UPDATES IN GYNECOLOGY

UPDATES IN GYNECOLOGYEDWARD BUCHANAN MD

THOMAS JEFFERSON UNIVERSITY

DEPARTMENT OF FAMILY AND COMMUNITY MEDICINE

GYNECOLOGIC UPDATES

Contraception

Opportunistic salpingectomy

Cervical cancer screening

CONFLICT OF INTEREST

• I am a trainer for the FDA mandated etonorgestrel implant insertion/removal course developed by Merck

• I am a former Merck stockholder

• I will be offering information that is not FDA approved in this lecture

PREGNANCY

6 million pregnancies/yr

50% of these are unintended• Of the unintended pregnancies,

50% of couples were using a contraceptive method at the time of conception

LONG ACTING REVERSIBLE CONTRACEPTION (LARCS)

• IUDs and subdermal implants

• LARC benefits• Equivalent effectiveness to tubal ligation (99.3-99.9%)

• Typical use effectiveness approaches Perfect use

• Reversible

• Preferred method for adolescents

• 10-15% of women using contraception are using a LARC

FDA APPROVAL

Copper IUD (Paragard)• 1984: 4 years• 1994: 10 years

LNG IUD (Mirena, Liletta)• Mirena 6 years in 2020 (in 2000 had 5 yr approval)• Liletta 6 years in 2019 (in 2015 had 3 yr approval)

Etonorgestrel implant (Nexplanon)• 2006: 3 years

CONTRACEPTIVE ARMS RACE

• Extending the time intervals for device efficacy

• Washington University, St. Louis

• CHOICE study (2010)

• Removing cost issues increased the use of LARCs—and reduced unintended pregnancy rate

• EPIC study (2015)

• Effectiveness of the etonorgestrel implant and levonorgestrel IUD for 1 yr beyond FDA approval

• EPIC 2 study (2017)

• Effectiveness of implants and levonorgestrel IUD for 2 yrs beyond FDA approval

EPIC 2• Etonorgestrel Implant

• 291 patients accounting for 444 woman-years of data

• 18-45 yo

• Followed for two years beyond FDA approved device duration of 3 yrs

• Endpoints: method failure (pregnancy) and serum etonorgestrel levels

• Results• No pregnancies in years 4 or 5 of use

• Median etonorgestrel serum levels (pg/ml) (90pg/ml required for ovulation suppression)

• Year 3: 207.7

• Year 4: 166.1

• Year 5: 153.0McNicholas C, Swor E, et. al. Prolonged use of the etonogestrel implant and levonorgestrel intrauterine device: 2 years beyond Food and Drug Administration–approved duration. Amer J Obstet Gynecol2017;216(6): 586.e1-586.e6,

WHO (2016)

• Multinational study

• Women 18-45 yo

• non-inferiority study of LNG implant vs. ENG implant at 4 & 5 yrs

• 204 women completed 5 years of use

• Results:• No pregnancies in either the LNG or ENG group in years 4 and 5

Ali M, Akin A, et al. Extended use of up to 5 years of etonorgestrel-releasing subdermal contraceptive implant: comparison to levonorgestrel-releasing subdermal implant. Human Reproduction 2017; 31(11):2491-2498.

EPIC 2

• LNG IUD• 496 patients contributing 696.9 woman-years of data

• 347 used for > 1 yr; 160 used for 2 yr

• 18-45 yo

• Followed for 2 years beyond FDA approved duration of 5 years (at the time)• Now FDA approved for 6 years

• Results• 2 pregnancies in extended use to 7 years

• Failure rate • Year 6: 0.25 per 100 woman-years

• Year 7: 0.43 per 100 woman-years

WHO (2016)

• Comparison of Copper IUD to LNG IUD pregnancy rates during 7 years of use

• Age 16-40 yo

• Randomized and Inserted: 1871 Copper T, 1884 LNG-IUD

• 7 year completion: 682 Copper T, 398 LNG-IUD

• Cumulative pregnancy rates:

• Copper IUD: 2.45%

• LNG-IUD: 0.53%Rowe P, Farley T et.al. Safety and efficacy in parous women of a 52-mg levonorgestrel-medicated intrauterine device: a 7-year randomized comparative study with the TCu380A. Contraception 2016 93(6): 498-506.

