Colorectal cancer (CRC) is the second most common cause of cancer-related death in the United States. CRC, however, is potentially preventable, and several strategies may be employed to decrease the incidence of and mortality from CRC. Understanding of individual risk and adherence to screening and surveillance recommendations undoubtedly will reduce CRC-associated deaths. Several natural and synthetic chemopreventive agents may prove effective for both primary and secondary CRC chemoprevention. Finally, dietary modifications (ie, increased dietary fiber, fruits and vegetables, and decreased red meat) and other lifestyle changes (ie, increased physical activity, weight maintenance, avoidance of smoking, and moderation of alcohol intake) also may lower the risk of developing CRC.
Worldwide, colorectal cancer (CRC) represents a major disease burden. CRC is the fourth most frequently diagnosed malignancy in men and third most common in women, with almost 1 million people developing colorectal cancer annually. Worldwide, CRC is the third most common cause of cancer death, responsible for 639,000 deaths annually. In the United States, CRC is the third most common cancer in men and women and the second most common cause of cancer-related death overall, accounting for 11% of cancers diagnosed. An estimated 147,000 cases were diagnosed in the United States in 2009, and approximately 50,000 people died from the disease.
Currently, the overall probability of an individual developing CRC in the United States over a lifetime is 5.5% in men and 5.1% in women. Because CRC is a survivable cancer, with 5-year survival rates adjusted for life expectancy of 64%, the prevalence of people living with a diagnosis of CRC in the population is substantial. In total, over 1 million Americans alive in 2006 have had a diagnosis of CRC.
CRC prevention
Several prevention strategies may be employed to reduce the risk of developing CRC. Primary cancer prevention targets individuals at average risk for CRC. Population-based CRC screening protocols are one example; others include chemoprevention, dietary modification, and other nondietary lifestyle changes. Secondary cancer prevention targets patients at increased risk for CRC, such as patients with a family history of CRC, a personal history of adenomatous polyps, or a known or suspected genetic predisposition to CRC. High-risk surveillance strategies, mostly involving colonoscopy, are one example. Chemoprevention, as well as dietary and lifestyle modification, also may play a role in high-risk patients, including those with a personal history of colorectal adenomas. This article focuses on primary and secondary CRC prevention: risk-reduction strategies for patients with average or increased risk of CRC, exclusive of hereditary colorectal cancer syndromes (discussed later in this issue).
Screening of average-risk individuals
There is considerable evidence that screening of asymptomatic individuals at average risk for CRC can detect cancers at a curable, early stage, resulting in decreased mortality. Although the percentage of average-risk Americans over 50 who have undergone recent screening for CRC has increased since 2005, data suggest that just over 53% of age-eligible Americans have availed themselves to available screening modalities based on a 2008 survey. Although there has been a recent push to establish colonoscopy as the preferred modality for CRC screening, barriers to colonoscopy related to insurance coverage, institutional policies, and resource availability may necessitate the need for other screening modalities. Colonoscopy has never been proven in a randomized trial to reduce mortality from CRC. However, a recent population-based, case–control study demonstrated that complete colonoscopy was associated with decreased mortality from left-sided CRC (adjusted odds ratio [OR] 0.33; 95% confidence interval [CI], 0.28–0.39), but not for right-sided cancers. This may be explained, in part, by variations in quality of colonoscopy (eg, inadequate cecal intubation rate). Patients who died from CRC were much less likely to have undergone complete colonoscopy (OR 0.63; 95% CI, 0.57–0.69, P <.001). Furthermore, colonoscopy can detect benign precursor lesions whose removal results in up to 50% decreased incidence of CRC. Two recent studies provide strong evidence that an interval between normal screening examinations of greater than 5 years is associated with a very low incidence of interval development of CRC or advanced adenomas. The US Preventative Services Task Force (USPSTF) recommends that colonoscopy not be routinely recommended to patients over age 75, and never for patients over age 85. In patients between 75 and 85 who have never been screened, colonoscopy may be appropriate.
