1) Cancer screening aims to detect asymptomatic potentially curable disease earlier through screening tests to improve outcomes and reduce cancer mortality and morbidity in the screened population. 2) Randomized clinical trials have shown that screening for breast and colorectal cancers can reduce cancer mortality when screening finds cancer at an earlier stage. 3) Screening tests have limitations including false positives, overdiagnosis, costs, and psychological impacts of screening that must be considered.

1. Cancer Screening
Facts & Fiction
Dr. Shad Salim Akhtar
MBBS, MD, MRCP(UK), FRCP(Edin), FACP(USA), MAUICC Fellows
Consultant Medical Oncologist &
Medical Director
Prince Faisal Oncology Center &
King Fahd Specialist Hospital
Buraidah, Al-Qassim

2. Fight against cancer
 Did you know?
 Average years of life lost
 Cardiac causes 11 years
 Cancer 15 years
 Curative treatment
 Prevention
 Early detection

3. CANCER UNDEFEATED
N Engl J Med1997;336:1569-74
In 1986, we concluded that “some 35
years of intense effort focused
largely on improving treatment must
be judged a qualified failure.” Now,
with 12 more years of data and
experience, we see little reason to
change that conclusion,…..
JOHN C. BAILAR III M.D., PH.D., HEATHER L. G ORNIK M.H.S.

6. Cancer screening-What is the
aim?
 Detect asymptomatic potentially curable
disease
 Earlier than otherwise would occur
 Earlier diagnosis should result in improved
outcome
 Reduce morbidity and mortality from a
particular cancer in screened population
 Reality xelpmoc (COMPLEX)

7. Suitable cancer for screening
 Substantial morbidity & mortality
 Major disease burden
 High prevalence in a detectable
preclinical phase
 Sojourn time
 Early detection should lead to improved
and effective therapy
 A good screening testgood screening test should be
available

8. Ideal Screening test
 Should separate the two populations
 Apparently well with the disease
 Those who do not have the disease
 Acceptable
 Inexpensive
 High specificity and sensitivity
 Least inconvenience and discomfort
 Feasible for use in large numbers
Kramer BS. NCI 1995

9. Relative risk of developing
Breast Cancer: Gail Model
Age at first live
birth
No of affected relative
0 1 >=2
<=20 1 2.6 6.8
20-24 1.2 2.7 5.8
25-29 or None 1.5 2.8 4.2
>=30 1.9 2.8 4.2
Gail MH et al:J Natl Cancer Inst 1989; 81:1879-86

11. Relative risk of developing
Breast Cancer

12. Evans DGR, Howells A: Breast Ca Res 2007; 9:213
Relative risk of developing
Breast Cancer

13. Evaluation of a screening test
 Sensitivity
 Positive if the disease is present
 High sensitivity
 Low false negative rate
 Specificity
 Negative if the disease is absent
 High specificity
 Low false positive rate

14. Is there a tiger?
NO NO NO NO
SENSITIVITY
SPECIFICITY
YES YES YES YES

15. Screening test evaluation
 Sensitivity TP/TP+FNX100 {a/a+cX100}
 Specificity TN/TN+FPX100 {d/d+bX100}
 PPV TP/TP+FP X100
 NPV TN/TN+FN X100
 Accuracy TP+TN/TP+FP+TN+FN X100
Test result Cancer present Cancer absent
Positive a {True Positive} b {False Positive}
Negative c {False Negative} d {True Negative}

16. Biases in screening
 Volunteer bias
 Different group from general population
 Motivated
 Different socioeconomic status
 Relatives of cancer patients
 High risk
 Lead time bias
 Erroneous increase in survival
 Screening symptoms death
Survival in screened population
Survival in unscreened population
Kramer BS: Urol Onc 2003;22:344-47

17. Biases in screening
 Length bias
 Overrepresentation of tumors with long
preclinical periods hence less rapidly
fatal
 Over diagnosis
 Diagnose a cancer which would
otherwise never become apparent

18. Evaluation of cancer screening
 Descriptive studies
 Not a good source
 Randomized clinical trials
 Mortality due to cancer
 Screened population vs
 Unscreened population
 Alternatives to RCT???
 Improvement in quality of life
measures in screened population
Meissner HI et al: Cancer 2004;101(5s):1251-9

