quality of life and menopause treatment after pelvic...
TRANSCRIPT
‘’ Hormones and cancer: an update”
Quality of life and Menopause treatment after pelvic cancers (endometrium, ovarian and cervix)
Marjolein De Cuypere University of Liège – Gynecological Oncology
Belgian Menopausal Society Saturday June 4, 2016
UMC Sint-Pieter – CHU Saint Pierre Hoogstraat 322 Rue Haute
Brussel 1000 Bruxelles
Belgian Menopausal Society, 4th of June 2016
Cancer profile
QOL impairment
HRT after pelvic cancer
Sexual health
Premature ovarian insufficiency
Belgian Menopausal Society, 4th of June 2016
Cancer profile - ENDOMETRIUM
- 1300/year Belgium – 1.7% liferisk - Majority Stage 1A-1B oestrogen induced with 85% cure rate - CORNERSTONE treatment:
Grade 1 Grade 2 Grade 3
E/P receptor 80% 40% 10%
± LN ±
Belgian Menopausal Society, 4th of June 2016
Cancer profile - OVARY
- 908/year Belgium – 1.5% liferisk - +/- 80% advanced Stage with 15% cure rate - ER/PR/AR in most EOC - CORNERSTONE treatment:
Chimiothérapie
Prof G Jérusalem
+
Belgian Menopausal Society, 4th of June 2016
Cancer profile - CERVIX
- 651/year Belgium – 0.8% liferisk - Majority squamous - early vs. LACC with 90 to 30% cure rate - No ER/PR/AR (except: adenoCa)
- CORNERSTONE treatment:
+ LNP
Early stage LACC
LNAo + +
Belgian Menopausal Society, 4th of June 2016
QOL impairment - SURGERY
Tsunoda A et al. Rev Col Bras Cir 2015;42(5):345-351.
Marin F et al. J of Med and Life 2014;7(1):60-66.
Late Complications ‘Adapted surgical technique’
Incisional hernias Bowel obstruction Persistent pelvic pain Lower limb lymphedema Bladder dysfunction (retention, dysuria, overflow urine incontinence, frequent urinary infection)
Bowel dysfunction Sexual dysfunction (orgasmic problems, dyspareunia, dryness, vaginal shortening, less vaginal sensitivity)
Ureteral strictures, urinary fistula
MIS Sentinel Lymph Node Autonomic nerve sparing surgery Less radical surgery (eg. SHAPE)
Belgian Menopausal Society, 4th of June 2016
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QOL impairment - RADIOTHERAPY
Radiation Induced Fibrosis (RIF) (1)
Belgian Menopausal Society, 4th of June 2016
Straub J et al. J Cancer Res Clin Oncol 2015;141:1985-1994.
QOL impairment - RADIOTHERAPY
The primary treatment - related factors are: - the total dose of RT and dose per fraction, - the volume of tissue treated - the course of treatment delivery - concurrent use of chemotherapy - incorporation of surgery pre- or post -RT
RIF usually occurs 4–12 months after radiation therapy and progresses over several years RIF may manifest as lymphedema, mucosal fibrosis, ulceration, fistula, hollow organ stenosis, and pain. The treatment is primarily symptomatic, with no effective method that offers complete remission at this time
Radiation Induced Fibrosis (RIF) (2)
Belgian Menopausal Society, 4th of June 2016
QOL impairment - CHEMOTHERAPY
Ezendam et al. Gynecol Oncol 2014;135:510-517. Wenzel LB et al. Psychooncology 2002;11:142.