Current screening controversies include the role of fecal DNA testing, virtual computed tomography (CT) colonography, and the relevance of sessile serrated polyps (SSPs). Although a detailed discussion of screening and surveillance for CRC is beyond the scope of this article, recent screening recommendations from the USPSTF, the National Comprehensive Cancer Network (NCCN), and joint guidelines from the American Cancer Society, US Multi-Society Task Force on Colorectal Cancer, and American College of Radiology (ACS-MSTF-ACR) are summarized in Table 1 .
| Screening Modality | Organization | Interval | ||
|---|---|---|---|---|
| USPSTF | NCCN | ACS-MSTF-ACR | ||
| Guaiac-based FOBT | Recommended | Recommended | Recommended b | 1 y |
| Fecal IHC test | Recommended b | Recommended | Recommended b | 1 y |
| Flexible sigmoidoscopy | Recommended with FOBT every 3 yrs | Recommended ± FOBT | Recommended (scope inserted 40 cm or to splenic flexure) | 5 y |
| Double contrast barium enema | Not recommended | Recommended if other tests not available | Recommended if other tests not available | 5 y |
| Colonoscopy | Recommended | Recommended | Recommended | 10 y |
| Stool DNA test | Not recommended c | Not recommended c | Recommended b | Interval not defined |
| Virtual CT colonography | Not recommended c | Not recommended c | Recommended | 5 y |
a Average-risk patients (age ≥50, no history of adenoma or colorectal cancer, no history of inflammatory bowel disease, negative family history).
b If sensitivity greater than 50%.
Screening of average-risk individuals
There is considerable evidence that screening of asymptomatic individuals at average risk for CRC can detect cancers at a curable, early stage, resulting in decreased mortality. Although the percentage of average-risk Americans over 50 who have undergone recent screening for CRC has increased since 2005, data suggest that just over 53% of age-eligible Americans have availed themselves to available screening modalities based on a 2008 survey. Although there has been a recent push to establish colonoscopy as the preferred modality for CRC screening, barriers to colonoscopy related to insurance coverage, institutional policies, and resource availability may necessitate the need for other screening modalities. Colonoscopy has never been proven in a randomized trial to reduce mortality from CRC. However, a recent population-based, case–control study demonstrated that complete colonoscopy was associated with decreased mortality from left-sided CRC (adjusted odds ratio [OR] 0.33; 95% confidence interval [CI], 0.28–0.39), but not for right-sided cancers. This may be explained, in part, by variations in quality of colonoscopy (eg, inadequate cecal intubation rate). Patients who died from CRC were much less likely to have undergone complete colonoscopy (OR 0.63; 95% CI, 0.57–0.69, P <.001). Furthermore, colonoscopy can detect benign precursor lesions whose removal results in up to 50% decreased incidence of CRC. Two recent studies provide strong evidence that an interval between normal screening examinations of greater than 5 years is associated with a very low incidence of interval development of CRC or advanced adenomas. The US Preventative Services Task Force (USPSTF) recommends that colonoscopy not be routinely recommended to patients over age 75, and never for patients over age 85. In patients between 75 and 85 who have never been screened, colonoscopy may be appropriate.
Current screening controversies include the role of fecal DNA testing, virtual computed tomography (CT) colonography, and the relevance of sessile serrated polyps (SSPs). Although a detailed discussion of screening and surveillance for CRC is beyond the scope of this article, recent screening recommendations from the USPSTF, the National Comprehensive Cancer Network (NCCN), and joint guidelines from the American Cancer Society, US Multi-Society Task Force on Colorectal Cancer, and American College of Radiology (ACS-MSTF-ACR) are summarized in Table 1 .
