What Is Chemoprevention?
Lara Bonner Millar, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: March 23, 2011
There is an overwhelming amount of information in the press and on the Internet that suggest certain foods, supplements, and/or medications prevent cancer. The term "chemoprevention" refers to efforts to prevent or delay the development of cancer by taking medicines, vitamins or other agents.*
Chemoprevention is divided into three groups:
- Primary prevention strategies seek to prevent malignancies (cancers) in an otherwise healthy population. These individuals may have a history that puts them at higher risk, such as a history of smoking or particular genetic mutations predisposing them to cancer development.
- Secondary prevention involves patients who have known premalignant (pre-cancerous) lesions utilizing medications or vitamins in an attempt to prevent the progression of these lesions into cancers.
- Tertiary prevention focuses on the prevention of new cancers in patients cured of an initial cancer or individuals who have been treated for premalignant lesions. Clinical trials of chemoprevention are based on the idea that interruption of the biological processes involved in carcinogenesis (the process of normal cells transforming into cancer cells) will inhibit this process and, in turn, reduce cancer incidence.
The ideal chemopreventive agent will not significantly alter quality of life, is inexpensive, safe, well tolerated, and effective. However, some chemopreventive drugs may have severe side effects in some patients, which is an issue when considering long-term administration of a compound to healthy people who may or may not develop cancer.
Chemoprevention in Breast Cancer
Breast cancer chemoprevention trials have set the standard for other disease types to follow. Tamoxifen is an oral selective antiestrogen agent (also called a SERM). Drugs like Tamoxifen work as breast cancer chemopreventive agents by interfering with the female hormone, estrogen. Besides influencing the growth of breast tissue, estrogen is involved in sexual development, proper functioning of the reproductive system, and maintaining bone strength. Many cells in the body, especially within estrogen-sensitive tissues like the breast, contain specialized proteins that bind estrogen. These proteins are known as estrogen receptors (ERs). Interfering with these receptors may decrease breast cancer risk, but can also increase osteoporosis risk and effect fertility and sexuality.
Tamoxifen was the first chemoprevention drug to receive FDA approval and is the most well-known and studied chemopreventive agent. The Breast Cancer Prevention Trial, showed that tamoxifen reduces a pre-or post-menopausal high-risk woman's chances of developing breast cancer by as much as one-half.* A woman is considered at high risk if she scores greater than 1.66 % according to the Gail model.* Importantly, tamoxifen only affected tumors that are estrogen receptor positive (ER+); there is no effect on tumors that are estrogen receptor negative (ER-). Additionally, complications of tamoxifen include increased risk of endometrial cancer and blood clot formation. Raloxifene is another SERM which helps prevent breast cancer in postmenopausal women. This is a drug that is also used to prevent and treat osteoporosis. Like tamoxifen, raloxifene works by blocking estrogen's effects in the breast and other tissues, and it has some of the same risks including increased risk of blood clots. Unlike tamoxifen, raloxifene doesn't exert estrogen-like effects on the uterus, so there is no increased risk of endometrial cancer. The National Surgical Adjuvant Breast and Bowel Project studied both tamoxifen and raloxifene in the STAR trial. Over 19,000 women were enrolled on this trial. Half were assigned to take tamoxifen and half were assigned to take raloxifene daily for five years. The results showed that tamoxifen and raloxifene both reduced the risk of invasive breast cancer in high-risk women by about 50%. The cumulative incidence rate was statistically equivalent for both drugs: 25.1 per 1000 women who took raloxifene compared to 24.8 per 1000 women who took tamoxifen.* Therefore, the decision to use tamoxifen or raloxifene as a chemopreventive agent should be highly individualized and involve a detailed discussion between the patient and their healthcare provider about the risks and benefits of this therapy.
