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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)
• Begin screening at age 21 yo
• 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
• 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
• This strategy is presently endorsed by AAFP
AMERICAN CANCER SOCIETY (2020)
• Begin screening at age 25 yo
• 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
• 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
• 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?