Colorectal Cancer Screening

1. Colorectal Cancer Screening Matt Clausen, MS3 Diagnostic Radiology Elective, December 2007

2. Clinical Significance • Disease Burden—Estimates for 20071 • Colorectal Cancer is the third leading cause of cancer death in the U.S. in both men and women. It passes breast/prostate cancer for 2nd place if both sexes are considered together. • 112,000 new cases in 2007. • 52,000 deaths in 2007. • Approximately 10% of cancer deaths.

3. More Disease Burden6 • A person at age 50 has a… • 5% lifetime risk of being diagnosed with colorectal cancer. • 2.5% chance of dying from it. • The average patient dying of colorectal cancer loses 13 years of life.

4. Colorectal Cancer Epidemiology5 • Peak incidence between ages 60 and 79. • Less than 20% of cases occur before age 50. • Worldwide distribution, but dramatic geographical differences in incidence and death rates thought to be due to environmental differences, particularly dietary practices. • Aspirin and other NSAIDS may be protective.

5. Hyperplastic Polyps3 • Constitute 90% of all polyps in the GI tract. • Found in ½ of all people 60 years or older. • Small, usually < 5 mm. • Non-neoplastic, with virtually no malignant potential.

6. Adenomas (Adenomatous Polyps) 3 • Intraepithelial neoplasms • Range from small, often pedunculated lesions to large, usually sessile, neoplasms. • Prevalence 20-30% before age 40, rising to 40-50% after age 60. • Adenomas are precursor lesions for invasive colorectal adenocarcinomas. • Malignant risk depends on size, histologic architecture, and severity of epithelial dysplasia. • Often asymptomatic. • The goal of screening programs is to detect asymptomatic adenomas before they progress to malignancy.

7. Colorectal Carcinogenesis6 • More than 80% of colorectal cancers arise from adenomatous polyps. • Fewer than 1% of adenomatous polyps less than 1 cm will eventually develop into cancer. • 10% of adenomatous polyps greater than 1 cm • become malignant within 10 years. • about 25% become malignant after 20 years.

8. Colorectal Carcinogenesis3 • Most colorectal cancers occur sporadically in the absence of well-defined familial syndromes. • There are conditions associated with risk of tumor development. • There is a well-described set of genetic alterations that occur ultimately leading from adenoma to colorectal carcinoma.

9. Pathologic Basis for The Adenoma-Carcinoma Sequence3 • Populations that have a high prevalence of adenomas have a high prevalence of colorectal cancer, and vice versa. • The distribution of adenomas within the colorectum is more or less comparable to that of colorectal cancer. • The peak incidence of adenomatous polyps antedates by some years the peak for colorectal cancer. • When invasive carcinoma is identified at an early stage, surrounding adenomatous tissue is often present • The risk of cancer is directly related to the number of adenomas, and hence the virtual certainty of cancer in patients with familial polyposis syndromes. • Programs that follow patients for the development of adenomas and remove all that are suspicious reduce the incidence of colorectal cancer.

10. The Adenoma-Carcinoma Sequence3 • “First hit.” Loss of one normal copy of the tumor suppressor gatekeeper gene APC occurs early. • “Second hit.” The loss of the remaining normal copy of the APC gene follows. • Mutations of the oncogene K-RAS occur next. • Additional mutations or losses of heterozygosity inactivate the tumor suppressor gene p53 and SMAD2 and SMAD4, leading finally to the emergence of carcinoma, in which additional mutations occur. • The accumulation of mutations, rather than their occurrence in a specific order, is more important than the temporal sequence of changes.

11. Distribution of Cancers in the Colorectum3

12. Gross Morphology3 • All colorectal carcinomas begin as in situ lesions, but evolve into different morphologic patterns. • Tumors in the proximal colon tend to grow as polypoid, exophytic masses. Obstruction is uncommon. • Tumors in the distal colon tend to be annular, encircling lesions that produce so-called napkin-ring constrictions of the bowel. The lumen may be markedly narrowed, and the proximal bowel may be distended.

13. Clinical Features5 • Colorectal cancers remain asymptomatic for years. • Symptoms develop insidiously and frequently have been present for months, and sometimes years, before diagnosis. • Cecal and right colonic cancers most often present with fatigue, weakness, and iron-deficiency anemia. • Left-sided lesions present with occult bleeding, changes in bowel habit, or crampy left lower quadrant discomfort. • Cancers of the rectum and sigmoid tend to be more infiltrative at the time of diagnosis than proximal lesions, and therefore have a somewhat poorer prognosis.

14. Prognosis5 • The single most important prognostic indicator of colorectal carcinoma is the extent of the tumor at the time of diagnosis (ie stage).