| Screening Modality | Organization | Interval | ||
|---|---|---|---|---|
| USPSTF | NCCN | ACS-MSTF-ACR | ||
| Guaiac-based FOBT | Recommended | Recommended | Recommended b | 1 y |
| Fecal IHC test | Recommended b | Recommended | Recommended b | 1 y |
| Flexible sigmoidoscopy | Recommended with FOBT every 3 yrs | Recommended ± FOBT | Recommended (scope inserted 40 cm or to splenic flexure) | 5 y |
| Double contrast barium enema | Not recommended | Recommended if other tests not available | Recommended if other tests not available | 5 y |
| Colonoscopy | Recommended | Recommended | Recommended | 10 y |
| Stool DNA test | Not recommended c | Not recommended c | Recommended b | Interval not defined |
| Virtual CT colonography | Not recommended c | Not recommended c | Recommended | 5 y |
a Average-risk patients (age ≥50, no history of adenoma or colorectal cancer, no history of inflammatory bowel disease, negative family history).
b If sensitivity greater than 50%.
Assessment of increased risk for developing CRC
The initial step to formulating a cancer prevention strategy for the individual patient is an assessment of individual risk of CRC ( Box 1 ). Age is one of the most important risk factors for CRC. Ninety percent of cases are diagnosed over the age of 50. In fact, as many as 30% to 50% of individuals older than 50 harbor one or more adenomatous polyps. The risk of CRC continues to increase with age; the incidence per 100,000 people age 80 to 84 years is over seven times the incidence in people age 50 to 54. However, CRC can occur at any age; the incidence of CRC in patients younger than age 50 may be increasing. When patients younger than 50 present with CRC, consideration must be given to the presence of a hereditary CRC syndrome (see discussion of early age-of-onset CRC elsewhere in this issue).
Average risk
Age greater than or equal to 50 years
No personal history of CRC or adenomas
Negative family history
No history of inflammatory bowel disease
Increased risk
Positive family history
Personal history of CRC
Personal history of adenoma or sessile serrated polyp (SSP)
Personal history of chronic ulcerative colitis or Crohn’s disease
High risk
Hereditary nonpolyposis colorectal cancer (HNPCC)/Lynch syndrome
Familial adenomatous polyposis (FAP)
Attenuated familial adenomatous polyposis (AFAP)
MYH -associated polyposis (MAP)
Other polyposis syndromes (eg, Peutz-Jeghers, juvenile polyposis, hyperplastic polyposis syndrome)
Individuals with a family history of CRC are at increased risk for development of CRC. In a recent meta-analysis involving 59 studies, the relative risk of developing CRC with one affected first-degree relative was 2.24 (95% CI, 2.06–2.43). The relative risk increased to 3.97 if two or more first-degree relatives were affected. This corresponds to a pooled lifetime risk for a 50-year-old of 1.8% with no family history, 3.4% with one affected first-degree relative, and 6.9% with two or more first-degree relatives. The clustering of CRC in some families may be attributed to an inherited predisposition, common environmental exposures, or a combination of both. The influence of a more distant family history, such as second-degree relatives with CRC, on individual risk has not been firmly established.
Some of the increased risk attributed to family history is secondary to inheritance of known CRC susceptibility genes, such as mutations in tumor suppressor genes (for example, the adenomatous polyposis coli gene [ APC ]), as well as the mismatch repair genes such as MLH1, MSH2 , and MSH6 . The familial syndromes resulting from these autosomal dominantly inherited mutations, FAP and HNPCC, will be discussed in detail elsewhere in this issue.
Despite the importance of family history on risk of CRC, up to 25% of individuals with an affected first-degree relative do not report having a positive family history. Those who do report a positive family history may not be aware of the associated increased risk. These errors may be compounded by physicians who do not take family history into account when determining appropriate intervals for surveillance, despite the family history information being present in the medical records. Failure to report a positive family history, recognize the significance of it, and incorporate family history into follow-up strategies greatly undermine the efficacy of screening and surveillance in preventing CRC.