19. Screening- Positive effects
 Improved prognosis
 Less radical treatment
 Reassurance for those with negative
test
 Resource saving if treatment costs
reduced
 Optimally reduced cancer related
mortality

20. Screening- Negative effects
 Economic consequences
 Psychological consequences
 Over diagnosis
 Carcinogenic effect of screening

21. Screening- Cost effectiveness
 Cost of diagnostic evaluation
 Therapy of screened population
 Cost benefit analysis
 Life or the benefit ascribed a value
 Cost effective analysis
 Cost to
 Detect one cancer
 Prevent one death
 Add a year or a quality adjusted year of life
Anderson MR et al:Cancer 2004;101(5s):1229-38

22. Screening- Cost effective analysis
 Marginal cost per year of life saved
 MCYLS =Marginal cost/marginal effectiveness
 Marginal cost of screening
 Total cost incurred in the program minus the
cost of case detection and management
without screening
 Marginal effectiveness
 Years of life expected and gained in screened
group minus years of life expected in the
group not screened
40,000 US$/MCYLS appropriate

23. Screening- Recommended sites
 Females
 Breast
 Endometrium
 Cervix
 Males
 Prostate
 Both sexes
 Colorectal
 Cancer related check up
American Cancer Society 2004

24. Breast cancer- Burden of
disease-US
 Invasive ductal ca > 200,000 women
per year
 DCIS >50,000
 >40,000 women die per year
 Second leading cause of cancer
related mortality
Jemal A et al: CA Cancer J Clin 2004;54:8-29

25. Chances of developing of and death
from breast ca within the next 10 yrs
Fletcher SW et al: N Engl J Med 2003;348:1672-80

26. 0
5
10
15
20
25
30
35
40
45
50
5 10 15 20 25 30 35 40 45 50 55 60 65 70 75
Age groups
Average age-specific incidence rate
for breast cancer-Saudi Arabia-NCR
94-96

27. Estimated age standardised (world population) incidence rates
of breast cancer in 1990

28. Makkah
Eastern
Riyadh
Madinah
Northern
Tabouk
Najran
Qassim
Hail
Al-Jouf
Jezzan
Asir
Baha
0
5
10
15
20
25
Breast Ca-age standardized rates
females NCR 94-96

29. Screening tools- Breast cancer
 BSE
 CBE
 Mammography
 Ultrasound
 Full Field Digital Mammography
 CAD Computer aided detection
 MRI
Smith RA et al:CA Cancer J Clin 2003;54:141-69

30. Randomized Clinical Trials of Breast Cancer Screening

31. New York trial
Reduction in Breast cancer
related death rate
30% at 10 years
23% at 18 years

32. Edinburgh trial
Reduction in Breast cancer
related death rate
19% at 12 years#
15% at 10 years@
age groups # 45-49 @ 50-64

33. Swedish two county trial
Reduction in Breast cancer
related death rate
None at 14.2 years#
23% at 11 years@
age groups # 40-49 @ 50-64

34. Stockholm trial
Reduction in Breast cancer
related death rate
None at 11.4 years#
30% at 11.4 years@
age groups # 40-49 @ 50-74

35. Canadian trials
Reduction in Breast cancer
related death rate
None at 13 years#
None at 10 years@
age groups # 40-49 @ 50-59

36. Boyle P: The Breast 2003; 12:351-6

37. Malmo trial
Canada a
Canada b
All
0.98 (0.93-1.04)
1.01 (0.88-1.16)
1.06 (0.96-1.18)
1.00 (0.96-1.05)
Relative risk (95% CI)
All cause
mortality
Medium quality
screening trials
Olsen O et al: The Lancet 2001;358:1340
mastectomies
tumorectemies

38. Cumulative survival of breast cancer patients aged 40–69 years at diagnosis
Tabar L et al: The Lancet 2003; 361:1405

39. Mammography other flaws
 Age 40-49
 Controversial
 Breast density?
 Shorter sojourn time of tumor
 (1.7 yrs vs >3.3 yrs in >50 yrs old)
 Risks
 Radiation
 10 yrs annual mammogram in 100,000
women one additional cancer

40. 11% reported
abnormal Cancer 0.3%
False positive 10.7%
Rate of false +ive α No of mammograms
50% after 10 mammograms
And 19% need open biopsy
Frequent in younger pts
Mammography false positive

