1. Mediterranean Task Force for Cancer Control (MTCC)
AIMS: To unify efforts to eliminate suffering and reduce mortality of cancer through decreasing incidence of adv. disease
Albania
Algeria
Croatia
Cyprus
Egypt
France
Greece
Italy
Jordan
Lebanon
Lybia
Macedonia
Malta
Morocco
Palestine
Portugal
Syria
Slovenia
Spain
Tunisia
Turkey

2. How screening is crucial in ensuring better cure and improved survival
Massimo CRESPI
National Cancer Institute
“Regina Elena”, Roma - Italy

3. CRC Incidence and Mortality in “Less” and “More” Developed Countries
In brutal figures …
More Developed
Less Developed
Incidence
M 353,390
M 196,037
F 312,341
F 159,664
T 665,731
65.2 %
T 355,701
34.8 %
Mortality
M 159,914
M 118,025
F 153,980
F ,184
T 313,894
59.4%
T 214,209
40.6 %
Globocan 2002

4. COLON cancer Incidence and Mortality in Mediterranean area

5. Terminology Prevalence Survival
Number of subjects diagnosed with a disease (CRC) still alive after x years (or months)
Survival
Time interval between diagnosis and death. Actuarial survival takes into consideration deaths by causes different from the index disease.
It’s considered like an ultimate parameter of efficiency of the Health System (timely diagnosis, stage of disease, level of treatment and post-treatment care, etc.)

6. Prevalence at 5y of CRC patients
5y prevalence
North America
618,403
Central America
28,350
South America
98,150
Europe
999,612
Africa
38,614
Asia
1,003,456
Australia and Pacific
43,630
(Globocan 2002)

7. 5y survival of CRC from Cancer Registries
England
(Not EU)
(Not EU)
EPICENTRO.ISS.IT
EUROCARE.IT
Scotland
Eurocare-3 study Annals of Oncology (Suppl. 5) vol. 14
(Not EU)
Wales

8. Possible actions for CRC Prevention
Physical activity
Energy intake
Fresh fruit and vegetable
Dietary fat
Calcium
Fiber
Anti-oxidant vitamines
Selenium
SCREENING
Anti-inflammatory drugs
Summary of action with level II or III of evidence
Level II: Obtained from at least one properly designed RCT
Level III: Obtained from a control trial without randomisation,
“ “ cohort or case-control analytic studies,
“ “ multiple time-series with/without the intervention

9. . . . . . protocol under Health authorities selected population target
Mass screening
protocol under Health authorities
selected population target
covers all degrees of risk
evaluation required
entry test (FOBTs / CTcolonography?) + 2nd level test (Colonoscopy)
or Colonoscopy as entry test when feasible and accepted . . . . .

10. Opportunistic screening
In volunteers subjects using primary diagnostic test as in screening
Low risk less compliant than high risk
Disadvantage: end-points not evaluable
Ensures further coverage of the population . . .

11. Expected effects of screening Expected effects of screening
Expected effects of screening
Expected effects of screening
Reduction in mortality
but lead time and delay time bias
Improved survival
down-staging
Reduction in incidence
in some cases like cervix and colon-rectum because of pre-cancer lesions
Reduction in mortality
but lead time and delay time bias
Improved survival
down-staging
Reduction in incidence
in some cases like cervix and colon-rectum because of pre-cancer lesions

12. CRC screening is feasible:
by historical methods of proven efficacy and efficiency (G-FOBT)
by actual methods I-FOBT or HeSENSA
Endoscopy (invasive, costly, but highly efficient in reducing also incidence by polypectomy)
by methods in development
Virtual Colonoscopy
Pill cam
Stool-DNA

13. FOBTs: for a fair evaluation … ... an important definition
application sensitivity
(once only testing)
vs.
programmatic sensitivity
(repeated testing every 1 or 2)
J E Allison AJG 2010

14. What is average risk for colorectal cancer?
Getting old!

15. INCIDENCE AND MORTALITY RATES OF CRC
BY AGE (x 100,000/YEAR)
Age (years)
40-44
45-50
50-54
55-59
60-64
65-69
70-74
75-79
Incidence
13.3
27.6
55.1
97.0
153.4
226.9
318.6
412.0
Mortality
4.6
9.6
19.0
34.4
55.4
85.6
125.9
171.9
from Miller et al.

