Colorectal cancer screening: today and tomorrow.

Abstract: Colorectal cancer remains a disease with significant morbidity and mortality. However, the prognosis can be greatly improved with early detection. Here, we review the current screening modalities and guidelines for patients at average, moderate, and high risk for colorectal cancer. New experimental modalities are also introduced.

Key Words: colorectal cancer, screening, colonoscopy

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Colorectal cancer (CRC) remains a disease with significant morbidity and mortality in the United States. Early detection can improve prognosis, but the recognition that virtually all colorectal cancers arise from a discrete and accessible precursor lesion raises the prospect that cancer can essentially be prevented with appropriate screening. Patients who present with symptoms such as hematochezia, melena, weight loss, or change in bowel habits require a prompt diagnostic workup and must be considered separately. The primary goal today is to identify the most sensitive and cost-effective screening approaches that will maximize patient compliance. We review the current screening modalities and guidelines for patients at average, moderate, and high-risk for CRC, and then introduce new, experimental approaches that lie on the horizon.

Epidemiology

It is estimated that there will be nearly 150,000 new cases of CRC in the United States in 2005. In addition, there will be over 56,000 deaths, making this the second leading cause of cancer-related death in men and women combined. The cumulative lifetime risk for the development of CRC in the general population is 6% Over the past several decades, a small but perceptible decline in the incidence and mortality for colon cancer has been observed. Although there are many potential explanations for this phenomenon, this clearly coincides with the initiation of widespread CRC screening programs. (1)

Rationale For Screening

Adenomatous polyps are benign precursors to colorectal cancer. Elegant work by Vogelstein and colleagues (2) has shown that CRC carcinogenesis occurs in a stepwise fashion, characterized by the accumulation of mutations in specific genes such as APC, K-ras, and p53. The "dwell time" between the initiation of a polyp and development of an invasive cancer has been estimated to be as long as 10 years. This provides an ideal opportunity to intervene and alter the natural history of the disease. Proof of this principle was provided by the National Polyp Study, which established that colonoscopic polypectomy can dramatically reduce the incidence of colorectal cancer. (3) Unfortunately, compliance with CRC screening guidelines is only fair. Data from the 2000 National Health Interview Study revealed that only 29% of respondents had undergone either sigmoidoscopy in the previous 5 years or colonoscopy in the previous 10 years. (4)

Risk Stratification 

As with any population-wide screening strategy, it is essential to stratify patients into risk groups for CRC. Patients at high risk include those with a hereditary colon cancer syndrome. Moderate risk individuals include those with 1) a personal history of adenomatous polyps or CRC, 2) a family history of adenomatous polyps or CRC, or 3) chronic inflammatory bowel disease. Average risk patients are those greater than 50 years old who do not have any of the risk factors listed above. The vast majority of the population (>70%) will fall into the average risk group. A description of the currently utilized modalities and recommendations for screening follows below. The guidelines are derived from consensus statements of several organizations including the American Gastroenterology Association, American Cancer Society, and US Public Health Task Force. (5-7) The ultimate choice of the specific test should be based upon individual discussions between the patient and physician.

Average Risk Patients

Fecal Occult Blood Testing

Recommendation. Annually, two samples from each of three consecutive stools should be examined without rehydration using a guaiac-impregnated slide. Patients are to avoid ASA/NSAIDS, foods high in vitamin C, and red meat for three days before the examination. Any positive test should be followed up with colonoscopy.

Rationale. Three large prospective, randomized controlled trials demonstrated that fecal occult blood testing (FOBT) decreased mortality from CRC by 15 to 33%. (8-10) A subsequent meta-analysis of multiple FOBT trials calculated an overall 23% reduction in mortality (relative risk of 0.77). (11) Although rehydration will increase the sensitivity of FOBT, a corresponding decrease in specificity would increase the false positive rate, resulting in unnecessary additional testing. In practice, a digital rectal examination often serves as the source of stool for the FOBT. A comparison of the "at-home" 6-sample FOBT to that from a single digital rectal examination revealed a sensitivity for the detection of advanced adenomas of 23.9% versus 4.9%, respectively. (12) Advanced adenomas are defined as: 1) a tubular adenoma > 10 mm in size, 2) an adenoma with villous histology or high grade dysplasia, or 3) invasive cancer. Potential explanations for these discrepant results between the 6-sample FOBT and a single digital rectal examination include the intermittent nature of hemorrhage from tumors or the uneven distribution of blood throughout stool, resulting in sampling error. As such, the digital FOBT is not routinely recommended.

