CANCER SCREENING TESTS EVALUATING THE EVIDENCE by fhy50518

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									CANCER SCREENING TESTS:
EVALUATING THE EVIDENCE


 Leah Karliner, MD, MAS
 Department of Medicine
         UCSF
                       CASE

56 y.o. man, healthy, no family history of GI cancer,
no current symptoms of rectal bleeding, changes in
stool or weight loss.

   “Doc, can I get one of those virtual
    colonoscopies?”
                     OUTLINE

 Evaluating Tests
 Colon cancer screening: old tests and new
 Breast cancer screening: mammograms and MRIs
 Prostate cancer screening: should we screen?
 Where to go for the evidence
(extra slides on ovarian and lung cancer screening)
         PRINCIPLES OF SCREENING

 Disease has high prevalence
 Disease has serious consequences
 Detectable preclinical phase
 Treatment for presymptomatic disease is more
  effective than after symptoms develop
 Positive impact on clinical health outcomes: early
  detection reduces cancer mortality
           EFFECTIVENESS OF TEST


   Tests should be simple, inexpensive and
    acceptable with a high sensitivity and
    specificity

   Number of false positives is acceptably low
             EFFECTIVENESS OF TEST
Questions to be answered when evaluating/comparing
  tests:
 Who will be tested?
 What tests will it supplement or replace?
 Is the new test safer?
 Is the new test less costly?
 Is the test more specific (excluding cases of non-
  disease)?
 Is the new test more sensitive (detecting more cases of
  disease)?
 Is wide-spread use of the test feasible in practice?
                    SCREENING:
               OTHER CONSIDERATIONS

   Screening in high risk groups
     – Selective vs universal screening
     – Rare diseases and false positive test results


   Involving patients in the decision
     – What are the co-morbid conditions?
     – Associated life expectancy, feasibility of treatment,
       effects of treatment on quality of life
COLON CANCER
                 COLORECTAL CANCER:
                 Principles of Screening
 Disease has high prevalence: Second most common
  form of cancer in the U.S.
 Disease has serious consequences: second highest
  cancer mortality rate overall in U.S.
 Detectable preclinical phase – polyps
 Treatment for pre-symptomatic disease is more
  effective than after symptoms develop - yes
 Screening reduces cancer mortality:
    – Several studies have shown that screening with fecal occult
      blood test (FOBT) or sigmoidoscopy is associated with a
      reduction in colorectal cancer mortality
                 HOW ARE WE DOING?
Adults > age 50, National Data from the Center for Disease Control:
 FOBT in past 2 years             27%
   – White                           – 28%
   – Black                           – 24%
   – Latino                          – 17%
   – Other                           – 20%
   – Multiracial                     – 27%
 Ever had a sig or colonoscopy    53%
   – White                           – 54%
   – Black                           – 49%
   – Latino                          – 39%
   – Other                           – 41%
   – Multiracial                     – 54%              »BRFSS, 2004
         COLON CANCER SCREENING
            RECOMMENDATIONS

   U.S. Preventive Services Task Force recommends
    screening all persons over 50
    – Benefits of screening outweigh potential harms
    – Quality of evidence, magnitude of benefit and potential
      harms vary with each method
    – Unclear which is the best test: FOBT, FOBT plus
      sigmoidoscopy, colonoscopy
                    AVAILABLE TESTS
 Tests should be simple, inexpensive and acceptable
  with a high sensitivity and specificity: ????
 Available/commonly used tests:
    – Fecal occult blood test
    – Sigmoidoscopy
    – Colonoscopy
   Newer tests:
    – Virtual Colonoscopy?
    – Fecal DNA testing?
    – Immunochemical FOBT?
                  WHICH TEST?


 Are the tests equally safe?
 Are the tests equally costly?
 Are the tests equally specific?
 Are the tests equally sensitive?
 Is wide-spread use of the test feasible in practice?
                            TEST ISSUES

   Sigmoidoscopy
    – Fair evidence for reducing mortality
    – Sigmoidoscopy alone can miss proximal neoplasia – a
      positive test needs to be followed by colonoscopy

   FOBT
    – Good evidence for reducing mortality
    – Trials used 6 sample every 1-2 years
    – Positive test needs to be followed by colonoscopy
    – Many providers use digital FOBT as a primary screening
      test - this is different use from in the trials - is in office single
      stool sample testing enough?
     FOBT vs. IN-OFFICE SINGLE FOBT


 Sensitivity for advanced neoplasia was 24% for 6
  sample FOBT vs 5% for digital FOBT
 Specificity was 94% for 6 sample FOBT and 98% for
  digital FOBT
 Digital FOBT is a poor screening method
       • Collins, 2005
       IS COLONOSCOPY “BETTER?”

