Transcript Diapositiva 1 - Club of Amsterdam

Cancer prevention and early
detection strategies
Summit of the Future 2006
Mercedes Lassus, MD
The Burden of Cancer Worldwide
Estimates for the year 2000*
 Ten
million new cases
 6.2 million deaths
 22.4 million living with cancer
 The
estimates indicate a 23% increase in
cancer incidence with respect to 1990
* Parkin DM. Eur J Cancer 37: S4-S66, 2001
Number of new cases and deaths worldwide for
the 15 most common cancers, 2000
European Journal of Cancer 37 (2001) S4-S66
The Burden of Cancer Worldwide
Although mortality from individual cancers is
decreasing in high income countries,
mortality continues to increase in
developing economies
Reducing the world cancer burden
 Better
therapies
 Screening for earlier detection: Smaller,
“younger” tumors have better prognosis
and may be curable
 Preventing malignancies
Cancer Screening World Wide: Status
 High
resource countries: evidence-based
guidelines recommend optimal
approaches to early detection, diagnosis
and treatment.
 But! These guidelines have limited
application in resource-limited, culturally
diverse, populations within the countries,
Cancer Screening World Wide: Status
 And!
These guidelines have limited
application in resource-limited, culturally
diverse, countries (WHO Executive Summary, Geneva, 2000)
 The definition of evidence-based,
economically feasible, culturally adequte
“best practices with limited resources” is
an urgent need. Several initiatives are
ongoing
Uterine Cervix Cancer
Cervical Cancer Burden

Most common cause of cancer deaths in women in
developing countries, despite being preventable.
 Year incidence ww is approx. 500 000
 Sequela of a sexually transmitted infection with HPV
 Year number of deaths ww: 230 000


83% of deaths occur in low-resource
countries, that have access to <5% global
cancer treatment resources. In high resource
countries, the majority of cervical cancer
cases and deaths occur in disadvantaged
groups.
Cervical Cancer is a disease of Inequality
Cervical cancer is highly preventable

There is an easily identifiable precancerous
lesion
 Transition from precancer to cancer occurs over
an extended period (average 10 years)
 Acceptable screening tests for early detection of
precancerous lesions are available
 Outpatients therapies of precancerous lesions
are available, safe, effective and relatively
inexpensive

Cervical Cancer is a failure of screening
Cervical Cancer and HPV infection

HPV DNA is detected in about 100% of invasive
squamous cell cancers.
 HPV is the most common sexually transmitted
disease, with prevalence rates of 19% - 46%.
 Major risk factors are early age at onset of
sexual activity, multiple partners, failure to use
barrier contraception, and coinfection with other
sexually transmitted disease.
 Most HPV infections are transient. But women
with chronic HPV tend to develop cervical
abnormalities
Precancerous cervical lesions
 HSIL:
significant precancerous lesion, high
risk
 LSIL: low risk precancerous lesion. Most
regress spontaneously in adolescents and
in 50% - 80% in adults.
 ASC-US: atypical squamous cells of
undeterminate significance
A comparision of deaths from cervical
cancer and maternal mortality in selected
developing countries in 2000.
Country
Cervical cancer deaths
Maternal deaths
Argentina
1,679
590
Brazil
8,286
8,700
Chile
931
90
Peru
2,663
2,500
South Africa
3,681
2,600
China
25,561
11,000
India
74,118
136,000
Thailand
2,620
520
Cervical Cancer Burden: the good news



The effectiveness of cervical screening programs has
been demonstrated in several countries, despite the
absence of randomized trials.
It is estimated that screening with cervical smears every
3 years can prevent 90% of cervical cancers if all women
participate in a screening program and all detected
lesions are adequately followed-up*.
National screening programs exist in several EU
countries
*IARC working group on evaluation of of Cervical Cancer Screening
Programes,Br. Med J 1986, 293, 659-654
Methods for cervix cancer screening
Established, standard in high resource environments:
 Pap smear
New methods, subject of completed or ongoing studies:
 Liquid-based Pap technology (2 approved by FDA and
EU as equivalent to conventional Pap smear)
 Automated methods
 HPV testing as screening method and/or supplementary
method in follow-up of cervical abnormalities (approved
by FDA and EU)
 Visual tests: Visual Inspection with Acetic Acid or with
Lugol’s iodine. By staining the cervix precancerous
lesions can be identified
European Union Recommendations
 Pap
smears should be the method used
 Screening should start at age <30 and >20
 Upper age limit should depend on
available resources and be > 60
 Screening intervals between 3 and 5 years
 Performed only in organised screening
programs with QA at all levels
 Programs should be organised in
accordance with the European guidelines
American Cancer Society Recommendations*


