Colon Cancer Screening- Rationale Behind the Guidelines

Problem #1 42 y.o. asymptomatic caucasian woman presents requesting CRC screening. Her mom, 69 y.o. was recently was diagnosed with Stage II colon cancer. No other significant medical or family history. 42 y.o. asymptomatic caucasian woman presents requesting CRC screening. Her mom, 69 y.o. was recently was diagnosed with Stage II colon cancer. No other significant medical or family history. Do you screen her? Do you screen her? How? How?

Problem #2 No longer employed by the US government and in private practice in Mississippi, you are asked by your hospital system to make recommendations to improve CRC screening within your system. Screening rates in your area are in the 40-50% range. Would you: No longer employed by the US government and in private practice in Mississippi, you are asked by your hospital system to make recommendations to improve CRC screening within your system. Screening rates in your area are in the 40-50% range. Would you: A. Insist that more patients be referred for optical colonoscopy (OC)? A. Insist that more patients be referred for optical colonoscopy (OC)? Recommend the hospital invest in Virtual Colonoscpy? Recommend the hospital invest in Virtual Colonoscpy? Direct and give guidance for a stool based detection program, and if you do this what test would you recommend? Direct and give guidance for a stool based detection program, and if you do this what test would you recommend?

Overview The “scope” of the problem The “scope” of the problem Disease burden. Who do we screen? How do we screen? Disease burden. Who do we screen? How do we screen? The guidelines The guidelines ACG-2009 ACG-2009 ASGE Screening pts with + family history ASGE Screening pts with + family history USPSTF Stop screening at 75? 85? USPSTF Stop screening at 75? 85? Rationale Rationale “Preferred modality” vs. “Menu of Options” “Preferred modality” vs. “Menu of Options” Evidence Evidence

Screening Tests Ideal test depends Ideal test depends The disease The disease Common, high morbidity and mortality Common, high morbidity and mortality The test The test Early detection/treatment can prevent mortality Early detection/treatment can prevent mortality Screening test must be effective Screening test must be effective The population The population Resources in community to provide screening Resources in community to provide screening Screening methods accepted by patients and practitioners Screening methods accepted by patients and practitioners

The Disease Colorectal cancer (CRC) is the #2 cause of cancer death Colorectal cancer (CRC) is the #2 cause of cancer death 5-6% of Americans develop CRC 5-6% of Americans develop CRC 2009: 2009: 145,000 new cases of CRC 145,000 new cases of CRC 50,000 deaths 50,000 deaths

Colon Cancer Well defined disease progression Well defined disease progression Treatable precancerous lesion Treatable precancerous lesion

How to screen?

How Do We Screen? Colon cancer prevention (ACG 2009) Colon cancer prevention (ACG 2009) Colonoscopy Colonoscopy Flexible sigmoidoscopy Flexible sigmoidoscopy CT colonography (CTC) CT colonography (CTC) DCBE DCBE Colon cancer detection (ACG 2009) Colon cancer detection (ACG 2009) FOBT FOBT FIT FIT sDNA sDNA

The Guidelines-ACG Prevention is better than detection. Optical colonoscopy (OC) is best. Prevention is better than detection. Optical colonoscopy (OC) is best.

The Guideline USPSTF Any screening is better than none Any screening is better than none “The USPSTF recommends screening for colorectal cancer using fecal occult blood testing, sigmoidoscopy, or colonoscopy in adults, beginning at age 50 years and continuing until age 75 years. The risks and benefits of these screening methods vary. “ “The USPSTF recommends screening for colorectal cancer using fecal occult blood testing, sigmoidoscopy, or colonoscopy in adults, beginning at age 50 years and continuing until age 75 years. The risks and benefits of these screening methods vary. “

Guidelines Points of significant departure Points of significant departure Preferred modality vs. menu of options Preferred modality vs. menu of options Early screening and interval colonoscopy for family history of polyps Early screening and interval colonoscopy for family history of polyps Age to stop screening Age to stop screening Virtual colonoscopy Virtual colonoscopy FIT vs. FOBT vs. sDNA FIT vs. FOBT vs. sDNA

Colonoscopy Pros Pros Examines entire colon Examines entire colon Detects precancerous lesions Detects precancerous lesions Can apply therapy Can apply therapy 10 year interval in average risk patients 10 year interval in average risk patients Cons Sedation Prep Invasive

Preferred modality-OC Substantial but indirect evidence that OC with polypectomy reduces mortality from CRC Substantial but indirect evidence that OC with polypectomy reduces mortality from CRC Thiis-Everson et al Scand J Gastrol;1999;34:

Preferred modality-OC Winawer et al. National Polyp Study: NEJM 1993 Winawer et al. National Polyp Study: NEJM 1993 Mueller et al. VA Cohort study: Annals 1995 Mueller et al. VA Cohort study: Annals 1995

