Chemoprevention- cancer risk reducing agents

Biomarkers as Cancer Risk–Reducing Agent Targets and Efficacy End Points:

A biomarker is a characteristic that is measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to therapeutic interventions.

A surrogate end point for cancer prevention assumes that a measured biologic feature will predict the presence or future development of a cancer outcome.


Biomarkers enable reduction in the size and duration of an intervention trial by replacing a rare or distal end point, with a more frequent, proximate end point.


Intraepithelial neoplasia has served as and continues to serve as a biomarker for invasive malignancy.
Biomarkers as Cancer Risk–Reducing Agent Targets and Efficacy End Points:

A biomarker is a characteristic that is measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to therapeutic interventions.

A surrogate end point for cancer prevention assumes that a measured biologic feature will predict the presence or future development of a cancer outcome.


Biomarkers enable reduction in the size and duration of an intervention trial by replacing a rare or distal end point, with a more frequent, proximate end point.


Intraepithelial neoplasia has served as and continues to serve as a biomarker for invasive malignancy.
Phase I cancer risk–reducing agent trials define an optimal cancer risk–reducing agent dose.
An optimal cancer risk–reducing agent dose is one that is usually nontoxic, scheduled once daily, and modulates a tissue, cellular, or serum biomarker of drug activity (e.g., the dose of aspirin that inhibits prostaglandin production in a target tissue site).

Phase II cancer risk–reducing agent trials begin to define cancer risk reduction efficacy. These short-term (6 months to 1 year) treatment periods gather evidence of risk reduction by assessing drug effects on tissue, cellular, or blood surrogate markers of carcinogenesis.

Phase III cancer risk–reducing agent trials define reduction in a hard cancer end point such as cancer incidence or mortality. Such trials using large, higher risk populations in a randomized, double-blinded intervention are designed to identify a standard of preventive care for a given risk population.

When tamoxifen binds to ERβ, which then binds to an AP1 type gene promoter, it functions as an estrogen agonist. When bound to ERα, which binds to an ERE target gene promoter, tamoxifen functions as an estrogen antagonist.

Tamoxifen has estrogen antagonist effects in the human breast; partial estrogen agonist effects in bone, the cardiovascular system, and CNS; and predominant estrogen agonist effects in the uterus, liver, and vagina.

The clinical finding that tamoxifen reduces the incidence of contralateral second primary breast cancers during adjuvant treatment regimens catalyzed the push for its development as a cancer risk–reducing agent.

Raloxifene has greater es

1. Cancer Risk Reducing Agents

2. Cancer risk reduction, commonly referred to as chemoprevention, is the use of a range of interventions from drugs to isolated dietary components to whole-diet modulation to block, reverse, or prevent the development of invasive cancer. Human cancer risk reduction asserts that interventions may be implemented at many steps over a decade’s long carcinogenic process. This prolonged latency provides opportunities to target multiple events , to customize the intervention to specific exposures or risk profiles over a long time frame. Successful deployment of cancer risk–reducing agent interventions requires evidence of reduced cancer-associated incidence and/or mortality.

3. Biomarkers as Cancer Risk–Reducing Agent Targets and Efficacy End Points: A biomarker is a characteristic that is measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to therapeutic interventions. A surrogate end point for cancer prevention assumes that a measured biologic feature will predict the presence or future development of a cancer outcome. Biomarkers enable reduction in the size and duration of an intervention trial by replacing a rare or distal end point, with a more frequent, proximate end point. Intraepithelial neoplasia has served as and continues to serve as a biomarker for invasive malignancy.