Pap smears should be the method used
Screening should start 3 years after onset of
vaginal intercourse and <21 years. All
adolescents should receive appropriate helath
care, and prevention counseling.
 Women > 70 yo with 3 consecutive normal
smears and no abnormal tests in the last 10
years may elect to cease screening
 Performed initially annually OR biannually if
liqui-based cytology is used. At > 30 years,
women with 3 conseutive normal results may be
screened every 2-3 years
* Saslow D, CA Cancer J Clin 2002;52;342-362
Performance of the Pap Test
 It
is not perfect
 Sensitivity for CIN: 70% - 80%. Sensitivity
depends on size of the lesion,
accessibility, presence of only few
abnormal cells on the slide, presence of
inflammation and/or blood.
Strategies for Reducing Cancer Disparities
 Improve
knowledge on cancer screening,
attitudes and behaviour among
underserved populations
 Increase physician compliance with the
recommendations
 Improve quality standard for laboratories
 Decrease the need for follow up: See-andTreat approach to manage cervical
displasia
Usual Approach to Screening (1/2)

First visit: a vaginal examination with speculum
is performed to collect cervical cells (Pap
smear).
 Slides are sent to a lab to be processed and
examined under the microcope by a trained
cytology technician. Selected results are verified
by a physician cytologist.
 Women with abnormal Pap are called for a 2nd
visit to perform colposcopy and eventually have
a biopsy.
 A third visit takes place where treatment is
initiated if the biopsty is abnormal
Usual Approach to Screening (2/2)

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

Colposcopy: high-powered illuminated
magnification of the cervi
It allows to determine the extent of lesions and
to take biopsies
It allows to provide directed treatment with
cryotherapy or loop electrosurgical excision
procedure (LEEP)
Performed as outpatient procedure
Non invasive (as opposed to cold knife
conization requiring anesthesia)
Costly equipment (up to $13.000) and training
Less complex screening strategies (1/3)
Two-visit approach
 Pap smear in the first visit
 Women with patological results undergo
treatment in the second visit
 Colposcopy is not performed
Less complex screening strategies (2/3)
See and Treat approach
 Pap smear and Colposcopy are
substituted by direct visual examination of
the cervix after application of an acetic
acid solution or lugol iodine.
 Screening and treatment can be
performed in only one visit, decreasing the
risk of losses to follow up.
Less complex screening strategies (3/3)
Two-test approach
 Direct visual inspection (DVI) and cytology, or
DVI and HPV, or HPV and cytology.
 An abnormal result in either test is considered a
positive screen
Sequential two tests
 Only women with a positive results in one test
undergo a second test, and if both are positive,
the patient is treated.
Cost effect Analysis*

Use of a mathematical model and a hypothetical
cohort of previously unscreened 30-yo black
South African women
 Results indicated that a single-lifetime screen
with DVI or HPV DNA testing coupled with
immediate cryotherapy for those with positive
results, compared to no screening reduced the
inidence of cervical cancer by 26% - 32% and
cost <$50 per woman
*Goldie SJ, JAMA 2001;285:3107-3115
Screening for Breast Cancer
Breast Cancer Burden