Preferred modality-OC Complete exam offers durable risk reduction Complete exam offers durable risk reduction Brenner H et al. Gut 2006;55:

Preferred Modality OC Detect lesions not seen on sigmoidoscopy Detect lesions not seen on sigmoidoscopy Rex et al GIE 1999 Rex et al GIE 1999 Lieberman et al, NEJM VA prospective cohort Lieberman et al, NEJM VA prospective cohort Jass et al. Clin Gastro-Hep Hyperplastic polyps, serrated adenomas, DNA methylation, mismatch repair genes Jass et al. Clin Gastro-Hep Hyperplastic polyps, serrated adenomas, DNA methylation, mismatch repair genes Lieberman et al. NEJM 2000;343:162-8

Is colonoscopy available? CRC in U.S reduces life expectancy, people aged years by 292 days. CRC in U.S reduces life expectancy, people aged years by 292 days. 2.9 to 6.0 colonoscopies per life year saved 2.9 to 6.0 colonoscopies per life year saved FOBT then Colo: FOBT then Colo: 1yr to 10 years to screen entire U.S population 1yr to 10 years to screen entire U.S population Inadomi & Sonnenberg GIE 2000 Seef et al. Gastro 2004

Colonoscopy and Polypectomy

Colonoscopy. Who? When? Average Risk: 10 year intervals. Average Risk: 10 year intervals. Black men and women, beginning at 45 Black men and women, beginning at 45 White men and women, beginning at 50 White men and women, beginning at 50 Single first degree relative with CRC or advanced adenoma Single first degree relative with CRC or advanced adenoma > 60 years at diagnosis: > 60 years at diagnosis: 10 year interval beginning at age year interval beginning at age 50. < 60 at diagnosis: < 60 at diagnosis: Colonoscopy every 5 years beginning at age 40 or 10 years younger than youngest affected individual Colonoscopy every 5 years beginning at age 40 or 10 years younger than youngest affected individual

The Guidelines-ACG If no HNPCC but + family history (cancer or advanced adenoma); early screening for 1 st degree and age < 60. If no HNPCC but + family history (cancer or advanced adenoma); early screening for 1 st degree and age < 60.

The Guideline ASGE

Family History of Advanced Adenoma or CRC ConditionScreening Recommendations Single 1 st degree relative with CRC or advanced adenoma > age 60 Same as average risk* Single 1 st degree relative with CRC or advanced adenoma < age 60 Begin at 40 or 10 years prior to diagnosis and then every 5 years Two or more 2 nd degree relatives with CRC or advanced adenoma Begin at 40 or 10 years prior to diagnosis and then every 5 years

Who do we screen? General population6% General population6% One 1 st degree relative with: One 1 st degree relative with: Advanced Adenoma12% Advanced Adenoma12% CRC12-18% CRC12-18% CRC diagnose before age % CRC diagnose before age % Two FDR with CRC18-24% Two FDR with CRC18-24% One 2 nd or 3 rd degree, CRC9% One 2 nd or 3 rd degree, CRC9% Two 2 nd degree, CRC12-18% Two 2 nd degree, CRC12-18%

Probability of Invasive CR cancer by Age and Gender Age (years)Men (%)Women (%) < (1/1,296)0.07 (1/1343) (1/109)0.72 (1/138) (1/65)1.10 (1/138) (1/22)4.16 (1/24) Lifetime5.51 (1/18)5.10 (1/20) Risk of death from CRC Lifetime 2.45 (1/41) Cancer Statistics, CA Cancer J Clin. 2009;59:

History of polyps Patients with personal hx of small TA is at no increased risk for CRC over the general population Patients with personal hx of small TA is at no increased risk for CRC over the general population Increased CRC risk correlates with size, villous histology, and number of adenomas Increased CRC risk correlates with size, villous histology, and number of adenomas Atkin WS et al. NEJM 1992 Atkin WS et al. NEJM ,464 patients w/ flex sig and 14 year follow up 22,464 patients w/ flex sig and 14 year follow up Polyps Seen# Incident CRC (IR) <1cm, not villous and < 3 4/7776 (0.5) >1cm, villous, or >3 31/842 ( )

Personal History of Polyps Condition Surveillance recommendations Sporadic hyperplastic polypsAverage risk screening recs 1-2 small adenomas5-10 years 3-10 adenomas or 1 adenoma > 10 mm or any villous or high- grade dysplasia 3 years and then every 5 years >10 adenomas<3 years Incomplete resection2-6 months

CRC African Americans Black Americans are 43% more likely to die of colon cancer Black Americans are 43% more likely to die of colon cancer Rates of CRC in whites down 20-25% since Rates for blacks are increasing Rates of CRC in whites down 20-25% since Rates for blacks are increasing