WU AND PICKLE (2014)

• Literature review

• 3 studies of TCu380A • Bahamondes (2005): pregnancy rate 0.0% for years 11-16

• WHO (1997): cumulative preg rate at Year 12: 2.2%; years 10-12 only: 0%

• Sivin (2007): observational study of women using IUD 10-20 yrs• Cumulative pregnancy rate for years 10-20: 0%

• Nulliparous women were excluded in all studies

• Conclusions• For parous women>= 25 yrs old at time of insertion, good evidence for use of TCu380A for 12 years

• Women age 35 yo at time of insertion can continue the device until menopause with negligible risk of pregnancy

WU AND PICKLE

• 4 studies of LNG-IUD• Diaz (1993): 50 women observed for 7 yrs. Pregnancy rate years 5-7: 0%

• Sivin (1991): 172 women observed for 7 yrs. Pregnancy rate years 6-7: 0%

• Ronnerdag (1991): 100 women observed for 6.6 yrs. Preg rate years5-6.6: 0%

• Hidalgo (2009): 67 women observed for 7 years. Pregnancy rate years 5-7: 0%

• Conclusion• Good evidence for use of LNG-IUD for 7 years for parous women >= 25 yrs old at time of

insertion

Wu JP, Pickle S. Extended Use of the Intrauterine Device: A Literature Review and Recommendations for Clinical Practice. Contraception 2014 89: 495-503.

FDA APPROVAL

• Copper IUD• 1984: 4 years

• 1994: 10 years

• 12 yrs if multiparous patient > 25 yo at time of insertion

• LNG IUD• Mirena 6 years in 2020 (in 2000 had 5 yr approval)

• Liletta 6 years in 2019 (in 2015 had 3 yr approval)

• 7 years may be acceptable

• Etonorgestrel implant• 2006: 3 years

• 4-5 years may be acceptable

NEW/UPDATED TECHNOLOGY IN CONTRACEPTION

CONTRACEPTION UPDATE WORKSHOP

• Drosperinone pill (Slynd)

• Segesterone/EE ring (Annovera)

• Lactic acid/citric acid/potassium bitartrate vaginal inserts (Phexxi)

• Use of progesterone secreting IUD for emergency contraception

SALPINGECTOMY FOR THE PREVENTION OF OVARIAN CANCER

OVARIAN CANCER

• 5th leading cause of cancer death in women• 21,500 cases diagnosed, 13,800 deaths annually

• Vague abdominal symptoms at time of presentation

• No effective screening strategies exist• 65% of tumors detected at Stage III or IV (5 yr survival 18%)

• Present day strategies target prevention in high risk women• BRCA mutations

• HNPCC (Lynch Syndrome)

STERILIZATION AND OVARIAN CANCER

• Ovarian anatomy and associated malignancies• Germ cell: teratoma, choriocarcinoma, endodermal sinus tumor

• Stromal cells: granulosa-thecal cell tumors, Sertoli-Leydig tumors

• Epithelial cells: serous and mucinous carcinomas, clear cell carcinoma, endometrioid carcinoma

• Epithelial ovarian tumors typically are most aggressive and account for 90% of all ovarian tumors (and 90% of ovarian ca deaths)

EPITHELIAL OVARIAN CARCINOGENESIS

• Traditional theories:• Recurrent ovulation creates dysplastic changes in capsule

• Ovarian capsule originates in the coelomic epithelium as migration occurs from mesonephros to form the gonadal ridge

• Over time this epithelial layer is susceptible to dysplastic change with leads to epithelial ovarian carcinoma

• This also explains the existence of primary peritoneal cancers via coelomic metaplasia

CHALLENGES TO TRADITIONAL THEORIES

• There has never been an identified ovarian cancer precursor found in the ovary

• Tubal ligation causes 24% reduction in ovarian carcinoma risk• Reduction primarily in endometrioid and clear cell carcinoma

• BRCA positive women who have prophylactic bilateral salpingo-oophorectomy show lesions in the distal fallopian tube that morphologically resemble ovarian serous carcinomas• Tubal intraepithelial carcinoma (TIC)

• TP53 mutation found in both TIC and serous carcinoma

• High grade serous carcinomas express müllerian tumor markers, not mesothelial markers

EPITHELIAL OVARIAN CARCINOGENESIS

• New Theory• Tubal intraepithelial carcinomas originate in the fimbria and distal portion of tube

• TICs either develop into tumors within the tube or drop onto the ovary during the pre-symptomatic phase of cancer development

• Ovarian tumors often discovered already involving both the tube and ovary

ALTERING COUNSELING AND TREATMENT

• Women at high risk for ovarian ca

• Traditionally, BSO after childbearing (35-40 yo for BRCA 1, 40-45 for BRCA2)

• 90% reduction in ovarian cancer, 50% reduction in breast ca risk

• However, this caused early abrupt menopause and consequent long term risks

• Earlier cardiovascular dz, earlier cognitive changes, osteoporosis, higher risk of death from all causes

• Society for Gynecologic Oncologists (2013)