Chemoprevention in Prostate Cancer
Prostate cancer is the most common cancer that occurs in men.* Screening for prostate cancer involves digital rectal exam and prostate-specific antigen.* Three factors have contributed to the ability to study chemoprevention in this cancer: the long period between the initial evidence of prostate cancer and the development of overt or fatal disease, the well-understood hormone dependency of these tumors, and the high rate of the disease. Several agents have been considered for preventive treatment of prostate cancer, including 5-reductase inhibitors (for example, Finasteride), aspirin, and various nutritional substances, such as lycopene, vitamin E, and the element selenium. Finasteride is a treatment for enlarged prostate, also known as benign prostatic hyperplasia (BPH), and is effective at reducing prostate size and symptoms of BPH. Finasteride is a drug that inhibits the conversion of testosterone to another form of the hormone called dihydrotestosterone (DHT). By depriving prostate cells of this hormone, it was hypothesized that prostate cancer could be prevented. The Prostate Cancer Prevention Trial (PCPT) demonstrated a 24.8% reduction in the risk of prostate cancer for men at low risk of prostate cancer who were randomized to receive Finasteride daily for 7 years.* The downside was that in men taking Finasteride who did develop prostate cancer, the cancer was much more aggressive [37% of these tumors were Gleason 7-10 (a more aggressive type), versus 22% in the placebo arm]. Some researchers believe that the increase in high-grade cancers was not valid, and that it was unlikely for an agent to increase the incidence of high-grade tumors and simultaneously decrease the incidence of low-grade tumors.* For now, Finasteride is still used in the treatment of BPH, and has not been FDA approved for prevention of prostate cancer.
Other drugs have also been proposed as chemopreventive agents for prostate cancer. Statin drugs, which are used to lower cholesterol, may also prevent prostate cancer, according to researchers from the Mayo Clinic.* In the laboratory setting, researchers have observed that statin medications prevent cancer cells from dividing and, in fact, may cause some cancer cells to die. Using a group of nearly 2500 men who were followed for 15 years, researchers determined that 6% of statin users were diagnosed with prostate cancer, while 18% of non-statin users received that diagnosis. It is thought that statins may lower the risk of prostate cancer, or, alternatively, they do not decrease the risk of cancer, but may lower PSA, resulting in lower rates of biopsy and prostate cancer diagnosis. Statins are not currently approved for prostate cancer prevention.
Naturally occurring compounds have also been the subject of chemoprevention studies. Lycopene is an antioxidant found in tomatoes and watermelon. A prospective cohort study showed found that increased lycopene intake was associated with a decreased risk of prostate cancer.* The Selenium and Vitamin E Cancer Prevention Trial (SELECT) enrolled over 35,000 men in the US, Canada, and Puerto Rico. This trial found that neither Selenium nor vitamin E, alone or in combination at the doses and formulations used, prevented prostate cancer in this population of relatively healthy men.*
Chemoprevention in Colon Cancer
Studies have shown that individuals reporting a regular intake of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) have a reduced risk of developing colorectal polyps and cancer. It is thought that NSAIDs exert their chemopreventive effects in the colon by restoring a normal frequency of cell death.* Because most colorectal cancers arise from adenomas (a type of colon polyp), it is believed that preventing adenoma formation can prevent cancer as well. In a study of 635 patients with a previous history of colorectal cancer who were randomized to receive either 325 mg of aspirin daily or placebo, there was a significantly reduced risk of development of an adenoma in the aspirin-treated group.* However, adenomas still developed in some patients in the aspirin-treated group, and therefore aspirin should not be a substitution for surveillance colonoscopy. Another NSAID, celecoxib, has been shown to reduce the mean number of polyps by 28% in patients with the rare genetic disorder familial adenomatous polyposis.* Because NSAIDS are associated with increased risk of gastrointestinal bleeding, renal impairment, and other toxicities, the United States Preventive Services Task Force does not recommend NSAID use for the prevention of colorectal cancer.
Chemoprevention is also being studied in other cancers such as head and neck, lung, and skin cancer. Only large clinical trials conducted for many years can demonstrate whether a compound will reduce the risk of cancer. Once a given chemopreventive agent is shown to be effective, patients and their care providers will need to have an individualized discussion of the risks and benefits.
* Fisher B, Jeong JH, Dignam J, et al. Findingsfrom recent National Surgical Adjuvant Breast
and Bowel Project adjuvant studies in stage I breast cancer. J Natl Cancer Inst Monogr 2001;30:62–66.