4. Phases of Cancer Risk–Reducing Agent Development Phase I cancer risk–reducing agent trials define an optimal cancer risk–reducing agent dose . An optimal cancer risk–reducing agent dose is one that is usually nontoxic, scheduled once daily, and modulates a tissue, cellular, or serum biomarker of drug activity (e.g., the dose of aspirin that inhibits prostaglandin production in a target tissue site). Phase II cancer risk–reducing agent trials begin to define cancer risk reduction efficacy . These short-term (6 months to 1 year) treatment periods gather evidence of risk reduction by assessing drug effects on tissue, cellular, or blood surrogate markers of carcinogenesis. Phase III cancer risk–reducing agent trials define reduction in a hard cancer end point such as cancer incidence or mortality. Such trials using large, higher risk populations in a randomized, double-blinded intervention are designed to identify a standard of preventive care for a given risk population.

5. B reast cancer risk reducing agents

6. Selective Estrogen Receptor Modulators(SERMs) and Aromatase Inhibitors for the prevention of breast cancer When tamoxifen binds to ERβ, which then binds to an AP1 type gene promoter, it functions as an estrogen agonist . When bound to ERα, which binds to an ERE target gene promoter, tamoxifen functions as an estrogen antagonist . T a moxifen has estrogen antagonist effects in the human breast ; partial estrogen agonist effects in bone, the cardiovascular system, and CNS; and predominant estrogen agonist effects in the uterus, liver, and vagina. The clinical finding that tamoxifen reduces the incidence of contralateral second primary breast cancers during adjuvant treatment regimens catalyzed the push for its development as a cancer risk–reducing agent. Raloxifene has greater estrogen agonist activity in bone but reduced estrogen agonist activity in the uterus. Aromatase converts adrenal androgens (testosterone and androstene dione ) to estrone and estradiol . Pharmacologically inhibiting aromatase reduces the peripheral estrone and estradiol conversion from androgenic sources, thus depriving neoplastic hormonally dependent cells of necessary estrogens.

7. SERMs The effectiveness of tamoxifen has been assessed in four and raloxifene in two randomized placebo‐controlled trials. Five years of treatment with tamoxifen resulted in a 33% (hazard ratio [HR] 0.67 ; 95% confidence interval [CI] 0.59–0.76) reduction in breast cancer risk.

8. Compared with the NSABP P1 trial where the reduction of risk was 50%, the effects in both the IBIS I and Royal Marsden (RM) trials were lower. In both of these studies additional HRT was allowed in women who had severe hot flushes. In IBIS I (but not the RM trial), addition of HRT to tamoxifen resulted in abrogation of its effectiveness (HR 0.87 [95% CI 0.64–1.19] vs nonusers 0.55 [0.42– 0.72]; p = 0 · 03). The long‐term effect of five years of tamoxifen treatment was reported In the IBIS I trial. It showed risk reduction for invasive breast cancer of 29% for years 0–10 from randomization , which was similar to the reduction of 31% in the period beyond 10 years .

9. For raloxifene, the MORE/ CORE trial (the MORE trial was for four years and continued for a further four years in the CORE extension, so a total of eight years of treatment) resulted in an overall 66% ( HR 0.34 ; 95% CI 0.22–0.50) reduction in risk. T he RUTH trial resulted in a 44% ( HR 0.56 ; 95% CI 0.38–0.83) reduction in risk . The STAR randomized trial directly compared the two selective oestrogen receptor modulators (SERMs). It demonstrated that raloxifene was less effective than tamoxifen after seven years of follow‐up: T he risk ratio (RR; raloxifene: tamoxifen) for invasive breast cancer was 1.24 (95% CI 1.05–1.47) and for noninvasive disease was 1.22 (95% CI 0.95–1.59).

10. Chemoprevention strategies in prostate cancer RATIONALE Three factors have contributed to the rationale for prostate cancer chemoprevention in men: T he long latency period between the initial evidence of prostate cancer and the development of overt or fatal disease. T he androgen dependency of these tumors and T he availability of intermediate endpoints for use in clinical trials.

