CANCER CHEMOPREVENTION

Chemoprevention of cancer involves the use of specific natural or synthetic chemical agents to reverse, suppress, or prevent carcinogenesis before the development of invasive malignancy.

Cancer develops through an accumulation of genetic changes that are potential points of intervention to prevent cancer. The initial genetic changes are termed initiation. The alteration can be inherited or acquired through the action of physical, infectious, or chemical carcinogens. Like most human diseases, cancer arises through an interaction between genetics and environmental exposures (Table 67-1). Influences that cause the initiated cell to progress through the carcinogenic process and to change phenotypically are termed promoters. Promoters include hormones such as androgens, linked to prostate cancer, and estrogen, linked to breast and endometrial cancer. The distinction between an initiator and a promoter is sometimes arbitrary; some components of cigarette smoke are "complete carcinogens," acting as both initiators and promoters. Cancer can be prevented or controlled through interference with the factors that cause initiation, promotion, or progression. Compounds of interest in chemoprevention often have antimutagenic, antioxidant, antiproliferative, or pro-apoptotic activity.

A number of chemoprevention strategies are undergoing clinical trials. However, tamoxifen is the only chemoprevention currently approved by the U.S. Food and Drug Administration; it lowers risk of breast cancer in high-risk women.

Multiple Cancer Site Prevention Trials  The Physicians' Health Trial involves 22,071 American male physicians. Participants were randomly assigned to receive ß-carotene, aspirin, and/or placebo in a 2 × 2 factorial design. All major medical events were recorded. In 1988, the aspirin arm was unblinded after the trial demonstrated that aspirin therapy causes a significant reduction in cardiovascular mortality. ß-Carotene was not associated with a decreased cancer risk compared to placebo.

The Women's Health Study, launched in 1992, is a 10-year trial involving 44,000 female nurses. Subjects are randomly assigned to ß-carotene, a-tocopherol, aspirin, and/or placebo in a factorial design yielding eight different treatment groups. The end points are total epithelial cancers, breast cancer, lung cancer, colon cancer, and vascular disease.

The Women's Health Initiative uses a partial factorial design that places women in 22 intervention groups. Participants can receive calcium and vitamin D supplementation, hormone replacement therapy, and counseling to increase exercise and cease smoking. Prevention of a number of cancers, cardiovascular disease, osteoporosis, and other diseases will be assessed. The portion of the trial comparing combined estrogen plus progestin replacement therapy to placebo in women with an intact uterus was halted in 2002 due to an excess of cardiovascular events and breast cancer in the hormone therapy arm. Colon cancer was decreased in the hormone therapy arm. Prior epidemiologic studies had consistently shown a decrease in cardiovascular disease in women taking hormone replacement therapy. The risk of developing Alzheimer's disease was doubled in the combined hormone therapy arm, and quality of life was not improved compared to placebo. Therefore the strength of evidence from prospective randomized, controlled trials is considered to outweigh the prior evidence of benefit. At present combined estrogen plus progestin therapy is not recommended for disease prevention because of the results of this study. The estrogen-only portion of the trial (in women with prior hysterectomy) is still in progress.

Chemoprevention of Cancers of the Upper Aerodigestive Tract  Smoking causes diffuse epithelial injury in the head, neck, esophagus, and lung. Patients cured of squamous cell cancers of the lung, esophagus, head, and neck are at risk (as high as 5% per year) of developing a second cancer of the upper aerodigestive tract. Cessation of cigarette smoking does not markedly decrease the cured cancer patient's risk of second malignancy, even though it does lower the cancer risk in those who have never developed a malignancy. Smoking cessation may halt the early stages of the carcinogenic process (such as metaplasia), but it may have no effect on late stages of carcinogenesis. This "field carcinogenesis" hypothesis for cancer of the upper aerodigestive tract has made "cured" patients an important population for chemoprevention of second malignancies. A randomized, placebo-controlled clinical trial has demonstrated that adjuvant isoretinoin (13-cis-retinoic acid) can reduce the incidence of second primary tumors in patients treated with local therapy for head and neck cancer. However, overall survival was not improved due to mortality from recurrences of the primary tumor.

Oral leukoplakia, a premalignant lesion commonly found in smokers, has been used as an intermediate marker allowing the demonstration of chemopreventive activity in smaller, shorter-duration, randomized, placebo-controlled trials. Response was associated with upregulation of retinoic acid receptor ß. Therapy with isoretinoin causes regression of oral leukoplakia. However, the lesions recur when the agent is withdrawn, suggesting the need for chronic administration of retinoids. Premalignant lesions in the oropharyngeal area have also responded to ß-carotene, retinol, a-tocopherol (vitamin E), and selenium. Further study to improve the definition of the activity of these drugs is ongoing. Isoretinoin was shown not to prevent second malignancies in patients cured of early-stage non-small cell lung cancer, and those who were current smokers had higher lung cancer mortality rates than those not taking isoretinoin.

Several large-scale trials have assessed agents in the chemoprevention of lung cancer in patients at high risk. In the Alpha-Tocopherol/Beta-Carotene (ATBC) Lung Cancer Prevention Trial, participants were male smokers, aged 50 to 69 at entry. At entry, participants had smoked an average of one pack of cigarettes per day for 35.9 years. Participants received a-tocopherol, ß-carotene, and/or placebo in a randomized, 2 × 2 factorial design. After a median follow-up of 6.1 years, lung cancer incidence and mortality were statistically significantly increased in those receiving ß-carotene. a-Tocopherol had no effect on lung cancer mortality, and no evidence suggested interaction between the two drugs. Patients receiving a-tocopherol had a higher incidence of hemorrhagic stroke.

