Colorectal cancer prevention: is an ounce of prevention worth a pound of cure?

Colorectal cancer (CRC) is among the most common human malignancies and remains a leading cause of cancer-related morbidity and mortality. Colorectal carcinogenesis is a multistep process characterized by molecular and cellular alterations that result in an identifiable precursor lesion, ie, the adenomatous polyp. The transition from normal mucosa to adenoma and its subsequent progression to carcinoma are protracted events that offer opportunities for preventive interventions. Suppression or reversal of the carcinogenic process in the colorectum with nonpharmacologic or pharmacologic agents, ie, chemoprevention, is an area of considerable research interest and activity. Interest in this field derives from multiple epidemiologic studies showing that regular and continued use of nonsteroidal anti-inflammatory drugs (NSAIDs), predominantly aspirin, is associated with significant reductions in both colorectal adenoma and carcinoma incidence. NSAIDs were first shown to be effective in patients with familial adenomatous polyposis (FAP). Subsequent randomized trials in FAP demonstrated that sulindac and the selective cyclooxygenase-2 (COX-2) inhibitor, celecoxib, can significantly regress existing adenomas, and resulted in Food and Drug Administration (FDA) approval of celecoxib for adjunctive management of these patients. Based on the aforementioned data, aspirin and coxibs have been or are currently being evaluated for the prevention of sporadic adenoma recurrence in high-risk patient populations. Evidence indicates that aspirin can reduce adenoma recurrence rates in patients with prior colorectal neoplasia; however, questions remain, including the optimal dosage, timing of initiation and duration of treatment, and clinical benefit versus potential harm to patients. These same issues apply to the nonpharmacologic agents such as calcium, folic acid, and selenium given as dietary supplements. Apart from aspirin, calcium carbonate is the only other agent that has been shown to modestly reduce sporadic adenoma recurrence rates in a randomized trial. Folate and selenium are being actively studied based on provocative preclinical data. In addition to demonstrating efficacy, chemopreventive agents must also be safe for long-term use, be well accepted by patients, and be cost-effective. In this review, the current status of CRC chemoprevention will be discussed, including the available evidence for selected pharmacologic and nonpharmacologic agents, particularly among high-risk populations.     

Chemoprevention of colorectal cancer: Past,present, and future

Chemoprevention began to be considered as a potential strategy for lowering the incidence of cancer and cancer‐related deaths in the 1970s. For clinical chemoprevention trials against cancer, including colorectal cancer (CRC), well‐established biomarkers are necessary for use as reliable endpoints. Difficulty in establishing validated biomarkers has delayed the start of CRC chemoprevention development. Chemoprevention trials for CRC have only recently been initiated thanks to the identification of reliable biomarkers, such as colorectal adenomas and aberrant crypt foci. Some promising agents have been developed for the prevention of CRC. The chemopreventive effect of selective cyclooxygenase 2 inhibitors has been shown, although these inhibitors are associated with cardiovascular toxicity as a crucial adverse effect. Aspirin, which is a unique agent among non‐steroidal anti‐inflammatory drugs (NSAIDs) showing minimal gastrointestinal toxicity and no cardiovascular risk, has prevented adenoma recurrence in some randomized controlled trials. More recently, metformin, which is a first‐line oral medicine for type 2 diabetes, has been shown to be safe and to prevent adenoma recurrence. A recommendation of the United States Preventive Services Task Force published in 2016 provides a Grade B recommendation for the use of aspirin for chronic prophylaxis against diseases, including CRC, in certain select populations. However, the roles of other agents have yet to be determined, and investigations to identify novel “post‐aspirin” agents are also needed. The combined use of multiple drugs, such as aspirin and metformin, is another option that may lead not only to stronger CRC prevention, but also to improvement of other obesity‐related diseases.     

Chemoprevention of colorectal cancer: two steps forward, one step back?