11. Long latency period  —  Progression to invasive cancer in men with high-grade prostatic intraepithelial neoplasia (PIN) may take 10 years or more .  As a result, chemoprevention strategies that do not reverse the premalignant condition but merely delay its progression to invasive cancer may be sufficient to improve survival or avoid the complications of the disease or its treatment. Androgen dependency  —  Men with 5-alpha reductase (5-AR) deficiency (the enzyme that converts testosterone to dihydrotestosterone [DHT], the most active androgen in the prostate) do not develop prostate cancer. The precursor lesion, high-grade PIN, is also hormonally dependent. These data suggest that interference with normal androgen balance may affect prostate cancer incidence. The use of 5-AR inhibitors or antiandrogens that block the androgen receptor may be associated with fewer side effects because serum testosterone levels remain unaltered.

12. Clinical trials biomarkers  —  Development of chemopreventive agent may be facilitated by the availability of biomarkers  serve as intermediate endpoints for clinical trials. Prostatic intraepithelial neoplasia  – PIN represents a spectrum of dysplastic changes that are limited to prostatic acini and do not invade the basement membrane. High-grade PIN is thought to be associated with an increased prostate cancer risk. Prostate-specific antigen  – Changes in serum prostate-specific antigen (PSA) concentration and its association with prostate cancer suggest that serum PSA may be a useful biomarker.

13. 5-ALPHA REDUCTASE INHIBITORS The 5-alpha reductase (5-AR) inhibitors finasteride and d utasteride -- used primarily for treatment of benign prostatic hyperplasia. They improve lower urinary tract symptoms by blocking the conversion of testosterone into the more potent androgen dihydrotestosterone (DHT). There are data from two randomized trials that support a reduced risk of prostate cancer in men receiving 5-AR inhibitors. N o survival benefit has been shown in either trial, and both raised concerns about a possible increased risk of high-grade prostate cancer.

14. Finasteride: PCPT  — In the Prostate Cancer Prevention Trial (PCPT) , 18,882 men were randomly assigned to finasteride (5 mg/day) or placebo between 1994 and 1997 . Men were considered at elevated risk of prostate cancer based on : Age≥55 years, African-American ethnicity, or H aving a first-degree relative with prostate cancer. All had a normal digital rectal examination (DRE) and a serum PSA ≤3 ng/ mL. Prostate biopsy was recommended if the annual PSA level, adjusted for the effect of  finasteride (which decreases the serum PSA by approximately 50 percent), was ≥4 ng/dL or if the DRE became abnormal . The PCPT was closed early because the primary study endpoint ( a decrease in the prevalence of biopsy-proven prostate cancer in the   finasteride population compared with placebo) was met . The initial analysis found a 25 percent decrease in the incidence of prostate cancer with seven years of finasteride, but there was also an observed increase in the absolute number and proportion of high-grade prostate cancers ( ie , Gleason score ≥7).

15. A long-term follow-up of this study (up to 18 years of follow-up ), which included the identification of 187 additional cases of prostate cancer, analyzed overall survival data by 2011 . ● There was a statistically significant decrease in the incidence of prostate cancer in men assigned to  finasteride compared with placebo (10.5 versus 14.9 percent, relative risk [RR] 0.70 , 95% CI 0.65-0.76). ● S tatistically significant increase in the risk of high-grade prostate cancer (Gleason score ≥7) with  finasteride (3.5 versus 3.0 percent, RR 1.17 , 95% CI 1.00-1.37, p = 0.05). ● The 15-year overall survival rates for the  finasteride and placebo groups were 78.0 and 78.2 percent , respectively (unadjusted hazard ratio [HR] 1.02, 95% CI 0.97-1.08). ● Among men who subsequently developed prostate cancer, there were no significant differences in the 10-year overall survival rates in men assigned to  finasteride or placebo. For men with low-grade prostate cancer (Gleason score ≤6), the 10-year overall survival rates were 83.0 and 80.9 percent, respectively, and F or those with high-grade prostate cancer (Gleason score ≥7), the 10-year overall survival rates were 73.0 and 73.6 percent, respectively.

16. The observed increase in the number of patients with high-grade cancers dampened enthusiasm for the use of  finasteride as a chemopreventive agent. T he observed increase in high-grade lesions did not represent a true alteration in the biology of the disease and, instead, likely indicated detection bias attributed to the fact that finasteride shrinks the prostate , thereby increasing the detection of high-grade disease.

