3. Top Ten Leading Cancer Site in Male 2000 - 2009
Lung 32.4
Prostate 14.8
Colon 13.6
Lymph Node 12.5
Liver 12.5
Rectal 11.4
Skin 11.2
Gastric 10.7
Larynx 8.2
Thyroid Gland 7.2
Nasopharynx 7
0 5 10 15 20 25 30 35
4. Ten Leading Cancer Sites by Gender Adjusted 2000 - 2009
119.9
Breast 24.1
Colorectal 23.3
Cervix 22.8
Ovary 21.2
Head and Neck 20.7
Lung 18.8
Corpus Uteri 16.6
Prostate 16.5
Thyroid Gland 11.3
Lymph Node
0 20 40 60 80 100 120
5. Site 1975-1977 1984-1986 1996-2002
All sites 50 53 66
Breast (female) 75 79 89
Colon 51 59 65
Leukemia 35 42 49
Lung and bronchus 13 13 16
Melanoma 82 86 92
Non-Hodgkin lymphoma 48 53 63
Ovary 37 40 45
Pancreas 2 3 5
Prostate 69 76 100
Rectum 49 57 66
Urinary bladder 73 78 82
*5-year relative survival rates based on follow up of patients through 2003.
†Recent changes in classification of ovarian cancer have affected 1996-2002 survival rates.
Source: Surveillance, Epidemiology, and End Results Program, 1975-2003, Division of Cancer Control and
Population Sciences, National Cancer Institute, 2006.
6.
7. Disease incidence should be high
Diagnosed at early stage but without any
signs
Early diagnosis and treatment should be
more effective than late treatment
Benefit of early treatment should be higher
than the cost and harmfulness of screening
8. Being a woman
Age
Genetic factors - mutations in BRCA1 or BRCA2;
50-60% of women inheriting a BRCA1 mutation
from either parent will have breast cancer by age 70
Family history of breast cancer (not related to
BRCA mutations)
Personal history of hyperplastic breast disease
9. Personal history of breast cancer
Race: incidence is higher in Caucasian compared
with African-American, Hispanic or Asian women
Radiation treatment: chest irradiation as a child/young
woman can significantly increase risk of developing
breast cancer
Menstrual history: early menarche (<12 yr) or late
menopause (>50yr) has some association with increased
risk. Also nulliparous, or first childbirth at >30 yrs.
10. Oral contraceptives - remains controversial
Hormone replacement therapy - >5 years of
therapy with combined estrogen and
progesterone may increase risk
Not breast feeding
Diet and obesity; physical activity
Smoking - still being investigated
Alcohol - 2-5 drinks/day can increase risk x 1.5
over non-drinkers.
11.
12. StudyAge Mortality reduction (%)
HIP 40-64 24
Malmö 45-69 19
Sweeden 40-74 32
Edinburgh 45-64 21
Stockholm 40-64 26
Canada-1 40-49 -3
Canada-2 50-59 -2
Gothenburgh 39-59 16
All studies 39-74 24
CA Cancer J Clin 2003; 53:141-169
13. All women starting at 40 years old should
be screened with mammography
15. Provide equivalent detection level
compared with conventional
mammography
Offers a lower average dose of radiation
Easier access to images and computer-
assisted diagnosis
Superior in pre and postmenopausal
women with dense breast and women
under the age of 50
16. Breast US
It is more subjective than mammography
Could not detect microcalcifications
Sonographic contrast is week between
tumor and adipous tissue
Documentation is problematic
Not useful for screening
17. Expensive
Higher sensitivity with lower spesificity
Not safe for detection of microcalcification
Useful for additional screening method for
high risk women having mammography
18. Highly sensitive but high false positive rate
Useful for screening BRCA patients
May be useful in staging known breast cancer
May become an important screening modality
20. Greatly increased risk RR>4.0
Inherited genetic mutations for breast cancer
≥ 2 first degree relatives with breast cancer
diagnosed at early age
Personal history of breast cancer
Age >65 (increasing risk with increasing age to 80)
21. Mammographic screening should be start at
30 years of age (rarely before this age)
Screening interval can be shorter (e.g. 6 mos)
MRI can be added
US can be added
22. Yearly mammograms are recommended starting at age 40.
A clinical breast exam should be part of a periodic health
examination, about every 3 years for women in their 20s and 30s.