Colorectal cancer (CRC) is a leading cause of cancer-related morbidity and mortality in the Western world. The poor survival rate has prompted the emphasis on prevention of this disease. Removal of adenomas at colonoscopy is highly effective and is the cornerstone of screening/surveillance strategies. However, screening efforts have had limited impact owing to low compliance with guidelines. Chemoprevention aims to prevent the development or recurrence of precancerous lesions and cancers with the use of compounds that block the carcinogenic process. A major advantage was the establishment and understanding of the multistage process of CRC carcinogenesis. Progress has been remarkable because of the availability of reliable animal models and clinical studies using colonic adenomas as a reliable and economic target for testing chemopreventive agents. Nonsteroidal anti-inflammatory drugs have drawn the most attention. Sulindac and celecoxib were shown to be effective in promoting polyp regression in high-risk individuals with familial adenomatous polyposis. In the more common sporadic setting, the Adenomatous Polyp PRevention On Vioxx (rofecoxib), Adenoma Prevention with Celecoxib and Prevention of Sporadic Adenomatous Polyps (celecoxib) trials have demonstrated a significant reduction in adenoma recurrence, but important concerns were raised regarding cardiovascular toxicity associated with selective cyclo-oxygenase-2 inhibitors. These landmark studies are very important, as they are a proof-of-concept that we can prevent CRC. More clinical studies are required to better select high-risk patients with safer regimens. Potential advantage versus risk for a given chemopreventive agent will have to be assessed on an individual basis. Currently, the only approved agent for chemoprevention is celecoxib in high-risk individuals with familial adenomatous polyposis.     

Colorectal cancer prevention.

Colorectal cancer is the second leading cause of mortality in the United States. In the United States, the cumulative lifetime risk of developing colorectal cancer for both men and women is 6%. Despite advances in the management of this disease, the 5-year survival rate in the United States in only 62%. Because only 38% of patients are diagnosed when the cancers are localized to the bowel wall, it is likely that widespread implementation of screening could significantly improve the outcome. Colorectal cancer screening is cost effective, irrespective of the methods used. In addition to currently available methods (fecal occult blood, flexible sigmoidoscopy, colonoscopy, and double contrast barium enema), computed tomographic colonography (virtual colonoscopy) and stool-based molecular screening are under development. Four classes of chemopreventive compounds have demonstrated efficacy in reducing recurrent colorectal adenomas and/or cancer in randomized, controlled trials. They are selenium, calcium carbonate, hormone replacement therapy, and nonsteroidal anti-inflammatory drugs. The mechanisms of action of nonsteroidal anti-inflammatory drugs include inhibition of the cyclooxygenase system as well as cyclooxygenase-independent effects. Considerable effort is being expended to define chemopreventive activity, optimal dose, administration schedule, and toxicity for the coxibs in adenoma recurrence prevention trials. The threshold for tolerating toxicities is very low in asymptomatic individuals at minimally increased risk for colorectal neoplasia.     

Cyclooxygenase-2 (COX-2) in Carcinogenesis and Selective COX-2 Inhibitors for Chemoprevention in Gastrointestinal Cancers

Introduction

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been reported to have a property to inhibit tumor development in some cancers while it shows various side effects such as gastrointestinal bleeding and renal disorder. Selective cyclooxygenase (COX)-2 inhibitors (coxibs) were originally developed as one of anti-inflammatory drugs to avoid side effect of NSAIDs. Fortunately, the coxibs was also proved to have an inhibiting effect on tumorigenesis by many experimental studies using cell lines and animal models like NSAIDs.

