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Key Words

Colorectal cancer, oral mucositis, palifermin. (Definitions of many terms related to cancer can be found in the Cancer.gov Dictionary ⁴.)

Summary

The drug palifermin reduced the frequency and severity of mouth sores caused by the chemotherapy drug fluorouracil in patients with advanced colorectal cancer. Patients who took palifermin were more likely than those taking a placebo to receive their full dose of chemotherapy.

Source

Journal of Clinical Oncology, November 20, 2006 (see the journal abstract)
(J Clin Oncol 2006 Nov 20; 24: 5194-200)

Background

Chemotherapy remains an important part of treatment for many types of cancer. Oral mucositis—the formation of sores and ulcers in the mouth and digestive system—is one of the most common side effects of many chemotherapy drugs. It can cause severe pain and infections, and limit patients’ ability to eat and drink normally. Patients who develop mucositis often need to have their dose of chemotherapy reduced, which can impact the effectiveness of the treatment.

Current therapies for mucositis are mostly palliative, meaning that they reduce the discomfort but cannot get rid of the problem itself. Currently, only cryotherapy—exposure to cold temperatures for an extended period of time—has been shown to reduce mucositis in patients receiving some types of chemotherapy.

This study examined the use of a drug called palifermin for the prevention of oral mucositis in patients receiving the chemotherapy drugs fluorouracil and leucovorin for advanced colorectal cancer. Fluorouracil is a drug known to cause mucositis. Palifermin is a laboratory-made, modified version of a human protein called keratinocyte growth factor (KGF), which stimulates cells in tissues such as the skin and the surface of the mouth to divide and grow. Palifermin is currently approved for use in certain blood cancers.

The Study

Investigators with this trial enrolled 64 eligible patients with advanced colorectal cancer who were scheduled to receive chemotherapy with fluorouracil and leucovorin. All patients were to receive two cycles of chemotherapy, with 28 days in each cycle.

Patients were randomly assigned to receive either palifermin or a placebo intravenously, immediately before rapid intravenous injection of fluorouracil. Trained clinic staff rated the severity of mucositis before treatment on various days of the study and at the end of both cycles. The observers graded mucositis on a scale from 0 to 4, with grade 4 being the most severe. They also assessed the frequency and severity of diarrhea. In addition to observation by trained staff, patients provided self-assessment of oral symptoms and diarrhea using a 10-question form.

The investigators compared the incidence, length, and severity of mucositis and diarrhea between the palifermin and placebo groups. They also monitored patients for adverse events and changes in certain substances in the blood.

The study’s principal investigator was Lee S. Rosen, M.D., from the John Wayne Cancer Institute in Santa Monica, California. The study was funded by Amgen, Inc., the manufacturer of palifermin.

Results

Out of the 64 patients, 28 received palifermin and 36 received a placebo. During the first cycle of chemotherapy, 61 percent of patients in the placebo group experienced grade 2 or higher mucositis, compared to 29 percent of patients in the palifermin group.

During the second cycle of chemotherapy, the incidence of grade 2 or higher mucositis decreased for both groups, but the incidence was still significantly lower for the palifermin group (11 percent versus 47 percent for the placebo group). In both cycles, the patient-completed questionnaires also showed a decrease in mouth and throat soreness with the use of palifermin.

In both cycles, a higher proportion of patients receiving palifermin had no symptoms of mucositis. Fewer patients receiving palifermin required a reduction in their chemotherapy dose of 10 percent or more. However, the addition of palifermin did not decrease the incidence or severity of diarrhea.

All patients experienced at least one adverse event during chemotherapy. Oral adverse events, such as a white coating on the surface of the tongue or problems with taste, were more frequent in patients receiving palifermin. Changes in the blood did not correlate with any clinical symptoms in patients taking palifermin, and returned to their pre-trial levels at the end of the study.

Limitations

One question that remains, stated the authors, is whether palifermin has any long-term effects on patient health. Palifermin is an artificial version of KGF, which stimulates epithelial cells, like the cells lining the mouth, to grow. There is some concern among researchers that KGF could also stimulate tumor cells to grow, or interfere with the effect of chemotherapy on tumor cells.

In this study, patients were followed for a median of 14.5 months. During that time, no differences were observed between the two groups in terms of how long it took for the patients’ cancer to progress or in their overall survival. This suggests “that palifermin did not affect disease outcomes in these patients,” state the investigators. However, they explain, “These results with a small patient sample cannot be considered conclusive and additional studies are needed to evaluate fully the long-term safety of palifermin in the solid tumor setting.”

“There is a theoretical concern about second primary cancers and tumor protection,” agreed Maria Sgambati, M.D., program director of the National Cancer Institute’s Community Oncology and Prevention Trials Research Group. “We’re still in the early studies of this drug, so it needs to be watched.”

Comments

“We demonstrated that palifermin can be administered safely in the multicycle chemotherapy setting in patients with metastatic [colorectal] cancer and is effective at the dose tested…in reducing the incidence and severity of mucositis…potentially allowing for uninterrupted full-dose treatment in patients receiving these chemotherapy regimens,” summarize the authors.

Currently, palifermin has only been approved by the U.S. Food and Drug Administration for use after high-dose therapy with bone-marrow transplantation in patients with cancers of the blood, explained Sgambati. But she thinks approval of the drug for other uses will be forthcoming: “I think we’re going to see more studies of this drug in different settings. It’s really the first agent to come along and really make a significant improvement in [oral mucositis in] certain populations.”

Glossary Terms

A statistics term. The middle value in a set of measurements.

The spread of cancer from one part of the body to another. A tumor formed by cells that have spread is called a “metastatic tumor” or a “metastasis.” The metastatic tumor contains cells that are like those in the original (primary) tumor. The plural form of metastasis is metastases (meh-TAS-tuh-SEEZ).

A complication of some cancer therapies in which the lining of the digestive system becomes inflamed. Often seen as sores in the mouth.

An inactive substance or treatment that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.

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.

Describes a mathematical measure of difference between groups. The difference is said to be statistically significant if it is greater than what might be expected to happen by chance alone. Also called significant.