CRC Obesity CRC risk increased obesity by fold CRC risk increased obesity by fold NIH-AAPR cohort study¹ NIH-AAPR cohort study¹ BMI increases CRC risk at young age (50-66) BMI increases CRC risk at young age (50-66) Risk higher in men than women who are obese Risk higher in men than women who are obese Meta-analysis: Obesity 33% higher risk CRC ² Meta-analysis: Obesity 33% higher risk CRC ² 1. Gunter MJ. J Nutr Biochem Bergstrom et al. Int J Can 2001

CRC Smoking Possibly 30% increased risk in smokers Possibly 30% increased risk in smokers > 20 pack years has 2-3x risk > 20 pack years has 2-3x risk Increase in advances adenomas and early cancers in smokers detected by colonoscopy Increase in advances adenomas and early cancers in smokers detected by colonoscopy Gianvannucci E. Cancer Epidemiol Biomarkers Prev 2001;10:725-31

What Am I Missing? Tandem colonoscopy- Meta analysis Tandem colonoscopy- Meta analysis Any size 22%, ≥ 10mm 2.1%, 5-9 mm 13%, 1-4 mm 26% Any size 22%, ≥ 10mm 2.1%, 5-9 mm 13%, 1-4 mm 26% CTC and OC tandem study CTC and OC tandem study OC prior to un-blinded CTC OC prior to un-blinded CTC Missed 55 of 511 polyps (10.8%) Missed 55 of 511 polyps (10.8%) Missed 21 of 210 adenomas >6mm Missed 21 of 210 adenomas >6mm Missed 5 of 51 adenomas > 1cm Missed 5 of 51 adenomas > 1cm 71+% missed colon adenomas on proximal fold 71+% missed colon adenomas on proximal fold Van Rijn JC. Am J Gastro 2006;101: Pickhardt, Annals 2004; 349: 219

Right Sided CRC and Colonoscopy Baxter et al, Ann Intern Med Jan 6;150(1):1-8. Attempted colonoscopy Attempted colonoscopy All cancer – OR of 0.69 ( ) All cancer – OR of 0.69 ( ) Right sided – OR of 1.07 ( ) Right sided – OR of 1.07 ( ) Left sided – OR of 0.39 ( ) Left sided – OR of 0.39 ( )

Colonoscopic Withdrawal Times 2053 screening colonoscopies * P<0.05 for all comparisons (>6 vs. <6 min) % * * * Barclay RL, et al. N Eng J Med. 2006;355:2533

Screening High Risk Populations ConditionSurveillance FAP or suspected FAPBegin age with annual flex sig or colo as appropriate Consider colectomy Genetic or clinical diagnosis of HNPCC Begin age (or 10 years prior youngest family member with cancer) and then colonoscopy every 1-2 years Inflammatory Bowel DiseaseBegin 8 years (pancolitis) or years (left-sided colitis) with colonoscopy every 1-2 years

The Guidelines-ACG FAP and HNPCC FAP and HNPCC Genetic testing Genetic testing

Post-CRC Surveillance “High quality” peri-operative clearing colonoscopy “High quality” peri-operative clearing colonoscopy Repeat intervals Repeat intervals 1 year after resection 1 year after resection 3 years later 3 years later 5 years later 5 years later

Alternative Prevention Tests Flexible Sigmoidoscope Flexible Sigmoidoscope Every 5-10 years Every 5-10 years Computed Tomographic Colonoscopy (CTC) Computed Tomographic Colonoscopy (CTC) Every 5 years Every 5 years

Computed Tomographic Colonoscopy (CTC)

CT Colonography Cons Prep Reproducibility Radiation 5 year interval Reimbursement/Cost Pro Pro No sedation No sedation Detects precancerous lesions Detects precancerous lesions Extra colonic findings Extra colonic findings

3D Multicenter Trial CT Colonography Multicenter – military hospitals Multicenter – military hospitals 1233 asymptomatic patients 1233 asymptomatic patients 10mm8mm6mm 10mm8mm6mm CT Sens AD by pt 94%94%89% CT Sens AD by pt 94%94%89% OC Sens AD by pt 88%92%92% OC Sens AD by pt 88%92%92% CT Specificity 96%92%80% CT Specificity 96%92%80% Pickhardt, NEJM 2003; 349: 2191

Copyright ©Radiological Society of North America, 2005 Zalis, M. E. et al. Radiology 2005;236:3-9 C-RADS

Copyright ©Radiological Society of North America, 2005 Zalis, M. E. et al. Radiology 2005;236:3-9 E-RADS

Screening CTC Cost Effectiveness CTC is cost effective compared to no screening CTC is cost effective compared to no screening CTC is effective but expensive compared to OC CTC is effective but expensive compared to OC