Flexible Sigmoidoscopy

Recommendation. Flexible sigmoidoscopy every five years.

Rationale. Two retrospective case-control studies in the early 1990s laid the foundation for endoscopically-based CRC screening by demonstrating a 60% reduction in mortality from colorectal cancer in those who had a screening flexible sigmoidoscopy. (13,14) The recommended five year interval is based on studies that demonstrated 1) a decrease in CRC mortality up to ten years after the initial screening flexible sigmoidoscopy and 2) a 0.6% incidence of advanced adenomas or cancer five years after a negative colonoscopy. (15,16) If an adenoma is identified on screening sigmoidoscopy, a full colonoscopy should be performed because synchronous proximal lesions are detected in as many as 30% of such cases. (17,18) Such a strategy based upon flexible sigmoidoscopy would be predicted to identify 70.3% of all advanced adenomas (adenomas > 1 cm in size, villous adenomas, adenomas with high grade dysplasia, or colon cancer) in men (19) but only 35.2% in women. (20)

Flexible Sigmoidoscopy And Fecal Occult Blood Testing

Recommendation. Annual FOBT coupled with flexible sigmoidoscopy every five years. FOBT should be performed first.

Rationale. It has been hypothesized that the combination of flexible sigmoidoscopy and FOBT would increase the overall detection rate of CRC. While this approach has not been rigorously tested, the sensitivity of this combined screening strategy was estimated by analyzing patients who had undergone both a full colonoscopy and FOBT. Lesions that would have been identified by flexible sigmoidoscopy were defined as those located in the portion of the examined colon up to the descending colon. FOBT, flexible sigmoidoscopy, and the combination of the two tests had a sensitivity for advanced adenomas of 23.9%, 70.3%, and 75.8%, respectively. (19) Thus, there was only an incremental increase in sensitivity by adding FOBT to screening sigmoidoscopy, and the majority of the benefit of this combined approach was achieved with the endoscopic component.

Double Contrast Barium Enema (DCBE)

Recommendation. DCBE every five years.

Rationale. In a direct comparison between DCBE and colonoscopy, the proportion of adenomas that were detected by barium enema was 32% for polyps <0.5 cm, 53% for polyps 0.6 to 1.0 cm, and 48% for polyps > 1 cm. (21) As such, DCBE is considerably less sensitive than colonoscopy. Another unappealing feature is that patients with an abnormal study will require a subsequent colonoscopic examination for polypectomy. Nevertheless, this does represent another modality for visualization of the entire colon, particularly in those cases in which the cecum cannot be intubated or there are contraindications to colonoscopy.

Colonoscopy

Recommendation. Colonoscopy every ten years.

Rationale. To date, there are no studies that have demonstrated a benefit in mortality from screening colonoscopy. However, extrapolation from the original studies of screening flexible sigmoidoscopy is reasonable. (13,14,16) Since colonoscopy visualizes the entire colon, it is likely that it would exhibit a comparable or greater reduction in CRC mortality. It has been convincingly demonstrated that colonoscopic polypectomy results in a decreased incidence of CRC, which is again likely to translate to a decrease in mortality from CRC. (3) Some of the potential shortcomings of colonoscopy include the higher cost, procedure-associated risks, discomfort of the colonic purge, and inconvenience secondary to time away from work. Recent studies have established the performance characteristics of screening colonoscopy. Although direct comparisons between colonoscopy and flexible sigmoidoscopy were not performed, estimates of the number of proximal lesions that would have been missed with a flexible sigmoidoscopy strategy were calculated. Two of these studies determined that 46 to 52% of patients with advanced proximal adenomas had no distal adenomas and therefore would have been missed by sigmoidoscopy. (22,23) A subsequent meta-analysis estimated that 2 to 5% of all patients undergoing screening colonoscopy may have isolated advanced proximal lesions. (24) Interestingly, women are twice as likely as men to have an isolated proximal neoplasm. (19,20) The complication rate of screening colonoscopy has been estimated to be 0.3%. (25) In a study of over 3,000 individuals, no perforations or deaths were attributed to colonoscopy, and lower GI bleeding was the most common adverse event.

