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Screening in colorectal cancers dr. ashutosh

Colorectal cancer screening provides benefits but also faces challenges. Effective screening requires tests that are sensitive, specific, reliable, reasonably cost, and low risk. Colonoscopy is considered the gold standard test due to its ability to detect polyps early and prevent cancer through removal. Guidelines from different organizations generally agree that average risk individuals should begin screening at age 50, but recommend different screening modalities and intervals.

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COLORECTAL CANCER SCREENING: BENEFITS AND CHALLENGES Dr. Ashutosh Mukherji Additional Professor Department of Radiotherapy, Regional Cancer Centre, JIPMER
Prevalence: CRC is 3rd in Cancer Incidence & Mortality in Both Sexes ~140k new cases each year ~50k yearly deaths Lifetime risk of CRC diagnosis in US is 5% (1 in 20)
Racial Disparities in CRC Mortality African Americans have 20% higher incidence and 45% higher mortality from CRC than whites
Essentials of Effective Screening Prevalence Reduction in Morbidity/Mortality Sensitivity, Specificity, Reliability Reasonable Cost Low Risk from Screening Test
Reduction in Morbidity/Mortality: Polypectomies Prevent Carcinomas 10% ⅓ 96% adenomas progress to colorectal cancer of colorectal cancers develop from adenomatous polyps over a period of 10-15 years of adults develop ≥ 1 polyps by age 50, this increases with age Early detection & removal of polyps eliminates the possibility they become cancerous. Routine screening could save ~19,000 lives per year
Genetic Model of Colorectal Cancer Bat-26 (Sporadic) p53 Late Adenoma Optimum phase for early detection Many decades APC K-ras Mutation Bat-26 (HNPCC) Courtesy of Barry M. Berger. MD, FCAP EXACT Sciences Late Cancer Early Cancer Adenoma Normal Epithelium Dwell Time: 2-5 years 2-5 years
Quantifying risk of CRC (NHMRC Guidelines 2005) If age is 5 years Risk 10 years Over 15 years 20 years 30 1 in 7000 1 in 2000 1 in 700 1 in 350 40 1 in 1200 1 in 400 1 in 200 1 in 90 50 1 in 300 1 in 100 1 in 50 1 in 30 60 1 in 100 1 in 50 1 in30 1 in 20 70 1 in 65 1 in 30 1 in 20 1 in 15 80 1 in 25 1 in 25
Quantifying risk based on family history of CRC (NHMRC Guidelines 2005) RR • No family history of CRC 1 • One 1o relative CRC >55 2 • One 2o relative CRC 1.5 • One 1o relative CRC <55 3-6 • Two 1o or one 1o and one 2o relative CRC at any age 3-6
Quantifying risk based on family history of CRC (NHMRC Guidelines 2005) If age is 5 years Risk 10 years Over 15 years 20 years 30 1 in 7000 1 in 2000 1 in 700 1 in 350 40 1 in 1200 1 in 400 1 in 200 1 in 90 50 1 in 300 1 in 100 1 in 50 1 in 30 60 1 in 100 1 in 50 1 in30 1 in 20 70 1 in 65 1 in 30 1 in 20 1 in 15 80 1 in 25 1 in 25
ACS 2003 CRC Prevention and Early Detection Recommendations • Fecal Occult Blood Testing (FOBT) – Guaiac – Immunochemical • Flexible Sigmoidoscopy (FSIG) • FSIG + FOBT • Colonoscopy • Double Contrast Barium Enema (DCBE)
Colonoscopy is considered the GOLD STANDARD for the detection of neoplastic lesions at risk of progression to CRC and is recommended as a first-line screening test in average and high-risk populations. 12
Category 1: Those at or slightly above average risk • No personal history of bowel cancer, advanced adenoma or chronic ulcerative colitis • Either no close relatives with CRC or one 1o OR 2o relative diagnosed >55
Category 2: Those at moderately increased risk • One 1o relative CRC <55 • Two 1o relatives or one 1o and one 2o relative on the same side of the family CRC diagnosed at any age
Screening recommendation for Category 1 patients • Faecal occult blood testing (FOBT) every second year from the age of 50 years (NBCSP) – ie NOT all patients with a first degree relative with CRC qualify for colonoscopic screening
Screening recommendation for Category 2 patients • Colonoscopy • Every 5 years • Starting at age 50, or ten years younger than the age of first diagnosis in the family, whichever comes first
Category 3: Those at potentially high risk • Three or more 1o and 2o relatives on the same side of the family with CRC (suspect HNPCC) • Two or more 1o and 2o relatives on the same side of the family with CRC and one or more of the following features – Multiple cancers in one person – CRC before the age of 50 years – Another relative(s) with related malignancy • Endometrium, ovary, stomach, small bowel, renal pelvis, ureter, biliary tract or brain
Category 3: Those at potentially high risk • At least one 1o relative with a large number of adenomas throughout the large bowel (suspected FAP) • A relative in whom the presence of high risk mutation in the adenomatous polyposis coli (FAP) or one of the mismatch repair genes (HNPCC) has been identified
Screening recommendations for Category 3 patients • FAP suspected – Flexible sigmoidoscopy annually (+/- dye spray chromoendoscopy or narrow band imaging) from 12-15 years to 30-35 years – Genetic testing for mutation on Chromosome 5q • If positive, – prophylactic total colectomy and ileorectal anastomosis or restorative proctocolectomy and ileal pouch anal anastomosis – Annual endoscopy of upper GI and Rectum or pouch for life
Screening recommendations for Category 3 patients • HNPCC suspected – Genetic testing for HNPCC • Immunohistochemistry or MSI testing of family members’ cancers and polyps, then gene testing if positive • If gene mutation established, genetic testing of family members • If positive – Yearly colonoscopy – Regular assessment of other organs – If cancer found, change of surgical approach • More extensive colectomy – ? Prophylactic colectomy • If negative, ??
SURVEILLANCE OF OTHER HIGH RISK GROUPS • Past personal history of CRC, repeat colonoscopy to be performed – If colonoscopy incomplete before surgery, between 3 and 6 months post op – If colonoscopy complete pre-op, 3 years after surgery (?? 1 year) – Every 3 years unless symptoms or adenomatous polyps found
SURVEILLANCE OF OTHER HIGH RISK GROUPS • Past personal history of adenomatous polyps, repeat colonoscopy at – 1 year if multiple polyps, poor bowel prep or potentially incomplete resection of adenoma – 3 years if large adenoma (>1cm), or those with villous change – 4-6 years if none of above risk factors
SURVEILLANCE OF OTHER HIGH RISK GROUPS • Long standing ulcerative colitis – Colonoscopic surveillance every 2 years with multiple biopsies (for dysplasia) starting ~8 years after diagnosis
SCREENING OF THE AVERAGE RISK POPULATION • Faecal occult blood test every 2 years starting at age 50 – Immunological test (tests for human haemoglobin) • National Bowel Cancer Screening Program
Screening Patients With a Family History • If patient has either: – CRC or adenomas* in a first-degree relative diagnosed at age >60 OR – Two second-degree relatives with CRC Begin screening at age 40 with any test recommended for average risk; repeat at usual intervals based on type of test and findings.** *Our expert opinion is that this applies to relatives with advanced adenomas (adenomas that are >1cm, villous, or with high-grade dysplasia) only, recognizing that this information is often unavailable. **The evidence base for these guidelines was not strong and some aspects are controversial. Source: Screening and Surveillance for the Early Detection of Colorectal Cancer and Adenomatous Polyps, 2008: A Joint Guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology
Screening Patients With a Family History • If patient has either: – CRC or adenomas* in a first-degree relative diagnosed before age 60 OR – Two or more first- degree relatives diagnosed at any age (with family history not suggestive of genetic syndrome) *Our expert opinion is that this applies to relatives with advanced adenomas (adenomas that are >1cm, villous, or with high-grade dysplasia) only, recognizing that this information is often unavailable. **The evidence base for these guidelines was not strong and some aspects are controversial. Source: Screening and Surveillance for the Early Detection of Colorectal Cancer and Adenomatous Polyps, 2008: A Joint Guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology Colonoscopy every 5 years starting at age 40, or 10 years before the youngest case in the family was diagnosed, whichever comes first.**
Surveillance of Patients with Adenomas at Prior Colonoscopy • Low-risk adenomas* – 1–2 tubular adenomas <10mm Colonoscopy in 5-10 years *These recommendations assume that the prior colonoscopy was complete and adequate. For serrated polyps, see Surveillance of Patients with Serrated Polyps at Prior Colonoscopy. Guidelines for Colonoscopy Surveillance After Screening and Polypectomy: A Consensus Update by the US Multi-Society Task Force on Colore
• High-risk adenomas* – 3–10 adenomas <10mm OR – >1 adenoma >10mm OR – >1 adenoma with villous features OR – >1 adenoma with high grade dysplasia – >10 adenomas Surveillance of Patients with Adenomas at Prior Colonoscopy Colonoscopy in 3 years *These recommendations assume that the prior colonoscopy was complete and adequate. For serrated polyps, see Surveillance of Patients with Serrated Polyps at Prior Colonoscopy. Guidelines for Colonoscopy Surveillance After Screening and Polypectomy: A Consensus Update by the US Multi-Society Task Force on Colore Colonoscopy in <3 years (consider syndrome)
Surveillance of Patients with Adenomas at Prior Colonoscopy • Any adenoma with piecemeal or possibly incomplete excision *These recommendations assume that the prior colonoscopy was complete and adequate. For serrated polyps, see Surveillance of Patients with Serrated Polyps at Prior Colonoscopy. Guidelines for Colonoscopy Surveillance After Screening and Polypectomy: A Consensus Update by the US Multi-Society Task Force on Colore Colonoscopy in 2-6 months
Recommendations for Adenoma Surveillance After First Surveillance Colonoscopy Baseline Colonoscopy Finding First Surveillance Colonoscopy Finding Interval for Second Surveillance (years) Low-risk adenoma (LRA) • HRA • LRA • No adenoma • 3 • 5 • 10 High-risk adenoma (HRA) • HRA • LRA • No adenoma • 3 • 5 • 5 Guidelines for Colonoscopy Surveillance After Screening and Polypectomy: A Consensus Update by the US Multi-Society Task Force on Colore
A Tale of Three Guidelines: All Were Published in 2008 • American Cancer Society/US Multi-society Task Force on Colorectal Cancer/American College of Radiology (ACS/USMSTF/ACR) • Kaiser Permanente Care Management Institute (KPCMI) • US Preventive Services Task Force (USPSTF)
Everyone Agrees, Screening for Colorectal Cancer Should Begin at Age 50 What Isn’t Currently Agreed Upon: •At what age should screening end? • Which screening methods are preferred?