16. Who is at average risk ?

17. Stool Tests
sDNA
G-FOBT
Immuno
FOBT

18. Relative efficiency of G-FOBT and I-FOBT for CRC and AA (330 subj
Relative efficiency of G-FOBT and I-FOBT for CRC and AA (330 subj. undergoing OC)
Sensitivity %
Specificity %
No. of OC / Neoplasia
G-FOBT (3samples)
53.1
59.4
8.1
I-FOBT (1 sample)
94.0
2.1
I-FOBT (2 samples)
68.8
91.9
AA not identified #
G-FOBT 15
I-FOBT 8
both 7
# mostly flat lesions in right colon
Rozen P. et al. 2009

19. Comparison g-FOBT vs i-FOBT (100 ng/ml)
770 subj. at average risk
both FOBTs (3 samples) + Colonoscopy (CS)
Sensitivity
Specificity
No. of CS to detect a lesion
g-FOBT
i-FOBT
Ad.Ad.
13.7
34.5
92.4
90.4
7.6
4.4
CRC
30.8
84.5
89.8
15.2
7.3
Both
16.7
43.7
92.9
91.9
5.1
2.7
Park D AJG 2010

20. CRC stool screening tests
DNA
Hemoccult II (guaiac)
Sensitivity
Adc
Adc N-Adenom-HGD
Adv.ad+ ADC
51.6
56.0
32.5
18.2
12.9
13.0
15.0
10.8
Cost (USD)
400 to 800 5
Imperiale TF et al, NEJM (2008) 351:274-14

21. SCREENING STRATEGIES AND AVAILABLE RESOURCES
In most developing nations, Africa, Asia (3.8 billion population), CRC screening is not a priority, resources are limited, awareness still low or restricted to the more affluent (private care)
The preferred and more affordable screening strategy worldwide is FOBT (trend towards iFOBT). Bleeding from worm infestation is a problem in developing countries
Primary TC / FS screening offered only in a few affluent nations (US, UK Germany, Italy, Austria, Luxemburg, Poland), FOBT as alternative

22. Alternate strategies in low resource settings
To aim at familiar / genetic risk for CRC
(just few key questions by a health professional)
In subjects aged <45 years (rates on total cases)
More Developed
Less Developed
Incidence
M 3.6 %
M %
F %
F %

23. Endoscopy

24. What is HIGH RISK for CRC: impact of familiar and hereditary factors
Average risk
Rosalind U. Clinics of North America Gastro. End. 2002

25. Who is at high risk ? COLONOSCOPY
25%

26. HOW identify them ?? … by a simple question
A specific dedication by General Practitioners is suggested being crucial in selecting subjects, by simple questions, for:
Ö Genetic syndromes
Ö Familiar risk
These patients NEED COLONOSCOPY
Accuracy 80 %
Church, Dis Colon Rectum, 2000
A bit of culture, a minimal effort, a great yield!

27. Advanced Adenoma (AA)
AA includes a range of lesions with variable (or different) cancer risk that was established as surrogate endpoint, more frequent than CRC

28. Endoscopic screening of CRC
Colonoscopy
Flexible
sigmoidoscopy

29. (results of more than 50 studies)
Miss rate of Flexible Sigmoidoscopy for proximal lesions in subjects with no-distal lesions
Range from 22.8 % to 65 %
(results of more than 50 studies)

30. Efficacy of colonoscopy in reducing incidence of CRC
An alternative screening method
Results of two multi-center studies based on long-term follow-up of asymptomatic subjects after a colonoscopy with polypectomy
US National Polyp Study (prospective) %
Italian Multicenter Study (retrospective) - 66 %
But COMPLIANCE in general population is low

31. Screening Colonoscopy (OC) in asymptomatic subjects
Meta-analysis of 10 studies, 68,324 participants
Complete (OC)
97 % (94 – 98 %)
CRC
0.78 % (0.13 – 2.97 %)
Stage I or II 77 %
Adenoma
19 % ( %)
Advanced Aden.
5 % (4 – 6 %)
Complication
Perforation 0.01 %
Bleeding 0.05 %
Niv Y et al, 2007