Moderate Risk Patients

Personal History Of Adenomatous Polyps

Recommendation. Patients with an advanced adenoma (> 1 cm, villous histology, high-grade dysplasia, or cancer) or [greater than or equal to] 3 adenomas should have a follow-up colonoscopy in three years. Patients with 1 or 2 small ([less than or equal to] 1 cm) tubular adenomas should have a follow-up colonoscopy in five years.

Rationale. The adenoma recurrence rate 3 years after removal of adenomatous polyps ranges from 35-50%. (26) However, the recurrence rate of adenomas with advanced histologic features at 3 years ranges from 4 to 11%. (26) Risk factors for recurrence of advanced adenomas at 3 years include [greater than or equal to] 3 adenomas, age at diagnosis > 60 years, and a family history of CRC. (27) Patients with only 1 or 2 small ([less than or equal to] 1 cm) adenomas without villous features are at low risk for a significant finding after three years. (28)

Personal History Of CRC

Recommendation. Patients with CRC should have a complete colonoscopy at the time of diagnosis to rule out synchronous lesions. Follow-up colonoscopy should be performed at three years and if normal, again at five years.

Rationale. After a surgical cure of CRC, patients are at increased risk for the development of metachronous CRC. (29,30) The cumulative incidence of a second case of primary colon cancer at 5 years ranges from 1.5% to 5.3%. (30,31)

Family History Of Adenomatous Polyps Or CRC

Recommendations.

1. Patients with one 1st degree relative with CRC or adenomatous polyps diagnosed at < 60 years old or two 1st degree relatives with CRC diagnosed at any age should start screening colonoscopy at 40 years old or 10 years before the earliest diagnosis in the family. This should be repeated every five years.

2. Patients with one 1st degree relative with CRC or adenomatous polyps diagnosed at > 60 years old or two 2nd degree relatives with CRC should begin screening at 40 years old. If normal, examinations should be repeated every 10 years.

Rationale. Approximately 20% of all cases of colon cancer arise in conjunction with a family history of the disease. For patients with one 1st degree relative with adenomatous polyps, the relative risk is 1.9, and for those with a 1st degree relative with CRC, the relative risk increases to 2.25. If the initial diagnosis was before 45 years old, the relative risk increases even further to 3.87. If there is more than one 1st degree relative with CRC, the relative risk jumps to 4.25. (32) In those with familial risks, the rate of progression of CRC is similar to the general population, but the age of onset of polyp formation may be as much as 10 years earlier. (33) The majority of these familial cancers are polygenic in nature. However, there are several specific hereditary colon cancer syndromes that are caused by a germline alteration in a single gene. These syndromes require more intensive surveillance and will be discussed below.

Inflammatory Bowel Disease

Recommendation. Surveillance colonoscopy is recommended every 1 to 2 years after 8 years of disease in patients with pancolitis and after 15 years in those with left-sided disease. Four-quadrant biopsies should be taken every 10 cm throughout the colon. Additional biopsies should be taken of any suspicious lesions.

Rationale. Chronic inflammatory bowel disease is associated with an increased risk of CRC. In patients with panulcerative colitis, there is an approximately 30% risk of CRC after 35 years. (34) A similar risk has been noted in patients with Crohn colitis. (35) Patients with biopsies demonstrating low- or high-grade dysplasia that have been independently verified by two expert pathologists should be advised to undergo colectomy. Differentiation between dysplasia-associated mass lesions (DALMs) and sporadic adenomas requires the combination of endoscopic appearance and histologic examination of the neighboring mucosa. It has been shown that adenoma-like DALMs can be treated with simple polypectomy followed by surveillance. (36)

High Risk Patients

Hereditary Colon Cancer Syndromes

Approximately 5% of all colorectal cancers occur in association with a hereditary colon cancer syndrome. Three of the most common and best understood are the Hereditary Nonpolyposis Colorectal Cancer (HNPCC), Familial Adenomatous Polyposis (FAP), and MYH-Associated Polyposis (MAP) syndromes.