Other conditions that may result in an increased risk of CRC development are chronic ulcerative colitis and Crohn’s disease, as well as a personal history of colorectal adenomas and CRC (see Box 1 ). Surveillance recommendations based on family history of CRC and personal history of adenomas or CRC are summarized in Table 2 .
| Family History | Organization | |
|---|---|---|
| ACS-MSTF-ACR | NCCN | |
| First-degree relative with CRC <60 | Colonoscopy every 5 years; begin at age 40, or 10 years before earliest diagnosis | Colonoscopy every 5 years; begin at age 40 a |
| First-degree relative with CRC ≥60 | Interval recommended for average risk; begin at age 40 | Colonoscopy every 5 years; begin at age 50 |
| Two or more first-degree relatives with CRC at any age | Colonoscopy every 5 years; begin at age 40, or 10 years before earliest diagnosis | Colonoscopy every 3–5 years; begin at age 40, or 10 years before earliest diagnosis b |
| Two or more second-degree relatives with CRC at any age | Interval recommended for average risk; begin at age 40 | Colonoscopy every 5 years; begin at age 50 b |
| One second-degree relative or any third-degree relative with CRC, or first degree relative with nonadvanced adenomas | No recommendation | Treat as average-risk |
| Finding at Colonoscopy | ||
| ≤2 adenomas or SSPs; <1 cm, tubular histology | Colonoscopy in 5–10 years | Colonoscopy in 5 years; if negative, 5–10 years |
| 3–10 polyps; ≥1 cm, villous or high grade dysplasia | Colonoscopy in 3 years; if negative or only 1–2 small tubular adenomas, 5 years | Colonoscopy in 3 years; if negative, 5 years |
| Incomplete or piecemeal polypectomy or polypectomy of large sessile polyp | Colonoscopy in 2–6 months to verify complete removal | Colonoscopy in 2–6 months based on clinical judgment |
| >10 cumulative adenomas | Colonoscopy <3years c ; consider polyposis syndrome | Individual management; consider polyposis syndrome |
| Personal history of curative intent resected CRC | Colonoscopy in 1 year; (within 3–6 months if no or incomplete preoperative colonoscopy; if negative 3 years, then 5 years) | Colonoscopy in 1 year; (within 3–6 months if no or incomplete preoperative colonoscopy; if adenoma/SSP repeat 1–3 years; if negative 2–3 years, then 3–5 years |
a If <50 years, same recommendation but repeat every 3–5 years depending on other family history; begin 10 years before earliest diagnosis.
b Individuals should be related.
Chemoprevention
Sporn first coined the term chemoprevention in 1976 to represent the use of specific natural or synthetic chemical agents to reverse, suppress, or prevent carcinogenic progression to invasive cancer. A wealth of epidemiologic, in vitro, and in vivo evidence suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) may be such agents. Other potential chemopreventive agents include folate, selenium, calcium, vitamin D, and beta carotene.
Aspirin and NSAIDS
There is considerable observational evidence that the use of aspirin or other NSAIDs is chemoprotective against CRC. The mechanism underlying the antineoplastic action of NSAIDs is incompletely understood, but it is believed to involve both cyclooxygenase (COX)-dependent and COX-independent pathways. At least 30 observational studies have been conducted to evaluate the influence of NSAID use on development of CRC. A consistent reduction in the risk of colorectal neoplasia (adenoma and invasive cancers) in NSAID users is consistently identified in these studies of various design.
A Cochrane review summarizing the results of randomized, controlled intervention trials has been published. The authors of this meta-analysis reviewed one population-based prevention trial (including 22,071 people), three secondary prevention trials in patients with sporadic polyps (including 2028 patients), and four trials in 150 patients with familial adenomatous polyposis. The authors concluded that, overall, there is some evidence for the effectiveness of intervention strategies using NSAIDs for the prevention of colorectal adenoma. However, the single primary prevention trial reviewed did not demonstrate a decreased incidence of CRC in the NSAID users. Subsequent primary prevention trials also did not demonstrate efficacy, leading to a recommendation by the US Preventive Services Task Force against aspirin/NSAID use for primary CRC prevention in average-risk individuals. However, a recent pooled analysis of two large randomized trials from the United Kingdom with over 20 years of follow-up revealed a statistically significant reduction in CRC incidence in aspirin users (relative risk [RR] = 0.63; 95% CI, 0.47–0.85, P = .002, if allocated to aspirin for 5 years or more), but only after a latency period of 10 years or longer.