17. Dutasteride REDUCE trial  —  D ouble-blind Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial . 8336 men were randomly assigned to dutasteride (0.5 mg/day for four years) or placebo. All men were considered at increased risk for prostate cancer based on age and serum PSA level, and all had a single negative prostate biopsy within six months prior to protocol entry. Men 50 to less than 60 years of age had a baseline serum PSA of 2.5 to 10 ng/mL, while those 60 to 75 years of age had a PSA 3 to 10 ng/ mL. Key findings included: ● The incidence of prostate cancer was significantly reduced in men assigned to  dutasteride compared with placebo (25.1 versus 19.9 percent, RR reduction 23 percent ). ● The decrease in incidence was limited to cancers with a Gleason score of 5 or 6, which constituted 70 percent of all cases diagnosed. There was no statistically significant reduction in risk of prostate cancer with Gleason scores of 7 to 10 . Mortality rates were similar in both groups, and no deaths were attributed to prostate cancer in either group.

18. OTHER AGENTS : A number of other agents are being studied to prevent prostate cancer. All of them remain experimental. Statins  — epidemiologic findings suggest that statin use may have a beneficial effect on the risk of prostate cancer progression and death. Prospective trials are lacking. Metformi n : I n a study of over 119,000 men ≥66 years old with incident diabetes, prostate cancer was subsequently diagnosed in 5306. There was no difference in the risk of prostate cancer (adjusted odds ratio [OR] 1.03, 95% CI 0.96-1.1). E ffect on the progression of disease in diabetic patients with prostate cancer. In a study that included 3837 patients older than 66 years with a new diagnosis of diabetes who were subsequently diagnosed with prostate cancer, prostate cancer-specific mortality was significantly decreased in those treated with metformin . ( H azard ratio [HR] for prostate cancer-specific mortality 0.76 for each additional six months of use of metformin). These observations require confirmation.

19. Vitamins and micronutrients The available data on vitamins and dietary supplements for chemoprevention are extensive and difficult to interpret.  Currently, available data have not established a role for any of these agents in the prevention of prostate cancer. The most extensively studied agents are  vitamin E  (alpha-tocopherol) and  selenium .

20. Two randomized trials designed to study the impact of  vitamin E   on prostate cancer incidence failed to provide any evidence supporting a chemopreventive role: The  Selenium  and  Vitamin E   Cancer Prevention Trial (SELECT) : T he role of selenium and vitamin E as agents to decrease the incidence of prostate cancer. In this trial, 35,533 men were randomly assigned to : S elenium (200 mcg/day), V itamin E (400 international units/day), B oth, or N either with appropriate placebos. This trial was stopped in October 2008 after an independent data safety monitoring committee found no evidence of a decrease in the incidence of prostate cancer. Dietary supplementation with vitamin E significantly  increased  the incidence of prostate cancer, and there were nonsignificant increases with selenium and the combination of vitamin E plus selenium compared with placebo (HR for developing prostate cancer 1.17, 1.09, and 1.05 , respectively)

21. The Physicians' Health Study II (PHS II) was a double-blind, placebo-controlled trial : 14,641 male clinicians ages 55 years and older were randomly assigned to   B eta-carotene ,  V itamin E , A scorbic acid, and/or A multivitamin. One of the primary endpoints of this study was the prevention of prostate cancer. The incidence of prostate cancer was not significantly reduced with any of the agents, including vitamin E (HR 0.97, 95% CI 0.85-1.09 ) .

22. Vitamin D analogs  —  A link between vitamin D levels and prostate cancer risk has been suggested, mainly based on the association of vitamin D deficiency with epidemiologic risk factors such as age, African-American race, and geographic area of residence. Preclinical studies support an antiproliferative, antimetastatic, and differentiating effect of vitamin D and its analogues in prostate cancer, providing a rationale for the consideration of these compounds as potential chemopreventive agents. No prospective trials have confirmed this effect.