A model for CRC carcinogenesis has been proposed in which a specific

mutation is required for each progressive stage along the adenoma-carcinoma sequence. Mutations in the Adenomatous Polyposis Coli (APC) gene are the critical initiating step in most cases of FAP and sporadic cancers. This is followed by the progressive acquisition of mutations in the Ki-ras oncogene and loss of heterozygosity (LOH) on chromosome 18q. Mutations in p53 are believed to be a late event, as advanced adenomas become invasive carcinomas. (2) HNPCC results from germline mutations in DNA mismatch repair (MMR) enzymes, including MLH1, MSH2, and MSH6. These enzymes repair mismatched nucleotide errors that occur during DNA replication. (37) A mutated enzyme is unable to correct these mismatch errors, as well as base insertions and deletions at polynucleotide repeats (microsatellites). This phenomenon of expansion and contraction of these repeats results in microsatellite instability (MSI). All tumors associated with HNPCC and 15% of sporadic cases of CRC exhibit MSI. Thus, testing a tumor for MSI is a useful screening tool when HNPCC is suspected. The remaining 85% of sporadic cases and those associated with FAP do not show this behavior and are termed microsatellite stable (MSS).

Genetic Testing 

The diagnosis of a hereditary colon cancer syndrome can be established either clinically or through genetic testing. Clinical diagnoses are based upon a constellation of disease characteristics in the index patient and/or related family members. It is fairly straightforward to recognize syndromes with dramatic phenotypes, as seen in FAP. However, a diagnosis can be problematic in syndromes that present with more subtle features or that require extensive family histories, as seen with HNPCC (see Table 1). Genetic diagnoses are based on identification of germline mutations in a proband. Genetic testing is performed by analyzing the DNA from white blood cells in the peripheral blood, and can be particularly helpful in cases where the clinical phenotype is atypical. Furthermore, the identification of a mutation in a proband then makes it possible to offer testing to asymptomatic family members for cancer risk assessment. In this manner, only those relatives who carry the same genetic alteration will require intensive cancer screening, and those who do not carry the family mutation will be spared the intensive screening. If a genetic mutation cannot be identified in the proband, all family members must be considered "at-risk." The benefits of genetic testing must be considered in the context of potential risks. As genetic testing identifies high-risk individuals before disease is clinically apparent, it raises several concerns. These include psychological stress and potential discrimination in terms of employment and health insurance. Legal protections have been established in most states. Nevertheless, genetic counseling and informed consent are essential components of genetic testing.

A list of hereditary colon cancer syndromes and their clinical and genetic features is provided in Table 2. The critical first step in the identification of a hereditary cancer syndrome is to obtain a careful family history of cancer. Some general guidelines that should trigger a referral to a specialist are listed in Table 3. Specific cancer screening guidelines for patients with FAP and HNPCC are outlined in Table 4.

New Screening Modalities

Virtual Colonoscopy 

CT colonography, also referred to as "virtual colonoscopy," is a rapidly emerging technique. Images are obtained with a thin-section, helical CT and sophisticated computer algorithms generate three-dimensional reconstructions of the colon. Although this is a noninvasive procedure performed without sedation, a standard colonic purge and bowel insufflation are still required. One of the first studies of 100 patients at high risk for colorectal cancer demonstrated that virtual colonoscopy detected all cancers, 91% of polyps > 1 cm, 82% of polyps 6 to 9 mm, and 55% of polyps < 6 mm. (38) A larger study of asymptomatic adults determined the sensitivity of virtual colonoscopy to be 93.8% for polyps > 1 cm, 93.9% for polyps > 8 mm, and 88.7% for polyps > 6 mm, suggesting that virtual colonoscopy compares favorably with optical colonoscopy for clinically relevant lesions. (39) However, an independent study of 614 patients revealed a far lower sensitivity: for lesions > 1 cm, the sensitivity of CT colonography was only 59% and for lesions 6 to 9 mm in size, the sensitivity was 51%. (40) Thus, virtual colonoscopy exhibits promise as an alternative screening tool, but its specific role remains to be determined.

