Cancer detection

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

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

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.

 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

 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

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.

 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.

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

 All women starting at 40 years old should
be screened with mammography

 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

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

 Expensive
 Higher sensitivity with lower spesificity
 Not safe for detection of microcalcification
 Useful for additional screening method for
high risk women having mammography

 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

 Tc99m sestamibi scan (Miraluma)
 Tomosynthesis (variation of mammogram)

 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)

 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

 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

 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

 should begin at21 years of age
 Screening done regardless of the age of onset
of sexual intercourse

 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.

 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.

 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

 It has been demonstrated, however, that the
rate of dysplasia decreases as the number of
sequential negative Pap test results increases

 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

 May discontinue cytology screening withthree
or more negative cytology test results in a row
and no abnormal test results in the past 10
years.

 70 % of cervical cancer result from infection
with HPV 16 and 18
 90% of Genital wart are caused by 6 and 11

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

 Anal Pap smears
 4000 cases of anal cancer in women in 2003 and in
contrast to cervical cancer the rates are increasing

 55 – 74:
> 30 pack years smoking history
ceased smoking < 15 years
 > 50 years

> 20 pack year smoking history
one additional risk factor

% Stage I
I-ELCAP 85
Mayo 69
Turino 73
Randomized Trials
LSS 43
Depiscan 38
DANTE 57
NELSON 64

 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

 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

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

• 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

 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

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

 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

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


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


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


• 20% Mortality Reduction from Lung Cancer
• 6.7% All Cause Mortality Reduction
• 320 Persons Needed to be Screened with
LDCT to Prevent One Death


 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

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)

 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

 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

 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.

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

.

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

.

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

.

 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

.

 False negative results

 False positive results

 Overdiagnosis

.

– 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

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

.


 PSA and/or DRE abnormal, but no cancer
found

 Can lead to worry, additional tests, and
increased costs

.



 Overdiagnosis
 Some (many?) cancers found by screening
grow very slowly and will never cause
problems

.

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)

 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

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

 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)

 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

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

 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

New Findings in Treatment

JAMA, September 2009

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

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

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

 50 years of age
 No history of adenoma or colon cancer
 No history of inflammatory bowel disease
 Negative family history

 Adenoma/sessile serrated polyp
 History of colorectal cancer
 Inflammatory bowel disease
 Positive family history

 Lynch Syndrome (hereditary nonpolyposis
colorectal cancer)
 Polyposis syndrome
 Classical familial adenomatouspolyposis
 Attenuated Familial AdenomatousPolposis
 MUTYH-Associated Polyposis
 PeutzhJeghers Syndrome
 Juvenile Polyposis Syndrome
 Serrated Polyposis Syndrome

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

Normal to Adenoma to Carcinoma
Human colon carcinogenesis
progresses by the dysplasia/adenoma
to carcinoma pathway

 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

 Fecal Occult Blood Testing (FOBT)
 Guaiac
 Immunochemical

 Flexible Sigmoidoscopy (FSIG)
 FSIG + FOBT
 Colonoscopy
 Double Contrast Barium Enema (DCBE)

 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

 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

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.

 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)

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

 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

 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

 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)

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

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

CTC Image Optical Colonoscopy

Courtesy of Beth McFarland, MD

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

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

Polyp Size

>10mm >8mm >6mm

CTC 92.2% 92.6% 85.7%

Colonoscopy 88.2% 89.5% 90.0%

Pickhardt et al, NEJM 2003

Most have limited clinical impact, but some are
important:
 Asymptomatic cancers outside of colon and rectum

 Aortic aneurysms

 Renal and gall bladder calculi

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

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

U.S. Preventive Services Task Force, Ann Intern Med 2008

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