 Two observational studies of patients undergoing
  colonoscopy
 Goal: Determine prevalence and location of
  colonic neoplasia in asymptomatic patients and
  the risk of proximal advanced neoplasia in
  patients with or without distal neoplasia
 Did NOT assess morbidity and mortality
         IS COLONOSCOPY “BETTER?”

   Colonoscopy showed some lesions that would
    have been missed by sigmoidoscopy alone
    – distal polyps were a predictor of proximal neoplasia,
    – but some patients with proximal neoplasia did not have
      distal polyps
   If sigmoidoscopy alone had been done and if
    every adenomatous polyp triggered
    colonoscopy, 80% of high risk lesions would have
    been detected
      SCREENING COLONOSCOPY?

 Would proximal lesions have been detected by
  FOBT?
 No assessment of morbidity and mortality
        SCREENING COLONOSCOPY?

 More sensitive than FOBT/sigmoidoscopy
 More specific than FOBT
 Higher risk (diagnostic colonoscopies have 1/2000
  perforation rate; with polypectomy 1/500-1000)
 More costly? (USPSTF says all of these screening
  methods are probably cost-effective)
 Presumed to save lives because used as diagnostic
  test in FOBT studies, but at higher rate than FOBT?
 Feasibility in practice dependent on availability of
  gastroenterologists and insurance coverage
                    WHICH TEST?

   Most preventable cases of colon cancer are
    found in those who have never been screened

   If we screened with the currently available tests at
    the recommended intervals, we could make a big
    impact – particularly in ethnic minorities

   Any screening is better than no screening for
    reducing colorectal cancer mortality
                NEWER TESTS

 Virtual Colonoscopy
 Fecal DNA
 Immunochemical FOBT (iFOBT)
             VIRTUAL COLONOSCOPY

 Non-invasive colon imaging method using thin
  section CT
 Test characteristics in largest study to date
    – N=1,233 average risk individuals
    – Sensitivity
       » 94% for polyps ≥8 mm
       » 89% for polyps ≥6 mm
    – Specificity
       » 96% for polyps ≥10 mm
       » 80% for polyps ≥6 mm
          • Pickhardt, 2003
          VIRTUAL COLONOSCOPY

 Study used 3 D technology which is not available
  everywhere
 Single center study
 Are these results reproducible? Is this feasible in
  widespread practice?
              VIRTUAL COLONOSCOPY

   Multicenter study of screening population
     – 615 participants at 9 hospitals
 Two-dimensional scans
 Sensitivity
     – 55% for lesions ≥10 mm
     – 39% for lesions ≥6 mm
   Specificity
     – 96% for lesions ≥10 mm
     – 91% for lesions ≥6 mm
           • Cotton, 2004
               VIRTUAL COLONOSCOPY
 Requires bowel prep and insufflation
 Patients do not necessarily prefer over colonoscopy
 Test interpretation is very time consuming
 Cost effectiveness
    – Assuming 100% sensitivity and specificity
    – To replace colonoscopy, it would have to be less than 50%
      the cost of colonoscopy and compliance would have to be
      15-20% better
         • Sonnenberg, 1999
                FECAL DNA TESTING

   DNA alterations in colorectal cancer can be
    detected in the stool

   Potential advantages
    – Non-invasive
    – No preparation
    – Detection along entire length of the colon
               FECAL DNA TESTING

 Recently evaluated as a screening test in
  asymptomatic individuals aged 50 and older
 Fecal DNA test (21 mutations), Hemoccult II and
  colonoscopy
 4404/5486 completed all three aspects of the
  study
 Subgroup of 2507 patients were analyzed
       • Imperiale, 2004
               FECAL DNA TESTING
                           Fecal DNA   Hemoccult
                                           II
Sensitivity for invasive     51.6%       12.9%
cancer
Sensitivity for invasive     40.8%       14.1%
cancer/adenoma with
high grade dysplasia
Sensitivity for              18.2%       10.8%
advanced neoplasia
Specificity                  18.2%       10.8%
             FECAL DNA TESTING

 20% of the subjects either did not provide samples
  or did not have colonoscopy
 Many were aged 65 and over
 Both FOBT and fecal DNA had relatively low
  sensitivities compared with what was expected
  based on prior studies
                  FECAL DNA:
              REMAINING QUESTIONS