Asymptomatic women aged 40 and older should continue to
undergo a clinical breast exam, preferably annually*.
Beginning in their early 20s, women should be told about the
benefits and limitations of breast-self examination. Women
should know how their breasts normally feel and report any
breast changes promptly to their health care providers.
Beginning at age 40 years, annual CBE should be performed prior to mammography
23.
24. incidence decreased >50%the past 30 years
American Cancer Society estimates 11,270
new cases of cervical cancer in the United
States in 2009, with 4,070 deaths from the
disease
25. should begin at21 years of age
Screening done regardless of the age of onset
of sexual intercourse
26. Even at a high rate of infection with HPV in
sexually active adolescents,
invasive cervical cancer is very rare in women
younger than 21 years old.
27. Cervical cytology screening :
21–29 years, every 2 years usingconventional or
liquid-based cytology.
30 years and older with three consecutive
cervical cytology test results that are negative
for CIN and malignancy may be screened
every 3 years
> 65 years old no testing.
28. May require more frequent cytology screening
Women who are infected with human
immunodeficiency virus (HIV)
Women who are immunosuppressed (such as those
who have received renal transplants)
Women who were exposed to diethylstilbestrol in
utero
Women previously treated for CIN 2, CIN 3, or
cancer
29. It has been demonstrated, however, that the
rate of dysplasia decreases as the number of
sequential negative Pap test results increases
30. Formal cost-effective analysis of data from this
national program showed that the most cost-
effective strategy for cervical cancer screening
is cytology testing no more often than every 3
years in women with prior normal screening
test results
31. May discontinue cytology screening withthree
or more negative cytology test results in a row
and no abnormal test results in the past 10
years.
32. 70 % of cervical cancer result from infection
with HPV 16 and 18
90% of Genital wart are caused by 6 and 11
33. Organization/NationStart Vaccine Catch Up
ACIP 11-12 13-2 6
American College of Ob-Gyn 9-26
American Cancer Society 11-18 None
World Health Organization 9-13
34. Anal Pap smears
4000 cases of anal cancer in women in 2003 and in
contrast to cervical cancer the rates are increasing
35.
36. 55 – 74:
> 30 pack years smoking history
ceased smoking < 15 years
> 50 years
> 20 pack year smoking history
one additional risk factor
37. % Stage I
I-ELCAP 85
Mayo 69
Turino 73
Randomized Trials
LSS 43
Depiscan 38
DANTE 57
NELSON 64
38. Many nodules that require follow-up
Potential Psychological Impact
Surgery for Benign Disease
Lung Cancer Deaths in Screened Participants
Interval Cancers (failure of screening)
Potential Overdiagnosis Cases
39. Prostate Lung Colo-rectal Ovarian Cancer
Screening Trial
Determine effects of screening in mortality
among men and women aged 55 to 74
Completed in 2005
40. Randomized 154,900 Individuals
Age 55-74 to CXR or Usual Care (4
years)
Screening Adherence Was 86%
Baseline and 79-84% Yearly
– 11% Screening Done in Usual Care
JAMA 2011; 306: 1865-1873
41. • Annual Screening with CXR (4 years)
Did Not Reduce Lung Cancer Mortality
Compared to Usual Care.
• In Subset Analysis of NLST Eligible
Participants, There Was No Mortality
Reduction in the Chest X-ray Screened
Arm.
