Download Gynecological Considerations for Breast Cancer Patients #83

Gynecological
Considerations for Breast
Cancer Patients #83
Michael L Krychman MDCM MPH FACOG
Executive Director of the Southern California Center for Sexual
Health & Survivorship Medicine
AASECT Certified Sexual Counselor
Associate Professor USC
Newport Beach, California
USA
Why Focus on Survivorship?

Rapidly growing population

Increasing patient and community
expectations for good quality of life

Increased funding of survivorship research
– NIH investment in survivorship
 $38,000,000 Fiscal 2001
(<$4.25 per survivor)
 $46,000,000 Fiscal 2004
What has contributed to this
remarkable progress?
Earlier detection
New and more effective therapies
often including multimodal and multi-agent
combinations
More effective adjuvant and/or maintenance therapies
Better supportive care
Growing attention to long-term surveillance
Survivors Needs
Lance Armstrong Foundation LIVESTRONG™ Poll n=1020

Secondary Health Problems
– 53% - secondary health problems
 54% - deal with chronic pain
 33% - infertility

Non-Medical Support
– 49% - non-medical cancer needs were unmet
– 53% - practical and emotional consequences of cancer are often
harder than medical issues

Emotional Support
– 70%- dealt with depression
– 78% - did not seek professional services

Relationships
– 58%- dealt with loss of sexual desire and/or sexual function
Cancer Survivorship is an
International Agenda

CDC Report 2004

– Enhance surveillance; identify ongoing health concerns
– Educate survivors and general
public about value of long-term

follow up care
– Establish clinical practice guidelines
for survivorship
– Establish multidisciplinary teams of
health care providers for survivors

Lance Armstrong Foundation
– Funding source
– Centers of Excellence
NCI
– Office of Cancer Survivorship
– Comprehensive Cancer Center
requirements
President’s Cancer Panel
2004
– Public education campaign
– Survivor care and standards
for communication
– Psychosocial care
– Insurance coverage
Why do Patients Need Long-Term Follow-Up?

Chronic side effects of chemotherapy

Late effects of
– radiation therapy
– surgery

Risk of secondary cancers

Other long-term health issues
Survivorship and QOL Concerns

Cancer Screening

General Health Maintenance
– Ovarian cancer screening
– Colon screening
– Pap smears
– Bone health
– Cardiovascular concerns

Reproductive Health Concerns
– Pregnancy
– Fertility
– Sexuality

Life Management
–
–
–
–
–
Diet
Exercise
Sleep management
Stress management
Time management
Breast Cancer-Related Complaints

Anatomical sequelae from
surgical intervention

Sequelae from adjunctive
therapy
– Chemotherapy
– Radiation changes

Maintenance therapies
– Hormonal
manipulation
– Immune modulators
– Cytostatic medications
Effect of Treatment:
Other Surgeries

Cosmetic
– cosmesis may not always be
satisfactory
– Nipples?

Prophylactic
– Bilateral Salpingo-oophorectomy
adversely affects sexual functioning
Van Oostrom et al (2003)
Early loss of estrogen has serious
medical concerns
- Prophylactic mastectomy
Fear of bilaterality
Fear of another primary
Major Concerns for
Gynecology Survivorship








Menopausal Hot Flashes
Genital Syndrome of Menopause
Sexual Complaints
Fertility
Other:
Cognitive and Sleep Disturbances
Musculoskeletal Changes
Bone
Menopausal Road blocks
Premenopausal women

Literature suggests that the adaptation after BC
diagnosis is more difficult for younger women

Standardized measures of depression and QOL for
younger women show greater changes in mood and
poorer emotional functioning

Reproductive health effects of adjuvant therapy that
specifically affect younger women
– infertility
– early menopause
Hot Flashes

Hot Flashes/Flushes:
–
sudden, transient sensations of warmth to intense heat with a
range of physiologic and emotional responses (flushing,
perspiration, palpitations, anxiety, embarrassment, irritation,
disruption of activities especially sleep) maybe associated with a
chill

Frequency not necessarily related to reported severity 
evaluation of hot flashes should include frequency and
patients’ subjective experience

10-15% of women have frequent debilitating hot flashes
lasting 1-5 minutes
1.
Couzi et al. 1995

Highest frequency
– in first 2 years of menopause
– decline thereafter
– Some persist for 10 years

