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Treatment in premature Menopause Serge Rozenberg - BMS, Brussels

Treatment in premature Menopause Serge Rozenberg - BMS, Brussels. Serge Rozenberg CHU Saint-Pierre Department of Gynaecology and Obstetrics, Free Universities of Brussels (ULB-VUB) Belgium. Serge.rozenberg@skynet.be. Together, we could fight Breast cancer!. Menopause, Premature.

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Treatment in premature Menopause Serge Rozenberg - BMS, Brussels

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  1. Treatment in premature MenopauseSerge Rozenberg - BMS, Brussels Serge Rozenberg CHU Saint-Pierre Department of Gynaecology and Obstetrics, Free Universities of Brussels (ULB-VUB) Belgium. Serge.rozenberg@skynet.be Together, we could fight Breast cancer!

  2. Menopause, Premature • The premature cessation of menses (MENSTRUATION) when the last menstrual period occurs in a woman under the age of 40. • It is due to the depletion of OVARIAN FOLLICLES. Premature MENOPAUSE can be caused by diseases; OVARIECTOMY; RADIATION; chemicals; and chromosomal abnormalities. • Medline Mesh

  3. Incidence of Amenorrhea after Common Adjuvant Treatments for Breast Cancer. Burstein, H. J. et al. N Engl J Med 2000;343:1086-1094

  4. Treatment of Menopause in breast cancer survivors whith premature menopause • Medline search : number of articles • 0

  5. % of BRCA survivors (n = 1, 098) reporting hot flashes, night sweats, and vaginal discharge according to type of adjuvant therapy, assessed about 3 years after diagnosis (adjusted for age and time since diagnosis) *For all values, P <0.0001. Chem = chemotherapy; Tam = tamoxifen. Adapted from Ganz Am J Medicine 2005

  6. Adapted from Ganz Am J Medicine 2005

  7. Randomized double-blind study to evaluate the efficacy of a polycarbophil-based vaginal moisturizer in women with breast cancer.Loprinzi et al J Clin Oncol. 1997 • vaginal dryness decreased by 62% and 64% in the placebo and Replens groups • Average dyspareunia scores also improved by 41% and 60%

  8. Up to 20% of patients with breast cancer consider stopping or actually cease endocrine treatment because of menopausal symptoms • Fellowes et al 2001.

  9. HRT After Breast Cancer: A Systematic Review and Quantitative Assessment of Risk • RR = 0.64, 95% CI, 0.36 -1.15 Col et al Journal of Clinical Oncology, 2001

  10. Safety of menopausal treatments after breast cancer: a qualitative systematic review Caroline Antoine, Fabienne Liebens, Birgit Carly, Ann Pastijn, Serge Rozenberg CHU Saint-Pierre Department of Gynaecology and Obstetrics, Free Universities of Brussels (ULB-VUB) Belgium EMAS, 7th European Congress on Menopause, June 2006, Istanbul Antoine et al Human Reproduction in press

  11. Results and discussion • 20 studies were selected • Number of included patients: 24 to 1122 • Number of patients using HT: 21 to 286 (underpowered!) • Huge heterogeneity in methodology and selection criteria • Only 2 randomised trials (HABITS Trial and Stockholm Trial)

  12. Results and discussion • Patients’ outcome • Most observational studies concluded that HT had no negative influence on breast cancer prognosis. • Stockholm randomized trial: • RH = 0.82, 95% CI = 0.35 to 1.9.

  13. HABITS (hormonal replacement therapy after breast cancer—is it safe?), a randomised comparison: trial stopped  Holmberg et al Lancet 2004

  14. Results and discussion • The HABITS Trial and the Stockholm Trial have a higher level of evidence • Difference in results may be due to • Heterogeneity in the assessed patients (higher number of involved nodes and a lower proportion of tamoxifen treated patients) in the HABITS trial • Heterogeneity in the regimens used (more often combined regimens) in the HABITS trial

  15. Recommendation • Combined HRT cannot be considered as first-line management for menopausal symptoms after breast cancer. • Uncertainty about whether type or regimen or receptor status have implications for the safety ? • HRT could be justified for quality of life when other interventions have failed and the woman is clearly informed of the risk • Hickey, et al Lancet 2005

  16. Other moleculesProgestagens • Prospective randomised trial breast cancer patients (most taking tamoxifen) • 85% reduction in hot flashes (20 mg megestrol acetate 2X/d) vs 21% with placebo. • Loprinzi et al. N Eng J Med 1994

  17. Safety of progestagens ? • Has not been established after breast cancer. • could be mitogenic in the breast ? • Addition of progestagen to oestrogen was associated with an increased risk of breast cancer in several trals (WHI) • Interactions between progestagens and antioestrogens ?

  18. Other moleculesTibolone • Only 4 studies • No increase of a new breast cancer event • Very small number of patients (underpowered!) • Ongoing trials: LIBERATE Trial in 2007 & Dana-Farber Cancer Institute Brigham and Women's Hospital Beth Israel Deaconess Medical Center Massachusetts

  19. Non-hormonal treatments • Strong placebo effects • 40% in vasomotor symptoms, can persist for several weeks • Few non-hormonal agents have been tested for hot flashes in breast cancer patients. • Generally poor quality of studies • Minimum recommended period by FDA/ EMEA is 12 weeks, but most studies of non-hormonal agents 4–6 weeks. • Most studies: mixture of patients with/without breast cancer (some of whom were taking anti-oestrogens).