41. Number of women 1000
Fletcher SW et al: N Engl J Med 2003;348:1672-80

42. DCIS-Guess what?
 Incidence per 100,000
 1973 2.4
 1998 30.7
 Initial stage of invasive cancer??
 Incidence of invasive cancer should have
decreased…but it is not happening
 DCIS is not an uncommon finding at
autopsy of Br ca unrelated death
 ? Reservoir ?…over diagnosis of a
neoplasm which would not become
manifest !!!!
Fletcher SW et al: N Engl J Med 2003;348:1672-80

43. Beyond mammography
 Breast US
 Dense breasts
 More sensitive less specific
 Additional to mammography
 Full field digital mammography
 Lower overall sensitivity
 Lower recall rate
 ? Incremental cancers detected
 CAD? Second film reader
 MRI more sensitive less specific
Irwig L et al: Br J Cancer 2004; 90:2118-22

44. Beyond mammography-An
internet advertisement
 Breast MRI screening “is proven to be three times better
at detecting early breast cancer than x-ray
mammography.”
 “Mammograms miss 2 out of 3 breast cancers.”
 Breast MRI screening “is so accurate it can find nearly all
breast cancer.”
 Breast MRI screening provides “the absolute best early
detection of breast cancer.”
 “Superior precision…differentiates between benign breast
changes and cancer.”
 Because breast MRI screening “is much more accurate
than regular x-ray mammography, women will not have
to undergo as many unnecessary biopsies for benign
changes of the breast.”
 Breast MRI screening “is so powerful that no woman
should suffer or die from this terrible disease.”
Lee H Carol et al: J Am Coll of Radiology 2004; 1:176-82

45. The Use of Magnetic Resonance
Imaging in Breast Cancer
Screening
Carol H. Lee, MD, Jeffrey C. Weinreb, MD
““However, at present, the use ofHowever, at present, the use of
MRI for routine screening forMRI for routine screening for
breast cancer is not justified.”breast cancer is not justified.”
J Am Coll Radiol March 2004;1:176-182.
Department of Diagnostic Radiology, Yale University School of Medicine,
New Haven, Connecticut, USA

46. Robson ME et al: JAMA 2004; 292:1368
Hereditary breast cancer-MRI vs other
modalities of breast imaging
Source No of BRCA pts
Sensitivity%
Specificity%
PPV

47. Wait a minute. Look at the
lesions we are picking?
Martin J Yaffe The Lancet Vol 364 September 25, 2004
We need to divide women into different groups and
MRI may be the investigation for high risk women?
Occult on
mammography
cancer picked up
by MRI,
enhancement due
to angiogenesis
from invasive
ductal ca

48. Colorectal cancer
 Third commonest cancer and second
leading cause of cancer death (USA)
 Grows slowly over several years
 Almost all develop in a polyp
 All polyps do not become cancerous
 Higher incidence of malignant
transformation
 Larger polyp (>10 mm)
 Sessile polyps
 Adenomatous vs hyperplastic
Levin B et al: CA Cancer J Clin 2003;53:44-55

49. Colorectal carcinoma ACS
guidelines-Men & Women >50yrs
Fecal occult blood annual or
Flexible sigmoidoscopy 5 yrly
Or both –preferred
Double contrast barium
enema 5 yrly
Colonoscopy every 10 yrs
Smith RA et al: CA Cancer J Clin 2004;54:41-52

50. Status of colorectal
screening?
 Early stage disease in 37% only at
diagnosis
 Of the eligible population only 40%
get screened
 Why?
 Uncomfortable procedures
 Preparation for the procedure worse
 Physicians do not advice???
 Can it be improved?
Levin B et al: CA Cancer J Clin 2003;53:44-55

51. FOBT present status
 Guaiac test most commonly used
 False positive/negative results
 Food items: meat, raw fruit, vegetables
 Drugs: vitamin c, aspirin
 Need to be repeated
 Adenomas may bleed infrequently
 Advantages
 Privacy
 Noninvasive
 Home collection
Levin B et al:CA Cancer J Clin 2003;53:44-55

52. FOBT pilot study of
screening for CRC UK
Positive test result=1.9%
Cancer detection rate
1.6/1000 screened
16.6% Polyp cancers
48% Dukes A

