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Endometrial and other cancers David W. Sturdee Slide 2 Endometrial cancer Hysterectomy specimen showing cancer invading myometrium following unopposed estrogen therapy for 15 years Slide 3 Endometrial cancer world-wide World age-standardized incidence and mortality rates (selected) North America Western Europe Northern Europe Southern Europe Eastern Europe Australia/New Zealand South America Western Africa Central America South-Eastern Asia Southern Africa Eastern Africa Eastern Asia Middle Africa Northern Africa South-Central Asia Western Africa 04812162024 Rate per 100,000 females Incidence Mortality Ferley J, et al. IARC Cancer Base No. 5, version 2.0, 2004 Slide 4 Endometrial histology in peri- and postmenopausal women without symptoms Atrophic37346.9 Proliferative 13316.7 Secretory546.8 Hyperplasia All415.2 Cystic313.9 Simple91.1 Adenomatous 10.1 Cellular atypia40.5 Cancer10.1 Insufficient tissue19524.5 Archer D, et al. Am J Obstet Gynecol 1991;165:31722 Histologyn% Slide 5 Unopposed estrogen and endometrial cancer Smith19754.5 Ziel19755.67.6 Mack19768 Antunes1979615 Jick197910 Hammond19793.8 Weiderpass19996.2 YearRisk ratio Slide 6 Unopposed estrogen and endometrial hyperplasia PEPI trial62% at 36 months Placebo2% at 36 months Other studies: OR = 5.4 (1.420.9) for 6 months 16.0 (9.327.5) for 36 months Lethaby A, et al. In The Cochrane Library, Issue 4, 2004 (ISSN 1464-780X) Slide 7 HRT in postmenopausal women: endometrial hyperplasia and irregular bleeding (Cochrane Review) Unopposed estrogen significantly increases hyperplasia Oral progestogen reduces rate of hyperplasia Suggestion that continuous therapy over long duration is more protective from hyperplasia Hyperplasia is more likely when progestogen is given every 3 months Lethaby A, et al. In The Cochrane Library, Issue 4, 2004 (ISSN 1464-780X) 30 randomized controlled trials were suitable for review Slide 8 HT: the addition of progestogen For at least 10 days in each cycle to prevent endometrial hyperplasia and carcinoma In sequential regimens to imitate the ovarian cycle and to promote a regular and predictable bleed Slide 9 Complex endometrial hyperplasia Slide 10 Atypical endometrial hyperplasia Slide 11 Malignant potential of endometrial hyperplasia Simple13% over 15 years Complex34% over 13 years Atypical25% over 11 years Norris HJ, et al. Clin Obstet Gynaecol 1986;13:72538 Deligdisch L, Cohen CJ. Cancer 1985;56:1452 5 Slide 12 Never used HRT387 (87.3)685 (89.0)1.0 Current users: Progestogen 1021 days per month 659 months12 (3.1)48 (6.2)0.7 (0.41.4) > 60 months12 (3.1)15 (1.9)2.7 (1.26.0) Endometrial cancer and duration of sequential estrogen/progestogen HRT Duration of HRTCases (%)Controls (%)Odds ratio Beresford SA, et al. Lancet 1997;349:45861 Slide 13 HRT and risk of endometrial cancer OR (95% CI) DurationSequential E + P < 5 years1.5 (1.02.2) > 5 years2.9 (1.84.6) Per year1.1 (1.061.15) Weiderpass E, et al. J Natl Cancer Inst 1999;911:11317 Slide 14 Period-free therapy Same benefits as sequential No cycle Period-free Atrophic endometrium Continuous combined therapy: estrogen + low-dose progestogen every day (CCEPT) or tibolone Slide 15 Normal226119 Simple91 Complex20 Atypical10 Cancer00 Total238120 PEPI study: endometrial hyperplasia at 3 years HistologyCEE + MPACEE + MPA or MP (cyclic)(continuous) CEE, conjugated equine estrogen 0.625 mg/day; MPA, medroxyprogesterone acetate 2.5 mg; MP, micronized progesterone 200 mg; Cyclic, MPA or MP 12 days The Writing Group for the PEPI Trial. JAMA 1996;275:3705 Slide 16 Endometrial histology during sequential and after changing to continuous combined therapy (estradiol 2 mg + norethisterone acetate 1 mg daily for 9 months) Unassessable18.037.3 Inactive/atrophic7.630.0 Proliferative15.12.3 Secretory47.426.2 Complex hyperplasia5.50.0 Sturdee DW, et al. BJOG 2000;107:1392400 * Including 42 with previous complex hyperplasia CSEPT (%)CCEPT (%) (n = 1192)(n = 823) * Slide 17 < 5 years1.5 (1.02.2)0.8 (0.51.3) > 5 years2.9 (1.84.6)0.2 (0.10.8) Per year1.1 (1.061.15)0.86 (0.770.97) DurationSequential Continuous E + Pcombined HT and risk of endometrial cancer OR (95% CI) Weiderpass E, et al. J Natl Cancer Inst 1999;911:11317 Slide 18 WHI study: gynecological cancers (annualized %) OutcomeCEE + MPAPlaceboHazard95% CI ratio n85068102 Duration (months)67.866.8 Ovary20 (0.04)12 (0.03)1.580.773.24 Endometrium27 (0.06)31 (0.07)0.810.481.36 Endometrioid (%)14 (51.9)17 (54.8) Cervix 8 (0.02) 5 (0.01)1.440.474.42 Anderson GL, et al. JAMA 2003;290:173948 Slide 19 Progestogen in HT Only needed to protect the endometrium Other effects, e.g. on breast, lipids Premenstrual syndrome-type side-effects Logical to give direct to the endometrium by intrauterine system Slide 20 MLS 10 g LNG/dayMirena 20 g LNG/day Slide 21 Intrauterine application of progestins in hormone replacement therapy Since 1991, 16 studies of intrauterine levonorgestrel in combination with different types