   Are health outcomes improved?
     – Even if we assume benefit based on FOBT trials, how
       much?
   Do the benefits outweigh the risks?
     – Public expectations about accuracy of DNA testing?
 Frequency of testing?
 Acceptability and availability?
 Cost
     – $400 to $800 vs $3 to $40 for FOBT
          IMMUNOCHEMICAL FOBT

Potential advantages:
 Easier to use
 Improved specificity
 Probably small increase in sensitivity (may not
  need as many samples)
 Test characteristics in large average risk
  populations has not been studied
            COLORECTAL CANCER
          SCREENING: CONCLUSIONS

   Any currently available screening is better than no
    screening for reducing colorectal cancer
    mortality

   Virtual colonoscopy, immunochemical tests and
    fecal DNA testing may have a role in the future
Breast Cancer
              BREAST CANCER SCREENING
   Disease has high prevalence: most commonly detected
    cancer in women in U.S.
     – but lower prevelance for women in 40’s
   Disease has serious consequences: second highest cancer
    mortality rate for women in U.S.
   Detectable preclinical phase – microcalcifications
   Treatment for pre-symptomatic disease is more effective than
    after symptoms develop – unclear in case of DCIS
   Screening reduces cancer mortality: Several studies have
    shown that screening mammography can reduce mortality
     – RCTs have not shown a mortality reduction in women in their 40’s
                   USPSTF

 UnitedStates Preventive Services Task Force
 recommends screening mammography with
 or without clinical breast examination every 1-
 2 years for women aged 40 and older
  –Data are most clear for women aged 50-69
  –For women in their forties the evidence is
   weaker
  –Benefit to women aged 70 and older if life
   expectancy not compromised by co-
   morbid disease
                       USPSTF

 Evidence insufficient for or against clinical breast
  examination alone
 Evidence insufficient for or against teaching or
  performing routine breast self-examination
                           TEST ISSUES

   Tests should be simple, inexpensive and
    acceptable with a high sensitivity and specificity:
    Increased density of pre-menopausal breast
    tissue leads to decreased sensitivity

   Number of false positives is acceptably low:
     – Cumulative risk of false positive result: 49% after ten
       mammograms
     – False positive rates were higher for women in their
       forties than for women age 50-69
        » (Elmore et al, 1998)
           MAMMOGRAPHY IN WOMEN
                AGED 40-49

 Increased density of premenopausal breast tissue
  leads to decreased sensitivity
 More cases discovered by mammography in
  women in their forties are ductal carcinoma in situ
  (DCIS) than in women in their fifties (40-45% vs 20%)
    – Clinical significance of DCIS is unclear
    – Only 20% will progress to invasive cancer over 10 years
      and those that do progress will do so slowly
    – Who will benefit from DCIS treatment?
       MAMMOGRAPHY IN WOMEN
            AGED 40-49


 Discuss the pros and cons of mammography
  screening and should consider patient risk factors
  in making a decision about screening
 If mammography is offered, it should be
  performed annually
                 MAMMOGRAPHY IN
                  ELDERLY WOMEN

 Age is the most important risk factor for breast cancer
 Nearly half (47%) of breast cancer is diagnosed in
  women over the age of 65 and 52% of breast cancer
  mortality occurs in this age group
 Competing mortality


     » Mandelblatt, JGIM 2005
        SCREENING HIGH RISK WOMEN

 Women with BRCA1 and BRCA2 mutations or with
  a family history of breast cancer are often
  diagnosed at a young age
 Screening is often offered to younger high risk
  women but efficacy is not known
    – Lower sensitivity of mammography in younger women
    – High tumor growth rate
    – Atypical mammography changes in women with BRCA
      mutations
                    MRI SCREENING

 Does MRI have a role for screening in high risk
  women?
 Sensitive method of breast imaging and has been
  used as a diagnostic tool in women with breast
  cancer
    – Not influenced by breast density
 Specificity is variable
 Expensive
                 MRI SCREENING

 236 Canadian women aged 25-65 with BRCA1
  and BRCA2 mutations had 1-3 annual screening
  examinations
 MRI, ultrasound, mammography annually
 Clinical breast examination every 6 months




    » Warner et al JAMA 2004
                 MRI SCREENING

   22 cancers detected
    – 6 DCIS
   All four screening modalities combined had a
    sensitivity of 95% vs 45% for mammography plus
    clinical breast exam
         SENSITIVITY AND SPECIFICITY