• Recommended counseling high risk women on bilateral salpingectomy after childbearing

• Follow this with bilateral oophorectomy closer to menopause

• Note this will not reduce breast cancer risk until oophorectomy is completed

WOMEN AT AVERAGE RISK• Falconer (2015)

• Retrospective cohort study on Swedish women with ovarian cancer. Age and parity matched to controls and compared previous tubal ligation or salpingectomy for benign conditions

• Demonstrated 28% reduction in ovarian cancer risk for pts with tubal ligation

• 65% reduction in ovarian cancer risk for those with previous bilateral salpingectomy

• Yoon (2016)• Meta-analysis: 3509 salpingectomy pts compared with 5x106 controls

• 30 yrs of follow up

• 49% reduction in risk of ovarian caFalconer H, Yin L, et. al. Ovarian Cancer Risk After Salpingectomy: A Nationwide Population-Based Study. JNCI Natl Cancer Inst (2015); 107(2): dju410.Yoon SH, Kim SN, et. al. Bilateral salpingectomy can reduce the risk of ovarian cancer in the general population: A meta-analysis. Eur J of Cancer (2016); 55: 38-46.

COUNSELING FOR WOMEN AT AVERAGE RISK

• Opportunistic salpingectomy at time of sterilization or hysterectomy

• Advantages:• No increase in complications from surgery

• Ovarian function does not appear to be affected

• Potential significant reduction in ovarian cancer risk

• Disadvantages• No possibility of future tubal reanastomosis

• Slight increase in surgical case time

CERVICAL CANCER SCREENING

PREVIOUS RECOMMENDATIONSUSPSTF, ACS, ACOG, AAFP (2012)

• Begin screening at age 21 yo

• Age 21-29: Cytology only screening every 3 years age 21-29 yo

• Age 30-65: Cytology only every 3 yr or Cytology/HPV (cotest) every 5 yrs

• Stop screening if • Age 65 and 2 cotests or 3 cytology results negative in last 10 years OR

• If patient is post hysterectomy with removal of cervix and no h/o CIN 2-3 or cancer

• Continue screening every 5 yr for 20 years after treatment for CIN 2-3

HPV PRIMARY SCREENING

• Originally described in studies in China, Brazil, India where access to cytology infrastructure was lacking

• ATHENA trial in 2015 showed HPV testing was at least as sensitive in screening for cervical ca as traditional pap/HPV testing starting at age 25 yo

• 2015: ASCCP, SGO, ACOG, ACS, ASCP publish interim guidance on the use of HPV testing as the primary screening method for cervical cancer

• Subsequent studies have demonstrated increased sensitivity using HPV primary screening while decreasing colposcopies compared to cotesting

USPSTF (2018)


• Age 21-29: Cytology only screening every 3 years age

• Age 30-65: HPV testing alone every 5 yrs, Cotest every 5 yrs, or Cytology alone every 3 yrs. Stop screening if:• Age 65 and 2 HPV primary screens, 2 cotests or 3 cytology results negative in last 10 years OR



• This strategy is presently endorsed by AAFP

AMERICAN CANCER SOCIETY (2020)


• HPV primary screening every 5 years is preferred method• Cytology alone and Cytology/HPV cotesting acceptable alternatives

• Stop screening if:• Age 65 and 2 HPV primary screens, 2 cotests or 3 cytology results negative in last 10 years OR



• Added future bonus: HPV primary screening may lead the way to self swabs (not FDA approved as yet)

ACOG (2021)

• Endorse the USPSTF screening guideline citing • Technology limitations

• Only two HPV screening methods are presently FDA approved for primary HPV screening

• Concern that if we push too quickly toward HPV primary screening, providers will mistakenly use non-FDA approved technology to screen in ways it wasn’t meant to

• Concern also for rural and minority communities may not have equal access to newer technology

• Age concerns• Advocate for continuing to start screening at age 21 due to:

• Continued low HPV vaccination rates among the adolescent and young adult population

• Screening rates for < 30 yo is already low. By keeping initiation at age 21, we may be identifying young individuals at risk even if they receive only sporadic screening

CERVICAL CANCER SCREENING

• Cervical cancer is a disease of the unscreened• Either ACS, USPSTF guidelines will detect individuals at risk

• Technology may be your present limiting factor

• In 2017, 40.6% of laboratories offered primary HPV screening

• With progress, primary HPV screening will become the screening strategy of the future

• ASCCP mobile app resource• Screening recommendations, colposcopy recommendations, post colposcopy and post LEEP

recommendations

• Screening recommendations given for cytology only, cotest, or HPV primary HPV screening

QUESTIONS?

UPDATES IN GYNECOLOGY

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