JAMA 2011; 306: 1865-1873
42. Incidence Rate of Lung Cancer:
per 10,000 Person Years on
Control Arm (Intervention)
Never Smoker: 2.5 (3.3)
Former Smoker: 18.7 (19.3)
Current Smoker: 71.4 (79.9)
Tammemagi et al. JNCI 2011; 103: 1058-68
43. 40,000 Low-dose fast spiral CT
PLCO
Smoker
Former smoker
30 pk yr Randomized
Age 55-74
CXR
10,000 0 1 2
ACRIN
Years
CP1066773-57
44. August 2002 - April 2004 Enrollment
Three rounds of screening through September 2007
Followed for Events through December 31,
2009
Median F/U = 6.5 years; Max 7.4 years
Adherence to Screening
95% on CT arm: 93% on CXR
Average annual rate of CT in CXR arm was 4.3%
NEJM 2011 epub June 29 NEJM.org
45. CT CXR
Abnormal Screen 24.2% 6.9%
False Positive 96.4% 94.5%
Clinically Significant
7.5% 2.1%
other abnormalities
Total Lung Cancers 1,060 941
LC per 100,000 person - years 645 572
NEJM 2011 epub June 29 NEJM.org
46. Diagnostic F/U of
Positive Screen CT CXR
• Imaging 58% 78%
– PET 8% 8%
• FNA 1.8% 3.5%
• Bronchoscopy 3.8% 4.5%
• Surgical: Mediastinoscopy,
4.0% 4.8%
Thorascopy, or Thoracotomy
NEJM 2011 epub June 29 NEJM.org
47. CT CXR
Total Lung Cancers 1,060 941
Screen-detected Lung Cancer 649 279
Lung Cancer after Negative Screen 44 137
Either Missed Screening or
367 525
After Screening Phase
NEJM 2011 epub June 29 NEJM.org
48. • 20% Mortality Reduction from Lung Cancer
• 6.7% All Cause Mortality Reduction
• 320 Persons Needed to be Screened with
LDCT to Prevent One Death
NEJM 2011 epub June 29 NEJM.org
49. Screening with LDCT is
Recommended for High-Risk
Individuals Meeting the NLST
Criteria (2A)
Also Recommend Screening for
(2B)
– Age >50 Years and ≥20 Pk Years and One
Additional Risk Factor Other Than Second
Hand Smoke
NCCN.org accessed 11/8/2011
50. 15 q 25
1) Amos et al. Nature Genetics 2008; 40:616-22.
2) Hung et al. Nature 2008; 452:633-37.
15 q 24
1) Thorgeirsson et al. Nature 2008; 452:638-42.
(Associated with nicotine dependence, lung
cancer and vascular disease)
51. Airway epithelial cells
Gene expression profiling
Chromosomal aneusomy – FISH
Gene methylation
Blood biomarkers
Serum proteins
Autoantibodies to tumor antigens
Gene expression profiles in PBMC
Breath analysis of VOC
Urine markers of carcinogens
52. 573 case/control study with match for age
sex and smoking
Sensitivity 40%; Specificity 90%; Accuracy 88%
Detect some cancers 3-5 years in advance of
symptoms
Autoantibodies to 6 cancer antigens
P53; NY-ESO-1; CAGE; GBU4-5; Annexin 1 and
SOX2
Murray et al Ann Oncol ePub Feb 2010 and
ASCO posters 2010
54. 1/3 of compounds detected by solid phase
microextraction were hydrocarbons
Aromatic hydrocarbons
Alcohols
Aldehydes
Ketones
Esters
Sulfur compounds
Nitrogen containing compounds
Halogenated compounds
Ligor M et al. Clin Chem Lab Med 2009; 47:550-60.
55.
56. Prostate Cancer Early Detection
Guidelines
>50 years with at least a 10 year life expectancy
should receive information regarding possible
benefits and limitations of finding and treating
prostate cancer early, and should be offered
both the PSA blood test and digital rectal exam
annually
Men in high risk groups (African Americans, men
with close family members---fathers, brothers,
or sons---who have had prostate cancer
diagnosed at a young age) should be informed
of the benefits and limitations of testing and be
offered testing starting at age 45
57. .