Modality USPSTF KPCMI ACS/USMSTF/ACR Standard gFOBT ✗ ✗ least preferred due to low sensitivity & low compliance ✗ HS-gFOBT/FIT ✔ Q1 ✔ Q1-2 no evidence of incremental benefit if normal colonoscopy in last 10 yrs ✔ Q1 FSIG ✔ Q5 with HS-gFOBT Q3 ✔Q10 +/- HS-gFOBT/FIT ✔ Q5 Q10 In high-quality centers, regular insertion beyond 40cm (splenic flexure) with good bowel prep; +/- annual HS-gFOBT/FIT Colonoscopy ✔ Q10 ✔ Q10 ✔Q10 CTC ✗ insufficient evidence ✗ insufficient evidence to support over other screening tests ✔Q5 comparable to optical colonoscopy with state-of-the-art techniques; repeat interval has not been studied sDNA ✗ insufficient evidence ✗ insufficient evidence to support over other screening tests ✔ high sensitivity, interval uncertain (one manufacturer recommends Q5 but insufficient data to support) DCBE was not considered; substantially lower sensitivity, not been subjected to screening trials, use is declining ✗ insufficient evidence to support over other screening tests ✔ Q5
Modality USPSTF Recommended? Standard gFOBT ✗ HS-gFOBT/FIT ✔ Q1 FSIG ✔ Q5 with HS-gFOBT Q3 Colonoscopy ✔ Q10 CTC ✗ insufficient evidence sDNA ✗ insufficient evidence DCBE was not considered; substantially lower sensitivity, not been subjected to screening trials, use is declining  between ages 50-75 years old, all are equally effective in life- years gained (assuming 100% adherence)  against routine screening in adults 76- 85 years old  strategies differ in total number of colonoscopies required to gain similar numbers of life-years USPSTF
Modality KPCMI Recommended? Standard gFOBT ✗ least preferred due to low sensitivity & low compliance HS-gFOBT/FIT ✔ Q1-2 no evidence of incremental benefit if normal colonoscopy in last 10 years FSIG ✔Q10 +/- HS-gFOBT/FIT Colonoscopy ✔ Q10 CTC ✗ insufficient evidence to support over other screening tests sDNA ✗ insufficient evidence to support over other screening tests DCBE ✗ insufficient evidence to support over other screening tests with history of routine screening, discontinue at 75 without history of routine screening, discontinue at 80 this study also includes screening recommendations for those at increased risk of CRC KPCMI
Modality ACS/USMSTF/ACR Recommended? Standard gFOBT ✗ HS-gFOBT/FIT ✔ Q1 FSIG ✔ Q5 Q10 In high-quality centers, regular insertion beyond 40cm (splenic flexure) with good bowel prep; +/- annual HS-gFOBT/FIT Colonoscopy ✔Q10 CTC ✔Q5 comparable to optical colonoscopy with state- of-the-art techniques; repeat interval has not been studied sDNA ✔ high sensitivity, interval uncertain (one manufacturer recommends Q5 but insufficient data to support) DCBE ✔ Q5  do not specify age to discontinue screening  if colonoscopy is contraindicated due to life-limiting co- morbidity neither CTC nor any other screening tests are appropriate ACS/USMSTF/A CR
Modality USPSTF KPCMI ACS/USMSTF/ACR Standard gFOBT ✗ ✗ least preferred due to low sensitivity & low compliance ✗ HS-gFOBT/FIT ✔ Q1 ✔ Q1-2 no evidence of incremental benefit if normal colonoscopy in last 10 yrs ✔ Q1 FSIG ✔ Q5 with HS-gFOBT Q3 ✔Q10 +/- HS-gFOBT/FIT ✔ Q5 Q10 In high-quality centers, regular insertion beyond 40cm (splenic flexure) with good bowel prep; +/- annual HS-gFOBT/FIT Colonoscopy ✔ Q10 ✔ Q10 ✔Q10 CTC ✗ insufficient evidence ✗ insufficient evidence to support over other screening tests ✔Q5 comparable to optical colonoscopy with state-of-the-art techniques; repeat interval has not been studied sDNA ✗ insufficient evidence ✗ insufficient evidence to support over other screening tests ✔ high sensitivity, interval uncertain (one manufacturer recommends Q5 but insufficient data to support) DCBE was not considered; substantially lower sensitivity, not been subjected to screening trials, use is declining ✗ insufficient evidence to support over other screening tests ✔ Q5
Many Available Screening Modalities Flexible Sigmoidoscopy (FSIG) Colonoscopy Double Contrast Barium Enema (DCBE) CT Colonography (CTC) (HS)-gFOBT/FIT Stool DNA (sDNA)
• Colonoscopy still GOLD STANDARD • 20-26% miss rates for all adenomas and 2% for large polyps. • However results can be improved by newer techniques such as 170-degree endoscope, 3rd eye retroscope, image enhancer endoscope AFI, capsule endoscopy, narrow band imaging. 39
Miss rates in back-to-back studies Heresbach et al Endoscopy 2008 Van Rijn et al Am J Gastro 2006 Kaltenbach et al Gut 2008 Iannaccone et al Radiology 2005 Year , n= All polyps Adenomas 5- 10mm Adenomas >10mm or advanced Systematic review (6 studies) <2004, n=465 21% 13% 2% (0.3-7.3%) Multi-centre study 2001-2005, n=286 28% 9% 11% Double colonoscopy with CT colon 2002-2003, n=88 36% 17% 13% (6-17%) single centre study vs. NBI 2006-2007, n=142 13% 9.5% 0% (0-1.1%)
Sensitivity, Specificity, Reliability • Sensitivity (Sn) – Hemoccult II < FIT ≤ Hemoccult SENSA < FSIG < colonoscopy • Specificity (Sp) – Hemoccult SENSA < FIT ≈ Hemoccult II < FSIG = colonoscopy • Reliability – FSIG, CTC, colonoscopy = operator-dependent (better training/more experience improve Sn) – quality standards/minimum volume requirements USPSTF (2008)
Sensitivity, Specificity, Reliability • Colonoscopy has superior single-test accuracy compared to other screening modalities – FS+FOBT failed to identify 24% of advanced colonic neoplasia in one study – CTC or DCBE missed 2.1% 10+ mm polyps and miss rate as high as 26% for smaller polyps • Single FOBT by DRE will miss 95% of CRC – Patients should take home 3 testing cards with 2 windows each, use one card per day – Cochrane review = 16% reduction in mortality (RR = 0.84, 95% CI = 0.78-0.90) – NNS = 1,176; 10k persons completing FOBT annually will prevent 8.5 deaths over 10 years AFP (2008)
Many Available Screening Modalities Flexible Sigmoidoscopy (FSIG) Colonoscopy Double Contrast Barium Enema (DCBE) CT Colonography (CTC) Detect both adenomatous polyps and cancers. Detect both adenomatous polyps and cancers.
