Colorectal cancer is one of the most common cancers around the world. Screening has been proven to detect cancers in early curable stages, and to even prevent them. Yet, few topics are as controversial as colorectal cancer screening in medicine today. We take an evidence based approach to examine what the science truly says about the different modalities of cancer screening.

1. Colorectal Cancer Screening
What does the Evidence Really Say?
Dr Jarrod Lee
Gastroenterologist and Advanced Endoscopist
Mount Elizabeth Novena Hospital

2. Scope
• Overview of CRC
Screening
• Screening Modalities:
– FOBT
– CTC
– Colonoscopy
• Quality Colonoscopy
• Final Words
2

3. Colorectal Cancer in Singapore
• Most frequent cancer in males, 2nd in females
• 1 400 patients per year
• Latest age standardized rates:
– 39.6 per 100 000 person-yrs in males
– 27.6 in females
• Latest age standardized mortality rates:
– 16.5 per 100 000 person-yrs in males
– 10.8 in females
3Singapore Cancer Registry Interim Annual Registry in Report 2007-2011

4. • Cancer trends from 1998-2009
• CRC incidence stable last decade:
– Higher than UK, USA, Western Europe
• Slight decline in age standardized mortality rate
& 5 yr survival:
– Attributed to better treatment rather than screening
– Mortality rates higher than UK, USA, Western Europe
– Survival rates comparable
4

5. Colorectal Cancer (CRC) Screening
• One of the most controversial areas in digestive
diseases
• 100,000 Pubmed references
– 25,000 Pubmed references last 5 yrs
• Many new/ revised guidelines by major
international organizations last 4 yrs:
– US MSF, NCCN, US PSTF, ACG, BSG, APWG, ACS,
ACP, EUG
5

6. The Argument for CRC Screening
• CRC is highly curable with 5 yr survival:
– >90% localized disease
– 70% regional disease
– <10% metastatic disease
• Most (>80%) occur in average risk individuals
• No reliable early symptoms  screening is only
way for early detection
6

7. When to Start?
• Average risk: 50 yrs
• Family history CRC:
– 1x 1st degree relative >60 yrs or 2x 2nd
degree relatives: 40 yrs
– 1x 1st degree relative <60 yrs or 2x 1st
degree relatives: 40 yrs or 10 yrs before
youngest case
– Applies to both CRC & advanced polyps
(high grade dysplasia, villous features,
size >1 cm)
7

8. When to Stop?
• Average lead time for adenoma to CRC:
10 yrs
• Consider life expectancy & benefit from
surveillance
• Surveillance until 75 yrs, then continue
depending on risk & co-morbidities
8

9. 9
Screening
Modalities

10. How to Screen?
• Tests that detect cancer
– Annual fecal occult blood
• Tests that detect adenomas & cancer
– Colonoscopy every 10 yrs
– CTC, flexible sigmoidoscopy every 5 yrs
• If above average CRC risk: colonoscopy
• Otherwise, 2 approaches described:
– “Menu of Options” vs “Colonoscopy First”
10

11. Fecal Occult Blood Test (FOBT)
11

12. FOBT Considerations
• 2 Types:
– Guaic FOBT (GFOBT)
– Fecal Immunochemical Test (FIT)
• Need to be repeated at regular intervals to be
effective; one time test ineffective
• Less likely to prevent cancer
• If abnormal, will need colonoscopy
• Limited compliance: 53-67%
121. BMJ 1998; 317: 559-65

13. • 50-80yrs participants randomized to FOBT vs
control (N = 46 551); 13 year follow up
• 13 year cumulative mortality from CRC
decreased by 33% in annual FOBT group
13BMJ 1998; 317: 559-65

14. • Subsequently, several large RCTs using GFOBT:
– Minnesota, Nottingham, Funen RCTs
– N = 46 551; 152 850; 137 485 respectively
– 15-33% decrease in CRC mortality rate
• Meta-analysis of 6 trials: 16% reduction in CRC mortality
14NEJM 2000; 343: 1603-7 Lancet 1996; 348: 1472-7 Lancet 1996; 348: 1467-71
BMJ 1998; 317: 559-65

15. FOBT is the
screening modality
of choice in many
programs
15

16. CT Colonography
16

17. • 2 600 asymptomatic patients, 15 centres
• CTC & colonoscopy same day
• Endoscopist blinded to CTC
17