Types of Tests
Diagnostic Tests - Tests done because of an
identified problem (disease is suspected)
Screening Tests -Test done on people who have
no symptoms of disease
There is widespread agreement on the use of
diagnostic tests for prostate cancer
Screening for prostate cancer is much more
controversial
58. .
Changes in the PSA Era
Tyrol, Austria
42% mortality reduction
Olmstead County, Minnesota
22% mortality reduction
SEER
Decreased mortality in white men
Department of Defense
Increased early stage disease
59. .
Prostate cancer death rates have fallen during
the PSA era, but it is not clear this is primarily
due to screening
Other possible reasons for this decline:
Disease is found earlier because of
increased awareness
utilization of diagnostic PSA testing
Improved treatments
61. .
False negative results
– PSA and DRE “normal”, but cancer is
present
– May lead to false reassurance,
delayed diagnosis
Research has shown that no cut-off value of
PSA is completely reliable to rule-out cancer
– Prostate Cancer Prevention Trial end
of study biopsies found cancer in some
men with PSA less than 1.0 ng/ml
62. 4.0+ Screen 10,000 Men
PSA 4+ 7.6% PSA 4+ 760
Positive biopsy 25% Cancer 190
High grade 19% High grade 36
<4.0
PSA <4 9240
Cancer 1386
“Normal PSA” 92.4% High grade 208
Positive biopsy 15%
High grade 15%
PSA
SEER, PCAW, Prostate Cancer Prevention Trial Data
63. .
False negative results
False positive results
PSA and/or DRE abnormal, but no cancer
found
Can lead to worry, additional tests, and
increased costs
64. .
False negative results
False positive results
Overdiagnosis
Some (many?) cancers found by screening
grow very slowly and will never cause
problems
65. .
New Findings in Screening
Results from 2 major, long-term studies reported this
year – their findings conflict
ERSPC (European Randomized Screening for Prostate
Cancer)
PLCO (Prostate, Lung, Colon and Ovarian)
66. Began in 1991 in seven European
countries
162,000 men aged 55 to 69
randomized to screening vs
usual care
Median follow-up about nine
years
67. Findings
More cancers detected with screening
5990 cancers in screening group
4307 cancers in control group
Fewer prostate cancer deaths in
screening group
261 deaths in screening group
363 deaths in control group
Conclusion: 20% lower prostate cancer
deaths in screening group
68. Multiple concerns/questions:
Minimal-to-no participation of men of African
origin
Different screening and follow-up protocols
Different PSA levels and DRE usage
Variable treatment and outcomes (quality
questions)
To prevent one prostate cancer death
1410 men screened
48 men treated (with attendant risks, side-
effects, complications)
Bottom line
Screening every 4 years, with PSA threshold
of 3 ng/ml may decrease chance of prostate
cancer death
Unclear how this correlates to current U.S.
pattern of annual screening with different PSA
“triggers” (2.5 – 4.0 ng/ml)
High level of overdiagnosis and
overtreatment with this approach (although
these numbers are likely to go down after
longer follow up period)
69. Began in 1993, ten U.S. Centers
73,000 men aged 55 to 74
randomized to screening
annually vs routine follow-up
Median follow-up about ten
years
70. Findings
At 7 years, screening found more cases of
cancer
2,820 prostate cancers in annual screening
group
2332 cases in “usual care” group
More prostate cancer deaths in
screening group
7 years: 50 deaths among annually screened
compared with 44 in usual care group
10 years: 92 deaths in annually screened vs 82
in usual care
Conclusion – No mortality benefit with
screening
Prostate cancer deaths similar in both groups
71. Questions/concerns with study
44% of men had at least one PSA test prior to
study
May have excluded more aggressive prevalent
cancers
Selectively included men with prostate cancers
not detected by PSA screening (bias against
showing a screening effect)
Many men in the “usual care” group were
screened during the course of the study
Initially powered for 20% contamination, later
revised to 38%
PSA screening in control group : 40% first year; 52%
by year 6
Less than half of those with a positive screen
result had a biopsy
Insufficient African American participation (< 5%)
to allow specific analysis of outcomes in this
group
Bottom line – no difference in death rates
at 10 years between intensively screened
and less-intensively screened men
73. Study published September 2009
14,500 men aged 65 + with localized
prostate cancer
No active treatment for at least 6 mos
following prostate cancer diagnosis
At 10 years, 9% of men had died of
prostate cancer
1017 men died of prostate cancer
5721 men died of other causes
7420 men still alive
Approximately 11% African Americans in study
population, but authors did not report findings
separately for this group
74. Summary
PotentialBe PotentialHar
nefits ms
• PSA screening detects cancers
• False positives are common.
