Sarah Feldman MD MPH
Co-Director Ambulatory Gynecologic Oncology
Brigham & Women ’ s Hospital
Dana Farber Cancer Institute
Lowell Cancer Center
Associate Professor
Harvard Medical School

I, Sarah Feldman. have been asked to disclose any significant relationships with commercial entities that are either providing financial support for this program or whose products or services are mentioned during my presentations.
I have no relationships to disclose.

Requires a programmatic approach including:
 primary vaccination
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 screening active management of abnormalities to prevent progression

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There are still 12,360 women diagnosed in the US annually with cervical cancer, and
4,020 deaths
The 5 year survival of this preventable disease is 67.9%
We have to do better…

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Evidence Based
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Logical, simple to understand and clearly written
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Clearly address areas of patient and provider confusion

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<21 No screening
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21-29 Pap q 3 years
 regardless of sexual activity(no HPV screening)
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30- 65 Pap alone q 3 years or Cotesting/Pap with HPV q 5 years
 if both results negative, and normal and negative screens
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> age 65 Stop screening if adequate screening
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Defined as 3 neg Paps within prior 10 years or 2 neg cotests within 10 years
Poorly screened women still need to be screened in this age group.
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S/p hyst with cervix removed & normal screening history No screening
Excluded “high risk patients”

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ASCCP excluded
ACOG: annual screening for immunosuppressed, DES unclear
NCCN: HIV, solid organ transplant, or long term steroid use, DES
USPTF: excluded
AMA: not addressed
WHO: HIV, prior treatment for dysplasia
ACP: Excluded

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Management of Abnormal Pap Smears
(cytology)
Management of Colposcopy Biopsies
(histology)
Follow up after treatment (excision, ablation)

Very complicated and difficult to follow

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30 pages long
12 algorithms
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7 for pap smear follow up
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5 for colposcopy finding follow up
Unclear which are evidence based and which are only expert opinion

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Review data:
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HIV positive
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Immunosuppressed
Patients with abnormal or inadequate prior screening histories

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Onset of screening within 1 year of sexual activity or by age 21; pap q 6 months x2
If normal results-> annual cytology and pelvic exam, including vulva, anus , cervix and vagina
All women with abnormal test results need evaluation and more frequent follow up
Status of disease (poor CD4 counts or expected life expectancy less than 2 years) may alter recommendation
New guidelines expected soon that may lengthen the interval for women with all normal results

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Definition of “immunocompromised” varies
May include various rheumatologic diseases, organ transplants or women on immunosuppressive medications
Increased rates of vulvar (greatest relative increase), vaginal and cervical cancer relative to immunocompetent women— need annual pelvic exam including the cervix, vagina, vulva and anal areas
Increased rates of LSIL abnormalities
Increased rates of cervical HSIL/cancer were generally modest
D o thorough pelvic exam, and make sure immunosuppressed patients at a minimum adhere to standard screening schedules. Consider more frequent screening for severely immunosuppressed patients.
Evaluate and treat all abnormal results

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Information mostly derived from Kaiser’s large dataset
Health system with excellent tracking, insurance, systems to bring patients back for appropriate testing and management
Data based on earlier screening practices with more frequent evaluation and more aggressive management true rates of cancer or pre-cancer with the current guidelines cannot be assessed (since patients are not being detected and treated as often)
May not be generalizable to all settings

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Kaiser data
>30 year old women, tested positive for HPV
Past positive HPV test OR abnormal Pap -significantly higher risk
CIN2+ than newly acquired infection unknown prior screening history for ASCUS /HPV+ women with unknown screening history:
-the 4 year cumulative risk of CIN2 was 23 % and of CIN3 was 13%
-similar to women known to have had known prior abnormal results
THUS KNOWLEDGE OF THE PAST SCREENING AND RESULT
HISTORY MATTERS

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Kaiser women >25 years old
Screening results antecedent to colposcopy affected 5 year risk of
CIN2
Pap cytology
Colposcopy histology
5 year risk of CIN2+
ASCUS/LSI
L
ASC-H
CIN1 or less 10 %
CIN1 or less 16%
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HSIL CIN1 or less 24%
No group had sufficiently low risk to return to
“routine” screening
If prior Pap showed ASC-H or HSIL, there was no co-testing

