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Cancer prevention and early detection strategies Summit of the Future 2006 Mercedes Lassus, MD


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Title: Cancer prevention and early detection strategies Summit of the Future 2006 Mercedes Lassus, MD

Cancer prevention and early detection
strategiesSummit of the Future 2006Mercedes
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
  • 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
  • Year number of deaths ww 230 000
  • 83 of deaths occur in low-resource countries,
    that have access to lt5 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
  • 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
  • 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
  • ASC-US atypical squamous cells of undeterminate

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
  • National screening programs exist in several EU
  • IARC working group on evaluation of of Cervical
    Cancer Screening Programes,Br. Med J 1986, 293,

Methods for cervix cancer screening
  • Established, standard in high resource
  • Pap smear
  • New methods, subject of completed or ongoing
  • 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 Lugols 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 lt30 and gt20
  • Upper age limit should depend on available
    resources and be gt 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 lt21 years. All
    adolescents should receive appropriate helath
    care, and prevention counseling.
  • Women gt 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 gt 30 years,
    women with 3 conseutive normal results may be
    screened every 2-3 years
  • Saslow D, CA Cancer J Clin 200252342-362

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
  • Improve quality standard for laboratories
  • Decrease the need for follow up See-and-Treat
    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
  • 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
  • A third visit takes place where treatment is
    initiated if the biopsty is abnormal

Usual Approach to Screening (2/2)
  • 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
  • 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
    lt50 per woman
  • Goldie SJ, JAMA 20012853107-3115

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
  • Incidence tends to be higher in high resource
    countries but fatality rates tend to be higher in
    low-resource countries
  • Incidence increases with age
  • gt 50 of cases occur in women without major

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 Deaths / 105 women
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
  • Ostergotland - Tabar L et al. Cancer 1995 75
  • Stockholm - Frissel J et al. Breast Cancer Res
    Treat 1997 45 263-70
  • Goteborg Bjurstam N et al. Cancer 1997 80
  • New York - Chu KC et al. J Natl Cancer Inst
  • Edinburgh - Alexander FE et al. Lancet 1999

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)
  • Summary RR 0.84 (CI0-77 0.91) equivalent to
    1224 women screened for each death saved, an
    average of 14 years after study entry
  • Women gt50 yo, RR 0.78 (0.70-0.87) with 838
    needed to screen. RR increases with time
  • Women 40-49 yo, RR0.85 (CI0.73-0.99) 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

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
  • Start mammography at age 30 or earlier
  • Shorter mammography intervals, e.g. every 6
  • 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
  • Invitation to mammography to women age 50-69 yo.
  • Screening is repeated every 2-3 years
  • For women 40-49 years old
  • Screening may be offered in some centers or
  • 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
  • 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
  • Presence of mutated BRCA1 or BRCA2 documented by
    genetic evaluation, or suspected by evidence of
    autosomal dominant inheritance

Autosomal Dominant inherance
  • gt 2 relatives with breast or ovarian cancer
  • breast cancer in relatives lt 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
  • Cancer Intervention and Surveillance Modeling

  • CISNET is a consorcium of investigators sponsored
    by NCI (Bethesda, Md) to measure the effect of
    cancer-control interventions on the incidence of
    and risk of death from caner in the general
  • 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 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
  • 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 service-based patient registration
The Breast Journal 12 Suppl. 1, 2006
Limited Level 2nd Tier resources
Services Facilities Record Keeping
Imaging services Radiation oncology services Early detection programs Imaging facility Radiation therapy Clinical information systems Health system network Facility-based medical records and centralized patient registration local cancer registry
The Breast Journal 12 Suppl. 1, 2006
Extended Level Third Tier resources
Services Facilities Record Keeping
Opportunistic screening programs Cancer follow-up Rehabilitation services Group support Centralized referral cancer center(s) Population-based cancer registry Facility-based follow-up systems 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
  • Likely to improve the stage at diagnosis where
    the majority of tumors are stage III or IV at
  • 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
  • Not using tobacco products
  • Not drinking too much alcohol
  • Eating gt5 daily servings of fruit and vegetables
  • Moderate fat intake
  • Maintaining a healthy weight
  • Being physically active
  • Protecting skin from sunlight

General Prevention strategies
  • Environmental
  • Secondhand tobacco smoke
  • Pesticides
  • Dioxins

Cervical Cancer Prevention
  • Avoidance of Human Papilloma Virus
  • Barrier protection and/or spermicidal gel during
    sexual intercourse
  • Vaccination
  • Screening to detect precancerous lesions and HPV
  • 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
  • Oral contraceptives and Estrogen/Progestin
    Replacement Therapy
  • Ionizing Radiation exposure
  • Obesity

Breast Cancer Prevention
  • Factors associated with decreased risk of Breast
  • 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 gt50 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

  • Included IBIS 1, BCPT and two smaller randomized
    studies that had shown conflicting results
  • 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 361296-300, 2003
  • Powles T, Lancet 35298-101, 1998 and Veronesi
    U, Lancet 35293-7, 1998 Martino S, Oncologist
    9 116-25, 2004

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
    gt50 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
  • 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 lt15 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
  • Provides immediate fixation
  • Decreases air-drying artifact, improving specimen
  • Residual material is available that may be used
    for ancillary testing