      Test        Sensitivity   Specificity

MRI                  77%           95%

Mammography          36%          99.8%

Ultrasound           33%           96%

Clinical Breast      9%            99%
Exam
                IMPACT FOR
             CLINICAL PRACTICE

 MRI may be useful in screening high risk women,
  although the effect of MRI screening on mortality
  is not yet known
 MRI is not currently recommended for screening
  average risk women
Prostate Cancer
                      PROSTATE CANCER:
                     SHOULD WE SCREEN?
   Disease has high prevalence: Most commonly diagnosed
    cancer in U.S. men
     – 10% lifetime risk
     – 30% of men have prostate cancer at autopsy
   Disease has serious consequences: variable; prostate cancer
    may be a benign disease for many men
   Detectable preclinical phase – ?PSA
   Treatment for pre-symptomatic disease is more effective than
    after symptoms develop - Does early detection do more good
    than harm or vice versa?
    Complications of prostate cancer treatment
     – 8.4% incontinence
     – 60% impotence
           • Prostate Cancer Outcomes Study 24 month follow up
   Screening reduces cancer mortality: ???
       IS TREATMENT OF EARLY DISEASE
                 EFFECTIVE?

   Does treatment of early prostate cancer reduce
    morbidity and mortality?
    – RCT showed reduction in mortality, prostate cancer
      mortality, metastatic disease and local progression
    – Absolute reduction in mortality is small

       » Bill-Axelson, NEJM 2005
    DOES SCREENING DECREASE MORTALITY?
          EPIDEMIOLOGIC EVIDENCE

 Prostate cancer mortality has decreased following
  the introduction of prostate cancer screening
 Reduction in mortality followed an initial increase
  in incidence
    – Due to PSA screening?
       » Short time interval
    – Changes in treatment
    – Is the decline most in the areas with most screening?
        RANDOMIZED CLINICAL TRIALS

   46,000 men underwent DRE and PSA
    – 11 year follow-up
    – 23 % of invited group and 6.5% of non-invited group
      underwent screening
    – Decrease in prostate cancer mortality, but small
      numbers of deaths overall
       » Labrie, Prostate 2004
 PLCO trial sponsored by the NCI is ongoing
 European Randomized Study of Screening for
  Prostate Cancer
        DIGITAL RECTAL EXAMINATION

 One-third of prostate cancers occur in areas
  which can be reached
 Higher sensitivity performed by urologists
 An abnormal digital rectal examination increases
  the likelihood of prostate cancer somewhat
 A negative examination does not change the
  likelihood of a clinically significant prostate
  cancer
    – Low sensitivity of the examination
          PSA SCREENING: TEST ISSUES

 15% of men over the age of 50 have an elevated
  PSA
 PSA >10 ng/ml:
    – 66% have prostate cancer
   PSA 4-10 ng/ml:
    – 22% have prostate cancer
          PSA SCREENING: TEST ISSUES

 Levels of 4.0 ng/ml or less have typically been
  considered to be normal
 Recent results from the Prostate Cancer Prevention
  Trial show that prostate cancer is not rare even in
  these men
    – 27% cancer in those with PSA 3.1 to 4.0
    – 24% in those with PSA 2.1 to 3.0
    – 17% in those with PSA 1.1 to 2.0
    – 10% in those with PSA 0.6 to 1.0
    – 7% in those with PSA up to 0.5
   How many cancers would be clinically important?
               PSA SCREENING:
               MODIFICATIONS

 PSA Density
 PSA Velocity
 Free and complexed PSA


So far, none of these modifications have proven
 superior to PSA alone
        PROSTATE CANCER SCREENING:
            RECOMMENDATIONS

   USPSTF: insufficient evidence to recommend for or
    against routine screening for prostate cancer
    using PSA or DRE
     – PSA can detect early prostate cancer, but inconclusive
       evidence about whether early detection improves
       health outcomes


   ACP: individualize the decision to screen after
    discussion with patient about potential benefits
    and harms
                SUMMARY OF
             RECOMMENDATIONS