Study of women across nations (SWAN) study
– ethnicity may play role

Surgical menopause is more severe

Severe hot flashes in 59% of BC patients
– severity associated with younger age at diagnosis and with
tamoxifen use1
Treatment Pearls

Medications
– Anti-hypertensives
– SSRI
– Venlafaxine
– Paroxitine ( FDA approved)
 HT Alternatives
–
–
–
–
–
Nutritional counseling
Exercise
Environmental changes
Rhythmic breathing
Menopausal
 PJ/ Chillow/ Sheets
– Supplements
– Integrative medicine
 Acupuncture
 Maitake
 Yoga





ATAC (Arimidex tamoxifen alone or in combination)
BIG (Breast International Group)
ITA (Italian Tamoxifen Anastrazole Trial)
IES (Intergroup Exemestane Study)
MA-17
Other ongoing trials
– AI have surpassed tamoxifen in treatment for recurrent breast cancer
– Same maybe for early breast disease
– Support AI use for Breast Cancer patients
Will need good treatments for FSD, atrophic
vaginitis, bone health and menopausal hot
flashes
Introduction

25% of new cases present before the menopause and 15% before the age
of 45. Younger age is associated with decreased social and emotional
function

Up to 90% BC survivors are suffering in silence. 20 years from diagnosis
29% report sexual problems attributable to having had BC1

FSD leads to changes in
 Compliance, Marital discord and Poor overall health

Sexuality is ignored and unaddressed

Few studies have rigorously addressed sexual dysfunction most are
retrospective studies
1. Kornblith et al. Cancer 15;98(4):679-89.
Urogenital and Vaginal Changes





Dryness
Vaginal irritation
Malodorous discharge
Sensitive vulva
Thinning of vaginal rugae





NAMS Menopause Practice a
Clinicians Guide
Urgency
Frequency
Urinary stress incontinence
Increased risk for UTI
Fecal incontinence maybe
caused by decreased
estrogen levels and
neuromuscular dysfunction
– The anorectum has
abundant estrogen
receptors

Breast cancer survivors can possibly use
minimally absorbed local vaginal estrogen
products like
– vaginal estrogen ring
– vaginal estradiol tablets
With very little systemic escape

Consider following estradiol levels, tailor
the treatment regime.
Cellular Shift Changes
Premenopausal
Superficial
Intermediate
Parabasal
Post menopausal
15%
80%
5%
Superficial
Intermediate
Parabasal
1%
60%
39%
Breast Cancer and Sexual Function
50% to 90% of breast cancer survivors complain of
some form of FSD
– “Yes I am thankful to be alive, but I am dead down there”
– “Breast cancer treatment contributed to the deterioration of my
excellent marriage”
– “They never told me I would feel like this…..”

Most common FSD: vaginal dryness with painful intercourse

Changes in self-esteem are very troublesome

Prophylactic surgeries adversely affects sexual functioning

Topical estrogen may not be associated with increased risk of
breast cancer recurrence
Dew JE et al. Climacteric. 2003;6:45-52.
AV Before & After Local Estrogen Therapy
Vaginal biopsy specimen
showing atrophic changes
Pandit L et al. Am J Med Sci. 1997;314:228-231.
Images courtesy of Lila Nachtigall, MD.
Vaginal biopsy specimen
from the same patient after
local estrogen therapy
Goals of Treatment

Relieve symptoms

Reverse anatomical changes

Improve sexual function and quality of life
Lubricants
Moisturizers
22
Hormonal Options: Estrogens

Systemic Hormonal
– Tablets
– Patches
– Gels/Lotions
 Estrasorb
 Estrogel®
– Creams?