15. Characteristics of a Good Screening Test2 • The condition must have a significant effect on the quality and quantity of life. • Acceptable methods of treatment must be available. • The condition must have an asymptomatic period during which detection and treatment significantly reduce morbidity and mortality. • Treatment in the asymptomatic phase must yield a therapeutic result superior to that obtained by delaying treatment until symptoms appear. • Tests that are acceptable to patients must be available, at a reasonable cost, to detect the condition in the asymptomatic period. • The incidence of the condition must be sufficient to justify the cost of screening.

16. Screening Modalities for Colorectal Cancer • Fecal occult blood testing (FOBT) • Sigmoidoscopy • FOBT combined with sigmoidoscopy • Double Contrast Barium Enema (DCBE) • Colonoscopy • CT Colonoscopy

17. U.S. Preventive Services Task Force Recommendations6 • Strongly recommends (Grade A recommendation) screening men and women over 50 years of age for colorectal cancer. • Acceptable methods of screening include… • FOBT • Flexible sigmoidoscopy • Combined FOBT and flexible sigmoidoscopy • DCBE • Colonoscopy

18. USPSTF Waffling6 “There are insufficient data to determine which strategy is best in terms of the balance of benefits and potential harms or cost-effectiveness. Studies reviewed by the USPSTF indicate that colorectal cancer screening is likely to be cost-effective (less than $30,000 per additional year of life gained) regardless of the strategy chosen. “It is unclear whether the increased accuracy of colonoscopy compared with alternative screening methods (for example, the identification of lesions that FOBT and flexible sigmoidoscopy would not detect) offsets the procedure's additional complications, inconvenience, and costs.”

19. Screening Goals6 • The goals of screening for colorectal cancer are to detect and remove early stage adenocarcinomas and adenomatous polyps, the precursor lesions to colorectal cancer. • Reduction in colorectal cancer morbidity and mortality through screening is achieved by… • Detecting disease at a more favorable stage. • Removing precursor lesions.

20. Fecal Occult Blood Test (FOBT)5 • Performed annually. • Detects the presence of blood in stool that my derive from colorectal cancer or from large polyps (>2 cm). • Small polyps tend not to bleed. • Bleeding from cancers tends to be intermittent. • Therefore annual testing recommended that involves obtaining serial specimens. • Positive result warrants further workup with DCBE or colonoscopy. • A one sample FOBT with stool collected on DRE, while convenient, has very poor sensitivity and is susceptible to false positive results due to DRE-related trauma.

21. FOBT Operating Characteristics6 • Reported sensitivities range from 50-90%. • Specificity 96-98%. • Hydration of specimen increases sensitivity to 60%, but reduces specificity to 90%. • In patients who have a positive FOBT • Using rehydrated slides • 2% will have cancer • 6-8% will have a large polyp • Using unrehydrated specimens • 5-18% will have cancer • 20-40% will have a large polyp

22. FOBT Screening Interval6

23. FOBT Effectiveness6 • Three randomized controlled trials show reductions in risk of death from colorectal cancer from 15-33% from periodic FOBT screening. • Two European trials, using biennial screening and unrehydrated test cards, found 15-18% reductions in mortality. • In a U.S. study, using rehydrated test cards, colorectal cancer mortality after 18 years of follow-up was 33% lower among persons advised to undergo annual FOBT compared to controls who received usual care (9.46 versus 14.09 deaths per 1,000 patients screened). • Biennial screening reduced mortality by 21%.

24. Sigmoidoscopy5 • Performed every 5 years. • Most commonly used sigmoidoscope is flexible and 60 cm long. • Minimal patient preparation involving saline enema 1-2 hours before the procedure. • Generally performed without sedation. • Skilled examiners can complete the exam in 10 minutes or less. • If positive, patient is usually referred for colonoscopy. • Biopsy during sigmoidoscopy is rare because… • Polyps in the distal bowel signal an increased risk of cancer in the proximal bowel. • Biopsy with electrocautery in the incompletely prepared bowel poses the risk of explosion of ignited hydrogen or methane.

25. Sigmoidoscopy Operating Characteristics6 • 1,000 first-time sigmoidoscopic screening examinations detect • approximately 7 cancers and • about 60 large or high-risk polyps • Sigmoidoscopy only visualizes the lower half of the colon, but it has been estimated to identify 80% of all patients with significant findings in the colon, because findings on sigmoidoscopy will trigger examination of the entire colon. • Difficult to quantify the false-positive rate of endoscopic screening. • Screening may lead to the removal of many polyps that are • of low malignant potential or • would not have caused clinical disease.

26. Sigmoidoscopy Effectiveness6 • Current evidence limited to several well-designed case-control studies, but 2 ongoing RCTs are expected to report results within 5 years. • A case-control study in a large health plan that had implemented rigid sigmoidoscopy screening suggested that screening reduced the risk of death from cancers within reach of the rigid sigmoidoscope by 59%. • A second case-control study in which 75% of the examinations were performed with a flexible instrument found similar protection.