  20. Oral clonidine in postmenopausal patients with breast cancer experiencing tamoxifen-induced hot flashes: Pandya et al Ann Intern Med. May 2000 • Double-blind, placebo-controlled :194 using tamoxifen • Oral clonidine hydrochloride, 0.1 mg/d/ placebo for 8 weeks. • Hot flash : -37% clonidine group -20% placebo group • Clonidine more difficulty sleeping (41% vs 21%; P = 0.02). • quality-of-life scores (+0.3 points: clonidine vs -0.2 points placebo; P = 0.02) at 8 weeks, although the median difference was 0 in both groups.

  21. Venlafaxine in management of hot flashes in survivors of breast cancer: a randomised controlled trial. Mean decreases in hot-flash scores. placebo vs 75 mg and 150 mg, p<0·0001; placebo vs 37·5 mg, P=0·008; Note that doses increased gradually in the 75 mg and 150 mg groups. Loprinzi CL, et al. Lancet 2000;356:2059–63

  22. Phase III evaluation of fluoxetine for treatment of hot flashes. Mean hot flash score changes from baseline for the two study arms Loprinzi CL, et al. J Clin Oncol 2002;20:1578–83.

  23. Paroxetine controlled release in the treatment of menopausal hot flashes: randomized controlled trial. Stearns V, et al JAMA 2003;289:2827–34

  24. New trials • Venlafaxine With or Without Zolpidem (NCI) Massachusetts General Hospital • Paroxetine (GSK) • DVS-233 SR (Whyeth) • Citalopram (not yet open) (NCI)

  25. Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. paroxetine statistically significantly reduced the concentrations of 4-hydroxy-N-desmethyl-tamoxifen (endoxifen), a metabolite resulting from CYP2D6-mediated hydroxylation of N-desmethyl-tamoxifen. Stearns V, et al. J Natl Cancer Inst 2003;95

  26. Recommendations for practice • 75 mg venlafaxine effective initially in the treatment of hot flashes after breast cancer, but seems not to continue for a clinically worthwhile duration. • Other SSRIs such as fluoxetine (10–30 mg a day), paroxetine (25 mg), and citalopram (10–20 mg) might be effective, but there are no data to show that this effect persists beyond 6 weeks. • advise that use of SSRI and SNRI are probably associated with anticholinergic side-effects and that it could potentially interfere with the metabolism of antioestrogens.

  27. Gabapentin • GABA analogue used in the treatment of epilepsy, neurogenic pain, restless-leg syndrome, essential tremor, bipolar disorder, and migraine prophylaxis

  28. Gabapentin for hot flashes in 420 women with breast cancer: a randomised double-blind placebo-controlled trial • 420 women with breast cancer • > 2 hot flashes/ day • placebo, gabapentin 300 mg/d or 900 mg/d P.O. in 3 doses for 8 weeks. • 1-week, self-report diary before (frequency, severity, and duration) and during weeks 4 and 8 of treatment. • Analyses were by intention to treat. • Pandya Lancet 2005

  29. Gabapentin for hot flashes in 420 women with breast cancer: a randomised double-blind placebo-controlled trial Pandya Lancet 2005

  30. NB gabapentin 2400 mg/d

  31. General recommendations • Achieve a normal BMI, • Identify triggers to their hot flashes (eg, alcohol, hot drinks, or spicy food) ? • Training in relaxation techniques could also be beneficial. • Stop smoking • Maintain a regular exercise

  32. Prevalence of vertebral fracture in women with non-metastatic breast cancer. • At the time of first diagnosis= general population (age-matched sample). • Nearly 5 times greater from the time of first diagnosis OR, 4.7; 95% CI: 2.3-9.9 • Kanis et al Br J Cancer. 1999 Mar;79(7-8):1179-81.

  33. Tamoxifen and osteoporosis • Tamoxifen led to a 32% reduction in osteoporotic fractures (RR = 0.68, 95% CI = 0.51 to 0.92). • Fisher J Natl Cancer Inst. 2005 Nov 16;97(22):1652-62

  34. Effects of third-generation aromatase inhibitors on bone McCloskey European Journal of Cancer ( 2 0 0 6 )

  35. Prevention and treatment • Regular physical exercise • calcium 1500 mg and vitamin D 800 U daily. • T-score < 2.5 & between -1.5 and -2.5 in the presence of a fragility fracture or vertebral compression fracture • Consider bisphosphonate therapy. • Paterson et alClin Breast Cancer. 2005 Feb;5 Suppl(2):S41-5.

  36. Celebrate yor birthday twice a year You will live twice as long

  37. Communicate with your physician. Together, we could fight Breast cancer!

  38. alternative medicine • There is insufficient evidence about efficacy and safety to support the use of alternative medicine in the treatment of menopausal symptoms after breast cancer.

  39. Phytoestrogens

  40. A randomized placebo-controlled crossover trial with phytoestrogens in treatment of menopause in breast cancer patients Nikander et al Obstet & Gynecol June 2003,

  41. New trials • St. John's Wort NCI August 2006 Wake Forest University • A Taiwan Isoflavone Multicenter Study (TIMS)

  42. New trials • Menopause and Meditation University of Pittsburgh(NIH) • Hypnosis National Cancer Institute (NCI) Scott and White Cancer Institute

  43. Endogenous Sex Hormones and Breast Cancer inPostmenopausal Women: Reanalysis ofNine Prospective Studies • RR of breast cancer by quintiles of hormone concentrations. (only those from informative matched case–control sets) J Natl Cancer Inst 2002;94:606–16

  44. Endogenous Sex Hormones and Breast Cancer inPostmenopausal Women: Reanalysis ofNine Prospective Studies • RR of breast cancer by quintiles of hormone concentrations. (only those from informative matched case–control sets) J Natl Cancer Inst 2002;94:606–16

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