earlier.
• Overdiagnosis and overtreatment
• Treating PSA-detected cancers
is a problem, but magnitude is
may be more effective, but
uncertain.
this is uncertain.
• Treatment-related side effects are
• PSA may contribute to the
fairly common.
declining death rate but the
extent is unclear
Bottom line: Uncertainty about degree of benefits and
magnitude of harms
75. Current ACS Screening Guidelines
Men age 50 and over with at least a 10 year life
expectancy should receive information
regarding possible benefits and limitations of
finding and treating prostate cancer early, and
should be offered both the PSA blood test and
digital rectal exam annually
Men in high risk groups (African Americans, men
with close family members---fathers, brothers,
or sons---who have had prostate cancer
diagnosed at a young age) should be informed
of the benefits and limitations of testing and be
offered testing starting at age 45
76.
77. 50 years of age
No history of adenoma or colon cancer
No history of inflammatory bowel disease
Negative family history
78. Adenoma/sessile serrated polyp
History of colorectal cancer
Inflammatory bowel disease
Positive family history
80. Sporadic (average risk)
(65%–85%)
Family
history
(10%–30%)
Rare
syndromes
(<0.1%) Hereditary nonpolyposis
colorectal cancer
(HNPCC) (5%)
Familial adenomatous
polyposis (FAP)
(1%)
CENTERS FOR DISEASE CONTROL
AND PREVENTION
81. Normal to Adenoma to Carcinoma
Human colon carcinogenesis
progresses by the dysplasia/adenoma
to carcinoma pathway
82. Cancer Prevention
Removal of pre-cancerous polyps prevent cancer
(unique aspect of colon cancer screening)
Improved survival
Early detection markedly improves chances
of long term survival
84. American Cancer Society
U. S. Multi-Society Task Force on Colorectal
Cancer
American Gastroenterological Association
American College of Gastroenterology
American Society of Gastrointestinal Endoscopists
American College of Radiology
85. Two new tests recommended:
stool DNA (sDNA) and
computerized tomographic colonography (CTC) –
sometimes referred to as virtual colonoscopy
The guidelines establish a sensitivity threshold
for recommended tests
The guidelines delineate important quality-
The full article can be accessed at:
related factors for each form of testing
http://caonline.amcancersoc.org/cgi/content/full/CA.2007.0018v1
86. Tests That Detect Adenomatous Polyps and Cancer
Flexible sigmoidoscopy (FSIG) every 5 years*, or
Colonoscopy every 10 years, or
Double contrast barium enema (DCBE) every 5 years*, or
CT colonography (CTC) every 5 years*
Tests That Primarily Detect Cancer
Annual guaiac-based fecal occult blood test (gFOBT) with high test sensitivity
for cancer *, ** or
Annual fecal immunochemical test (FIT) with high test sensitivity for cancer*,** or
Stool DNA test (sDNA), with high sensitivity for cancer*, interval uncertain
* Colonoscopy should be done if test results are positive.