27. Sigmoidoscopy plus FOBT6 • Combining FOBT and periodic sigmoidoscopy has been advocated to improve the sensitivity of screening. • In 3 randomized trials, performing flexible sigmoidoscopy in addition to FOBT yielded approximately 7 additional cancers or large polyps per 1,000 patients compared to FOBT alone. • Adding FOBT did not improve the yield over sigmoidoscopy alone at the initial screening in these studies, which used flexible sigmoidoscopy. • An earlier study which used rigid sigmoidoscopy, however, did show and improved yield.

28. Sigmoidoscopy plus FOBT Effectiveness6 • No randomized trials have examined whether combining FOBT and sigmoidoscopy would lower mortality or morbidity better than either test alone. • In a nonrandomized, controlled study involving more than 12,000 first-time attendees at a preventive health clinic screened using rigid sigmoidoscopy, the addition of FOBT • detected more cancers on initial screening than sigmoidoscopy alone • but mortality after 9 years was not significantly lower (0.36 in patients receiving both tests versus 0.63 per 1,000 patient-years in controls; P =0.11). • Uncertain whether results are generalizable to flexible sigmoidoscopy.

29. Barium Enema5 • Performed every 5 years. • Single contrast = barium • Double contrast = barium + instilled air • DCBE is more sensitive than single contrast. • Bowel prep involves clear liquid diet for 24 hours, followed by liquid laxatives and enemas. • Bowel prep is critical as residual stool can mask lesions or lead to false-positive results. • If positive, the patient is referred for colonoscopy.

30. Barium Enema Operating Characteristics and Effectiveness6 • Some studies have reported high sensitivity (86-90%) of DCBE for colorectal cancer and polyps, and high specificity (95%). • Others report a sensitivity of only 48% for polyps >1 cm with a specificity of 85%. • No trial has examined the ability of screening barium enema to reduce the incidence or mortality from colorectal cancer.

31. Colonoscopy5 • Performed every 10 years. • Requires extensive bowel prep involving 24 hour liquid diet followed by bowel stimulants and an 8-10 hour fast. • Exam terminates at cecum. • Patient is usually sedated for the procedure. • Usually performed in a hospital, but can be done in an outpatient setting. • Higher risk of complications compared to sigmoidoscopy. • Skilled operator can complete exam in approximately 30 minutes.

32. Colonoscopy Operating Characteristics6 • Accuracy difficult to determine as colonoscopy is generally considered to be the gold standard for detecting lesions in the colon. • Estimated sensitivity of a single exam is • 90% for large polyps and • 75% for small polyps (<1 cm). • As with sigmoidoscopy, many patients will have polyps detected or removed on colonoscopy, but only a minority of those would have developed cancer.

33. Colonoscopy Effectiveness6 • The effectiveness of colonoscopy to prevent colorectal cancer or mortality has not been tested in a randomized clinical trial. • The National Polyp Study, a randomized trial of different intervals of surveillance after polypectomy • estimated that 76-90% of cancers could be prevented by regular colonoscopic surveillance exams. • These results should be interpreted with caution. • They are based on historical controls. • Trial participants had more complete polyp removal than may occur in the screening setting. • A single case-control study suggests that colonoscopy is associated with • Lower incidence of colon cancer (OR, 0.47; 95% CI, 0.37 to 0.58). • Lower mortality from colorectal cancer (OR, 0.43; 95% CI, 0.30 to 0.63). • Slightly greater benefits of colonoscopy have been predicted in models that project benefits based on sensitivity of screening and rates of polyp progression.

34. Requires similar bowel prep to conventional colonoscopy, followed by instillation of air through a rectal tube. Exam takes 10-15 minutes. Relatively sensitive and specific in research settings (85% to 90%). May have less accuracy in clinical application. Small and flat polyps are less well visualized than cancers and large polyps. Virtual Colonoscopy/CT Colography5,6

35. Virtual Colonoscopy Debate4 • No studies yet examining clinical outcomes. • Optimists feel virtual colonoscopy may be a cost-effective filter for therapeutic colonoscopy and improve patient compliance with screening programs. • Pessimists (primarily gastroenterologists who have a substantial financial stake in the outcome of the debate) counter that it is not known whether leaving small polyps behind is safe. They didn’t tell me about the rectal tube!

36. Potential Harms of Screening6 • False-positive tests can lead to invasive procedures such as colonoscopy. • Sigmoidoscopy • Perforation 1-2 per 10,000 examinations. • Pain (14%), anxiety, bleeding (3%), gas or flatus (25%). • Barium Enema • important complications of any type occurred in 1 in 10,000 examinations. • perforation occurred in 1 in 25,000 examinations. • death in 1 in 55,000 examinations.