Discussion

Since a randomized study for polyp chemoprevention by celecoxib in familial adenomatous polyposis (FAP) patients demonstrated a significant reduction in the number of colorectal polyps, the clinical use of celecoxib was approved for FAP patients. Three large trials using celecoxib (the Adenoma Prevention with Celebrex and the Prevention of Spontaneous Adenomatopus Polyps) or refecoxib (the Adenomatous Polyp Prevention on Vioxx) for the recurrence of colorectal polyps in patients with a history of colorectal adenoma polypectomized confirmed chemopreventive effects on colorectal adenoma but two of three trails alerted us a hazard of cardiovascular (CV) events. Thereafter, some coxibs were withdrawn from the market because they showed to increase risk of serious CV events including heart attacks and strokes. But recent reports concluded that a merit of the reduction in gastrointestinal events by coxibs exceeded a demerit of the increase in serious CV events. In this review, a role of COX-2 in carcinogenesis of gastrointestinal tract and a future of coxibs for chemoprevention are discussed     

The influence of UGT1A6 variants and aspirin use in a randomized trial of celecoxib for prevention of colorectal adenoma

Aspirin and celecoxib prevent colorectal adenoma recurrence. Genetic variants in the UGT1A6 enzyme are associated with delayed aspirin metabolism and greater chemopreventive efficacy. We examined the effect of combining aspirin and celecoxib in relation to UGT1A6 T181A and R184S variants among 1,647 patients in the Adenoma Prevention with Celecoxib (APC) trial who were stratified according to the use of low-dose aspirin after removal of adenomas and randomized to placebo, 200-mg twice daily, or 400-mg twice daily celecoxib for 3 years. Patients underwent follow-up colonoscopies at 1 and 3 years to assess on-treatment efficacy. At 5 years, 538 patients underwent a colonoscopy to assess risk of recurrence after treatment was discontinued for at least 1 year. During treatment, the relative risk (RR) of recurrent adenoma was 0.68 [95% confidence interval (CI), 0.59-0.79] for 200-mg twice daily celecoxib and 0.54 (95% CI, 0.46-0.64) for 400-mg twice daily celecoxib compared with placebo. Aspirin use was not independently associated with recurrent adenoma (RR, 0.98, 95% CI, 0.86-1.15). These results did not vary according to UGT1A6 genotype. However, among those with a variant UGT1A6 genotype on aspirin, the RR of adenoma was 1.60 (95% CI, 0.81-3.15) after withdrawal of 200-mg twice daily and 1.98 (95% CI, 1.06-3.70) after withdrawal of 400-mg twice daily celecoxib compared with withdrawal of placebo. In contrast, there was no increased risk associated with discontinuing celecoxib among any other groups. Concurrent use of low-dose aspirin does not influence the efficacy of celecoxib in adenoma prevention. However, discontinuing celecoxib among aspirin-using individuals who initially developed adenoma despite a UGT1A6 variant genotype resulted in rapid reemergence of disease.     

The retinoid X receptor-selective retinoid,LGD1069, prevents the development of estrogen receptor-negative mammary tumors in transgenic mice

Despite the effectiveness of the selective estrogen receptor (ER) modulators in preventing ER-positive breast cancer, chemopreventive agents still need to be developed for the prevention of ER-negative breast cancers. The naturally occurring retinoids are promising agents for the prevention of human cancers but are too toxic for long-term chronic use. We previously demonstrated that the chemopreventive effects of the retinoids could be separated from the toxicity by using an RXR-selective retinoid, LGD1069. The studies described here demonstrate that LGD1069 effectively suppresses ER-negative tumor development in mouse mammary tumor virus-erbB2 transgenic mice with minimal toxicity. These studies suggest that receptor-selective retinoids are promising agents for the prevention of breast cancer and that they may be particularly useful in preventing ER-negative breast cancer.     

Inhibitors of cyclo-oxygenase 2: a new class of anticancer agents?