Vaginal Hormonal
– Cream
 Estrace® (micronized 17Estradiol)
 Premarin® (conjugated
equine estrogens)
– Ring
 Estring® (micronized 17Estradiol)
 Femring (systemic)
– Tablet
 Vagifem® ( 17B estradiol )
Minimally Absorbed Local Vaginal Topical
Estrogens
Composition
Dosing
Vaginal Cream 17 B Estradiol cream
Initial 2-4 g 1-2 wk
Maintenance: 1g/d(0.1mg active ingredient /g)
Conjugated estrogens
0.5-2.0 g/d ( 0.625 mg active ingredient/g)
(Formally conjugated equine estrogens)
Vaginal Ring
17 Beta Estradiol
Device contains 2mg
Releases 7.5 microgram per day for 90 d
Vaginal tablet
Estradiol hemihydrate
Initial dose: 1 tab q/day for 14day
Maintenance 1 tab BIW
(Tablet 10.3 mcg of estradiol
hemihydrate, equivalent to 10mcg of
estradiol)
North American Menopause Society. Menopause. 2007;14:357-369. Cirigliano M. J Womens Health (Larchmt). 2007;16:600–631.
Simon JA, et al. Obstet Gynecol. 2008;112:1053-1060. Simon JA, et al. Obstet Gynecol. 2010; 116 (4): 1-8
Effects of Local Estrogen

Improve sensory perception
Increase central and peripheral nerve transmission
Increase lubrication
Reduce pH
Increase peripheral blood flow
Augment capacity to develop muscle tension
Increase vibratory sensation
Increase vaginal vault relaxation
Increase vaginal vault size
Increase tissue elasticity

Increase vaginal collagen content









–
Sarrel PM. Sexuality in the middle years. Obstet Gynecol Clin North Am. 1987; 14: 49-52. Gescheider GA, Verillo RT, McCann JT, et al.
Effects of the menstrual cycle on vibrotactile sensitivity. Percept Psychophys 1984; 36: 586-592. Kow L, Pfaff D. Effects of oestrogen
treatment o the size of receptive field and response threshold of the pudendal nerve in the female rat. Neuroendocrinology 1973; 13:
299-313. Lara LA, et al. J Sex Med. 2009;6:30-39. NIH State-of-the-Science Conference Statement on management of menopause-
Surveys