Muscle cramps (39%) Ringing in ears or trouble hearing (29-35%)
Discomfort in feet (29%) Upper extremity discomfort (23%)
Trouble walking (16%) Numbness and weakness in the hands (10%)
More neuropathy symptoms reported: - Lower levels of functioning and QOL - More symptoms of fatigue, N/V, pain, insomnia, appetite loss, financial problems - Experienced the disease more as a burden - Were more worried about their health
Chemotherapy Induced Peripheral Neuropathy (CIPN)
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RIF Ovarian failure
Apoptosis of mature ovarian follicles
Alkylating (40% POI vs. non alkylating)
BSO
QOL impairment – OVARIAN FAILURE
Definite Probable Unlikely Unknown
N-Mustard L-phenylalanine Chlorambucil Busulfan Cyclophophamide Procarbazine
Doxorubicin Vinblastine Cytosine arabinoside Cisplatinum Carmustine Lomustine VP-16 (Etoposide)
Methotrexate Fluorouracil 6-mercaptopurine Vincristine
VM-26 Daunorubicin Bleomycin Melphalan Dacarbazine Vindesine
Fenton AJ. Midlife Health 2015;6(4):147-153. Gross E et al. Cancer/Radiothérapie 2010;14:373-375.
Belgian Menopausal Society, 4th of June 2016
Localized urogenital
Non - E
Moisturizers
Lubricants
E
17B-estradiol, estriol pessary,ring, cream,
tablet
Moderate to severe
Hormonal
E + P, E
E + bazedoxifene
Tibolone
Non-hormonal
SSRI/SNRI, Clonidine, Gabapentin, Hypnosis,
CBT, Weight loss
Sexual dysfunction
Consider Tibolone or
Testosterone
Contraindications
Estrogen dependent
cancers?
High risk of VTE/DVT or
thrombophilia
Personal wish not to use hormones
Severe active liver disease
Untreated hypertension
Caution > 60 or 10 years after menopause
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MHT after pelvic cancer
Shim et al.- Eur J Cancer 2014;50:1628-1637.
MHT after ENDOMETRIAL cancer
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19/896 64/1079
NRS
NRS
NRS
NRS
NRS
RCT
MHT after ENDOMETRIAL cancer
Shim et al.- Eur J Cancer 2014;50:1628-1637.
Belgian Menopausal Society, 4th of June 2016
MHT after ENDOMETRIAL cancer
Belgian Menopausal Society, 4th of June 2016
Shim et al.- Eur J Cancer 2014;50:1628-1637.
MHT after ENDOMETRIAL cancer
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3 yrs OS : 96.5%
3 yrs PFS : 94.8%
MHT after OVARIAN cancer
Eeles A et al. JCO 2015;33:4138-4144.
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Overall Survival Relapse - Free Survival
MHT after OVARIAN cancer
Li et al. Gynecol Oncol 2015;139:355-362.
Belgian Menopausal Society, 4th of June 2016
MHT after OVARIAN cancer
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MHT after OVARIAN cancer
Li et al. Gynecol Oncol 2015;139:355-362.
Belgian Menopausal Society, 4th of June 2016
Huffman L et al. Gynecol Oncol 2016;140:359-368.
Belgian Menopausal Society, 4th of June 2016
Sexual health
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Belgian Menopausal Society, 4th of June 2016
Sexual health
Basic triage and treatment strategies for the most common sexual health issues in cancer patients
+ flibanserin/day bedtime (HSDD)=?
+ ospemifene=?
Low dose vaginal E are not absorbed significantly: NO in embolic events, breast Ca and EC
Belgian Menopausal Society, 4th of June 2016
Prophylactic surgery
RRSO in BRCA1/2 mutation; Total hysterectomy and BSO in Lynch S.
In general, the symptoms of estrogen deficiency are often more severe and longer lasting than seen in women experiencing a natural menopause.
Fenton AJ. Midlife Health 2015;6(4):147-153.
Premature ovarian insufficiency
Distribution of incidence of malignacy
Belgian Menopausal Society, 4th of June 2016
CARDIOVASCULAR: rates of coronary artery disease, heart failure and mortality. BONE HEALTH: BMD (20% in 1st 18mths after RRSO), more consistent in fracture risk (especially when <50yrs) COGNITIVE and NEUROLOGICAL HEALTH: risk of dementia (earlier age at BSO), Parkinsonism, glaucoma and macular degeneration MENTAL HEALTH: mood disorders (lower self-esteem, more depression and anxiety) SEXUAL DYSFUNCTION
Long-term health CONSEQUENCES
Faubion SS et al. Climacteric 2015;18(4):483-491.