(HS)-gFOBT/FIT Stool DNA (sDNA) Detect primarily cancer.Detect primarily cancer.
2008 CRC Guidelines Update: Evidence Criteria and Limitations • Current evidence has a number of limitations: – Prospective studies are uncommon – Sample sizes tend to be small – Study participants often include higher risk, symptomatic patients and/or screening populations (magnitude of bias uncertain) • Priority placed on prospective studies of asymptomatic adults, with all subjects undergoing colonoscopy • Because adherence to regular screening is low, we are considering setting a test sensitivity threshold for test acceptance
CRC Screening Guidelines: What’s New? CRC screening tests are grouped into two categories: • Tests that detect cancer and precancerous polyps* • Tests that primarily detect cancer * It is the strong opinion of the consensus guidelines group that colon cancer prevention should be the primary goal of CRC screening. – Exams that are designed to detect both early cancer and precancerous polyps should be encouraged if resources are available and patients are willing to undergo an invasive test – If the full range of screening tests are not available, physicians should make every effort to offer at least one test from each category
2008 CRC Screening Guidelines Beginning at age 50, both men and women at average risk for developing colorectal cancer should use one of the screening tests below: Tests That Detect Adenomatous Polyps and CancerTests That Detect Adenomatous Polyps and Cancer Flexible sigmoidoscopy (FSIG) every 5 years*, or Colonoscopy every 10 years, or Double contrast barium enema (DCBE) every 5 years*, or CT colonography (CTC) every 5 years* Tests That Primarily Detect CancerTests That Primarily Detect Cancer Annual guaiac-based fecal occult blood test (gFOBT) with high test sensitivity for cancer *, ** or Annual fecal immunochemical test (FIT) with high test sensitivity for cancer*,** or Stool DNA test (sDNA), with high sensitivity for cancer*, interval uncertain * Colonoscopy should be done if test results are positive. ** For gFOBT or FIT used as a screening test, the take-home multiple sample method should be used. gFOBT or FIT done during a digital rectal exam
2008 CRC Guidelines Continue to Emphasize Options Because: • Evidence does not yet support any single test as “best” • Uptake of screening remains disappointingly low • Individuals differ in their preferences for one test or another • Primary care physicians differ in their ability to offer, explain, or refer patients to all options equally • Access is uneven geographically, and in terms of test charges and insurance coverage • Uncertainty exists about performance of different screening methods with regard to benefits, harms, and costs (especially on programmatic basis)
Ensure Everyone Can be Offered a Stool Blood Test Option • Some people will not or cannot have a colonoscopy. • Anyone who hesitates should be offered a Fecal Immunochemical Test. • In some settings, FIT needs to be offered as the primary screening strategy.
Stool Blood Testing Remains Important in the “Age of Colonoscopy” • Colonoscopy is now the most frequently used screening test for CRC. • However, when provided annually to average- risk patients with appropriate follow-up, stool occult blood testing with high-sensitivity tests can provide similar reductions in mortality compared to colonoscopy and some reduction in incidence. Evaluating Test Strategies for Colorectal Cancer Screening: A Decision Analysis for the U.S. Preventive Services Task Force
FOBT Sensitivity: Take Home vs. In-Office Sensitivity of Take Home vs. In-Office FOBT SensitivitySensitivity FOBT method (Hemoccult II) All AdvancedAll Advanced LesionsLesions CancerCancer 3 card, take- home 23.9 % 43.9 % Single sample, in-office 4.9 % 9.5 % Collins et al, Annals of Int Med Jan 2005
In-Office FOBT should be abandoned Conclusion • In-office FOBT is essentially worthless as a screening tool for CRC and must be strongly discouraged However; • In a recent national survey, nearly 30% of physicians reported using single-sample, in-office FOBT as their primary method of screening for colorectal cancer. Nadel et al, Annals of Int Med Jan 2005
Advantages of Stool Blood Testing • Stool blood testing • Is less expensive. • Can be offered by any member of the health team. • Requires no bowel preparation. • Can be done in privacy at home. • Does not require time off work or assistance getting home after the procedure. • Is non-invasive and has no risk of causing pain, bleeding, bowel perforation, or other adverse outcomes. Colonoscopy is required only if stool blood testing is abnormal.
Stool DNA Test (sDNA) • Rationale • Fecal occult blood tests detect blood in the stool – which is intermittent and non-specific • Colon cells are shed continuously • Polyps and cancer cells contain abnormal DNA • Stool DNA tests look for abnormal DNA from cells that are passed in the stool* *All positive tests should be followed with colonoscopy
Reasonable Cost: CRC Screening Compares Favorably to Other Preventive Interventions Regardless of screening method, the cost per life-year saved ($10-25k) compares favorably with other commonly endorsed preventive health care interventions Pignone et al. (2002), AFP (2008) Median cost of colonoscopy is $1,736
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Immunochemical FOB may be better in Asia FOB+ FIT+ SENS FOB SENS FIT SPEC FOB SPEC FIT + predict value FOB +predict value FIT Sumetchoti maytha et al 2007 12.6% Hemascree n 12.8% Occultec h 0.8% CRC 3.4% polyps 1.1% CRC 8.9% polyps Li et al 2003 35.6% 5.6% 0.2% CRC 0.6% adenomas Not specified (at best 1.3% CRC 3.7% adenomas) Wong et al 2007 41% 14% 100% 89% 70% 94% 16% CRC 42% CRC • Cost-effectiveness: Cost of tests + false positive test • Dietary manipulation is thought difficult in many Asian countries
CT Colonography (CTC) CTC Image Optical Colonoscopy
CT Colonography Rationale • Allows detailed evaluation of the entire colon • A number of studies have demonstrated a high level of sensitivity for cancer and large polyps • Minimally invasive (rectal tube for air insufflation) • No sedation required
CT Colonography Poly p 3-D view2-D view Polyp
CTC vs. Optical Colonoscopy: Meta-Analyses Halligan 2005, Mulhall 2005 Polyp SizePolyp Size CTC performa nce >10mm 6-9 mm Cancer PooledPooled SensitivitySensitivity 85-93% 70-86% 85.7% PooledPooled SpecificitySpecificity 97% 86-93% ----
CTC vs. Optical Colonoscopy: Sensitivities for All Polyps Pickhardt et al, NEJM 2003 Polyp SizePolyp Size >10mm >8mm >6mm CTCCTC 92.2% 92.6% 85.7% ColonoscoColonosco pypy 88.2% 89.5% 90.0%
CT colonography- detection rate • Sensitivity of CT colonography compared to 2 colonoscopies. • 2nd colonoscopy aware of all lesions detected from CT and initial colonoscopy • Minimised known miss rate- true sensitivity of CT results All polyps >6mm Neoplastic >6mm Neoplastic >10mm (n=7) All polyps All neoplastic Second colonoscopy 100% 100% 100% 100% 100% Initial colonoscopy 84% (69-92%) 91% (71-97%) 86% (49-97%) 83% (74-89%) 87% (73-94%) CT colon (3 observers) 86% (72-94%) 81% (60-92%) 100% (70-100%) 63% (53-72%) 64% (48-77%) Iannaccone et al 2005
The ACRIN CT Study • The ACRIN study is a multi-center study with each site using state-of-the-art technology • 15 participating sites • Patients underwent both CTC and colonoscopy • 2,531 asymptomatic patients studied • Findings published Sept 2008 in New England Journal
ACRIN Results SensitivitySensitivity SpecificitySpecificity Adenomas > 1 cm 90% 86% Polyps 6-9 mm 84% 86-89% Johnson et al, NEJM 2008
CT Colonography Limitations • Requires full bowel prep (which most patients find to be the most distressing element of colonoscopy) • Colonoscopy is required if abnormalities detected, sometimes necessitating a second bowel prep • Steep learning curve for radiologists • Limited availability to high quality exams in many parts of the country • Most insurers do not currently cover CTC as a screening modality
Limitations • Extra-colonic findings can lead to additional testing (may have both positive and negative connotations) • Questions regarding:  Significance of radiation exposure  Management of small polyps
