7/27/2017. I have no financial interests to disclose. I do not get kickbacks from my Hawaii recommendations. Lecture Plan

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Gynecologic Cancer Screening 2017: Updates and Controversies Disclosures I have no financial interests to disclose

San Francisco I do not get kickbacks from my Hawaii recommendations Lecture Plan Mortality 1-2 questions for each

test (ie ditch cytology altogether) Ovary: New RCT s are conflicting: should we be screening for it?

1 Gynecologic Cancer Screening 2017: Updates and Controversies Disclosures I have no financial interests to disclose Rebecca Jackson, MD Professor, Ob/Gyn & Reproductive Sciences Epidemiology & Biostatistics University of California, San Francisco I do not get kickbacks from my Hawaii recommendations Lecture Plan Mortality 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 4 th most common cancer in women, why don t we screen for it? Incidence 4th Ovary 22,440 Cervix 12,820 Cervix 4,210 1

Ovarian Cancer Endometrial Cancer Cervical Cancer In Waimea, dress

60-90% within 3 years of implementation Pap smears are the most

60% decrease in incidence and mortality Why does pap screening work?

accessible for screening Natural history is favorable : precursor

develops is long (>10yr) many opportunities to detect.

2 Ovarian Cancer Endometrial Cancer Cervical Cancer In Waimea, dress warmly Adding screening to naïve populations reduces incidence by 60-90% within 3 years of implementation Pap smears are the most effective screening test ever invented. 60% decrease in incidence and mortality 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. 2

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:.

3 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: : 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 ACOG 2016 ACS, ASCCP, ASCP 2012 USPSTF 2012 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 adeq screening) None recommend changes in screening for those who ve had HPV vaccine 3

4 What s new or different between guidelines? Co-test(HR-HPV + Cytology) in women>30yo 1st time USPSTF has recommended cotesting ( ok for women who want to extend interval to 5 yrs) ACS/ASCCP/ASCP & ACOG: prefer cotest 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 preinvasive lesions to invasive cancer Why is it ok to lengthen the screening interval? Large population based study showed safety of this approach. 1yr vs 3 yr screening: 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 HPV test also more sensitive for adenocarcinoma than cytology 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. Co-testing caveats 1. 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 Unclear how to deal with HPV+, cytology negative 4

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,

5 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 Now what? Cobas detects 14 high risk HPV types plus genotyping for 16 & 18 ACS/ASCCP/ACSP: Approximately 25% of committee members reported financial conflicts of interests with companies that make HPV tests FDA approved Roche Cobas HPV test as primary screen (no pap) in >25yo 5

6 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 1 large 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 ( ). More colpo in the HPV arm (5.8% vs 2.5%) Ronco Lancet Oncol strategies 1. Cytology : Cytology w reflex HPV for ascus 2. Hybrid : cytology for yo and cotest for >=30yo (current US strategy) 3. HPV primary for >=25yo. Algorithm: Neg HPV rescreen 3 yr +16/18 colpo + other HR types cytology Baseline: 10% HPV+; 6% positive cytology Cobas HPV: 3 separate results: hpv 16, hpv 18, 12 other high risk types 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. Colpo w/ biopsy at study end. Endpoints: CIN2+ detection, number screening tests and colpos Wright, GynOnc 2015 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 hrhpv group 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 costeffective analyses showed the HPV strategy to be most cost effective 6

Suggested Alogirthm Primary HPV screen with cytology reflex Not specified how, cotest?

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

of the study; collection, management, analysis, and interpretation of the data.

7 Suggested Alogirthm Primary HPV screen with cytology reflex Not specified how, cotest? >=3 yrs Huh, Obstet Gynecol, Feb 2015; GynOnc Feb 2015, J Low Genit Tract Dis April 2015 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 Questions remain: primary HPV screening Role of the sponsor Roche 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. 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? What should we do? Interpretation of evidence is complicated: Variety of comparison groups and strategies: co-test Answer: vs cyto alone, HPV vs cytology, HPV with cytology Wait for triage Differences the in colposcopy thresholds Many USPSTF studies have only reported 1 f/u round After 1 round, HPV higher detection; after 2 or update! more, no difference in detection in most studies Most studies have incomplete reporting of colposcopy rates Cobas HPV test Ipad App Is industry pushing us to use this or is it the right thing to do? 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. 7

Conclusions: Cervical Cancer Cervical cancer screening in the US

morbidity Goal now is to screen the unscreened AND decrease harm

less often (q 3yr) Use co-test to extend interval to 5yr in

treatment in younger women Racial disparity endometrial cancer

8 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 overtreatment: 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 Racial disparity endometrial cancer Incidence Mortality Gwen Ifill, PBS NewsHour co-anchor September 29, 1955 November 14,

9 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. 9

symptoms and when to seek care Very little public health messaging about EmCa or the need to get all postmenopausal

Given that irregular blding is characteristic of perimenopause and of EmCa, what is best way to tell patients to come

Rule of 2 s: come in if more than 2 periods in one month or more than 2 continuous weeks of bleeding.

10 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 eg can use facilities, sign for Mai Tai s Wear closed-toed shoes 10

11 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 PLCO RCT: Annual screening with CA TVUS for 6 yrs, 12 yr f/u (PLCO=pro, lung, colon, ovarian screening trial) 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 ( ) Stage 3&4 77% 78% ns Deaths 118 (3.1) 100 (2.6) 1.2 ( ) 20% increase in diagnosis AND death Buys S.JAMA 2011 UK Collaborative Trial of Ovarian Cancer Screening Ov ca Screening Harms 202,638 women, annual screening with 1. Multimodal screen (CA125 + u/s prn); 2. tvus, 3. control. Fu 11 yrs Primary analysis: No mortality benefit. MMS 0.85 ( ) TVUS 0.89 ( ) However, mortality benefit was seen for MMS if exclude peritoneal cancers and prevalent ovarian cancers: 0.80 ( ) p=0.02 False positive surgeries: 14 per 10,000 screens in MMS, and 50 per 10K in TVUS PLCO Conclusion: Screening does not reduce mortality but does increase medical procedures and associated 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% USPSTF currently updating their 2012 recommendation, which was a D 11

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.

12 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. 12

13 Questions? Kawaihae Harbor: Lunch fish truck 13

However, I sometimes hike in Kapu areas.!

However, I sometimes hike in Kapu areas.! Cancer Screening for Women: Updates and Controversies Rebecca Jackson, MD Professor, Ob/Gyn & Reproductive Sciences Epidemiology & Biostatistics University of California, San Francisco Disclosures I have