1.1 million new cases diagnosed worldwide per year
representing 10% of all new cancer cases. Approx 1 in
8.2 women will have a diagnosis of breast cancer in her
lifetime
First cause of cancer death in women worldwide
Incidence is increasing 0.5% - 3% per year, expected
new cases diagnosed in 2010 = 1.4 – 1.5 million.
Incidence tends to be higher in high resource countries
but fatality rates tend to be higher in low-resource
countries
Incidence increases with age
> 50% of cases occur in women without major
predictors.
Breast Cancer Burden: the good news
 Mortality
rates have started to decrease in
high-resource countries likely due to the
combined effect of early diagnosis through
Screening and more effective therapy
 Only in the USA mortality in 2000 has
decresed by 24% compared to 1990
Evolution of rates cancer of death from
breast cancer 1975-2000, women 30-79
years old – Deaths / 105 women
Deaths / 105 women
USA
1975
48.3
1990
49.7
2000
38.0
SEER Cancer Statistic Review 1975-2001 (2004)
Survival rates for women diagnosed with breast cancer
in England and Wales aged 20-49 years, and 70-79
years during 1971-93
Survival rates are
adjusted for mortality
rates in the general in the
General population and standarised
to the age distribution of women
Diagnosed of breast cancer during
1986-90. Incidence (1971-96) and
Mortality (1971-99) rates are
standareised to the European
population; mortality rates are also
adjusted to take account of changes
In death registration (1979-92) and in
coding if the underlying cause of
death (1984-92).
The Lancet 356. August 12,2000
Methods for breast cancer screening
 Mammography
 Clinical
breast examination
 Breast self-examination
Newer screening modalities:
 Digital mammoraphy
 Ultrasound
 MRI
 Computer-aided detection programs for
mammography
Efficacy of Mammography
 Evaluated
in several randomized clinical
trials. Endpoint: long-term breast cancer
mortality
 Efficacy demonstrated in several of those
trials and in two metaanalysis.
Randomized trials evaluating 500.000
women by mammographic screening

Malmo - Andersson I et al. BMJ 1988; 297: 943-48
 Canada - Miller AB et al. Can Med Assoc J 192; 147: 1459-76 &
1477-88

Kopparberg - Tabar L et al. Cancer 1995; 75: 2507-17
 Ostergotland - Tabar L et al. Cancer 1995; 75: 2507-17
 Stockholm - Frissel J et al. Breast Cancer Res Treat 1997; 45:
263-70
Goteborg – Bjurstam N et al. Cancer 1997; 80: 2091-99
 New York - Chu KC et al. J Natl Cancer Inst 1988;80:1125-32
 Edinburgh - Alexander FE et al. Lancet 1999; 353:1903-08

Effectiveness of mammography in
reducing breast cancer mortality

Individual trials: 4/7showed reductions between 9% 32%. One was statistically significant (RR: 0.68, 95% CI
0.59 – 0.80)

Metaanalysis by the US Preventive Services Task Force
(USPSTF, 2002):

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
Summary RR = 0.84 (CI:0-77 – 0.91) equivalent to 1224 women
screened for each death saved, an average of 14 years after
study entry
Women >50 yo, RR= 0.78 (0.70-0.87) with 838 needed to
screen. RR increases with time
Women 40-49 yo, RR=0.85 (CI:0.73-0.99) with 1792 needed to
screen to prevent one death. RR decreases with time
Randomized trials of mammographic
screening

Another review by the International Agency for
Research on Cancer (IARC) and the World
Health Organization in May 2002, concluded
that mammographic screening in women 50-69
years did reduce mortality from breast cancer by
39% (IARC handbooks of Cancer Prevention, vol 7, 2002)

Several national programs in high-resource
countries have confirmed the contribution of
screening.
Current Guidelines in North America

ACS 2003, USPSTF 2002*, NCCN 2006*
For women at average risk:


At age 20: Start CBE and information on benefits/limitations of
CBE & BSE within period health examination at least every 3y
At age 40: Start annual mammographic screening
For women at increased risk

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
Start mammography at age 30 or earlier
Shorter mammography intervals, e.g. every 6 months
Addition of MRI screening
Addition of ultrasound screening
* American Cancer Society, US Preventive Services Task Force, National
Compreensive Cancer Network
Current Guidelines in Europe

European breast cancer screening network*
For women 50 -69 years old:

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Invitation to mammography to women age 50-69 yo.
Screening is repeated every 2-3 years
For women 40-49 years old:
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Screening may be offered in some centers or regions
Women should be clearly informed about possible benefits and
adverse effects of screening
Organized programs should be set up, so that spontaneous
screening in units without adequate control systems is
discouraged
Two-view mammography with double reading
12-18 months interval
Data monitoring and prper evaluation should be mandatory
* Advisory Committe on Cancer prevention, Eur J of Cancer 2000, 36: 1473 - 1478
Factors of increased risk of breast cancer

Age
 Personal history of prior thoracic RT, atypical
hyperplasia or lobular carcinoma in situ (LCIS)
 Family history of breast and/or ovarian cancer,
with number, type and age of onset being
important.