Risks of Screening • Bowel Perforation – CTC = 0-6 per 10,000 – DCBE = 1 per 25,000 – FSIG = 1 per 25,000-50,000 – Colonoscopy = 1 per 2,000-3,000 (65% are sigmoid) • Serious Complications – death or event requiring hospitalization (perforation, major bleeding, diverticulitis, severe abdominal pain, and cardiovascular events) – FSIG = 3.4 per 10,000 procedures – Colonoscopy = 25 per 10,000 procedures
Risks of Screening • Conscious Sedation – FSIG = most performed without (some discomfort) – Colonoscopy = most performed with (cardiopulmonary complications are ~½ of all adverse events); patients will also miss a day of work and need a chaperone for transportation • Bowel Prep – FSIG = less intensive (complete or partial) – Colonoscopy = more intensive (complete required) – DCBE/CTC* = complete required, if same day colonoscopy not available a second bowel prep will be required
Risks of Screening • False Reassurance from False-Negative Results (gFOBT/FIT) • Unnecessary Invasive Tests Due to False- Positive Results (CTC) – 10% of first-time CT colonographies found to have extracolonic abnormalities which may or may not be clinically significant; potential for both benefit & harm
Risks of Screening • Radiation Exposure (CTC) – radiation exposure reported to be 10 mSv per CTC – at this level of exposure, 1 additional individual per 1000 would develop cancer in his or her lifetime – cumulative radiation risk should be considered in the context of the growing use of other diagnostic and screening tests that involve radiation exposure. – improvements in CT colonography technology and practice are lowering this radiation dose
Flat Lesions • Described in Japanese patients since 1980’s. Thought to be uncommon in the U.S. • Study published in March 2008 detected flat lesions at much higher rate than any previous U.S. reports • Colonoscopies in over 1800 veterans found: – Polyps in 37% – “Flat lesions” in 9.35% – 0.8% of flat lesions cancerous or pre-cancerous Soetikno, JAMA 2008
Flat Lesions Caveats • Most lesions not truly flat – Flat lesions found in only 6% – Cancer or pre- cancerous findings in only 0.3% Soetikno, JAMA 2008 New Sources of Risk Colorectal cancer prevention largely focuses on finding polyps, but flatter, less visible lesions that are not polyps are also cancer risks. Polyp Elevated lesion Flat lesion Depressed lesion The New York Times: Illustrations by JAMA
Flat Lesions Implications for screening • JAMA study led some to question the ability of CTC to detect flat lesions (although CTC was not utilized in the study) • Results from early CTC/flat lesion studies were extremely variable (sensitivity 13% - 65%) • Recent study of experienced radiologist using advanced technology and protocols found 80% sensitivity for flat lesions
Thank youThank you

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Screening in colorectal cancers dr. ashutosh

  • 1.
    COLORECTAL CANCER SCREENING:BENEFITS AND CHALLENGES Dr. Ashutosh Mukherji Additional Professor Department of Radiotherapy, Regional Cancer Centre, JIPMER
  • 2.
    Prevalence: CRC is3rd in Cancer Incidence & Mortality in Both Sexes ~140k new cases each year ~50k yearly deaths Lifetime risk of CRC diagnosis in US is 5% (1 in 20)
  • 3.
    Racial Disparities inCRC Mortality African Americans have 20% higher incidence and 45% higher mortality from CRC than whites
  • 5.
    Essentials of Effective Screening Prevalence Reductionin Morbidity/Mortality Sensitivity, Specificity, Reliability Reasonable Cost Low Risk from Screening Test
  • 6.
    Reduction in Morbidity/Mortality: PolypectomiesPrevent Carcinomas 10% ⅓ 96% adenomas progress to colorectal cancer of colorectal cancers develop from adenomatous polyps over a period of 10-15 years of adults develop ≥ 1 polyps by age 50, this increases with age Early detection & removal of polyps eliminates the possibility they become cancerous. Routine screening could save ~19,000 lives per year
  • 7.
    Genetic Model ofColorectal Cancer Bat-26 (Sporadic) p53 Late Adenoma Optimum phase for early detection Many decades APC K-ras Mutation Bat-26 (HNPCC) Courtesy of Barry M. Berger. MD, FCAP EXACT Sciences Late Cancer Early Cancer Adenoma Normal Epithelium Dwell Time: 2-5 years 2-5 years
  • 8.
    Quantifying risk ofCRC (NHMRC Guidelines 2005) If age is 5 years Risk 10 years Over 15 years 20 years 30 1 in 7000 1 in 2000 1 in 700 1 in 350 40 1 in 1200 1 in 400 1 in 200 1 in 90 50 1 in 300 1 in 100 1 in 50 1 in 30 60 1 in 100 1 in 50 1 in30 1 in 20 70 1 in 65 1 in 30 1 in 20 1 in 15 80 1 in 25 1 in 25
  • 9.
    Quantifying risk basedon family history of CRC (NHMRC Guidelines 2005) RR • No family history of CRC 1 • One 1o relative CRC >55 2 • One 2o relative CRC 1.5 • One 1o relative CRC <55 3-6 • Two 1o or one 1o and one 2o relative CRC at any age 3-6
  • 10.
    Quantifying risk basedon family history of CRC (NHMRC Guidelines 2005) If age is 5 years Risk 10 years Over 15 years 20 years 30 1 in 7000 1 in 2000 1 in 700 1 in 350 40 1 in 1200 1 in 400 1 in 200 1 in 90 50 1 in 300 1 in 100 1 in 50 1 in 30 60 1 in 100 1 in 50 1 in30 1 in 20 70 1 in 65 1 in 30 1 in 20 1 in 15 80 1 in 25 1 in 25
  • 11.
    ACS 2003 CRCPrevention and Early Detection Recommendations • Fecal Occult Blood Testing (FOBT) – Guaiac – Immunochemical • Flexible Sigmoidoscopy (FSIG) • FSIG + FOBT • Colonoscopy • Double Contrast Barium Enema (DCBE)
  • 12.
    Colonoscopy is consideredthe GOLD STANDARD for the detection of neoplastic lesions at risk of progression to CRC and is recommended as a first-line screening test in average and high-risk populations. 12
  • 13.
    Category 1: Thoseat or slightly above average risk • No personal history of bowel cancer, advanced adenoma or chronic ulcerative colitis • Either no close relatives with CRC or one 1o OR 2o relative diagnosed >55
  • 14.
    Category 2: Thoseat moderately increased risk • One 1o relative CRC <55 • Two 1o relatives or one 1o and one 2o relative on the same side of the family CRC diagnosed at any age
  • 15.
    Screening recommendation for Category 1patients • Faecal occult blood testing (FOBT) every second year from the age of 50 years (NBCSP) – ie NOT all patients with a first degree relative with CRC qualify for colonoscopic screening
  • 16.
    Screening recommendation for Category 2patients • Colonoscopy • Every 5 years • Starting at age 50, or ten years younger than the age of first diagnosis in the family, whichever comes first
  • 17.
    Category 3: Thoseat potentially high risk • Three or more 1o and 2o relatives on the same side of the family with CRC (suspect HNPCC) • Two or more 1o and 2o relatives on the same side of the family with CRC and one or more of the following features – Multiple cancers in one person – CRC before the age of 50 years – Another relative(s) with related malignancy • Endometrium, ovary, stomach, small bowel, renal pelvis, ureter, biliary tract or brain
  • 18.
    Category 3: Thoseat potentially high risk • At least one 1o relative with a large number of adenomas throughout the large bowel (suspected FAP) • A relative in whom the presence of high risk mutation in the adenomatous polyposis coli (FAP) or one of the mismatch repair genes (HNPCC) has been identified
  • 19.
    Screening recommendations for Category 3patients • FAP suspected – Flexible sigmoidoscopy annually (+/- dye spray chromoendoscopy or narrow band imaging) from 12-15 years to 30-35 years – Genetic testing for mutation on Chromosome 5q • If positive, – prophylactic total colectomy and ileorectal anastomosis or restorative proctocolectomy and ileal pouch anal anastomosis – Annual endoscopy of upper GI and Rectum or pouch for life
  • 20.
    Screening recommendations for Category 3patients • HNPCC suspected – Genetic testing for HNPCC • Immunohistochemistry or MSI testing of family members’ cancers and polyps, then gene testing if positive • If gene mutation established, genetic testing of family members • If positive – Yearly colonoscopy – Regular assessment of other organs – If cancer found, change of surgical approach • More extensive colectomy – ? Prophylactic colectomy • If negative, ??