18. ACRIN Trial
• Sensitivity vs colonoscopy:
– ≥10 mm lesions: 90%
– 5-9 mm: 65%
• Specificity: 86% for ≥10 mm lesions
• Colonoscopy referral rate for >5 mm: 12%
• Similar sensitivities in other trials:
– ≥10 mm: ≥90% (similar to colonoscopy)
– 5-9 mm: 70%
– <5 mm: <50%
18

19. CTC = Virtual Colonoscopy
• No pain, no prep, no risk
Not True!
• Discomfort:
– Gas inserted through rectal tube; need to change
position & breath hold
– No sedation; discomfort worse than colonoscopy in
some studies
• Full preparation needed; similar to colonoscopy
• Perforation risk: 0.05%
19

20. CTC Limitations
• Missed lesions: flat polyps, small polyps
• Impact of missed small polyps:
– 29-33% of high risk adenomas would be missed due
to size <5 mm
– 18-23% of high risk adenomas would be missed due
to size 6-9 mm
• Incidental extra-colonic lesions in 27-69%
– Additional work up may be required
– Significance & burden uncertain
20Am J Gastroenterol 2009; 104(1): 149-53 Clin Gastroenterol Hepatol 2007; 5(2): 237-44

21. • 10-20 mSv per CT (500-1000x plain XR)
• Single dose of 10 mSv  lifetime attributable risk
of 1:1000 for solid cancer/ leukaemia
• Risk is cumulative & extended
• 1.5-2.0% of cancers in US attributed to radiation
21NEJM 2007; 357: 2277-84

22. • Non cathartic bowel prep, low dose radiation protocol
• 8 833 members of general population, primary screening
• CT colonography had better participation rate
– 34% vs 22%; RR 1.56; P <0.0001
• Diagnostic yield for advanced neoplasia
– Colonoscopy higher per participant: RR 1.46, P =0.02
– Similar per invitee: RR 0.74, P =0.07
22Lancet Oncol 2012; 13: 55-64

23. Colonoscopy
23

24. Colonoscopy
• Considered „gold standard‟
• Allows complete examination of colon, resection
of polyps, biopsy for histology
• Final common pathway of screening programs
• Able to „prevent cancer‟
• Screening benefit:
– 53-72% reduction in CRC incidence
– 31% reduction in CRC mortality
– Based on cohort & case control studies
24

25. Limitations
• High cost
• Limited access
• Bowel preparation
• Highly operator dependent
• Complications:
– Perforation: <0.3%
– Thermal injury: 0.2%
– Bleeding: <2%, including delayed bleeding
– Sedation + cardiopulmonary risks: <1%
25

26. Does It Really Work?

27. • Patients with complete colonoscopy + ≥1 adenoma
removed (N = 1 418); average follow up 5.9 yrs
• Subsequent periodic colonoscopy: 1 + 3 yrs or 3 yrs
• CRC incidence compared to general population & polyps
not removed: lower by 76% & 88-90% respectively
27

28. • Population based case control study; N = 35 975
• CRC standardized incidence rate (SIR) compared to
general population
28JAMA 2006; 295 (20): 2366-73

29. Standardized Incidence Ratio
• CRC SIR: 0.66 at 1 year, 0.28 at 10 years
• Percentage of right sided CRC higher in colonoscopy
cohort (47% vs 28%, p <0.001)
29

30. • Population based case control study
– Patients with CRC mortality analyzed for previous
colonoscopy vs no colonoscopy
– 10 292 case patients; 51 460 controls
• Colonoscopy associated with:
– Fewer deaths from left sided CRC (OR 0.33)
– No difference for right sided CRC (OR 0.99)
• Results replicated in other studies since
30Ann Intern Med 2009; 150: 1-8

31. 31
Why the Variance?

32. Interval Cancers
• CRC rarely detected within 5 yrs of normal
baseline colonoscopy
• Interval cancers arise from1:
– Missed lesions: 52%
– New lesions: 24%
– Incompletely removed lesions: 19%
• 7.9% of CRC are interval cancers2
– 1 in 13 CRC result from missed lesions at colonoscopy
(done within 3 yrs)
321. Gastroenterology 2008; 134: A-111-2 2. Am J Gastroenterol 2010; 105(12): 2588-96

33. Missed Lesions
• Largest cause of interval cancers
• Missed polyps: overall rate 22%
– 6-12% for >10 mm; 25-50% for >5 mm
• Factors:
– Poor bowel preparation
– Flat polyps
– Operator Factors
33

34. Poor Bowel Preparation
• Higher rate of missed lesions:
– Per adenoma miss rate 47.9% (18% high risk)
– Lower detection of small (OR 0.84) & diminutive (OR
0.57) polyps
• Minimum standard for CRC screening program:
– 90% good preparation (Target: 95%)
34