32. CRC cannot be completely eliminated even with very intensive screening
Miss rate of right sided CRC by colonoscopy in Ontario in usual clinical practice (1997 – 2001)
CRC patients database: subjects
Missed cancers: 4% by colonoscopy performed between 6 – 36 months before
CRC diagnosis.
(Byrd RL 1989: missed lesions: 3%)
CRC cannot be completely eliminated even with very intensive screening
Bressler B et al 2004

33. Risk of CRC after negative colonoscopyRR
Overall
0.55
Left colon
0.16
0.12 – 0.33
Right colon
0.67
0.80
Singh 2009
Ransohoff 2009
About 80% subjects with CRC between 50 – 58y have already one adenoma at 50y
Geul K et al, 2007
QUALITY of OC !?
Fast-growing lesions !?

34. (gastroent. Vs non-gastroent.?) Flat non polypoid lesions
Differences in protection against right/left sided CRC after a negative index CS ?
Quality of CS
(gastroent. Vs non-gastroent.?)
Flat non polypoid lesions
(more in right colon ?)
Biology of proximal lesion
(MSI and CIMP status ?)
Why women worst ?
(RR 0.99 vs 0.89 men)

35. Low public compliance to screening colonoscopy (from Jack Tippit, Saturday Evening Post)

36. Virtual Colonoscopy
(CTC)

37. CTC ACCURACY 65% 78% 84% 87% 90% 89% 88% 87% 86% 45% 40% 35% 31% 25%
>5 mm
>6
>7
>8
>9
>10
Sensitivity
65%
78%
84%
87%
90%
Specificity
89%
88%
87%
86%
PPV
45%
40%
35%
31%
25%
23%
Johnson CD, NEJM 2008 37

38. Advanced adenomas detected in
Distribution of advanced neoplasia according to polyp size at screening colonoscopy (data from 4 studies with 20,562 subjects)
Advanced adenomas detected in
1155 subjects (5.6% overall)
of these
in diminutive polyps (≤ 5mm) %
in small polyps (6-9mm) %
in large polyps (≥ 10mm) 87.5%
Hassan C et al, 2009

39. Colon capsule (CE)
Ø11 mm
31 mm

40. Courtesy Dr Hassan

41. Important factors to improve compliance to screening
Awareness !!
The data from US and Europe show substantial differences

42. Trends in Incidence (M + F) of CRC in Europe vs USA Seer
selected Countries
Estimated

43. Prevalence of lower GI testing (CS, FS, FOBTs) in the last 10 years
Result of the SHARE program on 18,139 subj.
aged more than 50y in 11 European Countries
Lower GI Endoscopy from 6.1% Greece
to 25.1 % France
FOBTs from 4.1 % Netherlands
to 61.1 % Austria
WHAT A DISASTER !!
Stock C, Brenner H 2010

44. Ongoing CRC screening activities in Italy
2005
2006
Programs 52 69
Invited
827,473
2,107,000
Compliance
47.1% (6.7–78.1%)
46.5 % (4.8 – 81 %)
I-Fobt +
I 5.8 – II 4.1
I 5.3 – II 3.9
OC adherence
82 % (56 – 100 %)
81.2%(69.2 – 90.7%)
1st screen
CRC 0.37 % AA %
CRC 0.31 % AA %
2nd screen
CRC 0.11 % AA %
CRC 0.13 % AA %
TNM I or II
55 %
56 %
M. Zorzi et al 2006 survey - National Centre for Screening Monitoring

45. Ongoing CRC screening activities in Italy 2006 Regional variations
Theoretical extention #
Actual extension (invited)
North
66.1 %
50.2
Center
48.5 %
22.8
South
10.0 %
4.8
# Population covered by organized screening programs
M. Zorzi et al 2006 survey - National Centre for Screening Monitoring

47. 11.3
14.2
2.8
Screened by TC

48. Compliance to screening tests in average practice (in the real world !!)
Population based extent of CRC screening
in Ontario (Canada)
<20%
(Rabeneck L. et al. 2004)
Participation in colonoscopy population
screening in Australia
18.2%
(Scott RG et al. 2004)

49. ? The problem is: compliance to any screening test … …
How to increase compliance ?

