105

Document Sample
105 Powered By Docstoc
					Cervical Cancer Screening in the 21st Century
   : Is it Time to Retire the PAP Smear ?

         Clinical Obstetrics and Gynecology
            Vol 50/ Number 2/ June 2007
Abstract

Introduction

Limitations of Cytology

Performance of Cytology-based Prevention Programs

Human Papilloma Virus DNA Testing

Using HPV DNA Testing as an Adjunct to Cervical Cytology

Alterative Strategies for Using HPV DNA Testing for
Screening

Summary
                         Abstract

cytology-based cervical cancer prevention programs
    limited sensitivity
    expensive to maintain

→ programs based on testing for high-risk types of human
 papillomavirus (HPV)

HPV testing
   more sensitive than cytology (either conventional or liquid-based)
   >30 years old : specificity ↓(slightly)
                              Abstract


   Combination of cervical cytology and HPV testing to screen
  : cytology provides little benefit over using HPV testing alone to screen

→ HPV testing alone to screen

→ cervical cytology
  : a way to determine which HPV-positive women require additional
    follow-up or colposcopy
                         Introduction

Cervical cytology

   the cornerstone of cervical cancer prevention programs

   highly effective in many countries

   considered by some cancer control experts to be the single most
   successful approach to the prevention of any cancer

   the limitations inherent in cytology-based screening

→cytology-based screening programs have had even less of an impact
                  Limitations of Cytology
Relatively poor sensitivity

   the sensitivity of a single Papanicolaou test
 : 50% for identifying women with CIN 2,3 or cervical cancer (CIN 2+)
                             Meta-analyses that have reviewed the performance of cervical cytology


   sensitivity : 30% ~ 87%

   specificity : 86% ~ 100%
               meta-analysis conducted several years ago reviewed 94 screening studies

    overall sensitivity of cytology for CIN 2+ : 53% (95% CI 49%-57%)
   a review of recent European and North American cervical cancer screening studies by Cuzick et al


   19% in a German study

    77% in a recent large British study
                      Limitations of Cytology
                        liquid-based cytology               conventional cytology
for detecting     significantly more sensitive
CIN 2+


Systematic        no evidence that liquid-based
review            cytology improves the sensitivity
- publications    of cytology
  through 2003-

Positive          significantly reduced with a relative
predictive        PPV of 0.61 (95% CI 0.38-0.97)
value (PPV)       compared with conventional cytology


ASCUS cutoff,     71% (95% CI 58%-81%)                    84% (71%-92%).
the sensitivity


ASCUS cutoff,     9.4% (95% CI 7-12.3)                    11.4% (95% CI 8.5-15.0).
PPV
       Limitations of Cytology



liquid-based cytology vs conventional cytology

No significant differences of sensitivity or PPV
 for the identification of women with CIN 2+
         Limitations of Cytology



    novel cervical cancer screening strategies

alternative, non–cytology-based screening methods
 Performance of cytology-based Prevention
                 Programs


The goal of a cervical cancer prevention programs

   to identify high-grade cervical cancer precursors (CIN 2,3)

   to allow the lesions to be treated

   to prevent the subsequent development of cervical cancer
   Performance of cytology-based Prevention
                   Programs

The effectiveness of cervical cancer prevention programs
: depends on several factors + the sensitivity of the screening test

 Other factors that are important include ;
(1) whether or not there is heterogeneity among CIN 2,3 lesions

(2) the time it takes for a CIN 2,3 to progress to an invasive cancer
     (ie, the transit time)

(3) the frequency at which screening occurs

(4) screening coverage
   (ie, proportion of the target population that is actually screened)
  Performance of cytology-based Prevention
                  Programs


 Long transit time
 the time for a CIN 2,3 → an invasive cancer
 ☞ average 10 years

 the introduction of cervical cytology
→reductions in cervical cancer incidence
: highly variable between countries ( reduction range 20% ~ 90%)
                 - Epidemiologic studies from Canada, Scandinavia, and the United Kingdom
                           1970s ~ 1980s
                            : minimal impact on cervical cancer
                              incidence




FIGURE 1. Impact of the introduction of organized screening on the incidence of cervical cancer in the
           United Kingdom. Modified from BMJ. 1999;318:904–908.