53. UK Colorectal Cancer Screening Pilot Group:BMJ, (published 5 July 2004)

54. FOBT Efficacy
US UK Denmark
No of participants 46551 150251 61933
Follow up years 18 7.8 13
Rel Risk Mortality ann 0.67
RR Mortality biennial 0.79 0.85 0.82
Risk Reduction for
CRC death (biennial)
4.6
(2.9)
0.8 1.8
Walsh JM et al: JAMA 2003; 289:1288-96

55. Use of new technologies for
colorectal cancer screening?
 Immunochemical Fecal Occult
Blood Tests
 Detection of altered human DNA
in stool samples
 CT colonography (virtual
colonoscopy)
 Capsule video endoscopy
Reviewed by ACS Colorectal Advisory Group 2003

56. Immunochemical FOBT
 Monoclonal &/or polyclonal
antibodies
 Detect intact globulin protein portion of
human Hb
 Bind to hemoglobin in stools
 positive test
 No reaction with non human Hb or
other substances containing peroxidase
activity
J Allison et al: N Engl J Med 1996;334:155-159

57. InSureTM
Test
 Simple, quantifiable result
 Tested in 240 high risk people
 Two samples per person
 Sensitivity
 For cancer 87%
 For adenomas 47.4% (>10mm)
 Specificity (in normal population)
 97.9%
 Results confirmed by colonoscopy
 Increased compliance?
 No preparation needed
Greenberg PD et al:Am J Gastrenterol 2000;95:1331-38

58. DNA mutations in stool
 Adenoma Carcinoma
 Stool sample
 Extract colorectal epithelium DNA
 Amplify
 Detect mutations if any
 Noninvasive
 No preparation required
 Whole colon screened
DNA Mutations
Walsh JM et al: JAMA 2003; 289:1288-96

59. APC gene mutations in CRC
 APC gene mutations initiate CR neoplasm
 Stool samples
 46 neoplasia (28 CRC, 18 Adenoma) vs 28 controls
 DNA purified
 Amplification of the region between 1210 and
1581 codons
 Mutations identified in
 9/18 adenomas
 17/28 CRC
 0/28 controls
Traverso G et al:N Engl J Med 2002; 346:311-20

60. Digital Protein-Truncation Test
Traverso G et al:N Engl J Med 2002; 346:311-20

61. Total number of Mutations found 27
Deletions
Insertions
Base
substitutions
Spectrum of APC mutations in
fecal DNA
Traverso G et al:N Engl J Med 2002; 346:311-20

62. Colorectal Cancer Screening

63. What is this?
Pickardt PJ et al: N Engl J Med 2003;349:2191-200

64. CRC screening-CT colonography
 Obstacles to the procedure
 Bowel preparation
 Air insufflation
 Breath hold
 Comparable to colonoscopy
 Sensitivity
 10 mm polyps ~90%
 5 mm polyps ~50%
 Frank cancers ~100%
Walsh JM et al: JAMA 2003; 289:1288-96

65. CT colonography vs Optical
colonoscopy
 Virtual colonoscopy findings kept
blind from colonoscopist during initial
procedure
Size ≥6mm ≥7mm ≥8mm ≥9mm ≥10mm
Virtual
colonpy
180/120
85.7%
119/133
89.5%
88/95
92.6%
56/61
91.8%
47/51
92.2%
Optical
colonpy
189/210
90.0%
120/133
90.2%
85/95
89.5%
55/61
90.2%
45/51
88.2%
Pickhardt PJ et al: N Engl J Med 2003;349:2191-200

66. Believe it or not?
Pickhardt PJ et al: N Engl J Med 2003;349:2191-200

67. Virtual colonoscopy
 Accurate method to detect colorectal
neoplasia in asymptomatic individuals
 May be less invasive than optical
colonoscopy
 Second procedure to deal with positive
result
 Excision
 Biopsy
 Cost effectiveness?
Morrin MM et al:N Engl J Med 2003;349:2261-4

68. Capsule video endoscopy
 Camera in Capsule
 2 picture/second
 Images for up to 8 hours
 Works in conjunction with
 Given diagnostic system
 Portable data recorder
 Workstation producing video images
 FDA approved since Aug 2001
 Cannot picture colon yet
Levin B et al: CA Cancer J Clin 2003;53:44-55

69. Small bowel mass
Small bowel lymphoma
Hemagiosarcoma

70. This Dream May Come True Soon