The Beta-Carotene and Retinol Efficacy Trial (CARET) involved 17,000 American smokers and workers with asbestos exposure. Entrants were randomly assigned to one of four arms and received ß-carotene, retinol, and/or placebo in a 2 × 2 factorial design. This trial demonstrated harm from ß-carotene: a lung cancer rate of 5 per 1000 subjects per year for those taking placebo and of 6 per 1000 subjects per year for those taking ß-carotene. The difference was statistically significant.

These ATBC1 and CARET2 results demonstrate the importance of testing chemoprevention hypotheses before implementing them widely, because the results stand in contrast to a number of observational epidemiologic studies. In the ATBC trial, participants taking a-tocopherol had a one-third reduction in the incidence of prostate cancer, compared to those not taking a-tocopherol. The Physicians' Health Trial showed neither an increased nor a decreased risk of lung cancer in those using ß-carotene; fewer of its participants were smokers than those in the ATBC and CARET studies.

Chemoprevention of Colon Cancer  Many of the current colon cancer prevention trials are based on the premise that most colorectal cancers develop from adenomatous polyps. These trials use adenoma recurrence or disappearance as a surrogate end point to assess colon cancer prevention. Early clinical trial results suggest that nonsteroidal anti-inflammatory drugs (NSAIDs), such as piroxicam, sulindac, and aspirin, may prevent adenoma formation or cause regression of adenomatous polyps. The mechanism of action of NSAIDs is unknown, but they are presumed to work through the cyclooxygenase pathway. In the Physicians' Health Trial, aspirin had no effect on colon cancer incidence, although the 6-year assessment period may not have been long enough to evaluate this end point definitively. Studies evaluating NSAIDs as colon cancer chemopreventive agents have not yet been completed.

Cyclooxygenase 2 inhibitors may be even more effective at colon cancer prevention. High-dose celecoxib reduces the number of colorectal polyps in patients with familial adenomatous polyposis and is under study for prevention of sporadic colorectal cancer.

Epidemiologic studies suggest that diets high in calcium lower colon cancer risk. Calcium binds bile and fatty acids, which cause hyperproliferation of colonic epithelium. It is hypothesized that this effect reduces intraluminal exposure to these compounds. Early data from randomized studies suggest that calcium supplementation decreases the risk of adenomatous polyp recurrence by about 20%, even though it does not decrease the proliferative rate of the colonic epithelium. Epithelial proliferative rate may not be an adequate surrogate marker in colon cancer prevention trials. Trials of calcium with cancer incidence end points are underway.

The Women's Health Initiative demonstrated a significant reduction in colon cancer among women taking combined hormone replacement therapy. However, the increased risk of cardiovascular events and breast cancer probably outweighs the benefit.

Prevention of Hormonally Driven Cancers  Hormonal manipulation is being tested in the primary prevention of breast and prostate cancer. Tamoxifen is an antiestrogen with partial estrogen agonistic activity in some tissues, such as endometrium and bone. One of its actions is to upregulate transforming growth factor ß, which decreases breast cell proliferation. In randomized placebo-controlled trials to assess tamoxifen as an adjuvant in breast cancer treatment, this drug reduced the number of new breast cancers in the uninvolved breast by more than a third. In a randomized placebo-controlled trial involving >13,000 women at high risk, tamoxifen decreased the risk of developing cancer by 49% compared to placebo. Tamoxifen also reduced the risk of bone fractures; a small increase in risk of endometrial cancer, stroke, pulmonary emboli, and deep vein thrombosis was noted. A trial to compare tamoxifen with another selective estrogen receptor modulator, raloxifene, is ongoing. Raloxifene may have less risk of endometrial cancer.

Finasteride is a 5a-reductase inhibitor. It inhibits the conversion of testosterone to dihydrotestosterone, a more potent stimulator of prostate cell proliferation than testosterone. In an F344 rat model of carcinogen-induced prostate cancer, finasteride decreased the incidence of cancers. Finasteride produced a 20% decrease in overall prostate cancer, but a slight increase in high-grade (Gleason score 7-10) prostate cancer in men over age 55 years.

Selenium is being tested as a prostate cancer preventive agent based on laboratory studies and a small clinical trial aimed at prevention of skin cancer. Men taking selenium to prevent skin cancer were found to have a significantly reduced incidence of prostate cancer (16 on placebo arm; 4 on selenium arm). The ATBC1 study cited above showed that risk of prostate cancer was reduced in those taking vitamin E (99 prostate cancers on vitamin E; 151 cases on placebo). The findings on selenium and vitamin E were serendipitous and based on secondary analysis. A prospective study is underway.

Vaccines and Cancer Prevention  A number of infectious agents have been linked to the development of cancer, leading to interest in developing vaccines to protect against these agents. The hepatitis B vaccine is quite effective in preventing hepatitis and hepatomas due to chronic hepatitis B infection. Public health officials are encouraging widespread administration of this vaccine, especially in Asia, where the disease is epidemic. Human papilloma virus (HPV) vaccines are being developed to prevent cervical cancer, and Helicobacter pylori vaccines are aimed at gastric cancer. Antibiotic eradication of H. pylori may also be a cancer prevention strategy.