AACR Urges Development of Drugs for High-Risk Intraepithelial Neoplasia

SAN FRANCISCO—Drug therapies aimed at reducing or eradicating intraepithelial neoplasia (IEN) could reduce the burden of IEN and the incidence of malignancies, according to the American Association for Cancer Research (AACR) Task Force on the Treatment and Prevention of Intraepithelial Neoplasia. Three of the co-chairs of this Task Force reviewed key recommendations at a news briefing at the 93rd Annual Meeting of the AACR.

The IEN Task Force recommended the initiation of clinical trials to evaluate the usefulness of treating IEN only in high-risk populations. Individuals with, for example, severe Barrett’s esophagus, high-grade prostatic intraepithelial neoplasia, and women with abnormal breast cells who have been previously treated for breast cancer or who have a family history of breast cancer would be considered to be at high risk.

"The earlier you intervene, the more likely it is that you’ll have a good result. As cancer becomes invasive, it becomes increasingly resistant to treatment," noted Gary Kelloff, MD, a senior scientist in the National Cancer Institute’s Division of Cancer Treatment and Diagnosis.

Therapeutic Interventions Limited

Therapeutic interventions for IEN are limited, however. With only a few exceptions, IEN is currently treated with surgery, with its attendant risks and limitations. "Surgery gets only one focal lesion at a time, and often you have many lesions present, such as a damaged epithelium that has been insulted with cigarette smoke for 20 years," Dr. Kelloff said.

Disfigurement is another disadvantage associated with certain surgeries, such as mastectomies. Drug therapies for treating IEN would not have these disadvantages. Currently, however, there are only about five drugs on the market for treating intraepithelial neoplasia. "Why do we have so few?" asked Joyce O’Shaughnessy, co-director of breast cancer research, Baylor-Sammons Cancer Center, US Oncology, Dallas. "It’s because it takes over a decade, $50 to $100 million, and many thousands of patients to do a clinical trial to prove the effectiveness of a cancer prevention drug if you have to wait for the cancers to develop."

The major finding of the Task Force, she said, is that "we don’t have to wait for cancer to occur to prove that a drug is beneficial."

The Task Force co-chairs recommended borrowing an effective approach that has been used by another specialty. Gary Gordon, MD, chief scientific officer, Ovation Pharmaceuticals, Lincolnshire, Illinois, explained: "We’ve learned from our colleagues in the cardiovascular field that lowering cholesterol and treating hypertension are of great value, and companies were able to get drugs approved in these areas before they were able to show that treating hypertension or lowering cholesterol changed the number of people who died from strokes or cardiovascular disease."

FDA Receptive to Change

Although the FDA has not altered its requirements, agency officials have appeared to be receptive to accepting changes in endpoints where there is sufficient proof linking an intraepithelial neoplasia to the eventual development of cancer, such as the relationship between adenomatous polyps and colorectal cancer, Dr. Gordon said.

Evaluation criteria for drugs that are developed to treat IEN instead of cancer will differ in one key respect, the co-chairs said. Patients may have to be on these medications for years or even decades, so these medications will have to be extremely safe.

Although only about five drugs for treating IEN are currently available, many more are being studied. "A number of COX-2 inhibitors are in trial for colorectal polyp prevention as well as other IENs. There is work being done, for example, with DFMO [difluoromethylornithine], raloxifene [Evista], and finasteride [Proscar]," Dr. Gordon said.

Elevated/High-Risk Group

With the change in endpoints for clinical trials, Dr. Gordon predicted a growing trend that will lead to the development of more medications aimed at treating IEN.

"I think that the real significance of this Task Force report is not the report itself but that it has opened the dialog. It has opened the eyes of industry to the possibility that one can develop such drugs for a reasonable cost," Dr. Gordon said. "We will see many drugs developed for preventing and treating IEN, which ultimately should result in a reduced risk of developing cancer."

The Task Force report, "Treatment and Prevention of Intraepithelial Neoplasia," was published in the February issue of Clinical Cancer Research (8:314-346, 2002).