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Rebecca Jackson, MD

Professor, Ob/Gyn & Reproductive Sciences

Epidemiology & Biostatistics

University of California, San Francisco

Gynecologic Cancer Screening 2017: Updates and Controversies

I have no financial interests to disclose

I do not get kickbacks from my Hawaii recommendations

Disclosures

Lecture Plan

1-2 questions for each gyn cancer• Cervix: Why did guidelines change (interval, start and

stop ages); What about screening with only HPV test (ie ditch cytology altogether)

• Ovary: New RCT’s are conflicting: should we be screening for it?

• Endometrium: It’s the 4th most common cancer in women, why don’t we screen for it?

Mortality

Incidence

4th

Ovary 22,440

Cervix 12,820Cervix 4,210

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Endometrial Cancer

Cervical Cancer

Ovarian Cancer

In Waimea, dress warmly

Pap smears are the most effective screening test ever invented….

60% decrease in incidence and mortality

Adding screening to naïve populations reduces incidence by 60-90% within 3 years of implementation

Why does pap screening work?

• Sensitivity of pap/cytology not great BUT

• The organ is easily accessible for screening

• Natural history is favorable : – precursor exists that is detectable and treatable;

– time course before cancer develops is long (>10yr)

– many opportunities to detect . Even if one test is false negative, get another chance.

• It is cost-effective because many years of life are saved because cancer is actually prevented.

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• As with many other cancers, higher incidence and death rate in Black women.

• In Hispanic women, high incidence partly due to poor screening in immigrants’ home countries

• Cervical Cancer is preventable with screening– Lets not forget this as

we strive to fine tune screening guidelines

2012 USPSTF Cx Ca (curr being updated)

• STRONGLY RECOMMENDS (“A”)

• Who? Women with cervix, regardless of sexual history

• Begin: Start age 21 (regardless of sexual activity)

• Interval:. 21-29: cytology q 3yr; > 30yo: q3 yr cytology or q 5yr cyto+HPV (cotest) if want to extend interval

• End: Age 65 if adequate prior screening (as per

ACS/ASCCP) and not at high risk for cx cancer (HIV, DES,

immunocompromised). End at 70-75yo if prior screening inadequate

• Other: Recommends against HR-HPV screening in <30yo (“D” grade)

All US guidelines similar• All strongly recommend against starting

before age 21

• None recommends annual screening

• All recommend against HPV alone or as a co-test in women <30 (ok as a reflex test after abnormal pap per ACS/ASCCP)

• None recommend screening after hyst (as long as no history of CIN2+)

• All recommend stop at age 65 (if adeqscreening)

• None recommend changes in screening for those who’ve had HPV vaccine

ACOG 2016

ACS, ASCCP, ASCP 2012

USPSTF 2012

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What’s new or different between guidelines?

• Co-test (HR-HPV + Cytology) in women>30yo

– 1st time USPSTF has recommended co-testing (“ok” for women who want to extend interval to 5 yrs)

– ACS/ASCCP/ASCP & ACOG: prefer co-test with 5 yr interval; acceptable to do cyto alone q3yr

Why is less screening now recommended?

Why is it ok to delay screening until age 21?

• Cervical cancer extremely rare; HPV infection very common immediately after onset of intercourse. 90% cleared by host within 2 yrs

• If persistent, we will pick up at age 21, still with plenty of time to treat because long progression time of pre-invasive lesions to invasive cancer

• Large population based study showed safety of this approach. 1yr vs 3 yrscreening: decrease lifetime risk of mortality by 2 per 100,000, increase in lifetime colpo rates from 760/1000 to 2000/1000

• The more tests you the do, the more false positives.

Kulasingam, 2011, AHRQ

Why is it ok to lengthen the screening interval?

Why the difference between <30 and >30 yo?

HR-HPV co-testing only clinically useful after age 30. Why?• In <30yo: HPV often positive, usually transiently.

Cancer risk very low. CIN usually regress spontaneously. Therefore, HPV testing not clinically useful and leads to excess colpo and treatment without improving outcomes

• > Age 30: HPV positivity more likely to represent persistent HPV which is a significant risk factor for dysplasia/cancer. AND, HPV negativity is a strong negative predictor.