  • 21.
    SURVEILLANCE OF OTHER HIGHRISK GROUPS • Past personal history of CRC, repeat colonoscopy to be performed – If colonoscopy incomplete before surgery, between 3 and 6 months post op – If colonoscopy complete pre-op, 3 years after surgery (?? 1 year) – Every 3 years unless symptoms or adenomatous polyps found
  • 22.
    SURVEILLANCE OF OTHER HIGHRISK GROUPS • Past personal history of adenomatous polyps, repeat colonoscopy at – 1 year if multiple polyps, poor bowel prep or potentially incomplete resection of adenoma – 3 years if large adenoma (>1cm), or those with villous change – 4-6 years if none of above risk factors
  • 23.
    SURVEILLANCE OF OTHER HIGHRISK GROUPS • Long standing ulcerative colitis – Colonoscopic surveillance every 2 years with multiple biopsies (for dysplasia) starting ~8 years after diagnosis
  • 24.
    SCREENING OF THE AVERAGERISK POPULATION • Faecal occult blood test every 2 years starting at age 50 – Immunological test (tests for human haemoglobin) • National Bowel Cancer Screening Program
  • 25.
    Screening Patients Witha Family History • If patient has either: – CRC or adenomas* in a first-degree relative diagnosed at age >60 OR – Two second-degree relatives with CRC Begin screening at age 40 with any test recommended for average risk; repeat at usual intervals based on type of test and findings.** *Our expert opinion is that this applies to relatives with advanced adenomas (adenomas that are >1cm, villous, or with high-grade dysplasia) only, recognizing that this information is often unavailable. **The evidence base for these guidelines was not strong and some aspects are controversial. Source: Screening and Surveillance for the Early Detection of Colorectal Cancer and Adenomatous Polyps, 2008: A Joint Guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology
  • 26.
    Screening Patients Witha Family History • If patient has either: – CRC or adenomas* in a first-degree relative diagnosed before age 60 OR – Two or more first- degree relatives diagnosed at any age (with family history not suggestive of genetic syndrome) *Our expert opinion is that this applies to relatives with advanced adenomas (adenomas that are >1cm, villous, or with high-grade dysplasia) only, recognizing that this information is often unavailable. **The evidence base for these guidelines was not strong and some aspects are controversial. Source: Screening and Surveillance for the Early Detection of Colorectal Cancer and Adenomatous Polyps, 2008: A Joint Guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology Colonoscopy every 5 years starting at age 40, or 10 years before the youngest case in the family was diagnosed, whichever comes first.**
  • 27.
    Surveillance of Patientswith Adenomas at Prior Colonoscopy • Low-risk adenomas* – 1–2 tubular adenomas <10mm Colonoscopy in 5-10 years *These recommendations assume that the prior colonoscopy was complete and adequate. For serrated polyps, see Surveillance of Patients with Serrated Polyps at Prior Colonoscopy. Guidelines for Colonoscopy Surveillance After Screening and Polypectomy: A Consensus Update by the US Multi-Society Task Force on Colore
  • 28.
    • High-risk adenomas* –3–10 adenomas <10mm OR – >1 adenoma >10mm OR – >1 adenoma with villous features OR – >1 adenoma with high grade dysplasia – >10 adenomas Surveillance of Patients with Adenomas at Prior Colonoscopy Colonoscopy in 3 years *These recommendations assume that the prior colonoscopy was complete and adequate. For serrated polyps, see Surveillance of Patients with Serrated Polyps at Prior Colonoscopy. Guidelines for Colonoscopy Surveillance After Screening and Polypectomy: A Consensus Update by the US Multi-Society Task Force on Colore Colonoscopy in <3 years (consider syndrome)
  • 29.
    Surveillance of Patientswith Adenomas at Prior Colonoscopy • Any adenoma with piecemeal or possibly incomplete excision *These recommendations assume that the prior colonoscopy was complete and adequate. For serrated polyps, see Surveillance of Patients with Serrated Polyps at Prior Colonoscopy. Guidelines for Colonoscopy Surveillance After Screening and Polypectomy: A Consensus Update by the US Multi-Society Task Force on Colore Colonoscopy in 2-6 months
  • 30.
    Recommendations for AdenomaSurveillance After First Surveillance Colonoscopy Baseline Colonoscopy Finding First Surveillance Colonoscopy Finding Interval for Second Surveillance (years) Low-risk adenoma (LRA) • HRA • LRA • No adenoma • 3 • 5 • 10 High-risk adenoma (HRA) • HRA • LRA • No adenoma • 3 • 5 • 5 Guidelines for Colonoscopy Surveillance After Screening and Polypectomy: A Consensus Update by the US Multi-Society Task Force on Colore
  • 31.
    A Tale ofThree Guidelines: All Were Published in 2008 • American Cancer Society/US Multi-society Task Force on Colorectal Cancer/American College of Radiology (ACS/USMSTF/ACR) • Kaiser Permanente Care Management Institute (KPCMI) • US Preventive Services Task Force (USPSTF)
  • 32.
    Everyone Agrees, Screeningfor Colorectal Cancer Should Begin at Age 50 What Isn’t Currently Agreed Upon: •At what age should screening end? • Which screening methods are preferred?
  • 33.
    Modality USPSTF KPCMIACS/USMSTF/ACR Standard gFOBT ✗ ✗ least preferred due to low sensitivity & low compliance ✗ HS-gFOBT/FIT ✔ Q1 ✔ Q1-2 no evidence of incremental benefit if normal colonoscopy in last 10 yrs ✔ Q1 FSIG ✔ Q5 with HS-gFOBT Q3 ✔Q10 +/- HS-gFOBT/FIT ✔ Q5 Q10 In high-quality centers, regular insertion beyond 40cm (splenic flexure) with good bowel prep; +/- annual HS-gFOBT/FIT Colonoscopy ✔ Q10 ✔ Q10 ✔Q10 CTC ✗ insufficient evidence ✗ insufficient evidence to support over other screening tests ✔Q5 comparable to optical colonoscopy with state-of-the-art techniques; repeat interval has not been studied sDNA ✗ insufficient evidence ✗ insufficient evidence to support over other screening tests ✔ high sensitivity, interval uncertain (one manufacturer recommends Q5 but insufficient data to support) DCBE was not considered; substantially lower sensitivity, not been subjected to screening trials, use is declining ✗ insufficient evidence to support over other screening tests ✔ Q5
  • 34.
    Modality USPSTF Recommended? Standard gFOBT ✗ HS-gFOBT/FIT ✔ Q1 FSIG ✔Q5 with HS-gFOBT Q3 Colonoscopy ✔ Q10 CTC ✗ insufficient evidence sDNA ✗ insufficient evidence DCBE was not considered; substantially lower sensitivity, not been subjected to screening trials, use is declining  between ages 50-75 years old, all are equally effective in life- years gained (assuming 100% adherence)  against routine screening in adults 76- 85 years old  strategies differ in total number of colonoscopies required to gain similar numbers of life-years USPSTF
  • 35.
    Modality KPCMI Recommended? Standard gFOBT ✗ least preferred dueto low sensitivity & low compliance HS-gFOBT/FIT ✔ Q1-2 no evidence of incremental benefit if normal colonoscopy in last 10 years FSIG ✔Q10 +/- HS-gFOBT/FIT Colonoscopy ✔ Q10 CTC ✗ insufficient evidence to support over other screening tests sDNA ✗ insufficient evidence to support over other screening tests DCBE ✗ insufficient evidence to support over other screening tests with history of routine screening, discontinue at 75 without history of routine screening, discontinue at 80 this study also includes screening recommendations for those at increased risk of CRC KPCMI
  • 36.
    Modality ACS/USMSTF/ACR Recommended? Standard gFOBT ✗ HS-gFOBT/FIT ✔ Q1 FSIG ✔ Q5 Q10In high-quality centers, regular insertion beyond 40cm (splenic flexure) with good bowel prep; +/- annual HS-gFOBT/FIT Colonoscopy ✔Q10 CTC ✔Q5 comparable to optical colonoscopy with state- of-the-art techniques; repeat interval has not been studied sDNA ✔ high sensitivity, interval uncertain (one manufacturer recommends Q5 but insufficient data to support) DCBE ✔ Q5  do not specify age to discontinue screening  if colonoscopy is contraindicated due to life-limiting co- morbidity neither CTC nor any other screening tests are appropriate ACS/USMSTF/A CR
  • 37.