Presence of mutated BRCA1 or BRCA2 documented
by genetic evaluation, or suspected by evidence of
autosomal dominant inheritance
Autosomal Dominant inherance
>
2 relatives with breast or ovarian cancer
 breast cancer in relatives < 50 yo
 Relatives with both breast and ovarian
cancer or two independent breast cancers
 Male relatives with breast cancer
 Family history of breast or ovarian cancer
and Askenazi Jewish heritage
Teasing out the relative contribution of
screening, and newer therapies: the
CISNET* breast cancer working group
 Randomized
Clinical trials in patients with
breast cancer have shown that adjuvant
therapy following surgery for early disease
and newer therapies for metastatic
disease prolongs survival
* Cancer Intervention and Surveillance Modeling Network
CISNET



CISNET is a consorcium of investigators sponsored by
NCI (Bethesda, Md) to measure the effect of cancercontrol interventions on the incidence of and risk of
death from caner in the general population.
Seven independent teams developed statistical models
to assess the relative and absolute contributions of
screening mammography and adjuvant therapies to the
reduction in breast cancer mortality in the US from 1975
to 2000.
The models showed that both screening mammography
and treatment have helped reduce the rate of breast
cancer death in the US
New England Journal of Medicine; 353, 17, 2005
Estimate in actual rates of death from breast cancer among
women 30-79 years of age from 1975-2000 (Panel A) and
under hypothetical assumptions about the use of screening
mammographies and adjuvant treatment (Panel B)
New England Journal of Medicine 353; 2005
Low- resource countries
 Have
not always identified cancer as a
health care priority (infectious diseases
are the main health care issue)
 However, resources are spent on cancer
treatment, typically in advanced-stage
disease
The Breast Health Global Initiative (BHGI)


Objective: to establish breast health guidelines
for optimal care in countries with limited health
care resources.
Sponsors: Fred Hutchinsons Cancer Research
Center and the Susan G Komen Breast Cancer
Foundation
 Collaborating Organizations: 12 national and
international groups from areas with high and
low level of resources
 Affiliations with 3 WHO programs
 Two Global Summit Consensus Conferences
(2002, 2005)
2005 BHGI Global Summit Recommendations
 Care
Resources were stratified in 4
defined levels: basic, limited, enhanced
and maximal
 Recommendations were stratified by care
resources level, for:
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Diagnostic tools
Pathology method
Treatment and allocation of resources
Health care Systems and Public Policy
Basic Level: Indispensable Core Resources
Services
Facilities
Record Keeping
Primary care services
Surgical services
Pathology services
Oncology services
Nursing services
Palliative services
Health facility
Operating faclility
Pathology laboratory
Pharmacy
Outpatinet care facility
Individual medical
records and servicebased patient
registration
The Breast Journal 12; Suppl. 1, 2006
Limited Level: 2nd Tier resources
Services
Facilities
Imaging services
Imaging facility
Radiation oncology services Radiation therapy
Early detection programs
Clinical information
systems
Health system
network
The Breast Journal 12; Suppl. 1, 2006
Record Keeping
Facility-based
medical records and
centralized patient
registration local
cancer registry
Extended Level: Third Tier resources
Services
Facilities
Record Keeping
Opportunistic screening
programs
Cancer follow-up
Rehabilitation services
Group support
Centralized referral
cancer center(s)
Facility-based follow-up
systems
Population-based
cancer registry
Regional cancer
registry
The Breast Journal 12; Suppl. 1, 2006
Maximal Level
Services
Facilities
Record Keeping
Population-based
screening program
individual psychosocial
care
Satellite
(noncentralized or
regional) cancer
centers
National cancer
registry
The Breast Journal 12; Suppl. 1, 2006
Early Detection
Level of resources Detection method(s)
Basic
Breast health awareness (education +/- self
exaination)
Clinical breast examination (clinical
education)
Limited
Targeted outreach/education encouraging
CBE for at-risk groups diagnostic
ultrasound +/- diagnostic mammography
Enhanced
Diagnostic mammography
Opportunistic mammographic screening
Maximal
Population-based mammoraphic screening
other imaging technologies as appropriate:
high-risk groups, unique imaging
challenges
The Breast Journal 12; Suppl. 1, 2006
Clinical Breast Examination