Experimental studies have shown that cyclo-oxygenase 2 (COX2) is involved in tumour development and progression. Selective inhibitors of COX2 (coxibs) block tumour growth through many mechanisms, especially by antiangiogenic and proapoptotic effects. In experimental models, coxibs potentiate the activity of cytotoxic agents, hormones, and radiotherapy. Large clinical studies have shown chemopreventive activity of coxibs in colorectal cancer. The findings of preclinical studies coupled with the overexpression of COX2 observed in advanced human tumours are the basis for new therapeutic anticancer strategies based on combinations of coxibs with other anticancer treatment modalities. Early clinical studies have documented the feasibility, good tolerability, and promising activity of coxibs combined with chemotherapy in patients with advanced colorectal and non-small-cell lung cancers. Here, we describe the recent findings on the antitumour effects of coxibs with particular focus on the opportunities that have emerged for treatment of cancer.     

Combination chemoprevention: future direction of colorectal cancer prevention

Recent research has drawn attention to protective effects of chemopreventive agents that reverse, suppress, or prevent the carcinogenic progression using pharmacological or nutritional agents. Aspirin and celecoxib are the promising preventive agents to effectively reduce the risk of colorectal cancer, but such agents are associated with severe gastrointestinal and cardiovascular side effects in long-term administration at high doses. Recently, the strategy that combinational use with several chemopreventive agents at low doses induces greater inhibition of carcinogenesis has become the focus. The nonsteroidal anti-inflammatory drugs (NSAIDs) may combine with ornithine decarboxylase inhibitors, hydroxymethylglutaryl-CoA reductase inhibitors, epidermal growth factor signaling inhibitors, peroxisome proliferator-activated receptor-γ ligands, and tumor necrosis factor-related apoptosis-inducing ligand, to magnify the chemoprophylactic effect. It is noteworthy that the phase III trial of difluoromethylornithine combination with sulidac has shown greater and effective preventive roles, which pave the way for the use of combinations of other agents. The long-term statins and low-dose NSAIDs have also been associated with risk reduction in vitro, in vivo, and in retrospective studies; however, the data are inconsistent. Epidermal growth factor signaling inhibitors, peroxisome proliferator-activated receptor-γ ligands and tumor necrosis factor-related apoptosis-inducing ligand have been demonstrated to potentiate the preventive effects of NSAIDs in vitro and in vivo, but these combinational regimens have not yet been applied to clinical research. The major goal of this study was to review combination chemoprevention for colorectal cancer by means of combining low doses of potential preventive agents to increase their chemoprophylaxis efficacy and to minimize toxicity.     

Non-steroidal anti-inflammatory drugs for cancer prevention: promise, perils and pharmacogenetics

Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) show indisputable promise as chemopreventive agents. Possible targets include cancers of the colon, stomach, breast and lung. However, recent studies raise concern about potential cardiovascular toxicity associated with the use of NSAIDs that specifically target the enzyme cyclooxygenase 2. These findings, and others that show that inherited genetic characteristics might determine preventive success, argue for new strategies that are tailored to individual medical history and genetic make-up.     

The Fourth DeWitt S. Goodman lecture. Novel approaches to the prevention of colon cancer by nutritional manipulation and chemoprevention.

Large bowel cancer is one of the most common human malignancies in Western countries including North America. This report details the preventive strategies aimed at reducing the incidence and mortality of large bowel cancer by nutritional manipulation and chemopreventive agents. During recent decades, multidisciplinary research in epidemiology and laboratory animal model studies have contributed much to our understanding of the etiology of this cancer; more importantly, it has enabled us to approach cancer prevention. An impressive body of data thus far accumulated has provided important concepts about dietary factors such as fat and fiber as key modulators of large bowel cancer. Compelling experimental evidence indicates that certain dietary lipids and fibers influence tumorigenesis in the colon. Data obtained in metabolic epidemiological and laboratory animal model studies are sufficiently convincing in showing the enhancement of colon cancer by certain types of fat and protection against it by certain dietary fibers. Our approach to the primary prevention of large bowel cancer is to translate the findings from clinical epidemiological and laboratory studies into sound advice for patients and for the public at large to reduce fat intake and increase fiber intake, specifically cereals and grains. Preclinical efficacy studies have provided scientifically sound evidence as to how several phytochemicals and their synthetic analogues act to retard, block, or reverse carcinogenesis. Equally exciting are opportunities for effective chemoprevention with nonsteroidal anti-inflammatory agents, both synthetic and naturally occurring, or selective cyclooxygenase-2 inhibitors. Our exploration of the multistep process of carcinogenesis has provided substantial insights into the mechanisms by which chemopreventive agents modulate these events. Growing knowledge in this area has brought about an innovative combination of agents with different modes of action as a means of increasing efficacy and minimizing toxicity. There is growing optimism for the view that realization of preventive concepts in large bowel cancer will also serve as a model for preventing malignancies such as cancer of the prostate and breast.     