HPV test also more sensitive for adeno-carcinoma than cytology

Co-testing caveats1. HR-HPV has decreased specificity so if we co-screen more

often than q5 years, patients incur greater harm without benefit – Before doing co-test, ensure patient is willing to be screened every 5

years

2. HPV-based strategies also lead to more positives – Some are true positives but more of them are false positives. All

positives need work-up.

– More women will need prolonged surveillance

– Some women who would otherwise be able to stop at age 65 will require continued screening beyond age 65

3. Unclear how to deal with HPV+, cytology negative

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ACS/ACSSP/ACP guidelines

• Co-testing “preferred” method

• Preferred by whom?– USPSTF: co-testing is an option “for women

who want to lengthen the screening interval”

• Looking more deeply into the “preferred” recommendation…. Supplemental page

Co-testing “preferred”

• Weak recommendation– “substantial uncertainty surrounding the balance of benefits and

harms, and further research is needed to increase confidence in the results, or that benefits and harms are closely balanced, with decisions based largely on individual preferences and values”

• Why didn’t the authors more clearly disclose that the designation of co-testing as “preferred” was a weak recommendation?

Beware guideline bias

• ACS/ASCCP/ACSP: Approximately 25% of committee members reported financial conflicts of interests with companies that make HPV tests

Now what?

FDA approved Roche Cobas HPV test as primary screen (no pap) in >25yo

Cobasdetects 14 high risk HPV types plus genotyping for 16 & 18

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Terminology clarification

• HPV reflex test: With ASCUS, HPV is reflexively sent to determine whether or not to do colpo.

• HPV co-test: HPV and cytology at same time. HPV is adjunct to cytology

• Primary HPV screening: only HPV test is done. HPV is alternative to cytology– Cytology reflex: HPV is primary and cytology sent if

HPV+

• HPV genotyping: refers to specific test (Cobas) that tests for HPV 16 and 18

“HPV test” always refers to high risk HPV test

Primary HPV screening

• HPV tests more sensitive, less specific than cytology

• Even though FDA approved for >25, should be considered only for women>30yo (due to poor specificity and high likelihood of regression)

• Body of evidence is growing but still only 1 rct and 1large cohort study plus several diagnostic accuracy studies. (USPSTF 2012: Insufficient evidence)

• In Italian RCT of 35K women, increased detection of CIN3 (over 3.5yrs f/u): relative detection rate 1.57 (1.03-2.4). More colpo in the HPV arm (5.8% vs 2.5%)

RoncoLancet Oncol. 2010

• 3 strategies1. “Cytology”: Cytology w reflex HPV for ascus

2. “Hybrid”: cytology for 25-29 yo and cotest for >=30yo (current US strategy)

3. “HPV primary” for >=25yo. Algorithm:• Neg HPVrescreen 3 yr

• +16/18 colpo

• + other HR types cytology

• Baseline: 10% HPV+; 6% positive cytology

ATHENA: Addressing the Need for Advanced HPV Diagnostics: 3 yr cohort study N=41K >25yo. All had cyto + Cobas HPV test. Colpo if either pap or COBAS abnormal. Colpow/ biopsy at study end. Endpoints: CIN2+ detection, number screening tests and colposWright, GynOnc 2015

Cobas HPV: 3 separate results: hpv 16, hpv 18 , 12 other high risk types

• Primary HPV strategy had higher sensitivity than cytology and hybrid but lower specificity – BUT: Increased sensitivity of primary HPV

strategy was due was due to earlier initiation of HPV screening (age 25 for the primary hrHPVgroup vs age 30 for the hybrid group.)

– Primary HPV strategy had more colposcopies compared with cytology but similar to hybrid strategy

• Cytology had the lowest number of screening tests followed by HPV primary then hybrid strategy

Cobas HPV: 3 separate results for hpv 16, 18 and 12 other high risk types

Subsequent cost-effective analyses showed the HPV strategy to be most cost effective

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• hrHPV primary screening can be considered as an alternative to current U.S. cervical cancer screening methods for >=25yo (but not yet recommended in major guidelines)

• Rationale: A negative Cobas test provides greater reassurance of low CIN3+ risk than a negative cytology result

• Use only the FDA approved Cobas test>=3 yrs

Not specified how, cotest?