    Modality USPSTF KPCMIACS/USMSTF/ACR Standard gFOBT ✗ ✗ least preferred due to low sensitivity & low compliance ✗ HS-gFOBT/FIT ✔ Q1 ✔ Q1-2 no evidence of incremental benefit if normal colonoscopy in last 10 yrs ✔ Q1 FSIG ✔ Q5 with HS-gFOBT Q3 ✔Q10 +/- HS-gFOBT/FIT ✔ Q5 Q10 In high-quality centers, regular insertion beyond 40cm (splenic flexure) with good bowel prep; +/- annual HS-gFOBT/FIT Colonoscopy ✔ Q10 ✔ Q10 ✔Q10 CTC ✗ insufficient evidence ✗ insufficient evidence to support over other screening tests ✔Q5 comparable to optical colonoscopy with state-of-the-art techniques; repeat interval has not been studied sDNA ✗ insufficient evidence ✗ insufficient evidence to support over other screening tests ✔ high sensitivity, interval uncertain (one manufacturer recommends Q5 but insufficient data to support) DCBE was not considered; substantially lower sensitivity, not been subjected to screening trials, use is declining ✗ insufficient evidence to support over other screening tests ✔ Q5
  • 38.
    Many Available Screening Modalities FlexibleSigmoidoscopy (FSIG) Colonoscopy Double Contrast Barium Enema (DCBE) CT Colonography (CTC) (HS)-gFOBT/FIT Stool DNA (sDNA)
  • 39.
    • Colonoscopy stillGOLD STANDARD • 20-26% miss rates for all adenomas and 2% for large polyps. • However results can be improved by newer techniques such as 170-degree endoscope, 3rd eye retroscope, image enhancer endoscope AFI, capsule endoscopy, narrow band imaging. 39
  • 40.
    Miss rates inback-to-back studies Heresbach et al Endoscopy 2008 Van Rijn et al Am J Gastro 2006 Kaltenbach et al Gut 2008 Iannaccone et al Radiology 2005 Year , n= All polyps Adenomas 5- 10mm Adenomas >10mm or advanced Systematic review (6 studies) <2004, n=465 21% 13% 2% (0.3-7.3%) Multi-centre study 2001-2005, n=286 28% 9% 11% Double colonoscopy with CT colon 2002-2003, n=88 36% 17% 13% (6-17%) single centre study vs. NBI 2006-2007, n=142 13% 9.5% 0% (0-1.1%)
  • 41.
    Sensitivity, Specificity, Reliability • Sensitivity(Sn) – Hemoccult II < FIT ≤ Hemoccult SENSA < FSIG < colonoscopy • Specificity (Sp) – Hemoccult SENSA < FIT ≈ Hemoccult II < FSIG = colonoscopy • Reliability – FSIG, CTC, colonoscopy = operator-dependent (better training/more experience improve Sn) – quality standards/minimum volume requirements USPSTF (2008)
  • 42.
    Sensitivity, Specificity, Reliability • Colonoscopyhas superior single-test accuracy compared to other screening modalities – FS+FOBT failed to identify 24% of advanced colonic neoplasia in one study – CTC or DCBE missed 2.1% 10+ mm polyps and miss rate as high as 26% for smaller polyps • Single FOBT by DRE will miss 95% of CRC – Patients should take home 3 testing cards with 2 windows each, use one card per day – Cochrane review = 16% reduction in mortality (RR = 0.84, 95% CI = 0.78-0.90) – NNS = 1,176; 10k persons completing FOBT annually will prevent 8.5 deaths over 10 years AFP (2008)
  • 43.
    Many Available ScreeningModalities Flexible Sigmoidoscopy (FSIG) Colonoscopy Double Contrast Barium Enema (DCBE) CT Colonography (CTC) Detect both adenomatous polyps and cancers. Detect both adenomatous polyps and cancers.
  • 44.
    (HS)-gFOBT/FIT Stool DNA (sDNA) Detectprimarily cancer.Detect primarily cancer.
  • 45.
    2008 CRC GuidelinesUpdate: Evidence Criteria and Limitations • Current evidence has a number of limitations: – Prospective studies are uncommon – Sample sizes tend to be small – Study participants often include higher risk, symptomatic patients and/or screening populations (magnitude of bias uncertain) • Priority placed on prospective studies of asymptomatic adults, with all subjects undergoing colonoscopy • Because adherence to regular screening is low, we are considering setting a test sensitivity threshold for test acceptance
  • 46.
    CRC Screening Guidelines: What’sNew? CRC screening tests are grouped into two categories: • Tests that detect cancer and precancerous polyps* • Tests that primarily detect cancer * It is the strong opinion of the consensus guidelines group that colon cancer prevention should be the primary goal of CRC screening. – Exams that are designed to detect both early cancer and precancerous polyps should be encouraged if resources are available and patients are willing to undergo an invasive test – If the full range of screening tests are not available, physicians should make every effort to offer at least one test from each category
  • 47.
    2008 CRC ScreeningGuidelines Beginning at age 50, both men and women at average risk for developing colorectal cancer should use one of the screening tests below: Tests That Detect Adenomatous Polyps and CancerTests That Detect Adenomatous Polyps and Cancer Flexible sigmoidoscopy (FSIG) every 5 years*, or Colonoscopy every 10 years, or Double contrast barium enema (DCBE) every 5 years*, or CT colonography (CTC) every 5 years* Tests That Primarily Detect CancerTests That Primarily Detect Cancer Annual guaiac-based fecal occult blood test (gFOBT) with high test sensitivity for cancer *, ** or Annual fecal immunochemical test (FIT) with high test sensitivity for cancer*,** or Stool DNA test (sDNA), with high sensitivity for cancer*, interval uncertain * Colonoscopy should be done if test results are positive. ** For gFOBT or FIT used as a screening test, the take-home multiple sample method should be used. gFOBT or FIT done during a digital rectal exam
  • 48.
    2008 CRC GuidelinesContinue to Emphasize Options Because: • Evidence does not yet support any single test as “best” • Uptake of screening remains disappointingly low • Individuals differ in their preferences for one test or another • Primary care physicians differ in their ability to offer, explain, or refer patients to all options equally • Access is uneven geographically, and in terms of test charges and insurance coverage • Uncertainty exists about performance of different screening methods with regard to benefits, harms, and costs (especially on programmatic basis)
  • 49.
    Ensure Everyone Canbe Offered a Stool Blood Test Option • Some people will not or cannot have a colonoscopy. • Anyone who hesitates should be offered a Fecal Immunochemical Test. • In some settings, FIT needs to be offered as the primary screening strategy.
  • 50.
    Stool Blood TestingRemains Important in the “Age of Colonoscopy” • Colonoscopy is now the most frequently used screening test for CRC. • However, when provided annually to average- risk patients with appropriate follow-up, stool occult blood testing with high-sensitivity tests can provide similar reductions in mortality compared to colonoscopy and some reduction in incidence. Evaluating Test Strategies for Colorectal Cancer Screening: A Decision Analysis for the U.S. Preventive Services Task Force
  • 51.
    FOBT Sensitivity: Take Homevs. In-Office Sensitivity of Take Home vs. In-Office FOBT SensitivitySensitivity FOBT method (Hemoccult II) All AdvancedAll Advanced LesionsLesions CancerCancer 3 card, take- home 23.9 % 43.9 % Single sample, in-office 4.9 % 9.5 % Collins et al, Annals of Int Med Jan 2005
  • 52.
    In-Office FOBT shouldbe abandoned Conclusion • In-office FOBT is essentially worthless as a screening tool for CRC and must be strongly discouraged However; • In a recent national survey, nearly 30% of physicians reported using single-sample, in-office FOBT as their primary method of screening for colorectal cancer. Nadel et al, Annals of Int Med Jan 2005
  • 53.
    Advantages of StoolBlood Testing • Stool blood testing • Is less expensive. • Can be offered by any member of the health team. • Requires no bowel preparation. • Can be done in privacy at home. • Does not require time off work or assistance getting home after the procedure. • Is non-invasive and has no risk of causing pain, bleeding, bowel perforation, or other adverse outcomes. Colonoscopy is required only if stool blood testing is abnormal.
  • 54.
    Stool DNA Test(sDNA) • Rationale • Fecal occult blood tests detect blood in the stool – which is intermittent and non-specific • Colon cells are shed continuously • Polyps and cancer cells contain abnormal DNA • Stool DNA tests look for abnormal DNA from cells that are passed in the stool* *All positive tests should be followed with colonoscopy
  • 55.