Likely to be useful in the early diagnosis of
asymptomatic disease where mammography is
unavailable
 Likely to improve the stage at diagnosis where
the majority of tumors are stage III or IV at
diagnosis.
 Information from randomized trials not available
 Used for mass screening in Japan. A case
control study suggest benefit*
*Kanemura S. Jpn J Cancer Res 1999, 90: 607-613
General Prevention strategies
 Behavioural
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Not using tobacco products
Not drinking too much alcohol
Eating >5 daily servings of fruit and
vegetables
Moderate fat intake
Maintaining a healthy weight
Being physically active
Protecting skin from sunlight
General Prevention strategies
 Environmental

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Secondhand tobacco smoke
Pesticides
Dioxins
Cervical Cancer Prevention

Avoidance of Human Papilloma Virus

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
Barrier protection and/or spermicidal gel during
sexual intercourse
Vaccination
Screening to detect precancerous lesions and
HPV infection
 Avoidance of Tobacco use
 Avoidance of long term use of oral
contraceptives
Breast Cancer Prevention
 Avoidance
of Factors Associated with
Increased Risk of Breast Cancer
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Oral contraceptives and Estrogen/Progestin
Replacement Therapy
Ionizing Radiation exposure
Obesity
Breast Cancer Prevention
 Factors
associated with decreased risk of
Breast Cancer

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Selective Estrogen Receptor Modulators
Aromatase Inhibition or Inactivation
Exercise
Prophylactic mastectomy
Prophylactic oophorectomy
Selective Estrogen Receptor Modulators

Tamoxifen:

Breast Cancer Prevention Trial* (BCPT) – 13,388
women at high risk of breast cancer received
tamoxifen or placebo. A significant decrease en ER+
mammary tumors observed in the tamoxifen group
after 4 years and 7 years of follow up
• Increased incidence of endometrial cancer and
thrombotic events in >50 yo
* Fisher B, J Natl Cancer Inst 90: 1371-88, 1988 and J Natl Cancer Inst 97:
1652-62, 2005
Other Randomized studies of Tamoxifen for
prevention of breast cancer
 International
Breast Cancer Intervention
Study (IBIS-1)* - 7,152 women, 35 – 70
yo, with increased breast cancer risk,
received Tamoxifen or placebo:
31% risk reduction in ER+ breast
cancer. No reduction in ER- cancers
* Cuzik J, Lancet 360: 817-24, 2002
Metaanalysis#

Included IBIS 1, BCPT and two smaller
randomized studies* that had shown conflicting
results:

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ER+ tumors were decreased by 48%.
Rate of endometrial cancer was increased (RR: 2.4,
95% CI, 1.5-4.0)
Rate of thromboembolic events was increased (RR:
1.9, 95% CI, 1.4-2.6)
#Cuzik J, Lancet 361:296-300, 2003
* Powles T, Lancet 352:98-101, 1998 and Veronesi U, Lancet 352:93-7,
1998; Martino S, Oncologist 9: 116-25, 2004
BACK UP SLIDES
Evaluation of Mammographic Tests in the
Randomized screening trials

Sensitivity: using as denominator the total number of
breast ca cases diagnosede in a given interval: 71% 96% in the first round for a 1 year interval. Sensitivity
was higher in women >50 years old
 Specificity: 94% - 97%
 PPV: 2% - 22% for abnormal results requiring further
evaluation, & 12% - 78% for results requiring biopsy.
 Estimates from community settings suggest a continuous
increase in PPV with age.

Humphrey LL, Ann Intern Med 2002; 137: 347-360
Evaluation of individual programs

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UK national breast screening program: in 17 years it
esimated that 1400 lives are saved per year at a cost of
£3000 per year life saved. One in 8 fewer cancer deaths
in the target age group. Consistent with BErry in NEJM
2005. SEE REF
Two-view mammography initially followed by one-view
every 3 years. Only two-view since 2003.
Women 50-64 are invited since 1990, up to 70 years
since 2004
Coverage of 75%
63% of detected cancers are <15 mm and 75% node
negative at surgery. Survival was 93% at 5 years and
89% at 8 years
Liquid –based Pap Technology
 The
sample is directly placed into a liquid
fixative instead of being spread onto a
glass slide.
 Provides immediate fixation
 Decreases air-drying artifact, improving
specimen adequacy
 Residual material is available that may be
used for ancillary testing