Premature ovarian insufficiency
Belgian Menopausal Society, 4th of June 2016
MANAGEMENT: Menopausal Hormone Therapy
Premature ovarian insufficiency
Rebbeck et al. The PROSE study. JCO 2005;23:7804-7810.
Belgian Menopausal Society, 4th of June 2016
Unless contra-indicated, women with POI should receive MHT until the normal age of menopause. Higher than average doses of estrogen may be required to restore QOL (optimal dose?). There is a theoretical advantage in using transdermal E to preserve sexual function by minimizing any impact on SHBG levels. E or E+P (cyclical or continuous). The OC pill is an option when residual ovarian function.
MANAGEMENT: Menopausal Hormone Therapy
Faubion SS et al. Climacteric 2015;18(4):483-491.
Premature ovarian insufficiency
Belgian Menopausal Society, 4th of June 2016
ET has been shown to not fully protect against the increased risk of Parkinson, depression, anxiety and glaucoma. Particularly those with BSO may experience persistent problems with sexual dysfunction. Testosterone treatment has been associated with better sexual function and energy. -> However, the routine androgen supplements is not routinely advocated.
MANAGEMENT: Testosterone?
Faubion SS et al. Climacteric 2015;18(4):483-491. Buster et al. Obstet Gynecol 2005;105:944-952. Guerrieri GM et al.Menopause 2014;21:952-61.
Premature ovarian insufficiency
Belgian Menopausal Society, 4th of June 2016
MANAGEMENT: counseling
Faubion SS et al. Climacteric 2015;18(4):483-491.
Premature ovarian insufficiency
Cardiovascular disease prevention
Osteoporosis and fracture risk reduction
Psychological impact of early menopause Referral to a mental health professional
Belgian Menopausal Society, 4th of June 2016
Ovarian cancer: - Indication: EOC St 1A grade 1; BOT; germ cell - Ttt: adapted conservative surgery with adequate staging (LN/omentectomy) Endometrial cancer - Indication: Endometrioid grade 1 stage 1A (superficial) - < 40 yrs - Ttt: MPA: 400-600mg/d or MA: 160-320mg/d or IUD-LNG +/- GnRH agonist Inter- ovarian hysterectomy Cervical cancer - Indication: squamous St IB - IIB - Ttt: Ovarian transposition
ALTERNATIVE options for ovary preservation?
Gunderson CC et al. a systematic review. Gynecol Oncol. 2012;125:477-482. Shimada et al. Gynecol Oncol 2006;101:234-237.
Premature ovarian insufficiency
Belgian Menopausal Society, 4th of June 2016
MIS Transection utero-ovarian ligament. Transposition paracolic gutter
Relocation +/- 3cm above pelvic inlet -> +/- 1-10% of EBRT. Radio-opaque clips.
Gross E et al. Cancer/Radiothérapie 201;14:373-375. Mossa B et al. Eur Rev Med Pharmacol Sci 2015;19:3418-3425.
Premature ovarian insufficiency
OVARIAN TRANSPOSITION
Belgian Menopausal Society, 4th of June 2016
Gross E et al. Cancer/Radiothérapie 2010;14:373-375. Mossa B et al. Eur Rev Med Pharmacol Sci 2015;19:3418-3425.
Summary of the largest studies evaluating efficacy of ovarian transposition on ovarian preservation
3 prognostic factors: - Age <25
- Dose RT < 5Gy - Chemotherapy
Risks: - Meta’s more in adenoca and bulky tumor
- Ovarian cyst - Ovarian torsion
Premature ovarian insufficiency
OVARIAN TRANSPOSITION
Belgian Menopausal Society, 4th of June 2016
Hormone Replacement Treatment may be administered to patients after endometrial cancer stage (good prognosis/early stage) , epithelial ovarian cancer (ER?) and cervical cancer. The best regimen/dose; the duration of use and the timing of HRT initiating remains unclear.