CTC and Polypectomy No CRC reductions without polypectomy No CRC reductions without polypectomy C-RADS 2 (intermediate polyps) choice for colonoscopy vs. surveillance C-RADS 2 (intermediate polyps) choice for colonoscopy vs. surveillance Repeat CTC in 3 years for intermediate polyps Repeat CTC in 3 years for intermediate polyps Models suggest this will lead to 65 deaths and 735 cancers/100,000 compared to immediate referral for colonoscopy Models suggest this will lead to 65 deaths and 735 cancers/100,000 compared to immediate referral for colonoscopy Hur Cet al. Clin Gastroenterol Hep 2007;5:237-44

CTC Cost Effectiveness of Polypectomy Pickardt et al. Am J Rad Pickardt et al. Am J Rad Polypectomy for small polyps not cost effective Polypectomy for small polyps not cost effective

Flexible Sigmoidoscopy Pros Pros Easier prep Easier prep Technically easier procedure Technically easier procedure Less expensive Less expensive No sedation No sedation Cons Prep often limits exam Higher miss rates No sedation Limited extent of exam

Double Contrast Barium Enema (DCBE) Essentially no data for screening Essentially no data for screening Not recommended by ACG guidelines Not recommended by ACG guidelines DCBE replaced by CTC DCBE replaced by CTC Negative predictive value is low Negative predictive value is low May be useful if CTC not available May be useful if CTC not available

Cancer Detection Tests Offer only if cancer prevention test unavailable Offer only if cancer prevention test unavailable Fecal immunochemistry, FIT testing is preferred Fecal immunochemistry, FIT testing is preferred FOBT FOBT sDNA sDNA

Fecal Occult Blood Test (FOBT) Pros Pros Proven effective in randomized trials Proven effective in randomized trials Non-invasive Non-invasive Cost-effective Cost-effective Cons Relatively low mortality reductions (15-33%) High false positive Evaluation of pos results often inadequate Overused Mandel et al, N Engl J Med 1993;328:1365 Jorgensen et al, Gut 2002;50:29 Scholefield et al, Gut 2002;50:840 Lurie, Welch, J Natl Cancer Inst 1999;91:1641

False Positives and FOBT Foods Foods Red meat, turnips, broccoli, horseradish Red meat, turnips, broccoli, horseradish Drugs Drugs Colchicine, NSAIDs, anti-coagulants, iron supplements, reserpine, oxidizing agents Colchicine, NSAIDs, anti-coagulants, iron supplements, reserpine, oxidizing agents Recent dental procedures Recent dental procedures Sample obtained by DRE Sample obtained by DRE

Flex Sig plus FOBT Little data Little data VA Cooperative study (CONcERN) VA Cooperative study (CONcERN) Advanced lesions Advanced lesions Flex sig sens – 40-70% Flex sig sens – 40-70% FOBT sens – 24% FOBT sens – 24% Flex sig + FOBT – 45-76% Flex sig + FOBT – 45-76% Lieberman DA, et al, NEJM 2000 Schoenfeld et al, NEJM 2005

Preferred Detection Test FIT FIT has comparable sensitivity and higher specificity than FOBT = < false positives FIT has comparable sensitivity and higher specificity than FOBT = < false positives Easier to perform, no dietary restrictions Easier to perform, no dietary restrictions Improved compliance = better use of positives Improved compliance = better use of positives

Preferred Detection Test FIT Nakajima M et al. Br J Cancer 2003;89:23-8

FIT vs. FOBT ~10,300 in each arm 12.7% more FIT tests returned Cancers FOBT- 11 FIT- 24 Number to scope detection to detect cancer were similar Overall detection rates for adenomas and cancers, FIT is superior

Stool DNA Testing Detects DNA shed from cancers and adenomas Detects DNA shed from cancers and adenomas 5 targets – K-RAS, P53, APC, BAT-26, long DNA 5 targets – K-RAS, P53, APC, BAT-26, long DNA Sensitivity Sensitivity Cancer – 52% Cancer – 52% Advanced adenoma – 15% Advanced adenoma – 15% Specificity – 94% Specificity – 94% Feasibility and cost are major issues Feasibility and cost are major issues

Screening Intervals – Average Risk Colonoscopy – 10 years Colonoscopy – 10 years CTC – 5 years CTC – 5 years DCBE – 5 years DCBE – 5 years Flex Sig – 5 years Flex Sig – 5 years FIT, sDNA, FOBT – 1 year FIT, sDNA, FOBT – 1 year

Stopping Screening-USPSTF Cancer Intervention and Surveillance Modeling Network (CISNET) Cancer Intervention and Surveillance Modeling Network (CISNET) Life years saved outweighs costs and harms in patients years undergoing FOBT, flex sig, colonoscopy in US persons aged Life years saved outweighs costs and harms in patients years undergoing FOBT, flex sig, colonoscopy in US persons aged No clear benefit in these models after age 75. No clear benefit in these models after age 75.

Questions?