and routes of estrogen (n = 809) Duration 6 months 5 years IUS + oral CEE and E2, patch, gel and implant New 10 g system: 3 studies for 12 years All 0% hyperplasia Riphagen FE. Climacteric 2000;3:19921 Confirms endometrial safety for this application Slide 22 Endometrial and breast cancer in the Million Women Study Standardized incidence rates/1000 women/5 years Endometrial and breast cancer in the Million Women Study Standardized incidence rates/1000 women/5 years CCEPTCSEPTTiboloneE onlyNever use CCEPT, combined continuous estrogen and progestogen therapy; CSEPT, combined sequential estrogen and progestogen therapy Million Women Study Collaborators. Lancet 2005;365:154351 Breast3028191813 Endometrial23653 Total3231252316 Slide 23 THEBES Tibolone Histology of the Endometrium and Breast Endpoint Study Multicenter world-wide Tibolone 1.25 and 2.5 mg vs. CEE/MPA 0.625/2.5 mg (Prempro) 24 months 3240/3000 subjects (1:1:2 randomization) Endometrial histology hyperplasia and cancer Endometrial thickness, bleeding, breast pain, health-related quality of life Slide 24 THEBES LivialPrempro 2.5 * 1 endometrial stromal sarcoma Archer DF, et al. J Clin Endocrinol Metab 2007;92:91118 n15981626 Women-years24022415 Endometrial hyperplasia02 (0.1%) Endometrial cancer00 * Polyps at 1 year33 (2.6%)40 (3.1%) Polyps at 2 years24 (2.5%)25 (2.5%) Slide 25 Estimated cumulative additional cancers over 10 years HT per 1000 women UnopposedCombined estrogenE + P Breast cancer519 Endometrial cancer100 Million Woman Study collaborators. Lancet 2003;362:419 27 Million Women Study Slide 26 Breast cancer and hormone therapy little advantage to using estrogen/progestogen in preference to estrogen-only HRT for women who still have a uterus Million Women Study collaborators. Lancet 2003;362:419 27 Million Women Study Slide 27 Is combined estrogen/progestogen therapy worth the risk? Combined estrogen/progestogen therapy associated with four-fold greater risk of breast cancer than unopposed estrogen therapy Risk of endometrial cancer from unopposed estrogen therapy much less After cessation of unopposed estrogen, risk of endometrial cancer persists for many years Other implications of unopposed estrogen Against perceived wisdom over last 25 years Hysterectomy rate Slide 28 Raloxifene: endometrial health Uterine bleeding no difference from placebo Endometrial thickness by transvaginal ultrasound scan no difference from placebo Endometrial biopsy no stimulation of atrophic endometrium Cummings S, et al. JAMA 1999;281:2189 97 Slide 29 Impact of recent reports and regulatory authorities Lowest dose for shortest time Lower dose regimens being produced Is there a threshold dose/circulating level of estrogen at which symptoms can be relieved and bone spared without causing endometrial stimulation? Is there a similar threshold for progestogen at which the endometrium will still be protected without affecting breast tissue? Slide 30 Womens HOPE, Womens Health, Osteoporosis, Progestin, Estrogen; CEE, conjugated equine estrogens; MPA, medroxyprogesterone acetate Endometrial hyperplasia rates after 1 and 2 years of low-dose E + P Womens HOPE Study Hyperplasia rate (%) 0.625 mg0.625/ 2.5 mg 0.45 mg0.45/ 2.5 mg 0.45/ 1.5 mg 0.3 mg0.3/ 1.5 mg Placebo CEECEE/MPA 0.00 Year 1 Year 2 Pickar JH, et al. Fertil Steril 2003;80:1234 40 Slide 31 Unopposed ultra-low-dose transdermal estradiol 417 postmenopausal women (6080 years) mean 67 5 years Randomly assigned to placebo or transdermal 14 g/day for 2 years Baseline serumE2 = 4.8 pg/ml On treatmentE2 = 8.6 pg/ml Johnson SR, et al. Obstet Gynecol 2005;105:779 87 Slide 32 Unopposed ultra-low-dose transdermal estradiol Endometrial effects: Proliferation8.5% vs 1.1%p = 0.6 Bleeding12.4% vs 8.6%p = 0.3 Atypical hyperplasia 1 Adenosarcoma 1 Johnson SR, et al. Obstet Gynecol 2005;105:779 87 Conclusions: This therapy apparently causes little or no endometrial stimulation Slide 33 HT and endometrial safety Endometrial cancer still a risk for postmenopausal women taking HT Duration of progestogen important Change to CCEPT for long-term endometrial health ? Ultra-low-dose combination or unopposed estrogen Slide 34 Hormone therapy and ovarian cancer David W. Sturdee Slide 35 Ovarian cancer: background Ovarian cancer is the second leading cause of death from gynecologic cancers 1 Ovarian cancer is usually diagnosed in its advanced stage An estimated one woman in 70 will develop ovarian cancer in her lifetime, and one in 100 will die from the disease 2 Median age of diagnosis is 63 years 2 1 American Cancer Society. Cancer Facts and Figures 2003. Available at: www.cancer.org/docroot/STT/stt_0.asp. 2 Schneider HPG. Maturitas 2002;43:S35 52 Slide 36 Centers for Disease Control meta-analysis: ovarian cancer and HRT Relative risk (95% CI) European/Australian Case-Control Studies Hospital/Clinic Controls Booth et al, 1998 La Vecchia et al, 1982 Parazzini et al, 1994 Polchronopolou et al,

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