRAS. Numerous studies ⁷ have shown that only patients with normal KRAS genes benefit from drugs that target EGFR, including cetuximab. Patients with mutant KRAS who were given cetuximab had a significantly shorter progression-free survival than patients in the chemotherapy and bevacizumab arm; for patients with normal KRAS, cetuximab had no effect on progression-free survival.

The cause of these unexpected negative results are not clear, explained the authors, though a negative interaction between cetuximab and bevacizumab is one possibility.

Glossary Terms

An animal with a disease either the same as or like a disease in humans. Animal models are used to study the development and progression of diseases and to test new treatments before they are given to humans. Animals with transplanted human cancers or other tissues are called xenograft models.

The protein found on the surface of some cells and to which epidermal growth factor binds, causing the cells to divide. It is found at abnormally high levels on the surface of many types of cancer cells, so these cells may divide excessively in the presence of epidermal growth factor. Also called EGFR, ErbB1, and HER1.

The time from either diagnosis or treatment at which half of the patients with a given disease are found to be, or expected to be, still alive. In a clinical trial, median survival time is one way to measure how effective a treatment is. Also called median overall survival and median survival.

Having to do with metastasis, which is the spread of cancer from the primary site (place where it started) to other places in the body.

The length of time during and after treatment in which a patient is living with a disease that does not get worse. Progression-free survival may be used in a clinical study or trial to help find out how well a new treatment works. Also called PFS.

A study in which the participants are assigned by chance to separate groups that compare different treatments; neither the researchers nor the participants can choose which group. Using chance to assign people to groups means that the groups will be similar and that the treatments they receive can be compared objectively. At the time of the trial, it is not known which treatment is best. It is the patient's choice to be in a randomized trial.

A substance made by cells that stimulates new blood vessel formation. Also called VEGF.