    Reasonable Cost: CRCScreening Compares Favorably to Other Preventive Interventions Regardless of screening method, the cost per life-year saved ($10-25k) compares favorably with other commonly endorsed preventive health care interventions Pignone et al. (2002), AFP (2008) Median cost of colonoscopy is $1,736
  • 56.
  • 57.
  • 58.
    Immunochemical FOB maybe better in Asia FOB+ FIT+ SENS FOB SENS FIT SPEC FOB SPEC FIT + predict value FOB +predict value FIT Sumetchoti maytha et al 2007 12.6% Hemascree n 12.8% Occultec h 0.8% CRC 3.4% polyps 1.1% CRC 8.9% polyps Li et al 2003 35.6% 5.6% 0.2% CRC 0.6% adenomas Not specified (at best 1.3% CRC 3.7% adenomas) Wong et al 2007 41% 14% 100% 89% 70% 94% 16% CRC 42% CRC • Cost-effectiveness: Cost of tests + false positive test • Dietary manipulation is thought difficult in many Asian countries
  • 59.
    CT Colonography (CTC) CTCImage Optical Colonoscopy
  • 60.
    CT Colonography Rationale • Allowsdetailed evaluation of the entire colon • A number of studies have demonstrated a high level of sensitivity for cancer and large polyps • Minimally invasive (rectal tube for air insufflation) • No sedation required
  • 61.
  • 62.
    CTC vs. OpticalColonoscopy: Meta-Analyses Halligan 2005, Mulhall 2005 Polyp SizePolyp Size CTC performa nce >10mm 6-9 mm Cancer PooledPooled SensitivitySensitivity 85-93% 70-86% 85.7% PooledPooled SpecificitySpecificity 97% 86-93% ----
  • 63.
    CTC vs. OpticalColonoscopy: Sensitivities for All Polyps Pickhardt et al, NEJM 2003 Polyp SizePolyp Size >10mm >8mm >6mm CTCCTC 92.2% 92.6% 85.7% ColonoscoColonosco pypy 88.2% 89.5% 90.0%
  • 64.
    CT colonography- detectionrate • Sensitivity of CT colonography compared to 2 colonoscopies. • 2nd colonoscopy aware of all lesions detected from CT and initial colonoscopy • Minimised known miss rate- true sensitivity of CT results All polyps >6mm Neoplastic >6mm Neoplastic >10mm (n=7) All polyps All neoplastic Second colonoscopy 100% 100% 100% 100% 100% Initial colonoscopy 84% (69-92%) 91% (71-97%) 86% (49-97%) 83% (74-89%) 87% (73-94%) CT colon (3 observers) 86% (72-94%) 81% (60-92%) 100% (70-100%) 63% (53-72%) 64% (48-77%) Iannaccone et al 2005
  • 65.
    The ACRIN CTStudy • The ACRIN study is a multi-center study with each site using state-of-the-art technology • 15 participating sites • Patients underwent both CTC and colonoscopy • 2,531 asymptomatic patients studied • Findings published Sept 2008 in New England Journal
  • 66.
    ACRIN Results SensitivitySensitivity SpecificitySpecificity Adenomas> 1 cm 90% 86% Polyps 6-9 mm 84% 86-89% Johnson et al, NEJM 2008
  • 67.
    CT Colonography Limitations • Requiresfull bowel prep (which most patients find to be the most distressing element of colonoscopy) • Colonoscopy is required if abnormalities detected, sometimes necessitating a second bowel prep • Steep learning curve for radiologists • Limited availability to high quality exams in many parts of the country • Most insurers do not currently cover CTC as a screening modality
  • 68.
    Limitations • Extra-colonic findingscan lead to additional testing (may have both positive and negative connotations) • Questions regarding:  Significance of radiation exposure  Management of small polyps
  • 69.
    Risks of Screening •Bowel Perforation – CTC = 0-6 per 10,000 – DCBE = 1 per 25,000 – FSIG = 1 per 25,000-50,000 – Colonoscopy = 1 per 2,000-3,000 (65% are sigmoid) • Serious Complications – death or event requiring hospitalization (perforation, major bleeding, diverticulitis, severe abdominal pain, and cardiovascular events) – FSIG = 3.4 per 10,000 procedures – Colonoscopy = 25 per 10,000 procedures
  • 70.
    Risks of Screening •Conscious Sedation – FSIG = most performed without (some discomfort) – Colonoscopy = most performed with (cardiopulmonary complications are ~½ of all adverse events); patients will also miss a day of work and need a chaperone for transportation • Bowel Prep – FSIG = less intensive (complete or partial) – Colonoscopy = more intensive (complete required) – DCBE/CTC* = complete required, if same day colonoscopy not available a second bowel prep will be required
  • 71.
    Risks of Screening •False Reassurance from False-Negative Results (gFOBT/FIT) • Unnecessary Invasive Tests Due to False- Positive Results (CTC) – 10% of first-time CT colonographies found to have extracolonic abnormalities which may or may not be clinically significant; potential for both benefit & harm
  • 72.
    Risks of Screening •Radiation Exposure (CTC) – radiation exposure reported to be 10 mSv per CTC – at this level of exposure, 1 additional individual per 1000 would develop cancer in his or her lifetime – cumulative radiation risk should be considered in the context of the growing use of other diagnostic and screening tests that involve radiation exposure. – improvements in CT colonography technology and practice are lowering this radiation dose
  • 73.
    Flat Lesions • Describedin Japanese patients since 1980’s. Thought to be uncommon in the U.S. • Study published in March 2008 detected flat lesions at much higher rate than any previous U.S. reports • Colonoscopies in over 1800 veterans found: – Polyps in 37% – “Flat lesions” in 9.35% – 0.8% of flat lesions cancerous or pre-cancerous Soetikno, JAMA 2008
  • 74.
    Flat Lesions Caveats • Mostlesions not truly flat – Flat lesions found in only 6% – Cancer or pre- cancerous findings in only 0.3% Soetikno, JAMA 2008 New Sources of Risk Colorectal cancer prevention largely focuses on finding polyps, but flatter, less visible lesions that are not polyps are also cancer risks. Polyp Elevated lesion Flat lesion Depressed lesion The New York Times: Illustrations by JAMA
  • 75.
    Flat Lesions Implications forscreening • JAMA study led some to question the ability of CTC to detect flat lesions (although CTC was not utilized in the study) • Results from early CTC/flat lesion studies were extremely variable (sensitivity 13% - 65%) • Recent study of experienced radiologist using advanced technology and protocols found 80% sensitivity for flat lesions
  • 76.

Editor's Notes

  • #8 Colorectal cancer is a disease in which many DNA mutations associated with the process of carcinogenesis have been characterized. DNA is stable in the stool, it is shed continuously, and, through the use of amplification tests, such as polymerase chain reaction, can be detected in minute amounts. No single mutation has been found that is expressed in all colorectal cancers, but advances in technology have made it possible to examine the stool for an array of mutations. Mutational “hot spots” have been identified on K-ras, APC, and p53 genes, mutations on Bat-26 (a microsatellite instability marker) and long DNA. Methylated Vimentin has also surfaced as an important marker.
  • #12 Most or all of these have been recommended as CRC screening methods since at least 2003 by major health care organizations including: -American Cancer Society -U.S. Preventive Services Task Force -U.S. Multisociety Taskforce on Colorectal Cancer Screening
  • #39 Others = PillCam
  • #41 May be worse in real life: these were known trials, with generally expert performers (perhaps less emphasis in CT trial: no withdrawal time, bowel prep description etc) Withdrawal time emphasised by Barclay 2006 NEJM ONLY LAST STUDY BY VETERAN AFFAIRS HAD WITHDRAWAL TIME &amp;gt;6MINS in all cases
  • #44 Others = PillCam
  • #45 Others = PillCam
  • #47 Individuals and health care professionals should understand that screening tests for colorectal cancer broadly fall into two categories. In one category are the partial or full structural exams (endoscopic and radiographic) which directly or indirectly examine the colon lumen and wall, and are effective at detecting both cancer and premalignant adenomatous polyps. In the other category are the fecal tests, i.e., gFOBT, FIT, and sDNA, which are tests that primarily are effective at identifying colorectal cancer. Some premalignant adenomatous polyps may be detected, providing an opportunity for polypectomy and the prevention of colorectal cancer, but the opportunity for prevention is both limited and incidental and is not the primary goal of colorectal cancer screening with these tests.