Nutritional intervention studies in cancer prevention

Nutritional intervention trials are important tools in the search for efficient cancer prevention strategies. They can be divided into two types of trials; chemoprevention in which intervention is a defined chemical agent or a micronutrient, and diet trials in which intervention is a change in dietary habits. The most commonly used chemopreventive agents are retinoids, beta-carotene, and vitamins. The chemopreventive trials are directed to general cancer prevention or focus on target organs. The diet intervention studies include subjects at increased risk for cancer, cancer patients and community-based intervention programs. Although several completed chemopreventive studies indicate that certain micronutrients can prevent neoplastic growth, the follow-up period is still too short for most nutritional intervention studies to determine whether their preventive strategies are effective.     

Coxibs and other nonsteroidal anti-inflammatory drugs in animal models of cancer chemoprevention

Coxibs, including celecoxib, and other nonsteroidal anti-inflammatory drugs (NSAID), including aspirin, are among the most promising cancer chemopreventive agents in development today. This article examines the data on the efficacy of these agents in animal model studies of cancer prevention carried out by the authors. The studies evaluated here are restricted to our rodent models of colon/intestinal, bladder, and nonmelanoma skin cancer, in which celecoxib and other NSAIDs were administered as either cancer preventive or therapeutic agents. These studies may shed light on several questions. Is celecoxib unique compared with other NSAIDs, and if so, what implications would this have for human use? Are standard NSAIDs (which inhibit both COX-1 and COX-2) as effective as celecoxib in animal studies? Is the efficacy of celecoxib in particular or NSAIDs in general due to their off-target effects or to their effects on COX-1 and COX-2? What is the likely efficacy of low-dose aspirin? Some questions raised by human trials and epidemiology are discussed and related to our observations in animal model studies. We also discuss the problem of cardiovascular (CV) events associated with coxibs and certain other NSAIDs and whether results in animal models are predictive of efficacy in humans. On the basis of epidemiologic studies and its CV profile, aspirin seems to be the most promising NSAID for preventing human colorectal, bladder, and skin cancer, although the animal data for aspirin are less clear. A comprehensive understanding of the results of coxibs and other NSAIDs in animal studies may help inform and shape human trials of these commonly employed, relatively inexpensive, and highly effective compounds.     

Chemoprevention of colorectal cancer

Colorectal cancer is a disease with a high mortality rate and it has been increasing in prevalence worldwide. Chemoprevention, as well as primary and secondary prevention, for colorectal cancer have attracted much attention. Many chemopreventive trials have been performed, and several agents, including nonsteroidal antiinflammatory drugs, such as aspirin and sulindac, cyclooxygenase-2 selective inhibitors, such as celecoxib, vitamin D, folate, and calcium, have been shown to have some effect. In these chemopreventive trials, the targeted lesions used for evaluation were mainly polyps. However, the chemopreventive effects of some agents on polyps may require several years to evaluate. Further, larger polyps may not be susceptible to chemopreventive agents. Aberrant crypt foci (ACF) are tiny lesions at the earliest stage of colorectal carcinogenesis, which consist of large, thick crypts identified by dense, methylene blue staining. We succeeded in identifying human ACF in situ using magnifying endoscopy and found that the number of ACF, particularly dysplastic ACF, increased significantly from normal subjects to adenoma patients and then to cancer patients. We also found that the number, size, and dysplastic features of ACF are significantly correlated with the number of adenomas in adenoma patients. Thus, it was surmised that ACF are precursor lesions of the adenoma-carcinoma sequence in humans and that ACF may be the most appropriate lesions as targets for chemoprevention. We have shown that the number of ACF was significantly reduced in patients treated with sulindac. We are currently proceeding with a randomized, double-blind, chemopreventive trial targeting ACF.     