Fecal DNA Analysis

Because of the invasive nature of endoscopy, poor patient compliance, and limited endoscopic resources, a highly sensitive and specific noninvasive screening method to preselect those individuals who require colonoscopy would be desirable. One possible approach is fecal DNA analysis. As described previously, colorectal carcinogenesis is dependent upon the accumulation of multiple mutations in specific oncogenes and tumor suppressor genes. (2) This screening test is based on the hypothesis that abnormal cells from polyps or cancers are sloughed off and admixed into stool. DNA can be isolated from stool and analyzed for mutations in APC, K-ras and p53. In an early study, the sensitivities for adenomas > 1 cm and cancer were 82% and 91%, respectively, with a specificity of 93%. (41) A subsequent prospective study compared fecal DNA analysis with FOBT in a cohort of over 2,500 patients undergoing screening colonoscopy. The fecal DNA panel detected only 51.6% of invasive cancers, and the sensitivity of FOBT was even lower at 12.9%. (42) While this approach did demonstrate superior sensitivity to FOBT for the detection of colon cancer, its sensitivity for the detection of advanced adenomas was low (18.2%).

Proteomics

Proteomics involves the separation and identification of peptides and proteins in complex mixtures of biologic samples. Identification of cancer-specific proteins can be utilized to develop novel diagnostic tests. For optimal clinical use, a CRC biomarker should be present in a readily accessible fluid such as blood. Past efforts have employed labor-intensive approaches to study a single marker protein that is over-expressed by tumors. However, recent advances in mass spectrometry technology now enable us to take an unbiased look at the complex mixture of proteins as a whole in the plasma compartment. (43,44) This approach is based on the general hypothesis that the pattern of proteins in the blood will reflect the underlying disease state of an organ.

Multiple groups have used proteomics-based approaches to develop screening tools for cancer. In these studies, surface enhanced laser desorption and ionization-time of flight (SELDI-TOF) mass spectrometry is used to generate proteomic spectra from patient sera. (43-45) A training set of spectra is generated from patients with cancer and healthy controls. Using iterative artificial intelligence searching algorithms, a subset of mass spectral peaks is identified that discriminates cancer patients from healthy controls. This mass spectral pattern is then used to classify a masked population of cancer-bearing and healthy controls. In an initial study, ovarian cancer patients were identified with a sensitivity and specificity of 100% and 95%, respectively. (46) In another initial study on prostate cancer patients, a mass spectral signature was discovered that correctly identified 95% of patients with cancer and 78% of patients with benign disease. (47) SELDI-TOF mass spectrometry has also been used in the study of 182 serum samples from patients with colorectal cancer. A set of seven potential biomarkers was identified that could differentiate carcinomas from adenomas with a sensitivity of 89% and a specificity of 83%, and from healthy controls with a sensitivity of 89% and a specificity of 92%. (48) Clearly, a proteomic approach holds much promise.

Conclusions

Screening can be an effective strategy to prevent colon cancer. A variety of screening modalities are available, and the choice of the specific approach should be individualized. Unfortunately, rates of compliance with established guidelines for colorectal cancer screening remain low. Effective application of these guidelines depends upon accurate risk stratification, and a careful family history is one of the most important risk factors to consider. Advances in our understanding of the molecular basis of colon cancer have led to the development of genetic tests for the diagnosis and management of hereditary colon cancer syndromes. Although colonoscopy remains the mainstay of colorectal cancer screening today, newer molecular approaches are poised to transform clinical practice in the future.

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50. Jo WS, Chung DC. Genetics of hereditary colorectal cancer. Semin Oncol 2005;32:11-23.</p> <pre> No one is useless in this world who lightens the burdens of another. --Charles Dickens </pre> <p>Kenneth E. Hung, MD, PHD and Daniel C. Chung, MD

From the Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA.

Reprint requests to Daniel C. Chung, MD, Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114. Email: [e-mail]

Dr. Chung is a consultant for Myriad Genetics. Dr. Hung has no disclosures to declare.

Accepted December 21, 2005.