Oncology providers can make a significant impact on the QOL of gynecologic cancer survivors by adressing sexual health concerns. Simple strategies can be implemented into clininical practice to discuss and treat many sexual issues. Referral to specialized sexual health providers may be needed to address more complex problems.
POI is associated with numerous adverse health outcomes. Unless a strong contraindication exists, hormone therapy is recommended at least until the natural age of menopause to protect against these negative effects. Counseling regarding CVD prevention, osteoporosis and fracture risk reduction is suggested.
Conclusion
Belgian Menopausal Society, 4th of June 2016
Thank you
Belgian Menopausal Society, 4th of June 2016
Belgian Menopausal Society, 4th of June 2016
MHT after OVARIAN cancer
Eeles A et al. JCO 2015;33:4138-4144.
Belgian Menopausal Society, 4th of June 2016
Adverse Effects during Follow-Up
MHT after OVARIAN cancer
Eeles A et al. JCO 2015;33:4138-4144.
Belgian Menopausal Society, 4th of June 2016
Causes of death in patients
Belgian Menopausal Society, 4th of June 2016
Menopausal symptom management
Localized urogenital
Non - E therapy
Moisturizers
Lubricants
E therapy
17B-estradiol, estriol pessary,ring, cream, tablet
Moderate to severe
Hormonal treatment
E + P
E
E + bazedoxifene
Tibolone
Non-hormonal treatment
SSRI/SNRI, Clonidine, Gabapentin, Hypnosis, CBT
therapy, Weight loss
Sexual dysfunction
Consider Tibolone or testosterone therapy
Contraindications
Estrogen dependent cancers
High risk of VTE/DVT or
thrombophilia
Personal wish not to use hormones
Severe active liver disease
Untreated hypertension
Caution > 60 or 10 years
after menopause
Jane FM. Climacteric 2014;17:564-579.
Belgian Menopausal Society, 4th of June 2016
Premature Ovarian Insufficiency (POI) – Early Menopause
Is a member of the TGFBeta superfamily and is secreted by the granulosa cells of the preantral and small antral follicles within the ovaries. Is used as a marker of ovarian reserve and has been considered to be relatively unaffected by other hormonal or health influences. It is lowered by the use of GnRH and the OC pill. An unmeasurable AMH after 2 years of cancer therapy is usually associated with a low chance of menstruation returning.
Anti-Mullerian Hormone (AMH)
Faubion SS et al. Climacteric 2015;18(4):483-491.
Belgian Menopausal Society, 4th of June 2016
Premenopause The epithelium is well-estrogenized, multi-layered with a good blood supply, and the superficial cells are rich in glycogen.
Postmenopause There is estrogen-deficiency atrophy with marked thinning of the epithelium, the blood supply is reduced and there is loss of glycogen.
Belgian Menopausal Society, 4th of June 2016
Vaginal atrophy
Sentinel lymph node mapping
If there is no mapping on a hemi-side, a side-specific LND is performed
Any suspicious nodes must be removed regardless of mapping
Excision of all mapped SLN
Cervical cancer ≤2cm, no clinical LN Endometrial cancer St 1, no clinical LN Low to intermediate risk
SLN surgical algorithm
Detection rate: 92-98% Sensitivity : 100%; NPV:100% Senticol 1 JCO 2011;29:1686-91.
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Rob et al. Syst Review. Expert Rev Anticancer Ther 2013;13(7):861-870.
Belgian Menopausal Society, 4th of June 2016
Schematic depiction of the effects of oestrogen on the vaginal epithelium
Archer DE. Menopause 2010; 17:194-203.