NSAIDs and aspirin may play an important role in secondary chemoprevention of colorectal adenomas and cancer. Logan and colleagues reported a randomized, double-blind trial of aspirin and folate in the prevention of recurrent colorectal adenomas. Patients randomized to aspirin 300 mg/d had a significantly reduced risk of recurrent adenoma compared with the placebo group (RR = 0.79; 95% CI, 0.63–0.99). Baron and colleagues randomized 2587 to either the COX-2 inhibitor rofecoxib 25 mg/d versus placebo. Adenoma recurrence was less frequent for rofecoxib subjects than for those randomized to placebo (41% vs 55%; P <.0001; RR = 0.76; 95% CI, 0.69–0.83).
Continued use of NSAIDs may have additional benefits. Long-term follow-up of the Aspirin/Folate Polyp Prevention Study revealed that patients who used regular NSAIDs in the 4 years following the study intervention (3 years of 81 mg aspirin/d) had a persistent reduction in development of adenoma versus patients who were infrequent poststudy NSAID users (RR = 0.62; 95% CI, 0.39–0.98). In addition, regular aspirin use may result in lower cancer-specific mortality in patients with a history of CRC.
Unfortunately, serious gastrointestinal (GI) complications may occur in regular users of aspirin and NSAIDs. Hospitalizations for GI complications occur in 7 of 1000 to 13 of 1000 chronic users of NSAIDS per year. Celebrex and Vioxx, two COX-2 specific inhibitors, have been associated with significant cardiovascular adverse effects, resulting in the removal of Vioxx from the US market. Thus, their use in primary chemoprevention cannot be supported.
The answer may not lie with single agents, however, but rather with combination therapy. Combinatorial strategies in cancer therapy can provide dramatic improvements in safety and efficacy over monotherapy, particularly when agents differ in mode of action. In a rat model of CRC, the combination of curcumin (a nontoxic, naturally occurring polyphenol derived from the tumeric plant) and celecoxib resulted in a significantly reduced number of aberrant crypt foci compared with either agent alone. Importantly, the concentration of celecoxib in that study can be achieved in people with a standard anti-inflammatory dose of 100 mg twice daily (half the daily dose associated with cardiovascular complications). In a recent randomized, placebo-controlled trial patients with a history of prior adenomas who received daily sulindac at 150 mg by mouth in combination with 500 mg of difluoromethylornithine (DFMO) for 36 months had a significantly reduced incidence of recurrent adenomas (12% vs 41%, P <.001) compared with placebo. Serious adverse events did not differ between groups.
Other Chemoprevention
Antioxidants
Several antioxidants have been studied as potentially protective against CRC. These agents reduce intrinsic oxidative damage and may also inhibit carcinogenesis by stimulating the immune system directly. The most promising appear to be the carotenoids, including beta carotene and selenium. Although prior intervention trials did not demonstrate efficacy against recurrent adenoma in patients treated with beta carotene, recent data are more promising. In a prospective trial involving 864 patients randomized to receive either beta carotene or placebo, beta carotene was associated with a marked decrease in the risk of one or more recurrent adenomas among subjects who neither smoked cigarettes nor drank alcohol (RR = 0.56; 95% CI, 0.35–0.89). However, beta carotene supplementation conferred a modest increase in the risk of recurrence among those who smoked (RR = 1.36; 95% CI, 0.70–2.62) or drank (RR = 1.13; 95% CI, 0.89–1.43).
Selenium also has shown promise. In a randomized, placebo-controlled trial of 1312 patients with a history of skin cancer followed for 6.4 years, patients randomized to selenium had a statistically significant 58% reduction in CRC incidence, as well as a decreased incidence of adenomas. However, in the recently published Selenium and Vitamin E Cancer Prevention Trial (SELECT), neither selenium nor selenium plus vitamin E was associated with a decreased incidence of CRC compared with placebo. Ongoing, prospective randomized trials will further clarify the role of both beta carotene and selenium in reducing the risk of CRC.