In 1988, the National Health Service introduced a comprehensive cytology-based
screening program that incorporated a comprehensive system of audits.
The audits included the
       clinicians obtaining the cytology specimens
       laboratories evaluating the specimens
       specialists treating women with precursor lesions
    Performance of cytology-based Prevention
                    Programs


“call-recall” system
every woman in England of the targeted ages receives a regular invitation to be screened


 screening coverage (1988 ~1995)
 : 40% → 85% (↑)
   → incidence of invasive cervical cancer : dropped by 40%

                         death rate from cervical cancer
                        : reduced by almost 50%. (by 2004)
  Performance of cytology-based Prevention
                  Programs
Compensating for the poor sensitivity of cytology
→ frequent screening

In U.S.
    most women are overscreened
    some women do not undergo regular screening

 10,000 women who develop cervical cancer each year in the U. S.
- recent screening (X) : half of them
- recent screening (O) : half of them
Human Papilloma Virus DNA Testing
      Human Papilloma Virus DNA Testing

  invasive cervical cancer
: 15 “high-risk” or “oncogenic” types of human papilloma virus (HPV)

 molecular test for detecting the DNA of high-risk types of HPV in clinical
 specimens is a solution hybridization test called Hybrid Capture 2 (hc2)
 (Digene Diagnostics, Gaithersburg, MD)


 overcome the limitations of cervical cytology for screening

 lower cost

  13 high-risk types of HPV
 : 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68
      Human Papilloma Virus DNA Testing




TABLE 1. Performance of Hybrid Capture 2 and Cervical Cytology for Screening in Women 30
Years of Age and Older in Cross-sectional Studies*The target age for the study was 30 years and
older for women and 97% of the women enrolled were in the target age.Modified from references J Natl
Cancer Inst. 2006;98:765–774; Lancet. 2003;362:1871–1876; Br J Cancer. 2003;88:1570–1577; and Br
J Cancer. 2005;93:575–581. presents the results from recent large European trials.
Human Papilloma Virus DNA Testing

 Sensitivity

 HPV DNA testing > cervical cytology
 for identifying women with CIN 2,3 or cancer (CIN 2+)

 negative predictive value
 : cytology(-) & high-risk HPV DNA (-)

 →extremely high (> 99.9% in most of the studies)

 → risk of having an undetected CIN 2+ lesion in women who are
    screened with both tests
    : very low (approximately 1 in 1000)
Human Papilloma Virus DNA Testing
late adolescent females and young women

: multiple partners within several years of initiating sexual activity

 → prevalence of high-risk HPV DNA positivity ↑↑

 → multiple sequential infections with different types of HPV

 Ω most of these infections : transient

women 30 years and older

   older they tend, fewer new sexual exposures resulting in fewer
   new HPV infections

    HPV prevalence ↓
Human Papilloma Virus DNA Testing


 Specificity
: cervical cytology > HPV DNA testing > 2 tests in combination

 women ≥ 30 years old, who are screened using both cytology and
 high-risk HPV DNA testing
 → an abnormality on one or the other test

 → require either workup or additional follow-up
    --------------------------------------------------------10%
     Using HPV DNA Testing
as an Adjunct to Cervical Cytology
     Using HPV DNA Testing as an Adjunct to
               Cervical Cytology




FIGURE 2. Management of women using a combination of cervical cytology and HPV DNA testing for primary
screening in women 30 years and older. Modified from Obstet Gynecol. 2004;103:304–309.
      Using HPV DNA Testing as an Adjunct to
                Cervical Cytology
         both high-risk HPV DNA and cytology negative
         → recommended that not require rescreening for 3 years

         supported by the results of 2 studies


Study       NCI study followed women enrolled     study from France
            from Kaiser Permanente Portland, OR
F/U         up to 10 years                        for 36 months
result      high-risk HPV DNA (-)                 cervical cytology
                                                                    (-)
            → the risk of developing              high-risk HPV DNA
               biopsy-confirmed CIN 3             →biopsy-confirmed CIN 2+
             : low                                : 0.08%
 Using HPV DNA Testing as an Adjunct to
           Cervical Cytology

 How to manage HPV DNA (+), cytology (-)
 → reflect these women's risk for having, or developing, CIN2+

HPV DNA (+) & Cytology (-)   In the French study   study from England
CIN 2+ risk                         4.2%                  2.8%


  HPV DNA (+), cytology (-)
    Lower risk for having CIN 2+ than are women with ASC-US ( 5~17%)
   Using HPV DNA Testing as an Adjunct to
             Cervical Cytology
 HPV DNA(+), cytology(-)
→ colposcopy not be performed                  the 2004 Interim Guidance recommends



→ retested in 6 to 12 months using both cervical cytology and HPV
  DNA testing (Fig. 2)
             In the French & English studies    in the Kaiser Permanente Northern
                                                California
HPV DNA(+) half of women were persistently      only 35% were persistent at 12
           at 6 months                          months


  persistent HPV infections or
  cytology ≥ low-grade squamous intraepithelial lesions
  → colposcopy
Using HPV DNA Testing as an Adjunct to
          Cervical Cytology


    transiently shed HPV DNA

    → very low risk for having CIN 2+

    both repeat tests : cytology(-), HPV DNA (-)

     → 3 yearly screening
Alterative Strategies for Using HPV DNA
          Testing for Screening