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Kaiser >30 year old women
5 year risks of recurrence after treatment varied by antecedent screening result and path
Pap – Cytology Colpo biopsyhistology
CIN 2 ASCUS/HPV+ or
LSIL
ASCUS – H or worse CIN3/ACIS
5 year risk of recurrence post rx
5%
16%
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No subgroup of women achieved risk sufficiently low to return to the new routine screening
Recommendation is co-test at 12,24,36 months then
“routine”

-after any abnormal cytology ?
-after any abnormal histology?
-after treatment for histologic abnormality?
Recommendations for surveillance post abnormality -based on weakest data, may be misleading

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Cost effectiveness study
Surveillance strategies after treatment for HSIL
Hypothetical
Women >30 yo British Columbia Cohort Study
Results: Paps at 6 and 12 months followed by annual conventional cytology surveillance reduced cervical cancers and cancer death compared with triennial cytology
HPV cotesting increased cost but did not improve outcome
Adding colposcopy at 6 months for high risk women, increased life expectancy

Makes key points with respect to how data is interpreted and understood with respect to guideline development.
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Cost and benefits need to be considered and may vary with different life situations/populations.
Q 3 year Pap or q 5 year cotesting are known to increase cancer rates relative to annual cytology.
Adverse effects of treatment (LOOP) may have been overstated.
Annual cytology remains the gold standard for cancer prevention

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Studied cost-effectiveness of current screening practice v. guideline screening
Used data from New Mexico HPV Pap registry
Assumed pap q 3 years 21-65 OR pap q 3 years 21-30 and Cotesting q 5 years
Assumed 100% compliance with colposcopy for abnormals and 100% compliance with excisional procedures as per guideline
Found that the most cost-effective option was pap q 3 years with evaluation of all abnormals and excisional treatment of all precancers as per guideline
Over and under screening/management were both less cost-effective
Did not stratify by risk group or prior treatment

From: Inefficiencies and High-Value Improvements in U.S. Cervical Cancer Screening Practice: A Cost-
Effectiveness AnalysisImproving U.S. Cervical Cancer Screening Practice
Ann Intern Med. Published online September 29, 2015. doi:10.7326/M15-0420
Date of download: 10/15/2015 Copyright © American College of Physicians . All rights reserved
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Screen q 3 years or cotest q 5 after 30 if all normal results
Evaluate all abnormal results
Treat all HSIL, AIS or persistent LSIL (in some cases)
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Ensure 100% compliance with screening, evaluation and management
Treat all patients with a history of abnormal results or an inadequate screening history as “high risk” and increase surveillance of this group

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HPV 16/18 account for 77% cervical cancers and 54% high grade lesions in US
As successive cohorts are vaccinated, fewer women may get these infections
Primary screening with HPV and triage to cytology might be the logical next step

Canadian Cervical Cancer Screening Trial
Women ages 30-69
Compared conventional Pap and HC2
Mayrand, M-H. N Engl J Med 2007 Human
Papillomavirus DNA versus Papanicolou Screening
Tests for Cervical Cancer

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Combined results of 4 studies (Sweden, the
Netherlands, England and Italy).
Primary HPV 60-70% greater protection against invasive cervical cancer than primary cytology after first 2.5 years.
Negative HPV at 5 years had better negative predictive value (NPV) than normal cytology at 3 years.
However, studies involved many different treatment and management algorithms reporting markedly different costs for screening, depending on strategies used.

Methods:
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Cobas HPV test
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Cytology and HPV co-collected
Options compared included:
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Reflex HPV
Hybrid (cytology under 30 and cotesting above 30)
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Primary HPV with 16/18 triage or cytology triage (if
HPV12+)
Results:
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Primary HPV detects more CIN2+ but at cost of more colposcopies
Only 3 years of follow up data
Patients managed by specific study algorithms which may not be available in all clinic settings.

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12,000 women are still getting cervical cancer in the US—could we initiate primary
HPV screening on unscreened women?
Young women who have been vaccinated have a lower risk of getting HR HPV, so fewer women will test positive and need evaluation. HRHPV screening may increase detection of AIS in this age group.

Cytology
Primary HPV
Screening
Options for triage for
HPV+
VIA Colpo 16/18
• Different situations determine which is best
• Need ongoing studies to guide management
See & Treat

Ultimately a combination of vaccine in younger women and screening for carcinogenic HPV in older women may revolutionize cervical cancer prevention
See Schiffman, M, Castle, PE. The Promise of Cervical Cancer Prevention.
NEJM 353:20, 2101-2104, 2005