35. Flat Polyps
• Present in 9.4% of subjects
• 10x more likely to contain cancer
35
JAMA 2008; 299: 1027-35

36. 36
Operator Factors

37. 37
• Colonoscopy based CRC screening program with 186
endoscopists; 45 026 subjects
• Study effect of Cecal Intubation Rate & Adenoma
Detection Rate (ADR) on risk of interval cancer
NEJM 2010; 362: 1795-803

38. Adenoma Detection Rate (ADR)
ADR is an independent predictor of the risk of
interval CRC after screening colonoscopy
38
ADR Hazard Ratio
≥ 20.0% 1.00
15.0 – 19.9% 10.94
11.0 – 14.9% 10.74
< 11.0% 12.5
Months

39. • Population based observational study
• Patients with CRC & colonoscopy within 36 months of
diagnosis (n = 14 064)
• Interval cancers: overall 9%
– More in proximal vs distal cancers: 12.4% vs 6.8%
– Lower in proximal CRC if previous colonoscopy by
done by high PDR endoscopist: OR 0.61, p <0.0001
39Gastroenterology 2011; 140: 65-72

40. • Population based case control study
• CRC cases vs controls with adenoma detected at
colonoscopy in past 10 yrs
• Cases (n= 3 148) & controls (n=3 274) examined for
colonoscopy & polyp related factors
• 41.1% of CRC due to colonoscopy factors, 21.7% due to
polyp factors  colonoscopy factors more important
40Ann Intern Med 2012; 157: 225-32

41. Specialist Training Standards
• Endoscopy training standards differ by specialty
• Studies show gastroenterologists (GE) better:
– Non GE 5x more likely to miss cancer1
– Non GE 70-330% more interval CRC over 3 yrs2
– Surgeon 40% more interval CRC over 5 yrs3
– Colorectal surgeon 45% more interval CRC4
• “Head to head” study
– GE vs GS trainees, >2nd yr; 3 079 colonoscopies
– GE significantly better ADR: 14% vs 9% (p =0.0065)
41
1. Gastroenterol 1997; 112: 17-23 2. Am J Gastroenterol 2010; 105: 663-73
3. Clin Gastoenterol Hepatol 2010; 8: 275-9 4. Cancer 2012; 118: 3044-52
5. Endoscopy 2011; 43: 935-40

42. • Population based study: patients with CRC mortality
• „Exposure‟ to colonoscopy > 6 mths before diagnosis
• CRC mortality cases less likely „exposed‟ to colonoscopy
vs controls: 11.3 v 23.7%; OR 0.4
• Stronger association for gastroenterologist vs surgeon:
OR 0.35 vs 0.55 (1.00 if no colonoscopy)
42J Clin Oncol 2012; 30(21): 2664-9

43. 43
Dated 2011

44. 44
Other Considerations

45. • 787 000 individuals in Singapore aged 50-75 yrs
• Age standardized CRC rate of 30-40 per 100k in 2009
• Markov modelling to study outcomes, cost effectiveness
& net health benefit
45

46. Net Health Benefit
• Single
sigmoidoscopy
best at low WTP
• 10 yearly
colonoscopy at
high WTP
• FOBT from 50-60
yrs & colonoscopy
from 60-75 yrs
may be best
balance
46

47. • 997 participants, average CRC risk
• Randomized to colonoscopy, FIT or personal choice
• Adherence to colonoscopy lower than FIT or personal
choice (38% vs 67% vs 69%, p <0.001)
• Conclusion:
– Recommending colonoscopy decreases compliance
– Patient preference should be considered
47Arch Int Med 2012; 172 (7) : 575-82

48. 48
Final Answer?

49. • NPS patients (1980-90) with adenomas (n=2 602;
median follow up 15.8 yrs)
• Compared to CRC mortality in general population
• 53% reduction in mortality
49

50. • RCT in asymptomatic adults 50-69 yrs, n = 57 474
• Interim baseline results; final 10 yr results from 2021
• Colonoscopy vs 2 yearly FIT
– Lower participation: 24.6% vs 34.2% (p <0.001)
– Similar CRC detection: 0.1% vs 0.1%
– Higher advanced adenoma detection: 1.9% vs 0.9%
50NEJM 2012; 336: 697-706

51. Back to the
Questions
51

52. 52
• CRC screening
decreases CRC
mortality
• Optimal strategy
& modality still
uncertain
• Choose your
endoscopist
wisely
Conclusion

53. 53
Questions?Thank You