HPV testing as an adjunct to cytology : long-standing problems

 - large numbers of cytotechnicians

 - the variability in abnormal rate between laboratories

 - relatively slow turnaround times

To maximize the benefits of incorporating HPV testing into screening

→ identify as many women with CIN 2+ as possible at the initial visit,

  while limiting the number referred to colposcopy
Alterative Strategies for Using HPV DNA
          Testing for Screening

Goal of cervical cancer screening

                                    • to reduce
   the risk of cervical cancer
                                    • not eliminate


   the level of risk reduction

       the costs

       potential inconvenience or harm to those being screened
Alterative Strategies for Using HPV DNA
          Testing for Screening
 common misperception : receive regular screening

 → completely protected against cervical cancer

 → develop cancer

 → their clinician or the cytology laboratory, has failed them

 → frequent litigation for a failure to diagnose cervical cancer

 compensatory overscreening by clinicians to try and assure that
 none of their patients develop cervical cancer

 → increases the costs of screening

 → unnecessary interventions such as colposcopy
    Alterative Strategies for Using HPV DNA
              Testing for Screening

    sensitivity of HPV DNA testing : high

               HPV DNA testing         Cytology with              Cytology-based screening
                with cytology      adjunctive HPV testing          → HPV-based strategy
 CIN 2+       cytology : no cases 1 ~ 3 cases /10,000            12 ~ 30 additional cases
dectection    of CIN 2+ that were compared with using             / 10,000
              missed by HPV       HPV testing alone
              testing
              In 2 South African   In other European screening
              screening studies    studies



             utilizing HPV DNA testing alone as the primary screening test
Alterative Strategies for Using HPV DNA
          Testing for Screening
 several potential approaches that can be used for managing HPV
 DNA positive women

: Novel HPV-based screening strategies incorporating either “reflex”
  cytology HPV genotyping, or a combination of both

→ a specimen would be obtained from all women using a liquid
  collection media suitable for both HPV DNA testing and cytology

→ initially be tested for high-risk types of HPV

→ HPV DNA (+)
    processed for cytology
 or
    perform HPV genotyping
FIGURE 4. Novel HPV-based screening strategies incorporating either “reflex”
cytology HPV genotyping, or a combination of both.
Alterative Strategies for Using HPV DNA
          Testing for Screening
most of the high-risk HPV DNA positive
→ developed biopsy-confirmed CIN 3
  : HPV 16 or HPV18              In the Kaiser Portland, OR, follow-up study


 other high-risk types of HPV
: slightly increased risk

high-risk types of HPV such as HPV 16, 18, 33, 45, or 31
(the 5 most common HPV types found in cervical cancers)

→ to be referred to colposcopy

 other high-risk types of HPV

→ followed-up in 12 months with a repeat HPV DNA test
FIGURE 3. Impact of HPV status on the development of CIN 3 in women 30 years and older
enrolled from Kaiser, Portland, OR. Solid circles represent women who were HPV 16 positive
entry, open circles are those who were HPV 18 positive, solid triangles are women with other
high-risk types of HPV, and open triangles are women who were high-risk HPV DNA negative.
Modified from J Natl Cancer Inst. 2005;97:1072–1079.




                                                                                HPV16(+)



                                                                                HPV18(+)




                                                                                Other high risk
                                                                                types of HPV
                                                                                High-risk
                                                                                DNA (-)
Alterative Strategies for Using HPV DNA
          Testing for Screening


Alternative strategy

: screen using HPV DNA testing alone

→ then use a combination of both reflex cytology and HPV
 genotyping to identify which HPV DNA positive women need
 colposcopy

- even more promising
                          Summary

 novel HPV-based screening

→ overcome many of the limitations of cervical cytology

→ will maximize the number of women with CIN 2+ identified at the
  screening visit

→ make loss to follow-up less of a concern

 HPV-based screening strategies : sensitivity↑

→ safely extend screening intervals from 3 to 5 years

    → less expensive to the health care system

    → more convenient for patients
Thank you
 for your
attention !
Summary
Alterative Strategies for Using HPV DNA
          Testing for Screening


Several studies have now clearly demonstrated that women infected
with certain high-risk types of HPV are at much greater risk for
developing CIN 2+ than are women infected with other high-risk types
of HPV.
Alterative Strategies for Using HPV DNA
          Testing for Screening
 The problem with eliminating cytology is that when both cytology
 and HPV DNA testing are utilized, the cytology result allows HPV
 DNA positive women to be triaged into 2 groups, those requiring
 colposcopy and those who can simply be followed-up.