37. Screening colonoscopy poses higher risks than FOBT or sigmoidoscopy. It is a more invasive procedure. It is generally used with conscious sedation. Risks depend on whether it is used simply for screening and diagnosis, or whether it is also used for therapeutic procedures. In 2 studies of screening colonoscopies in more than 5,000 patients, 0.2-0.3% had major complications during or immediately after the procedures, the most common being bleeding. Rates of perforation for diagnostic procedures in 16 published studies range from 0.03-0.61%. The complication rates for therapeutic procedures are higher in some studies: 0.07- 0.72% for perforations and 0.2- 2.67% for bleeding. Death is rare (between 1 in 16,000 to 1 in 27,000) and more likely in patients with comorbid conditions. Complication rates could increase, if widespread adoption of colonoscopy leads to more procedures by less skilled endoscopists. No data on complications for virtual colonoscopy. Colonoscopy Risks6

38. Patient Adherence6 • Some patients may find FOBT unpleasant to perform, but 50-70% will complete FOBT when advised to do so by a doctor. • A reminder system can increase adherence by an average of 14%. • Adherence for sigmoidoscopy is 25-50% for the initial test. • No data on adherence to repeat examinations.

39. Patient Preferences6 • When given information about screening options and offered the choice of FOBT alone, sigmoidoscopy alone, or both tests together • Most patients preferred both tests or FOBT alone. • Only 8% to 13% preferred sigmoidoscopy alone. • Patient adherence to combined testing is lower than it is for sigmoidoscopy or FOBT alone. • Patients’ acceptance of barium enema screening has not been evaluated. • Studies examining the relative discomfort of barium enema and colonoscopy have produced inconsistent results. • The acceptability of virtual colonoscopy has not been examined.

40. Cost Effectiveness6 • The USPSTF has found that screening for colorectal cancer by any of the standard screening strategies reduced colorectal cancer mortality for adults older than age 50 at average risk of colorectal cancer. • Most strategies have an average cost-effectiveness of $10-25 thousand per year of life saved. • compares favorably with other commonly endorsed preventive health care interventions, such as screening mammography or treatment of moderate hypertension. • The most “cost-effective” strategy depends on the cost threshold beyond which one no longer wishes to “pay” for additional years of life saved. • Assuming one does not wish to pay more than $20,000 per life-year saved, at least 1 analysis found annual FOBT, sigmoidoscopy every 5 years, or colonoscopy every 10 years to be the optimal method of screening. • As one’s willingness to pay to save more life-years increases, either colonoscopy every 10 years, or the combination of annual FOBT and sigmoidoscopy every 5 years, becomes favored. • No study has examined the cost of patient time missed from work for screening and treatment.

41. Screening Test Cost Estimates Used in Cost Effectiveness Studies6 • No data for DCBE given. • Real world costs to patients and 3rd party payers likely greater than reported here.

42. Take Home Points • The vast majority of colonic polyps are benign. • Most colorectal carcinomas start as adenomatous polyps, but <1% of small adenomas (<1cm) progress to cancer. • Prognosis depends heavily on extent of disease at diagnosis. • Screening programs aim to detect early stage cancers or adenomas before malignant transformation. • FOBT, flexible sigmoidoscopy, FOBT + flexible sigmoidoscopy, DCBE, and colonoscopy screening programs all reduce colorectal cancer mortality. • Colonoscopy carries more risks than other screening methods. • It is not yet clear which screening strategy is the most cost-effective.

43. Selected References • American Cancer Society. Cancer Facts and Figures 2007. Available at: www.cancer.org/docroot/STT/content/STT_1x_Cancer_Facts__Figures_2007.asp. Accessed December 12, 2007. • Dickey LL. Health Promotion and Disease Prevention. In: Mengel MB, Holleman WL, Fields SA, eds. Fundamentals of Clinical Practice, 2nd ed. New York: Kluwer Academic; 2002:364-365. • Liu C, Crawfor JM. The Gastrointestinal Tract. In: Kumar V, Abbas AK, Fausto N, eds. Robbins and Cotran Pathologic Basis of Disease, 7th ed. Philadelphia: Elsevier Saunders; 2005:856-867. • Isselbacher KJ. 10/11/2007: Hot Topic: CT Colonography vs. Colonoscopy in the Detection of Colon Cancer. In: Harrison’s Online. Available at: www.accessmedicine.com. Accessed December 12, 2007. • Smith RA, Mettlin CJ. Cancer Detection. In: Lenhard RE, Osteen RT, Gansler T, eds. Clinical Oncology. Williston, VT: Blackwell Publishing; 2001:93-99. • U.S. Preventive Services Task Force. Screening for Colorectal Cancer. Agency for Healthcare Research and Quality. Recommendations and supporting documents available at: http://ahrq.gov/clinic/uspstf/uspscolo.htm. Accessed December 12, 2007.