January 10, 2003

COX-2 studied as treatment for rectal cancer at Vanderbilt

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Dr. Raymond DuBois is internationally known as an investigator in the link between colon cancer, arthritis drugs and an enzyme called cyclooxygenase-2 (COX-2). (photo by Dean Dixon)

COX-2 studied as treatment for rectal cancer at Vanderbilt

Vanderbilt-Ingram Cancer Center researchers are studying COX-2 inhibitors to determine if these drugs can help in the treatment of cancers that arise in the rectum.

The enzyme cyclooxygenase-2 (COX-2) has been widely studied in colon cancers, and aspirin-like drugs that inhibit COX-2 (like Celebrex or Vioxx) are being studied to determine if they can help prevent the development of precancerous colon polyps. Use of these drugs has been approved for prevention of polyps in a particular inherited form of colon cancer.

“We think COX-2 inhibitors may also play a role in rectal cancers, but that hasn’t been looked at very carefully,” said Dr. Anuradha Chakravarthy (Bapsi Chak), assistant professor of Radiation Oncology, who is leading two clinical trials of COX-2 inhibitor celecoxib (the generic name for Celebrex) in rectal cancer.

The colon and rectum are parts of the digestive system that, together, form a long muscular tube called the large intestine (or large bowel). The colon makes up the first six feet, and the rectum makes up the last six to eight inches.

Cancers that develop in the colon and rectum are often classified together as colorectal cancer, and they carry many of the same risk factors, symptoms and screening recommendations. Rectal cancer is diagnosed in about 40,000 Americans each year and is responsible for almost 9,000 deaths.

The two studies are part of Vanderbilt-Ingram’s Specialized Program of Research Excellence (SPORE) in gastrointestinal cancer. Dr. R Daniel Beauchamp, John Clinton Foshee Distinguished Professor of Surgery and Chair of the Section of Surgical Sciences, is co-investigator on these studies.

The studies, both of which will be conducted over a five-year period, are designed to learn more about what biologic effects inhibition of the COX-2 pathway has on rectal cancer at certain stages of disease.

One study will involve 150 patients with early stage rectal cancer that has not advanced through the bowel wall. Patients will undergo a biopsy at the start of the study, followed by therapy with celecoxib (400 milligrams twice daily) for five to seven days. A tissue sample will be taken after the therapy ends, when the tumor is surgically removed.

The study will examine changes in the tumor and adjacent normal tissues as well as biochemical markers for cell growth.

“While the participants in this study will receive no direct clinical benefit from taking celecoxib, we are very grateful for their willingness to participate,” Chak said. “These studies will help us to eventually develop better treatment regimens for cancers of the rectum.”

The other study will involve 50 patients with rectal cancer that is more advanced, either extending through the bowel wall or spread to the nearby lymph nodes. This study aims to see if adding a COX-2 inhibitor will increase the efficacy of standard therapy with drugs and radiation.

Again, patients will undergo a biopsy first, followed by a week of celecoxib therapy. A second biopsy will be taken followed by five weeks of twice-daily celecoxib doses taken concurrently with radiation treatments and continuous infusion of standard chemotherapy. At that point, the patient will undergo surgery and a third tissue sample will be taken.

“We will be looking to see if there are any changes in biologic markers and will use mass spectrometry and proteomics to look for new proteins whose expression changes as a result of the therapy,” Chak said. “We hope to discover patterns of gene and protein expression that predict how a particular patient will respond to a specific treatment regimen. In the future, this may allow us to tailor therapies based on an individual tumor’s response to particular agents.”

Celecoxib is approved by the Food & Drug Administration and primarily marketed as a pain and inflammation reliever for arthritis and similar conditions.

Delaying surgery or standard chemotherapy/radiation for a week while the patients take celecoxib alone is also not expected to pose any risk to participants, Chak said.

COX-2 inhibitors are considered to be among the newer targeted therapies because they selectively interrupt a specific signaling pathway involved in the growth and spread of cancer cells.

“There is some evidence to suggest that using celecoxib with chemotherapy and radiation may be more effective,” Chak said. “However, we cannot be sure that these drugs have an effect at these stages of disease without testing them in patients. Certainly, the knowledge gained from patients participating in such clinical trials will be invaluable as we move toward more targeted therapies for cancer treatment.”