** For gFOBT or FIT used as a screening test, the take-home multiple sample method should be used.
gFOBT or FIT done during a digital rectal exam in the doctor's office is not adequate for screening.
87. Evidence does not yet support any single test
as “best”
Uptake of screening remains disappointingly low
Individuals differ in their preferences for one test
or another
Primary care physicians differ in their ability
to offer, explain, or refer patients to all options
equally
Access is uneven geographically, and in terms
of test charges and insurance coverage
Uncertainty exists about performance of different
screening methods with regard to benefits, harms,
and costs (especially on programmatic basis)
88. Sensitivity of Take Home vs. In-Office FOBT
Sensitivity
FOBT method All Advanced Cancer
(Hemoccult II) Lesions
3 card, take-home 23.9 % 43.9 %
Single sample, in-
office 4.9 % 9.5 %
Collins et al, Annals of Int Med Jan 2005
89. Rationale
Fecal occult blood tests
detect blood in the stool –
which is intermittent and
non-specific
Colon cells are shed
continuously
Polyps and cancer cells
contain abnormal DNA
Stool DNA tests look for
abnormal DNA from cells
that are passed in the stool*
*All positive tests should be followed with colonoscopy
90. Three versions of the previously marketed sDNA
test have been evaluated
Version 1 (K-ras, APC, p53,BAT-26, DIA) was evaluated
in the Imperiale trial
Version 1.1 (K-ras, APC, P53), PreGen-Plus is the currently
marketed test
Version 2 (Vimentin only, or Vimentin + DIA) is currently
under evaluation and is expected to enter the market in Fall
2008
Earlier and more recent tests were evaluated
in smaller, mixed populations
91. Testing evaluates stool for Study with One-Time Sensitivity for
the presence of altered DNA Testing (v) Cancer
in the adenoma-carcinoma Ahlquist, et al
sequence 91%
Gastro, 2000 (1)
No dietary restrictions Imperiale, et al
51.6%
NEJM, 2004 (1)
No stool sampling (utilizes
the entire stool) Syngal, et. al
63%
Cancer, 2006 (1)
Several studies suggesting Whitney, et al
strong patient acceptance J Mol Diagn, 2004 (1.1)
70%
Testing interval uncertain Chen, et al
46%
JNCI, 2005 (2)
Uncertainty about the
meaning of false positives Itzkowitz, et al
88%
DDW-AB, 2006 (2)
92. Limitations
Misses some cancers
Sensitivity for adenomas with current
commercial version of test is low
Technology (and test versions) are in
transition
Costs much more than other forms of stool
testing (approximately $300 - $400 per test)
Not covered by most insurers
93. Limitations (cont.)
Appropriate re-screening interval is not
known
Not clear how to manage positive stool DNA
test
if colonoscopy is negative
FDA issues
Test availability
94. CTC Image Optical Colonoscopy
Courtesy of Beth McFarland, MD
95. Rationale
Allows detailed evaluation of the entire colon
A number of studies have demonstrated a high
level of sensitivity for cancer and large polyps
Minimally invasive (rectal tube for air
insufflation)
No sedation required
96. Polyp Size
CTC
>10mm 6-9 mm Cancer
performance
Pooled
85-93% 70-86% 85.7%
Sensitivity
Pooled
97% 86-93% ----
Specificity
Halligan 2005, Mulhall 2005
98. Most have limited clinical impact, but some are
important:
Asymptomatic cancers outside of colon and rectum
Aortic aneurysms
Renal and gall bladder calculi
99. Limitations
Requires full bowel prep (which most patients
find
to be the most distressing element of
colonoscopy)
Colonoscopy is required if abnormalities
detected,
sometimes necessitating a second bowel prep
Steep learning curve for radiologists
Limited availability to high quality exams in
many parts of the country
Most insurers do not currently cover CTC as
100. Limitations
Extra-colonic findings can lead to additional
testing
(may have both positive and negative
connotations)
Questions regarding:
Significance of radiation exposure
Management of small polyps