Suggested AlogirthmPrimary HPV screen with cytology reflex

Huh, Obstet Gynecol, Feb 2015; GynOnc Feb 2015, J Low GenitTract Dis April 2015 Questions remain: primary HPV screening

• Any strategy that includes HPV screening increases the number of positive results and number of colposcopies performed. – Need comparative effectiveness studies that consider lifetime number

of screening tests, colpos, follow-up visits and cost comparisons

• Unclear why the recommendation to do primary HPV screening at >25yo when USPSTF recommends against any HPV testing in <30yo (“D” grade)

• Long-term outcomes remain uncertain. (studies only 3-5 yrs. ATHENA only one screening round)

• Given strong potential for bias due to study sponsorship by Roche, should we wait for more studies before adopting?

Role of the sponsorRoche Molecular Systems, Pleasanton, CA was involved in all aspects of the design and conduct of the study; collection, management, analysis, and interpretation of the data. Catherine Behrens and Abha Sharma who are Roche employees were integral to the preparation of the manuscript and the sponsor reviewed the final manuscript.

Answer: Wait for the USPSTF update!

What should we do?

Interpretation of evidence is complicated:

• Variety of comparison groups and strategies: co-test vs cyto alone, HPV vs cytology, HPV with cytology triage

• Differences in colposcopy thresholds

• Many studies have only reported 1 f/u round – After 1 round, HPV higher detection; after 2 or

more, no difference in detection in most studies

• Most studies have incomplete reporting of colposcopy rates

Can we do better?• Half of cervical cancers occur in women who

are not screened or inadequately screened. These women tend to be poor, uninsured, with lack of access to care

– A more sensitive test like HPV will not fix this problem!

– If we really wanted to decrease cervical cancer, this is where we would focus

• In poor countries, cervical cancer remains a huge problem.

Cobas HPV test Ipad App

Is industry pushing us to use this or is it the right thing to do?

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Conclusions: Cervical Cancer

• Cervical cancer screening in the US very successful in decreasing cervical cancer incidence and morbidity

• Goal now is to screen the unscreened AND decrease harm by decreasing false + and over-treatment:– Screen later (age 21) and less often (q 3yr)– Use co-test to extend interval to 5yr in patients who

desire this– Use less aggressive follow-up and treatment in

younger women

Gwen Ifill, PBS NewsHour co-anchor

September 29, 1955 – November 14, 2016

Racial disparity endometrial cancer

Incidence Mortality

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Endometrial Cancer

• 4th most common cancer in women• Average age 61 but 25% occur pre-menopausally• Presents at early stage with bleeding; rare in the

absence of bleeding. • Majority effectively treated with simple

hysterectomy

• Risk Factor = Increased estrogen (long h/o anovulation eg PCOS, obesity).

Given how common it is, why don’t we screen for it?

Why don’t we screen for EmCa?

• Although prevalence is high, mortality is low (case fatality rate is low)

• Majority of patients (75-90%) present with abnormal uterine blding and 2/3 have disease confined to uterus with 95% 5-year survival

– Would yet earlier detection offer any advantage?

– What are the harms of screening and is it acceptable?

• Given the already good outcomes, it is easier to shift the balance toward harm

What’s the evidence for EmCa screening? • 2 options: endometrial biopsy (emb) and transvaginal

ultrasound (TVUS) to measure endometrial stripe– EMB sensitive and specific, but uncomfortable and invasive

– TVUS: sensitive in postmenopausal women WITH bleeding, but less sensitive without blding and specificity poor (60%) leading to many biopsies

• No RCT’s have been done of routine screening (with either EMB or TVUS) of asymptomatic women with mortality as outcome

• Nonetheless, because of the favorable disease characteristics, all guidelines recommend against screening

Other EmCA screening Q’s

1. Should women on Tamoxifen be screened?No. Same natural history as other EmCa so do EMB or TVUS only if bleeding occurs

2. Should women with Lynch syndrome be screened?Yes-per expert opinion. Annual EMB starting at age 35yo

3. What about TVUS with incidental thickened endometrium in asymptomatic post-meno women?

Based on decision analysis, >11mm in asymptomatic woman carries same EmCa risk as women with PMB and >5mm stripe.