RELATED ARTICLE: Key Points

* Everyone over age 50 should be screened for colon cancer.

* Patients with 1) a personal history of adenomas and/or colorectal cancer, 2) a family history of adenomas and/or colorectal cancer, or 3) chronic inflammatory bowel disease are considered to be at moderate risk and require more frequent screening.

* A careful family history is necessary to recognize hereditary colon cancer syndromes, and a genetic evaluation can establish the diagnosis.

Table 1. Amsterdam II criteria for the diagnosis of hereditary
nonpolyposis colorectal cancer (HNPCC) (49)

Three or more relatives with HNPCC-related cancers (colon, uterine,
  stomach, ovarian, small bowel, and urinary tract).
One affected relative is a 1st degree relative of the other two.
Affected relatives span two different generations.
One of the cancers must be diagnosed before age 50 years old.

Table 2. Hereditary colorectal cancer syndromes (50)

Syndrome                  Genetic Mutation  Inheritance

Familial Adenomatous      APC               Autosomal Dominant
  Polyposis (FAP)
Attenuated Familial       APC               Autosomal Dominant
  Adenomatous Polyposis
  (AFAP)
MYH-associated Polyposis  MYH               Autosomal Recessive
Hereditary Non-Polyposis  MLH1, MSH2, MSH6  Autosomal Dominant
  Colon Cancer (HNPCC)
Peutz-Jegher Syndrome     LKB1              Autosomal Dominant
Juvenile Polyposis        MADH4, BMPR1A     Autosomal Dominant
  Syndrome

Syndrome                  Clinical Characteristics

Familial Adenomatous      Hundreds to thousands of adenomatous polyps in
  Polyposis (FAP)           colon, fundic gland polyps, duodenal/
                            ampullary adenomas, desmoid tumors,
                            osteomas, thyroid, and brain tumors
Attenuated Familial       Fundic gland polyps, duodenal, ampullary
  Adenomatous Polyposis     adenomas, <100 colonic polyps
  (AFAP)
MYH-associated Polyposis  3-100 colonic adenomatous polyps
Hereditary Non-Polyposis  Tumors of stomach, small intestine, colon,
  Colon Cancer (HNPCC)      genitourinary tract, biliary tree, and skin
Peutz-Jegher Syndrome     Characteristic mucocutaneous pigmentation,
                            tumors of breast, lungs, uterus,
                            reproductive organs, pancreas, and
                            gallbladder
Juvenile Polyposis        Tumors of stomach and duodenum
  Syndrome

Table 3. General guidelines that should trigger further evaluation by a
specialist in hereditary colorectal cancer syndromes

1. Two or more close family members with colon cancer or related cancers
   (gastric, uterine, ovarian, urinary tract, biliary).
2. A personal history of two or more colon cancers or related cancers
   (gastric, uterine, ovarian, urinary tract, biliary).
3. A personal or family history of young onset colon cancer (before age
   50 yrs).
4. A personal or family history of multiple adenomatous polyps (> 10
   cumulatively).

Table 4. Screening recommendations for patients with familial
adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal
cancer (HNPCC)

                      FAP                    HNPCC

Screening guidelines  Annual sigmoidoscopy   Colonoscopy every 1-2 years
  for CRC               starting at 10-12      starting at age 20-25
                        years old              years or 10 years earlier
                      In attenuated FAP,       than the youngest case of
                        full colonoscopy       CRC diagnosis in the
                        should be performed    family. Annual
                        annually starting      colonoscopy after age 40
                        at age 25 years.       years.
Screening guidelines  1. Upper endoscopy     1. Annual transvaginal
  for other cancers      every 1-3 years,       ultrasound, endometrial
                         including a side       biopsy, and pelvic exam
                         viewing endoscope      to screen for
                      2. Annual thyroid         endometrial and ovarian
                         ultrasound             cancer
                      3. Annual alpha        2. Upper endoscopy every 2
                         fetoprotein and        years starting at age
                         liver ultrasound       30-35 or 5 years earlier
                         during 1st decade      than the youngest case
                         of life                of gastric cancer
                                             3. Annual renal ultrasound,
                                                urinalysis, and urine
                                                cytology