* Jemal A, Siegel R, Ward E; et al. Cancer statistics, 2008. CA Cancer J Clin. 2008;58(2):71-96.
* Barry MJ. Clinical practice. Prostate-specific-antigen testing for early diagnosis of prostate cancer. N Engl J Med 2001; 344: 1373–1377.
* Thompson IM, Goodman PJ, Tangen CM, et al. The influence of finasteride on the development of prostate cancer. N Engl J Med 2003; 349: 215–224.
* Redman MW, Tangen CM, Goodman PJ , et al, Finasteride Does Not Increase the Risk of High-Grade ProstateCancer: A Bias-Adjusted Modeling Approach Cancer Prev Res August 2008 1:174-181.
* Breau RH, Karnes RJ, Jacobson DJ et al. The Association Between Statin Use and the Diagnosis of Prostate Cancer in a Population Based Cohort J Urol 2010; 184(2):494-500.
* Giovannucci E, Ascherio A, Rimm E, Stampfer M, Colditz G, Willet W. Intake of carotenoids and retinol in relation to risk of prostate cancer. J Natl Cancer Inst 1995;87:1767-1776.
* Lippman SA, Klein EA, Goodman PJ , et al. Effect of Selenium and Vitamin E on Risk of Prostate Cancer and Other Cancers. JAMA. 2009;301(1):39-51.
* Chan TA. Nonsteroidal anti-inflammatory drugs, apoptosis, and colon-cancer chemoprevention. Lancet Oncol 2002; 3: 166-74.
* Baron JA, Cole BF, Sandler RS, et al. A randomized trial of aspirin to prevent colorectal adenomas. N Engl J Med 2003; 348: 891-9.
* Steinbach G, Lynch PM, Phillips RK, et al. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med 2000; 342: 1946-52.
Fisher B, Jeong JH, Dignam J, et al. Findingsfrom recent National Surgical Adjuvant Breast and Bowel Project adjuvant studies in stage I breast cancer. J Natl Cancer Inst Monogr 2001;30:62–66.
Vogel VG, Costantino JP, Wickerham DL, et al. The Study of Tamoxifen and Raloxifene (STAR): Report of the National Surgical Adjuvant Breast and Bowel Project P-2 Trial. JAMA 2006;295:2727–41.
Jemal A, Siegel R, Ward E; et al. Cancer statistics, 2008. CA Cancer J Clin. 2008;58(2):71-96.
Barry MJ. Clinical practice. Prostate-specific-antigen testing for early diagnosis of prostate cancer. N Engl J Med 2001; 344: 1373–1377.
Thompson IM, Goodman PJ, Tangen CM, et al. The influence of finasteride on the development of prostate cancer. N Engl J Med 2003; 349: 215–224.
Redman MW, Tangen CM, Goodman PJ , et al, Finasteride Does Not Increase the Risk of High-Grade ProstateCancer: A Bias-Adjusted Modeling Approach Cancer Prev Res August 2008 1:174-181.
Breau RH, Karnes RJ, Jacobson DJ et al. The Association Between Statin Use and the Diagnosis of Prostate Cancer in a Population Based Cohort J Urol 2010; 184(2):494-500.
Giovannucci E, Ascherio A, Rimm E, Stampfer M, Colditz G, Willet W. Intake of carotenoids and retinol in relation to risk of prostate cancer. J Natl Cancer Inst 1995;87:1767-1776.
Lippman SA, Klein EA, Goodman PJ , et al. Effect of Selenium and Vitamin E on Risk of Prostate Cancer and Other Cancers. JAMA. 2009;301(1):39-51.
Chan TA. Nonsteroidal anti-inflammatory drugs, apoptosis, and colon-cancer chemoprevention. Lancet Oncol 2002; 3: 166-74.
Baron JA, Cole BF, Sandler RS, et al. A randomized trial of aspirin to prevent colorectal adenomas. N Engl J Med 2003; 348: 891-9.
Steinbach G, Lynch PM, Phillips RK, et al. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med 2000; 342: 1946-52.