quality of life and menopause treatment after pelvic...

‘’ 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


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 ±


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

+


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 + +


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)


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QOL impairment - RADIOTHERAPY

Radiation Induced Fibrosis (RIF) (1)


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)


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)


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.


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


19/896 64/1079

NRS

NRS

NRS

NRS

NRS

RCT


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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.


Overall Survival Relapse - Free Survival


Li et al. Gynecol Oncol 2015;139:355-362.



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Li et al. Gynecol Oncol 2015;139:355-362.


Huffman L et al. Gynecol Oncol 2016;140:359-368.


Sexual health

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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


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.


Distribution of incidence of malignacy


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.



MANAGEMENT: Menopausal Hormone Therapy


Rebbeck et al. The PROSE study. JCO 2005;23:7804-7810.


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




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.



MANAGEMENT: counseling



Cardiovascular disease prevention

Osteoporosis and fracture risk reduction

Psychological impact of early menopause Referral to a mental health professional


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.



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.


OVARIAN TRANSPOSITION


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


OVARIAN TRANSPOSITION


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


Thank you


Eeles A et al. JCO 2015;33:4138-4144.


Adverse Effects during Follow-Up


Eeles A et al. JCO 2015;33:4138-4144.


Causes of death in patients


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.


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)



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.


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.


Rob et al. Syst Review. Expert Rev Anticancer Ther 2013;13(7):861-870.


Schematic depiction of the effects of oestrogen on the vaginal epithelium

Archer DE. Menopause 2010; 17:194-203.

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