51. Sampdoria - Parma (21 Feb 04)

52. TV: March 2005

53. Established concepts
For early detection and prevention of CRC and polyps
Colonoscopy
For early detection of Advanced neoplasia
FOBTs

54. In the real world….
Uptake of screening opportunities is not exceeding 40 to 50% even in the more developed, wealthy nations
In unselected general population it is as low as 20% (Australia, Canada)
The scarce convincememnt of GPs in advising CRC screening and the embarassment to discuss bowel matters are problems that only a strong action towards increased awareness may overcome

55. Results of European / USA RCTs based on FOBT
Europe (4 studies - biennial FOBT - 320,000 subjects) 15 – 18 % reduction in mortality
In subjects complying to all periodic recalls, reduction was 43 %
Early stage were 41 % in intervention arm vs 11% in controls
USA (Minnesota), annual FOBT, reduction in mortality in participating subjects was 55 %
FOBT is the method of choice worldwide

56. Mortality reduction in the active participating population
- Funen : %
- Nottingham : - 39%
- Burgundy : %
- Minnesota : %

57. FOBT long-term results
The Danish RCT study
Biennial guaiac-FOBT on 3 fecal samples
9-rounds of screening completed
Compliance 1st invitation 67%
“ to re-testing 90%
Overall colonoscopy rate 5.3%
Dukes A in screened 36% (11% controls)
Overall reduction in mortality 11%
Reduction in mortality in those attending all 9-rounds %
Kronborg O. 2004

58. Downstaging
Proportion of TNM stage 1 cancer in the screened and control population
Positive test
Test not done
Control population
Funen
40% 9%
11%
Nottingham
44%
12%
Burgundy
16%
20%

59. Conclusions: no need for RCTs to implement screening (not ethical)
RESULTS OF A CRUCIAL COHORT STUDY (JPHC) ON CRC SCREENING IN JAPAN
42,150 subject – 551,459 person/years f.u. (13 years)
RR death from CRC in screened 0.28 ( ) a 70% reduction
RR death from all causes 0.70 ( ) a 30% reduction
Incidence of CRC similar but RR 0.41 for advanced CRC
Conclusions: no need for RCTs to implement screening (not ethical)
KJ Lee et al, 2007

60. Summary: effects of CRC screening as shown by RCTs
Summary: effects of CRC screening as shown by RCTs
Reduction in mortality
beyond lead time and delay time bias
achieved: -15 to -55 %
Improved survival (down-staging)
achieved: up to 65%
Reduction in incidence
by removals of precancerous lesions (polyps)
achieved: up to 70%

61. Results of a large ecological study on colonoscopy coverage and CRC mortality / incidence in Ontario
2,412,077 subj. (mean age 64y, female 53%)
14y follow-up (1993 – 2006)
CRC Incidence 62,819 cases (2.6 %)
Mortality 23,743 deaths (0.9 %)
Result: for every 1% increase in Colonoscopy rate, 3% decrease in CRC mortality
Rabeneck L AJG 2010

62. Eurocare-3 study Annals of Oncology 2003 (Suppl. 5) vol. 14
Colorectal Cancer (Males) y Survival (%)
EPICENTRO.ISS.IT
EUROCARE.IT
Eurocare-3 study Annals of Oncology (Suppl. 5) vol. 14

63. The best screening test is the one which is done
CONCLUSIONS
i-FOBT (every 12 months) is the best accepted and affordable at population level (crucial awareness by GPs and public)
CTcolonography is possibly a 1st step substitute, but technical and professional skills are crucial
A “good” colonoscopy is still the gold standard if feasible (health facilities) and accepted (awareness)... test of choice in high risk subjects
The best screening test is the one which is done

64. For me: Colonoscopy !! And for you ??? Finally . . .
What would you advise as optimal screening test for yourself or your beloved ones ?
For me: Colonoscopy !!
And for you ???