Chemoprevention in the 21st Century
Chemoprevention is a sensible way to reduce cancer mortality. Since it is unlikely that we can avoid carcinogens in the environment or change genetic composition, it would be appropriate to use an agent (or drug) to suppress, reverse, or prevent carcinogenesis. Conceptually, carcinogenesis is a multistep and multifocal process, with accumulation of molecular alteration that eventually leads to invasive cancer. Thus, inhibition or suppression at one or more steps along the carcinogenesis pathway may impede development of cancer. In this issue, the article on the Role of COX-2 Inhibitors in Cancer elaborates on the story of a promising chemopreventive agent. The early observation of regression of familial polyposis induced by non-steroidal anti-inflammatory drugs was accidental, but the subsequent investigations of the molecular pathway of cyclooxygenase (COX) enzyme inhibition were based on excellent science. The USA Food and Drug Administration has formally endorsed a COX-2 inhibitor as the standard therapy for familial adenomatous polyposis. Ongoing randomised trials are investigating its role in prevention of recurrent sporadic colorectal polyps.
We are hopeful, but must remain sceptical, of the concepts of chemoprevention. A sound scientific concept may not be verified in clinical practice. Familial polyposis accounts for less than 1% of all colorectal cancers. Prevention of colorectal polyps does not necessarily imply reduction in the incidence or mortality of colorectal cancer. Besides, not all polyps will become malignant. In order to demonstrate the role of COX-2 inhibitors in reduction of colorectal cancer mortality, a large-scale randomised controlled study is required. To date, we don't have the benefit of this information.
Chemoprevention of lung cancer by  -carotene had once raised high hopes but failed to show a benefit in large-scale randomised controlled studies. The Alpha-Tocopherol Beta-Carotene Cancer Prevention Study included 29,313 male smokers aged 50 to 69 years in this 4-group 2 x 2 factorial design study.1 After 8 years of follow-up, the authors found smokers receiving -carotene (alone or with  -tocopherol) to have a higher incidence of lung cancer (relative risk, 1.18) and higher mortality (relative risk, 1.08). The Beta-Carotene and Retinol Efficacy Trial, which involved 18,314 smokers, former smokers, or asbestos-exposed workers has also shown a harmful effect associated with -carotene over placebo (relative risk, 1.28).2 Etretinate and isotretinoin are retinoids that can reverse squamous metaplasia in bronchial epithelium, but both agents have failed to show the same advantage in randomised controlled studies. To date, none of the randomised controlled trials of chemoprevention of lung cancer have demonstrated a beneficial effect.
Tamoxifen is also a promising chemopreventive agent for breast cancer. This drug has been shown to prevent second primary breast cancers in the contralateral breast. Subsequently, a large-scale chemoprevention trial of tamoxifen versus placebo was completed in 13,388 women with increased risk of breast cancer.3 After a mean follow-up of 4 years, there was a 49% reduction of invasive breast cancer in the group receiving tamoxifen. There was also a reduction in non-invasive breast cancer with 59 cases in the placebo group and 31 cases in the tamoxifen group. However, a significant increase in endometrial cancer and thromboembolic events may have offset the benefit. The net benefit, which could be age-dependent, remains controversial. The new generation of selective estrogen receptor modulators (SERMs) such as raloxifene may reduce the incidence of breast cancer without increases in endometrial cancer. The Multiple Outcomes of Raloxifene Evaluation enrolled 7,705 postmenopausal women.4 After a relatively short follow-up of 40 months, there was a significant reduction in breast cancer incidence of 76%. The risk of endometrial hyperplasia was not increased but it is premature to conclude on the risk of endometrial carcinoma. Thrombovascular complications were 3-fold higher in the raloxifene group. A randomised study by the National Surgical Adjuvant Breast and Bowel Project will directly compare raloxifene with tamoxifen.5
Chemoprevention for the 3 most common malignancies is being actively investigated. With advances in knowledge of the molecular pathway of carcinogenesis, chemoprevention may become the main modality of cancer prevention, but this remains to be proven by randomised controlled trials.
References
1. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med 1994;330:1029-1035.
2. Omenn GS, Goodman GE, Thornquist MD, et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 1996;334:1150-1155.
3. Gail MH, Costantino JP, Bryant J, et al. Weighing the risks and benefits of tamoxifen treatment for preventing breast cancer. J Natl Cancer Inst 1999;91:1829-1846.
4. Cummings SR, Eckert S, Krueger KA, et al. The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation. JAMA 1999;281:2189-2197.
5. Lippman SM, Lee JJ, Sabichi AL. Cancer chemoprevention: progress and promise. J Natl Cancer Inst 1998;90: 1514-1528.
TSK Mok
Professor
Department of Clinical Oncology
Prince of Wales Hospital
Hong Kong
China
|