Reducing the risk of colorectal cancer by intervening in the process of carcinogenesis: a status report

Risk factors for colorectal cancer have been identified, and significant advances have been made in understanding the process of colorectal carcinogenesis. The transition from normal colonic mucosa to adenomatous polyp to adenocarcinoma is a gradual process involving genetic and epigenetic instability that can take decades, offering numerous opportunities for early detection (e.g., colonoscopy screenings), lifestyle changes (e.g., reduced red meat intake, increased physical activity, and reduced alcohol/ tobacco exposure), and chemopreventive interventions. Aspirin and various other nonsteroidal anti-inflammatory drugs may have chemopreventive benefits for colorectal cancer and other human epithelial carcinomas, butthe long-term use of nonsteroidal anti-inflammatory drugs is associated with serious gastrointestinal side effects. Recently, overexpression of cyclooxygenase-2 has been documented in colorectal tumors and numerous other pre-cancers and cancers. The development of selective cyclooxygenase-2 inhibitors, such as celecoxib, provides an opportunity for preventive intervention in the carcinogenic process. Celecoxib has been approved for the management of familial adenomatous polyposis and is under investigation for the management of sporadic colorectal polyps and for its potential as a chemopreventive agent for other cancers.     

Chemoprevention of superficial bladder cancer

The American Cancer Society estimates that 57,400 new cases of bladder cancer will be diagnosed in the USA in 2003 and that approximately 70% of these cases will be superficial bladder tumors. Due to the high risk of recurrence, patients with superficial bladder cancer represent an ideal group for chemoprevention. Intravesical chemotherapy or immunotherapy is often administered in an attempt to prevent tumor recurrence in high-risk patients, although it is not without toxicity. A large body of evidence links diet and nutrition with bladder cancer. This review summarizes the efficacy of natural and synthetic agents that have purported chemopreventive activity.     

Chemoprevention of superficial bladder cancer

The American Cancer Society estimates that 57,400 new cases of bladder cancer will be diagnosed in the USA in 2003 and that approximately 70% of these cases will be superficial bladder tumors. Due to the high risk of recurrence, patients with superficial bladder cancer represent an ideal group for chemoprevention. Intravesical chemotherapy or immunotherapy is often administered in an attempt to prevent tumor recurrence in high-risk patients, although it is not without toxicity. A large body of evidence links diet and nutrition with bladder cancer. This review summarizes the efficacy of natural and synthetic agents that have purported chemopreventive activity.     

Chemoprevention of prostate cancer

Chemoprevention is prevention of cancer by administering natural or synthetic chemicals. Anti-androgens are among the promising chemopreventive agents for prostate cancer because prostate epithelium is androgen dependent. A National Cancer Institute supported large, randomized, clinical prostate cancer chemoprevention trial has been conducted to test the efficacy of finasteride, an inhibitor of 5--reductase, which converts testosterone to 5-hydroxy-testosterone. Now the focus is on micronutrients and phytochemicals, which have potential preventive effects against prostate cancer. Lycopene, soy isoflavones, vitamin E and selenium are among the most promising nutritional chemopreventive agents. Another NCI supported large clinical chemoprevention trial was recently started to investigate the efficacy of selenium and vitamin E, alone or in combination in the prevention of prostate cancer. Inclusion of appropriate biomarkers in clinical trials will help elucidate the mechanisms by which genetic and epigenetic pathways of carcinogenesis are modulated by nutrients and phytochemicals.