23. Retinoids  —  Retinoids are metabolites and analogs of vitamin A that are required for the proper differentiation of various epithelial tissues, and they play a regulatory role in the activation of cytokines and the extracellular matrix . Fenretinide , a synthetic retinoid --> evaluated in men with prostate cancer in preliminary studies . T hese trials have not yielded evidence of activity , and this class of agents is not under active investigation for chemoprevention against prostate cancer.

24. Dietary factors  —  Phytoestrogens (flavones, isoflavones, lignans) are naturally occurring plant compounds that have estrogen-like activity. Phytoestrogens may reduce prostate cancer risk either by I nherent estrogenic properties (which favorably alter the hormonal milieu) or B y inhibition of 5-alpha reductase (5-AR), which decreases concentrations of the more prostate-active androgen dihydrotestosterone (DHT). The higher intake of soy products among Asian men has been hypothesized to be one reason for the lower incidence of prostate cancer among these men. In humans, most of the case-control studies have shown a modest protective benefit of soy on prostate cancer risk.

25. SUMMARY AND RECOMMENDATIONS In randomized trials, 5-alpha-reductase (5-AR) inhibitors have been shown to significantly decrease the incidence of prostate cancer . However, no trials have demonstrated an impact on prostate cancer mortality. With long-term follow-up of the randomized trials, there is no clear evidence that these agents increase the incidence of higher grade prostate cance r or are associated with increased prostate cancer-specific mortality.

26. The potential side effects (gynecomastia, decreased libido, erectile dysfunction), benefits (decreased symptoms from benign prostatic hyperplasia), and areas of persisting uncertainty (long-term side effects) should be explained to men considering chemopreventive therapy. For most men, various guidlines suggest not using chemopreventive therapy with a 5-AR inhibitor . However, chemopreventive therapy with a 5-AR inhibitor in conjunction with monitoring serum PSA may be appropriate for those who consider preventing cancer more important than the side effects associated with such therapy. There are no data that support the use of  vitamin E ,  selenium , or other agents for routine use, and such agents remain experimental .

27. Chemoprevention of lung cancer T here is no convincing evidence (phase III studies) that any approach (other than smoking cessation) can decrease the risk of lung cancer. RATIONALE Patient population  — For chemoprevention to be feasible, A high-risk population must be identified and A n effective chemopreventive agent with minimal side effects must be available. Current or former smokers with an annual risk of up to 2 percent are identifiable using a combination of clinically available risk factors , including: smoking history, age, gender, presence of COPD , environmental/occupational exposure, a history of a tobacco-related aerodigestive cancer, and family history of lung cancer .

28. Pathology and genetics  —  All of the histologic cell types of lung cancer are genetically complex, with squamous cell demonstrating the highest frequency of mutations. No common mutation is shared across a majority of lung cancers, making a targeted approach to chemoprevention challenging. But Common pathways for the early stages of premalignancy (pulmonary inflammation, tissue hypoxia, ageing) or distinct phenotypes susceptible to lung carcinogenesis may be definable and targeted for intervention  .

29. Clinical settings  —  Chemoprevention is classified as primary, secondary, or tertiary, based upon the target population: ● Primary chemoprevention – Primary chemoprevention refers to preventing cancer in healthy individuals who are at increased risk. This population primarily includes current and former smokers, as well as those with exposure to known lung carcinogens such as asbestos and radon. ● Secondary chemoprevention – Secondary chemoprevention focuses on blocking the development of cancer in individuals in whom a precancerous lesion has been detected. ● Tertiary chemoprevention – Tertiary chemoprevention targets patients who had a previous lung or other tobacco-related cancer in an effort to prevent the development of a second primary tumor .