 This triage function is needed since 5% to 8% of women 30 years
 and older will be found to be high-risk HPV DNA positive (Table
 1)
Over the next decade, the extraordinary advances that have been made in
our understanding of the pathogenesis of cervical cancer are going to allow
us to develop novel HPV-based screening strategies that will be able to
overcome many of the limitations of cervical cytology.
These strategies will maximize the number of women with CIN 2+ identified
at the screening visit and make loss to follow-up less of a concern.
Because of the increased sensitivity of these HPV-based screening
strategies, we will be able to safely extend screening intervals from 3 to
5 years.
This will be less expensive to the health care system and more
convenient for patients.
Already large randomized screening trials are underway in Europe to
evaluate whether we can replace cervical cytology with HPV DNA
testing.
Hopefully such trials will begin in the United States in the near future.
              Limitations of Cytology
When liquid-based cytology was first introduced, a number of studies
found that liquid-based cytology was significantly more sensitive
than conventional cervical cytology for detecting CIN 2+.
These studies had 1 of 2 designs.
 With 1 design, clinicians collect both a conventional cytology and a
liquid-based cytology from the same patient at the same time.
This allows a direct comparison of the performance of the 2 types of
cytology.
 The other study design compares the results obtained using liquid-
based cytology with results obtained by the same laboratory using
conventional cytology before the introduction of liquid-based cytology
(ie, historical controls).
Unfortunately, in the majority of the studies the end point was a
cytologic one (ie, detection of low-grade squamous intraepithelial
lesions or high-grade squamous intraepithelial lesions) rather than a
histologic one (ie, detection of biopsy-confirmed CIN 2,3).
Moreover, both types of studies can be easily biased.
 Because of these limitations, many in the screening community have
remained skeptical that liquid-based cytology is truly more
sensitive than conventional cytology.
              Limitations of Cytology
A recent systematic review of publications through 2003 that
compared the performance of liquid-based cytology with that of
conventional cytology concluded that only 4 of 56 published
studies provided sufficient verified data to allow any estimates of
sensitivity and specificity and comparisons of test performance to
be made.
 The systematic review concluded that there is no evidence in
high-quality studies that liquid-based cytology improves the
sensitivity of cytology.
The review also concluded that randomized clinical trials were needed.
Since the systematic review was completed, several randomized trials
have been published comparing the performance of the 2 cytology
methods.
One large randomized study of Italian women 25 to 34 years of age
reported that the sensitivity of liquid-based cytology was not
significantly higher than that of conventional cytology.
 The relative sensitivity of liquid-based cytology for CIN 2+ using
an atypical squamous cells of undetermined significance cutoff was
1.24 (95% CI 0.75-2.03) compared with that of conventional cytology.
                Limitations of Cytology
However, the positive predictive value (PPV) of liquid-based cytology was
significantly reduced with a relative PPV of 0.61 (95% CI 0.38-0.97) compared
with conventional cytology.
Another publication from the same group focused on women 35 years of age
and older and found similar results.
The relative sensitivity of liquid-based cytology in the older population was 1.06
(95% CI 0.72-1.55) compared with conventional cytology.
 In this study, the PPV of liquid-based cytology was also significantly reduced
(relative PPV=0.58, 95% CI 0.33-0.98) compared with conventional cytology.
In a recent randomized study from South Africa in which all women underwent
colposcopy at the time of screening, we found no significant differences in
either the sensitivity or PPV of liquid-based cytology compared with
conventional cytology for the identification of women with CIN 2+.
At an atypical squamous cells of undetermined significance cutoff, the sensitivity
of liquid-based cytology was 71% (95% CI 58%-81%), whereas that of
conventional cytology was 84% (71%-92%).
The PPV of liquid-based cytology was 9.4% (95% CI 7-12.3) whereas that for
conventional cytology was 11.4% (95% CI 8.5-15.0).
   Performance of cytology-based Prevention
                   Programs

In Norway after the introduction of opportunistic (ie, nonorganized)
screening, the incidence of cervical cancer actually increased through the
mid-1970s and only subsequently began a somewhat slow decline.

 In large part, the minimal impact was attributable to the fact that relatively
few women were being screened (ie, there was low coverage) and the
screening frequency was too infrequent.

 However, in 1995 Norway introduced an organized cytology-based
cervical cancer screening program and since its introduction the
rates of invasive cervical cancer have dropped considerably.
Human Papilloma Virus DNA Testing

 Recently, Kaiser Permanente of Northern California began offering
 HPV DNA testing to all women 30 years of age and older.

 On the basis of the data from over 200,000 women, the overall
 prevalence of high-risk HPV DNA positivity was just 6.4%.

 For comparison, 7.8% of the women had some degree of
 cytological abnormality.

 14 In Kaiser, a total of 11.6% of the women had either a
 cytologic abnormality or were high-risk HPV DNA positive.

				
DOCUMENT INFO
Shared By:
Categories:
Stats:
views:7
posted:12/3/2010
language:English
pages:47