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Can we do better--EmCa?

• Given that the reason for low mortality is that the cancer presents early with symptoms, patients/public should know symptoms and when to seek care– Very little public health messaging about EmCa or the need to

get all postmenopausal bleeding evaluated (10% of PMB=cancer).

• Given that irregular blding is characteristic of perimenopause and of EmCa, what is best way to tell patients to come in to be evaluated?– Rule of 2’s: come in if more than 2 periods in one month or more

than 2 continuous weeks of bleeding.

Lots of health education around cervical and ovarian cancers

What about Em Ca Education?

• This is only 1 found in Google search in US

• It says nothing about early warning symptoms, ie bleeding

Path to Mauna Kea Resort

• Part of Ala Kahakai Trail

• 1.5 miles

• Access to the right of Hapuna property—up on grassy area (not down on beach)

• Mauna Kea=sister resort egcan use facilities, sign for Mai Tai’s

• Wear closed-toed shoes

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Ovarian Cancer Screening?

• The answer for a long time has been….Don’t screen….

But….

• A new RCT from UK reportedly shows mortality benefit

• The PLCO RCT from US showed no mortality benefit

PLCO: Ovarian Cancer Arm

Ovarian Cancer (per 10K person-yrs)

Screen Control RR (95% CI)

39,105 39,111 –

Ov Ca 212 (5.7) 176 (4.7) 1.2 (1.0-1.5)

Stage 3&4 77% 78% ns

Deaths 118 (3.1) 100 (2.6) 1.2 (0.8-1.7)

20% increase in diagnosis AND death

PLCO RCT: Annual screening with CA-125 + TVUS for 6 yrs, 12 yr f/u

(PLCO=pro, lung, colon, ovarian screening trial)

Buys S.JAMA 2011

UK Collaborative Trial of Ovarian Cancer Screening

• Primary analysis: No mortality benefit. – MMS 0.85 (0.7-1.03)

– TVUS 0.89 (0.73-1.07)

• However, mortality benefit was seen for MMS if exclude peritoneal cancers and prevalent ovarian cancers:– 0.80 (0.65-1.02) p=0.02

• False positive surgeries: 14 per 10,000 screens in MMS, and 50 per 10K in TVUS

202,638 women, annual screening with 1. Multimodal screen (CA125 + u/s prn); 2. tvus, 3. control.Fu 11 yrs

Ov ca Screening Harms

• PLCO: 3285 women (8%) with false positive screens

– 1080 surgical follow-up

– 163 serious surgical complications (15%)

– PPV=6% (94% of those with + test did NOT have cancer)

• UK study: For each cancer detected, 2 women in MMS and 10 in TVUS had a false positive surgery. Complication rate 3%

PLCO Conclusion:

Screening does not reduce mortality but does increase medical procedures and associated harms.”

USPSTF currently updating their 2012 recommendation, which was a “D”

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Why can’t we screen for ovarian cancer?

1. No known histologic precursor lesions

2. Unknown time for development or for progression from Stage 1 to Stage 4 – mathematical models suggest 8 months for

development which would be impossibly short to detect by screening

3. For false positives, about 1/3 undergo surgery as the confirmatory test which is more morbid than confirmatory tests for others types of cancer screening

Why can’t we screen for ovarian cancer?

4. Very low prevalence compared to other cancers– Peak prevalence(age 55), 50/100,000 (yearly

incidence=14/100k)– Breast cancer: 6/1000; cervical dysplasia and

colonic adenomas: ~4%

5. Given low prevalence, even if a test had a specificity of 99.5%, PPV would only be 7%. – Large number would undergo unnecessary

surgery to detect 1 case of ovarian cancer– In practice, specificity always lower than in

research studies

Last words• Preventive interventions (including screening)

require a high burden of proof: the “do no harm” principle.

• Screening is complex—its not detection we care about—its decrease in mortality and that can only be determined by RCT

• Choose your guidelines and evidence carefully: beware vested interests in guideline groups.

• Guidelines are designed to maximize population benefits and minimize population harms—this is hard to explain to an individual patient.

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Questions?

Kawaihae Harbor: Lunch fish truck