Calcium and vitamin D
A substantial amount of evidence supports the beneficial effect of calcium on the prevention of CRC. Calcium binds and precipitates bile and fatty acids as insoluble soaps, thereby preventing these potentially mutagenic compounds from contacting epithelial cells. Calcium may also directly influence proliferation of mucosal cells via protein kinase C and K- ras . Two Phase 3 intervention trials of calcium for the prevention of recurrent adenoma demonstrated that calcium supplementation (1200 mg daily for 4 years or 2000 mg daily for 3 years) was associated with a reduction of recurrent adenoma. However, only one study achieved statistical significance. In a recent meta-analysis of the two studies, the relative risk of recurrent adenomas was 0.74 for patients randomized to receive calcium versus placebo.
The role as calcium as a primary chemopreventive agent is less clear. Several recent cohort studies have reported an inverse relationship between calcium intake and CRC incidence, with RR between 0.68 and 0.84 in men and 0.64 and 0.70 in women. However, a randomized, placebo-controlled trial of calcium plus vitamin D supplementation involving 36,282 postmenopausal women produced conflicting results. Women randomized to 1000 mg daily of elemental calcium plus 400 IU vitamin D for an average of 7 years had an RR of CRC of 1.08 (95% CI, 0.86–1.34) compared with women who received placebo.
Vitamin D as a single agent also may have a chemopreventive effect via modulation of calcium absorption and gene expression. In a case–control study nested within the Multiethnic Cohort Study, plasma 25(OH)D level was measured in 229 patients with CRC and 434 matched controls. An inverse trend was observed between Vitamin D level and risk of CRC (OR, per doubling of 25(OH)D = 0.68; 95% CI, 0.51–0.92). Two recent meta-analyses investigated the relationship between circulating 25(OH)D levels and Vitamin D intake on the incidence of colorectal adenomas and CRC. In the first, circulating 25(OH)D was inversely correlated with the incidence of adenomas (OR = 0.70; 95% CI, 0.56–0.87). A similar finding was noted for high versus low vitamin D intake (OR = 0.89; 95% CI, 0.78–1.02). In the second, in patients with an increase of 25(OH)D by 20 ng/mL, the OR for CRC incidence was 0.57 (95% CI, 0.43–0.76). However, a meta-analysis of 10 cohort studies involving 2813 cancer cases reported that increased vitamin D intake was associated with a nonsignificant 6% reduction on CRC risk (RR = 0.94; 95% CI 0.83–1.06).
Folate
Folate, a B vitamin, is critical for normal methylation of DNA. Folate deficiency may lead to CRC through disruption of DNA synthesis and repair, as well as loss of control of proto-oncogene activity. Numerous prior retrospective epidemiologic studies, as well as prospective cohort studies, have demonstrated a statistically significant difference or trend toward a significant relationship between increased folate intake and a reduced risk of CRC or adenoma.
Two recent prospective, randomized intervention trials examined the role of folate as secondary chemoprevention in patients with a history of adenomas. There was no association between folate use and the rate of recurrent adenoma in either study. Of concern, patients receiving folate in one study had a trend toward a higher incidence of advanced adenoma (11.4% vs 8.6%), and at least three adenomas (9.9% vs 4.3%). Taken together, these studies demonstrate that folate supplementation is unlikely to be of benefit as secondary prevention in patients with a history of colorectal adenomas, and may actually be detrimental.
Folate may play a dual-modulator role. There may be a protective influence of moderate dietary increases of folate initiated before the establishment of neoplastic foci. Early prevention is likely due to protection against DNA damage by maintaining adequate methyl groups for DNA methylation and nucleotide synthesis. However, a promoter effect may occur on pre-established, clinically occult neoplastic foci secondary to increased provision of nucleotide precursors to rapidly replicating neoplastic cells. Further research is required to establish the role of folate supplementation as CRC chemoprevention.
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