  • #52 A study of over 2600 patients showed the extremely low sensitivity (4.9%) of the in-office FOBT done at the time of rectal exam. In other words, this approach missed 95% of significant abnormalities. This is in marked contrast to the much higher detection rates seen for the recommended 3-card, take home FOBT. Although the sensitivities (44% for cancers, 24% for all abnormalities) may still appear somewhat low, it is important to keep in mind that fecal occult blood testing on a one-time basis has never been purported to be of great value. The test derives it&amp;apos;s benefit from a program of screening over a number of years - which is why our guidelines explicitly state that if FOBT is the method chosen for screening it must be done annually.
  • #53 In a study published in the same journal, investigators found that nearly one-third of primary care physicians use the in-office FOBT as their primary method of screening. This was common among all types of primary care physicians (Family Medicine, Internal Medicine and Ob/Gyn). In addition, although the recommendations for follow up of a positive FOBT are clear and unequivocal (colonoscopy), a third of patients who reported having a positive fecal occult blood test stated that their doctor followed this positive with another FOBT, or they had no diagnostic work-up for this finding! Getting the best results from any test requires that the test be used as directed. Clearly, based on the findings from these nationwide surveys, many physicians are not following recommendations when it comes to FOBT.
  • #55 Knowledge of molecular genomics provides the basis of a new method of CRC screening that tests stool for the presence of known DNA alterations in the adenoma-carcinoma sequence of colorectal carcinogenesis. Adenoma and carcinoma cells that contain altered DNA are continuously shed into the large bowel lumen and passed in the feces. Because DNA is stable in stool, it can be differentiated and isolated from bacterial DNA found in the feces
  • #59 Li’s study did NOT specify separate findings for FIT and FOB positive cases. Therefore calculated numbers are optimum predicitve values (ie all cases of CRC and polyps were detected by each test
  • #60 CT colonography is an imaging procedure that uses computer programming to combine multiple helical CT scans in order to create two or three-dimensional images of the interior of the patients’ colon. These images can be rotated for different views and even combined for a complete view of the colon that can be “flown through.” The term “virtual colonoscopy” was coined in 1994 by researchers at Wake Forest University who described this procedure as simulating conventional colonoscopy. “CT colonography” has become the accepted medical terminology to describe the procedure, with “virtual colonoscopy” being used as the popular lay term.
  • #61 Adequate bowel preparation and gaseous distention of the colon are essential to insure a successful examination. Patients typically undergo full cathartic preparation along with a clear liquid diet the day before the study, similar to the requirements for colonoscopy. Tagging of residual solid stool and fluid with barium and/or iodine oral contrast agents is being increasingly used and validated in large trials. At CT, a small-caliber rectal catheter is inserted into the rectum, followed by automated or manual insufflation of room air or carbon dioxide. Intravenous contrast generally is not given to patients undergoing screening, but can be helpful in some patients with more advanced symptoms. Typically the entire procedure on the CT table takes approximately ten minutes, with no sedation or recovery time needed.
  • #62 Computer imaging graphics allow for visualization of 3D endoscopic flight paths through the inside of the colon, which can be simultaneously viewed with interactive 2D images. The integrated use of the 3D and 2D techniques allows for ease of polyp detection, as well as characterization of lesion density and location. The 2D images also allow for limited evaluation of the extracolonic structures.
  • #63 In 2005, two meta-analyses reviewed the cumulative published CTC performance data, including both high risk and screening cohorts, with one analysis representing 33 studies on 6393 patients.{Halligan, 2005 #60; Mulhall, 2005 #61} On a per-patient basis, pooled CTC sensitivity and specificity for large (≥ 10 mm) polyps was found to be 85-93% and 97%, respectively. Pooled sensitivity and specificity for detection of small polyps (6-9 mm) was 70-86% and 86-93%, respectively. Of note, the pooled CTC sensitivity for invasive colorectal cancer was 96%,
  • #64 The first large, multi-institutional screening trial using more advanced CTC techniques demonstrated very favorable performance. Pickhardt et al. studied 1233 asymptomatic adults and introduced the techniques of stool tagging and primary 3D polyp detection. This trial reported a 92.2% sensitivity for large adenomas, with a per-patient sensitivity for adenomas ≥ 6 mm of 85.7%.
  • #65 95% confidence interval in brackets
  • #66 Initial results from smaller screening trials {Cash, 2006, Graser 2006} have shown CTC performance characteristics similar to that of Pickhardt et al, providing at least a measure of independent validation for this screening technique. The recently completed American College of Radiology Imaging Network (ACRIN) Study 6664: National CT Colonography Trial, was sponsored and funded by the National Cancer Institute. The primary aim of this trial was to assess CTC performance for large adenomas and advanced neoplasia in a large screening cohort of more than 2,500 patients across 15 institutions. State-of-the-art technique includes oral contrast tagging, colonic distention with automated carbon dioxide delivery, multi-detector row CT (≥ 16 slice) with thin collimation, and both 2D and 3D polyp detection on dedicated CTC software systems. Nearly all patients had colonoscopy.
  • #67 Although the findings of this trial have not yet been published in the peer-reviewed literature, preliminary findings were announced at the 2007 annual meeting of ACRIN on September 28, 2007 Like the earlier Pickhardt study, these results demonstrated similar performance between CTC and OC, with per-patient sensitivity of 90% for advanced lesions 9 mm or larger, and 84% for 6-9 mm polyps. .
  • #68 Research into non-cathartic approaches to minimize the bowel preparation is underway, but this technique has not yet been validated in a multi-center screening trial. Under conditions where same-day or next-day referral for colonoscopy is possible, one drawback of non-cathartic CTC is that a cathartic bowel preparation would still be required prior to removal of polyps.
  • #69 Inappropriate management of incidental extracolonic findings could potentially compromise clinical care and cost effectiveness. The incidence of clinically significant extracolonic findings at CTC has ranged from 4.5-11% in various patient cohorts. In an asymptomatic screening population, the incidence of unsuspected but potentially important extracolonic findings is approximately 4.5 %, but findings of minimal or moderate potential clinical significance, such as cholelithiasis (6%) and nephrolithiasis (8%) are more common. Detection of major abnormalities (abdominal aortic aneurysm, renal cancer,…) is uncommon, but potentially lifesaving. Concerns have been raised about radiation dose, and potential harms from dose effects from CTC continue to be debated. Published CTC protocols employ radiation doses that are similar to the double-contrast barium enema. In a recent position statement issued by the Health Physics Society, the health effects of low-dose radiation exposure (defined as below 50-100 mSv - a threshold many times higher than typical CTC levels) were considered to be “either to small to be observed or are nonexistent”. Current ACR guidelines for CTC stress the use of low dose techniques for CT colonography will be essential to minimize radiation dose in screening and surveillance patients. There is consensus that all patients with one or more polyps ≥ 10mm or 3 or more polyps ≥ 6 mm should be referred for colonoscopy. Patients with one or two 6-9 mm polyps identified on CTC should be offered therapeutic colonoscopy. Patients who decline referral to colonoscopy or who are not good candidates for colonoscopy should be offered surveillance with CTC. In studies that have been limited to screening cohorts, among individuals whose largest polyp is 6-9 mm in size the prevalence of advanced features tends to be low (3.4 – 6.6%).{Kim, 2007; Moravec, 2007}. Optimal management of patients whose largest polyp is &amp;lt;6mm detected on CTC is controversial. Experts from AGA, ACG and ACR have reported a range of policies on how to handle these lesions.{American College of Radiology, 2006; Rex, 2006; Rockey, 2007}. In general, radiologist would prefer not to report lesions smaller than 5 mm seen at CTC, while gastroenterologist would prefer that all detected polyps be reported and patients referred for diagnostic/therapeutic colonoscopy. There is general agreement that the risk of advanced features in patients whose largest polyp is ≤ 5 mm is very low.
  • #75 In the JAMA study and elsewhere, flat lesions are defined as those growths that are wider than they are tall. In reality, most of these lesions are not totally flat; they may be elevated above the colon wall or depressed below the colon wall (appearing like a small crater). Obvious, detection may vary significantly depending on which of these forms a lesion takes.
  • #76 The focus of the JAMA study described in the preceding section was the detection of flat lesions by colonoscopy, and the shortcomings of colonoscopy as traditionally performed in the U.S. To date only a few studies have attempted to assess the ability of CTC to detect flat lesions. Results have varied widely, ranging from sensitivities of 13%-65% in early CTC studies {Fidler, 2002} to 80% sensitivity in the hands of experienced radiologists using advanced technologies (MDCT) and protocols (combined 3D-2D polyp detection) that are recommended today {Pickhardt, 2004}.