30. Incidental observations with three agents : I nhaled corticosteroids, L ow-dose  aspirin , A nti-interleukin 1 beta [IL-1 beta] monoclonal antibodies) . H ave attracted interest as possible agents for lung cancer chemoprevention. These approaches do not have a defined role, and further evaluation in randomized trials is required:

31. Inhaled corticosteroids – Pulmonary inflammation induced by tobacco smoke may contribute to the development of lung cancer. Inhaled corticosteroids have impressive preclinical data in murine models to support a chemopreventive role. An analysis of patients at Veterans Affairs Medical Centers who were prescribed inhaled corticosteroids for chronic obstructive pulmonary disease ---> revealed a significantly reduced risk of lung cancer. T he mean duration of these trials was only 26 months , which may have been too short to demonstrate a chemopreventive effect .

32. Aspirin-- I n a retrospective cohort study of almost 13 million participants in the Korean National Health Information Database, I ntake of low-dose  aspirin  (100 mg or less) for at least 5 years was associated with a modestly reduced risk of lung cancer ( eg , compared with no aspirin use; HR 0.96 with 5 to 6 years of aspirin use and reaching 0.89 with 9 years of aspirin use). After stratified analysis, a more pronounced reduction of lung cancer risk was observed among people aged 65 years or older and among people without diabetes .

33. T he monoclonal antibody  canakinumab  that targets IL-1 beta was studied in a randomized, placebo-controlled trial : T he primary endpoint ---> reducing vascular events in patients with a previous myocardial infarction and an elevated level of high-sensitivity C-reactive protein (2 mg/L or greater). Lung cancer incidence was a prespecified secondary endpoint and was reduced significantly in the canakinumab group in a dose-dependent fashion ranging from HRs of 0.61 to 0.33 over a median follow-up period of 3.7 years. The short follow-up period makes it unlikely that canakinumab inhibits early events in lung carcinogenesis, but more likely affects progression or metastasis. Overall mortality was not improved, largely due to an increase in death from sepsis.

34. Secondary chemoprevention  — Secondary chemoprevention refers to the prevention of progression to lung cancer for people who have evidence of premalignancy.  A number of studies have used bronchoscopy to target premalignant airway lesions but few of these have met their primary endpoints. Examples include : Negative results have been reported for 13 cis retinoic acid, beta carotene, vitamin B12 and folate, and inhaled corticosteroids. A study of anethole dithiolethione , a compound found in green tea, did not achieve its primary endpoint of reducing new dysplastic lesions but d id decrease the rate of worsening of endobronchial lesions , a secondary endpoint. One trial of the oral prostacyclin analog,  iloprost , compared with placebo demonstrated a statistically significant improvement in the primary endpoint, bronchial dysplasia , but only in former smokers .

35. Prevention trials have also started to evaluate modulation of the immune response. Immunoprevention trials evaluating checkpoint inhibitors are recruiting ( nivolumab  for premalignant squamous cell lesions [ NCT03347838 ], and a trial of  pembrolizumab   in pulmonary nodules [ NCT03634241 ]). Nivolumab for the Reversal of Squamous Dysplasia in High Risk Current and Former Smokers ( Recruting ). This is a single-institution, open-label, single-arm, two-stage, phase II study of the PD-1 inhibitor nivolumab in patients at high risk for lung cancer. Nivolumab 240 mg IV will be administered every two weeks for a total of four doses (8 weeks). Participants undergo bronchoscopy with endobronchial biopsy at study entry, 2 months, and 6 months The primary endpoint will be change in bronchial dysplasia between study entry and the 6 month timepoint.

36. Randomized Phase II of Immunotherapy With Pembrolizumab for the Prevention of Lung Cancer (IMPRINT-Lung) ---> Recruting Subjects: Patients with no history of lung cancer, who have IPNs detected by low dose CT (LDCT)-guided lung cancer screening with 15-30% cancer probability by Brock University cancer prediction equation . Patients with history of stage I-II non-small cell lung cancer (NSCLC), who have completed curative treatment and have persistent IPNs. Primary Outcome : Regression rate of high-risk indeterminate pulmonary nodules (IPNs) at 6 months. Secondary Outcome : Incidence of lung cancer -up to 6 months.