Colon cancer: any screening is better than no
  screening, use commonly available tests
Breast cancer:
  – women aged 50 to 69 should undergo mammography
    every 1-2 years
  – discuss the pros and cons of mammography screening
    with women aged 40-49 and over age 70
  – MRI screening may be useful in high risk women
Prostate cancer: discuss pros and cons of PSA with
  eligible men; await PLCO trial
                      SUMMARY OF
                   RECOMMENDATIONS
   Cervical cancer:
     – Begin screening w/in 3 years of onset of sexual activity or at age 21;
     – Screen at least every 3 years;
     – Stop screening at age 65 in low risk women with adequate screening
       history                                (USPSTF 2003)
     – ‘reflex’ HPV testing on pap smears read as ASCUS (ACOG 2003)
   Ovarian cancer:
     – maybe in high risk women only; await PLCO trial
     – women at high risk should consider oral contraceptives (37%
       reduction in incidence)
   Lung cancer: do not screen; await PLCO trial
     – Smoking Cessation!
           WHERE TO GO FOR THE
                EVIDENCE

 U.S. Preventive Services Task Force
http://www.ahrq.gov/clinic/uspstfix.htm
 Technology Evaluation Center / Blue Cross - Blue
  Shield Association
http://www.bcbs.com/tec/whatistec.html
 California Technology Assessment Forum / Blue
  Shield of California Foundation
http://www.ctaf.org/
OVARIAN AND LUNG CANCER
       SCREENING
                 OVARIAN CANCER:
                SHOULD WE SCREEN?

   Lifetime risk of ovarian cancer
     – No affected relatives          1.2%
     – One affected relative          5%
     – 2 affected relatives           7%
     – Hereditary syndrome            40%
   Ovarian cancer limited to the ovaries is
    associated with a much higher survival rate
           OVARIAN CANCER:
         SCREENING TECHNIQUES


 Serum CA-125 assay
 Trans-vaginal ultrasound
 Serum CA-125 plus ultrasound
       OVARIAN CANCER SCREENING:
             CLINICAL TRIAL

 22,000 U.K. women
 Annual screening vs no screening for 3 years with
  7 year follow-up
 Screening
    – CA-125
    – Ultrasound if elevated CA-125
    – Surgical evaluation if ultrasound abnormal
 Slight increase in mean survival
 No difference in mortality
       » Jacobs et al, Lancet 1999
         OVARIAN CANCER SCREENING:
               CONCLUSIONS

 Many women must be screened to detect a few
  cases
 Small increase in survival:
     – Is it worth it?
   Low disease prevalence limits utility of the tests
    despite high sensitivity and specificity
                  SCREENING
               RECOMMENDATIONS

 USPSTF: potential harms outweigh potential benefits
 NIH Consensus Conference: Insufficient evidence
 Many organizations recommend annual pelvic
  examination
    – No evidence
   Although there are no data regarding screening in
    high risk women, experts recommend:
    – annual screening with rectovaginal pelvic examination,
      CA-125 and transvaginal ultrasound
                  FUTURE DIRECTIONS

   PLCO Trial
     – 74,000 women aged 55-74
     – CA-125 at entry and annually for 5 years
     – Annual transvaginal ultrasound
     – 13 year follow-up
   United Kingdom Trial of Ovarian Cancer Screening
     – 200,000 women with 7 year follow-up
   Lysophosphatidic Acid (LPA)
     – Tumor marker which shows promise
        LUNG CANCER: SHOULD WE
               SCREEN?

 Lung cancer is the number one cause of cancer
  mortality in both men and women
 If screening works for so many other cancers, why
  don’t we screen for lung cancer?
          LUNG CANCER SCREENING:
             SYSTEMATIC REVIEW

 Does screening for lung cancer reduce lung
  cancer mortality
 Included 7 trials of lung cancer screening
 Frequent screening with chest x-rays was
  associated with an increase in mortality
    – RR 1.11 (95% C.I. 1.00-1.23)
   No difference in chest X-ray plus cytology vs
    chest X-ray alone
                       ROLE OF CT

 No evidence that screening CT reduces mortality
 Lung Cancer Screening Study
     – NCI sponsored
     – High risk patients
     – CT or chest X-ray
     – Results available soon
   At this time, spiral CT should not be routinely used
    in clinical practice
       USPSTF RECOMMENDATIONS

 Evidence is insufficient
 Screening with x-ray, low dose CT, sputum
  cytology or combination can detect lung cancer
  early, but there is no evidence that any screening
  strategy reduces lung cancer mortality.
          PRIMARY PREVENTION OF
              LUNG CANCER

 Smoking cessation
 Smoking cessation
 Smoking cessation
 Smoking cessation
 Smoking cessation
 Smoking cessation
 Smoking cessation
 Smoking cessation!!!!!

								
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