Smoking and Colorectal Cancer Neoplasia: Implications for Screening ?

1. Smoking and Colorectal Cancer Neoplasia: Implications for Screening ? Joseph Anderson, M.D. Sept 19, 2008

2. Adenoma to Carcinoma Pathway Normal Adenoma Cancer APC loss K-ras mutation Chrom 18 loss p53 loss Normal Epithelium Hyper- proliferation Early Adenoma Intermediate Adenoma Late Adenoma Cancer

3. ACS New Categories for Screening for Colorectal Neoplasia • Tests that detect polyps as well as cancer • Colonoscopy • Flex Sig • CTC • DCBE • Tests that detect primarily cancer • Guaiac tests • Immunochemical based tests • Stool DNA

4. Polyp Characteristics • Histology; Villous, Tubular, TV or Hyperplastic • Size: 1 cm or more significant • Location; Right or Left by the Splenic Flexure • Dysplasia; Every adenoma is dysplastic and High Grade Dysplasia is Carcinoma • Morphology; Flat or Protruding

5. Advanced Adenoma • Villous tissue • Any Adenoma > 1 cm • Adenocarcinoma • High Grade Dysplasia

6. What are the risk factors for colorectal neoplasia?

7. Risk Stratification for Colorectal Cancer Screening • Age • Family history of CRC • Other factors ?

8. Race, Gender and Colorectal Cancer Screening • Males at 50 years have similar risk to women at 55 • American College of Gastroenterology called for consideration of screening African Americans at 45 years • Should we be targeting high risk individuals? Lieberman AJG 2007

9. Other Important Risk Factors • Gender • Smoking • Body Mass Index • Alcohol Use • Diabetes Mellitus

10. Smoking and Cancer • Burning of tobacco produces genotoxic compounds • These compounds include aromatic hydrocarbons, heterocyclic amines and nitrosamines • Associated with lung, stomach, bladder, pancreas

11. Smoking Exposure • Total in Pack Years = Packs per x Years • Intensity: packs per day • Duration: years smoked • Years since quitting • Change in pattern • Smokers are good at recall Martinez et al Prev Med 2004

12. Smoking and CRC • Smoking had been linked with many cancers • Early studies (1950’s and 1960’s) did not show association between smoking and CRC • Adenomas studies in 1980’s and 1990’s showed positive correlation

13. Why the lack of association between CRC and smoking? • Smoking increases risk for precursor but not the cancer • Lag time may be long (35 years?) • Recent studies show association • 15/16 show association between CRC and smoking • Above true for men if study after 1970 and 1990 for women Giovannucci et al 2001

14. Smoking and CRC • Detection of adenomas changed literature • Studies examined duration, past smoking, total pack years • 21/22 studies showed association between smoking and adenomas • Disagreement regarding exposure level Giovannucci et al 2001

15. Smoking as a high risk factor? • Definite association between CRC and smoking not accepted by all • Some argue that relationship has less than two fold risk so confounding variables can not be excluded • Risk for adenomas 2-3 fold risk • Lag time: 40 years for CRC and 25 years for adenomas Giovannucci et al 2003

16. Smoking and Colorectal Neoplasia • Smoking is associated with an increased risk for CRC • Giovannucci has suggested that smokers may be considered a high risk group • Zisman et al found that smokers with CRC were younger than non-smokers Arch Int Med 2006 • Impact in screening population less established

17. Identification of Risk Factors Colorectal Neoplasia and Their Relative Importance • Risk Modification • Triage of Screening Resources • Risk stratification for screening

18. CRC and Smoking as of 2000

19. Limitations of Studies • Symptomatic populations • Not all had endoscopy of full endoscopy • Relevance to adenomas (New ACS rec)

20. Relative importance of risk factors for colorectal neoplasia: Need asymptomatic population

21. VA Cooperative Study Group 380 • 3121 asymptomatic patients • Colonoscopy performed on all • Risk factors examined • Compared those with advanced adenomas versus those without any neoplasia

22. Risk Factors for Colonic Neoplasia Lieberman et al JAMA 2003

23. VA 380 Risk Factors for Colonic Neoplasia in 3191 Male VA Patients Family hx of CRC :OR=1.66 95% CI:1.16-2.35 Current Smoking: OR=1.85 95% CI:1.33-2.58 Lieberman et al JAMA 2003

24. CONCeRN • 1463 women • Aged 50 to 79 years • Full colonoscopy performed on all

25. CONCeRN Trial

26. Risk Factors for Advanced Adenomas in CONCeRN Trial

27. CONCeRN vs VA 380 Schoenfeld et al DDW 2006

28. Use of Colonoscopy as a Primary Screening Test for Colorectal Cancer in Average Risk People • 2210 consecutive patients • Older than 40 years of age • Examined variables other than age • Developed a score assigning points for significant factors examining advanced adenomas Betes et al AJG 2003

29. Results of Multivariate Analysis Betes et al AJG 2003

30. Results of Betes Trial • Age and Gender significant factors • BMI significant as well • Did not include smoking

31. SBU Cross-Sectional Study • Began in 1999 to examine known risk factors in consecutive patients • All patients undergoing screening • Includes patients older than 40 years • Currently 2707 patients • Analysis performed after 2000 and 2500 patients enrolled

32. Methods • Data are collected by nurse practitioner as part of our routine colorectal cancer risk assessment and modification • Questions based on Behavioral Risk Factor Surveillance System • Data entered to standard form in patients chart • Validation of data by endoscopist • Patients with symptoms are excluded • After endoscopy, data (including pathology results) are collected from chart into data base

33. Data collected in office • Demographics: Age, gender, height, weight, ethnicity and educational status • Family history of colorectal neoplasia • Smoking history • Alcohol use • NSAID use • Symptoms • Lifestyle: exercise, fruit/vegetable intake, red meat intake

35. Demographics of Smoking Groups Anderson et al AJG 2003

36. Endoscopic Findings Anderson et al AJG 2003

37. Risk of Neoplasia in Screening Population Anderson et al AJG 2003

38. Risk of Neoplasia in Screening Population

39. Botteri et al Gastro 2008

40. What data is needed to establish smoking as a “high risk factor”? • Overall risk for colorectal neoplasia is high • Risk is high relative to other risk factors • Risk is high in younger patients especially those less than 50 years • Exposure level • Do they require colonoscopy of is flex sig adequate?

41. Distribution of Colorectal Lesions Transverse 15% Ascending 25% Cecum Descending 5% Sigmoid 25% Rectum 20% Rectosigmoid 10%

42. Who may harbor isolated proximal neoplasia ? Anderson et al AJG, 2004

43. Pack Years vs Risk for SCRN DDW 2007

44. Smoking and Colorectal Neoplasia After multivariate analysis BMI, Fam Hx and Age Anderson et al JCG (In Press)

45. Prevalence and Risk of Significant Neoplasia in Patients 40 to 50 years of Age Anderson et al JCG 2009 P<0.003; OR results of MV analysis controlling for BMI, Fam Hx and gender

46. Average Age of Patients with Significant Colorectal Neoplasia • Smokers: 59.5 years • Non-Smokers: 62.5 years p<0.04

47. Risk and Gender

48. Flat Adenomas • Flat or depressed lesions • Height < 1/2 diameter • Typically smaller than polypoid lesions • Aggressive nature

49. Rex et al Gastro Dis 2006

50. Normal cecum ?