Results of Prevention Trials in Prostate, Colon, Breast Cancer

COLUMBUS, Ohio—Chemopre-vention trials in recent years have led to new chemoprevention agents and also unexpected negative findings, Winfred F. Malone, PhD, MPH, said at the 4th Annual Congress of the Society for Nutritional Oncology Adjuvant Therapy (NOAT). He described a number of published and ongoing clinical trials.

Dr. Malone is section chief of the Chemoprevention Branch of the NCI’s Division of Cancer Prevention & Control. The Chemoprevention Branch is currently sponsoring more than 70 clinical trials, with more than 700 compounds under investigation.

“The chemoprevention of breast cancer has seen spectacular breakthroughs and progress culminating in the approval of tamoxifen [Nolvadex] last October as an agent to reduce the incidence of breast cancer in high-risk women,” he said.

Other chemoprevention trials have achieved “notoriety for both positive and negative findings,” Dr. Malone said. The ATBC (alpha-tocopherol, beta-carotene) Cancer Prevention Study, for instance, found a 41% drop in prostate cancer mortality in men taking alpha-tocopherol (vitamin E). But it also showed an unanticipated increase in lung cancer among male smokers who took a beta carotene supplement.

Selenium Surprises

“Many promising chemopreventive agents for prostate cancer are also under investigation,” Dr. Malone said. Agents in phase II trials include selenium, vitamin E, vitamin D analogs, sulindac, finasteride (Proscar) analogs, flutamide (Eulexin), bicalutamide (Casodex), and toremifene (Fareston).

Investigators have hypothesized that selenium supplementation may reduce the incidence of nonmelanoma skin cancer. A randomized, double-blind che-moprevention trial of 1,312 patients with a history of basal cell or squamous cell carcinoma of the skin found that the incidence of these skin cancers was unaffected by selenium. However total cancer incidence was lower in the selenium group. The selenium group also had fewer prostate, colorectal, and lung cancers (Clark LC et al: JAMA 276:1957-1963, 1996).

COX Inhibitors

Cyclooxygenase (COX) inhibitors are receiving a great deal of attention for their possible role in colorectal cancer chemoprevention. Investigators are looking at nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin and sulindac, and the selective COX2 inhibitor celecoxib (Celebrex, recently approved for use in arthritis).

The COX1 and COX2 enzymes are involved in the production of prostaglandins, which are necessary for inflammation and may play a role in cancer development. COX inhibitors are thus believed to interfere with cancer development through the modulation of prostaglandin production.

COX inhibitors, however, have gastrointestinal side effects that limit their routine use. Scientists hope to reduce these side effects by developing drugs such as celecoxib that target only COX2. The COX1 enzyme is found throughout the body, whereas COX2 is generally not expressed in normal tissues.

A large, phase III trial investigating the prevention of polyps with aspirin and folic acid is currently being conducted by John Baron, MD, PhD, of Dartmouth Medical School. The trial has enrolled about 1,000 patients. The daily aspirin dose is 80 mg or 325 mg. The endpoint for the study is the appearance of an adenomatous polyp between randomization and year 3 of the study.

An earlier trial failed to establish an association between aspirin and a reduction in colorectal cancer during 5 years of randomized treatment (Gann PH et al: J Natl Cancer Inst 85:1220-1224, 1993).

A randomized, double-blind trial of 22 patients with familial adenomatous polyposis (FAP) found a regression of polyps in patients treated with sulindac (Giardiello FM et al: N Engl J Med 328:1313-1316, 1993).

An ongoing phase II multidose safety and efficacy study of celecoxib is being conducted at M.D. Anderson and St. Mark’s, London, England. The study has enrolled more than 75 patients with FAP. “One significant outcome of the study has been a 40% change in number of adenomas relative to the baseline,” Dr. Malone said.

Despite the interest in COX inhibitors for colorectal cancer prevention, he said, “much remains to be learned about its use, including appropriate dosage, length of treatment, and target populations.”

Calcium and Colorectal Adenomas

Calcium is another agent being examined for its role in the prevention of colorectal adenomas. The results of a randomized trial of more than 800 patients found that calcium supplementation reduced the risk of at least one recurrent adenoma by 17%. “This was a modest but important result,” Dr. Malone noted (Baron JA et al: Gastroenterology 114:A563, 1998).

Breast Cancer Prevention

Several agents are under investigation for the chemoprevention of breast cancer. Although the effectiveness of tamoxifen has been demonstrated, it has significant side effects, including an increase in endometrial cancer. “In January, the National Cancer Institute was scheduled to begin funding a trial of raloxifene [Evista] vs tamoxifen with 22,000 patients,” Dr. Malone said.

Raloxifene, although similar to tamoxifen, selectively avoids estrogenic stimulation of the uterine endometrium. The results of the Multiple Outcomes of Raloxifene Evaluation (MORE) trial showed that it reduced the incidence of breast cancer without affecting the endometrium. The National Surgical Adjuvant Breast and Bowel Project (NSABP), the same group that conducted the tamoxifen trial, will conduct the Study of Tamoxifen and Raloxifene (STAR).

The chemoprevention of contralateral breast cancer with the agent fenretinide (4-HPR) is the subject of an ongoing study. As of 1998, 1,670 patients had completed the study, and 203 patients were still enrolled. The patients in the study are women with previously resected stage I or II breast cancer with limited lymph node involvement.

Interim analyses in 1995-1997 showed no significant differences in contralateral disease, overall neoplastic events, or survival in the study population overall. However, fenretinide was found to reduce contralateral breast cancers in the premenopausal group. A phase II study is examining the effects of low-dose tamoxifen given in combination with fenretinide.