37. Phase III trials   Vitamin E   and beta carotene – T wo primary chemoprevention trials have evaluated: T he combination of vitamin E and beta carotene (the alpha tocopherol beta carotene or ATBC study ), B eta carotene and retinol ( CARET ), or beta carotene alone. None showed benefit, and both CARET and ATBC demonstrated statistically significant increases (relative risk [RR] = 1.28 and 1.18, respectively) in lung cancer risk in the treatment groups receiving beta carotene. Selenium  supplementation was ineffective in a tertiary prevention trial with second primary lung cancer as the endpoint.

38. SUMMARY : Never smoking and smoking cessation among smokers clearly reduces the risk of lung cancer, and the leading prevention effort for current smokers should be smoking cessation. Agents to prevent lung cancer have included a variety of agents, including beta carotene, retinoids,  selenium , and multivitamins. None have been successful in phase III trials, and beta carotene supplementation actually increases lung cancer risk , emphasizing that the administration of supplements with a good biologic rationale to reduce risk is not necessarily good.

39. Chemoprevention Of Colorectal cancer Aspirin and Other Nonsteroidal Antiinflammatory Drugs Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) are the most widely studied agents for the chemoprevention of colorectal cancer. Folate Calcium Hormone-Replacement Therapy

40. Aspirin and Other Nonsteroidal Anti inflammatory Drugs

41. Any benefit of these agents is likely to be transient , since an increase in the number and size of polyps has been noted in patients three months after sulindac is discontinued. These treatments should not now replace the standard of care for patients with familial adenomatous polyposis, which is surgical removal of the colon, since there is insufficient information on the long-term benefits of chemoprevention.

42. Folate Epidemiologic studies have found a lower incidence of colorectal cancer among those with the highest dietary folate intake,57,58 whereas those with diets low in folate appear to have an increased risk of colorectal adenomas and carcinomas. Although large amounts of folate in the diet appear to be protective against the development of colorectal adenomas (relative risk, 0.8), the degree of benefit is greater among those who take folate supplements (relative risk, 0.66 ) The protective effect of folate supplementation appears to be greatest for those who are genetically predisposed to colorectal cancer .

43. Calcium Diets rich in red meat and animal fat are associated with an increased risk of colorectal adenomas and cancer. T hese diets increase the production of secondary bile acids , which may cause hyperproliferation of the colorectal epithelium and which promote tumor formation in studies in animals. Calcium may inhibit colon carcinogenesis by binding bile acids and fatty acids in the bowel lumen or by directly inhibiting the proliferation of colonic epithelial cells. There is inverse association between high-calcium diets or calcium supplementation and the risk of colon cancer or colorectal adenoma. The chief drawback of all these studies is imprecise assessment of calcium intake and the potential confounding effects of other dietary constituents.

44. Hormonal Replacement Therapy Estrogens may prevent colorectal cancer by decreasing the production of secondary bile acids , by decreasing the production of insulin-like growth factor I, by exerting direct effects on the colorectal epithelium. The Cancer Prevention Study II found a significant decrease in mortality from colon cancer with the use of hormone replacement therapy (relative risk, 0.71). The effect was stronger in women currently receiving therapy (relative risk, 0.55) and in those who had received continuous therapy for more than 11 years (relative risk, 0.54).

45. Summary A spirin and other NSAIDs, supplemental folate and calcium, and postmenopausal hormone-replacement therapy (estrogen) have a chemopreventive benefit. Since the value of such prophylactic strategies has not yet been confirmed in double-blind, placebo-controlled, randomized studies, chemoprevention cannot yet be accepted as standard practice . Chemoprevention should not replace periodic fecal occult-blood tests and endoscopic screening, as well as modification in known risk factors for colorectal cancer, such as reduction in the intake of red meat, appropriate exercise, smoking cessation, and weight control. Any protective benefit must also be balanced against the potential side effects of the long-term ingestion of any chemopreventive agent, including the gastric irritation and platelet dysfunction associated with aspirin and other NSAIDs, which are thought to be due to the inhibition of COX-1.

46. Thank you