Pfizer
– ReVeal ( Revealing Vaginal Effects at Mid Life)
– Healthy Women

NovoNordisk
– VIVA ( Vaginal Health Insight, Views and Attitudes)
– CLOSER Study

Shionogi
– REVIVE (REal Women’s VIews of Treatment Options
for Menopausal Vulvar/Vaginal ChangEs)
Many Users Claim Vaginal Estrogen Interrupts
Routine and Requires Privacy
On
average,
takes
81%
ensure they
have privacy
before applying
vaginal estrogen
therapy
1 min,
50 secs
to apply
25%
68%
apply in
bedroom
apply in
the bathroom
21% 11%
61%
apply in
morning
at night
early
evening
29
B15c, B15d, B19, B20, B20B, B21, B22; C15, C16
Base:
Ever treated VVA with topical estrogen (n=858); Have partner and use topical estrogen (n=305), Partner is aware (n=295)
Dislikes with Current VVA Therapies
OTC
K-Y
Vagisil
Astroglide
Rx
K-Y Silk E
Replens
Estrace
Premarin
Vagifem
Vagina not
Vagina not
Not enough relief
Safety for long
It's expensive
It's messy (48%) It's messy (40%) It's messy (39%) restored to natural
restored to natural
VVA symp (37%)
term use (41%)
(40%)
(43%)
(43%)
Vagina not
Vagina not
Vagina not
Vagina not
Safety for long Concern hormone Not enough relief
restored to natural restored to natural restored to natural It's messy (40%) restored to natural
term use (38%) exposure (38%) VVA symp (38%)
(40%)
(32%)
(35%)
(37%)
Can’t be sexually
Vagina not
Can’t be sexually
Administering it is
Not enough relief
Concern breast
Safety for long
spontaneous
It's messy (36%)
restored to natural
spontaneous
annoying (27%)
VVA symp (39%)
cancer (36%)
term use (34%)
(27%)
(36%)
(25%)
Can’t be sexually
Vagina not
Not enough relief Not enough relief Not enough relief
It's expensive
Concern hormone
It's expensive
spontaneous
restored to natural
VVA symp (24%) VVA symp (23%) VVA symp (25%)
(33%)
exposure (32%)
(36%)
(24%)
(29%)
Administering it is Inconvenient to Administering it is Inconvenient to
annoying (21%)
take (21%)
annoying (21%)
take (18%)
Vaginal discharge Risk of side effects Administering it is Concern hormone
(26%)
(27%)
annoying (29%) exposure (29%)
Inconvenient to
take (17%)
Vaginal discharge
(17%)
Inconvenient to Administering it is Administering it is
annoying (18%) annoying (23%)
take (18%)
It's not discrete
(13%)
Can’t be sexually
spontaneous
(16%)
It's not discrete
(12%)
It's not an oral pill Safety for long
(8%)
term use (15%)
Safety for long
term use (5%)
It's expensive
(5%)
It's expensive
(25%)
It's messy (28%)
Concern breast
cancer (26%)
It's not discrete Takes long time to Not enough relief Risk of side effects Risk of side effects
(12%)
work (22%)
VVA symp (24%)
(24%)
(25%)
Vaginal discharge
(8%)
Can’t be sexually
spontaneous
It's messy (23%)
(22%)
Concern breast
cancer (23%)
Dosing schedule
difficult (17%)
It's not an oral pill Don't like touching It's not an oral pill It's not an oral pill Administering it is Inconvenient to It's not an oral pill
(15%)
body (5%)
(7%)
(13%)
annoying (19%)
take (23%)
(14%)
Takes long time to Takes long time to It's not an oral pill Interrupts daily
work (4%)
work (10%)
(5%)
life (5%)
Safety for long
term use (12%)
B11a. What do you dislike about the treatment(s) you are currently taking for your vaginal/vulvar symptoms?
Base: Currently treating VVA
Inconvenient to
take (18%)
Vaginal discharge Takes long time to
(19%)
work (13%)
30
Putting WHI Risks Into
Perspective
EPT
EPT
ET
ET
Relative
Risk
Absolute Risk
(number per
10,000 women)
Relative Risk
Absolute Risk
(number per
10,000 women)
CHD
1.29
7 more
0.91
5 less
Stroke
1.41
8 more
1.39
12 more
VTE
2.11
18 more
1.33
7 more
Breast
cancer
1.26
8 more
0.77
7 less
Event
Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:321-333.
Women’s Health Initiative Steering Committee. JAMA. 2004;291:1701-1712.
Comparative Risk of Breast Cancer in RCT of
Hormone Therapy and Statin Therapy
Placebo: No of Breast Cancer Therapy
No Of Breast Cancer
Relative Risk
Additional cases per 10,000 women per year of therapy
150
25
199
32
1.20
1.3
8
12
11
9
5
18
13
7
1.65
1.44
1.44
15
15
5
1
10
37
51
12
10
34
38
12.17
1.0
0.93
0.75
77
0
‐2
‐10
ET
WHI‐ET
161
129
0.82
‐8
17 B Estradiol
WEST
5
5
1.0
‐2
Therapy/Study
EPT
WHI‐ EPT
HERS
Statin Therapy
PROSPER
AFCAPS/TexCAPS
4S ( 10yr Follow up)
CARE
LIPID
ALLHAT‐LLT
HPS

Hodis; Cleveland Clinic Journal of medicine: 17;S4 3-12
VVA and Sexual Function

Cross-sectional, population-based study of
1,480 sexually active, postmenopausal women

57% had vulvovaginal atrophy

55% had female sexual dysfunction

Women with sexual dysfunction ~4X more likely to also
have vulvovaginal atrophy

Conclusion: Reducing symptoms of one condition may also
relieve symptoms of the other
–
Levine KB, et al. Menopause. 2008;15(4 pt 1):661-666.
Is Local Really Local?

Kendall et. al. cautions that vaginal estradiol is
contraindicated in postmenopausal women on adjuvant
aromatase inhibitors1.

Labrie et. al. demonstrate that even small doses of vaginal
preparations
– Vagifem 25 μg; Premarin Vaginal Cream result in significant
systemic absorption through estrogen naive vaginas(2).


Naessen et al showed that 7.5 μg/24h could improve the
lipid profile and bone density without affecting the
endometrium3-5.
1Kendall A, et. al. Ann Oncol 2006;17:584-587. 2Labrie F, et. al. Menopause 2009;16:30-36. 3-5Naessen T, et. al. J Clin Endocrinol
Metab 2001;86:2757-2762.; Am J Obstet Gynecol 1997;177:115-119.; Am J Obstet Gynecol 2002;186:944-947.
Kendall M., Dowsett et al:
Caution: Vaginal estradiol appears to be contraindicated in
postmenopausal women on adjunctive aromatase inhibitors
Annals of Oncology: 1/27/2006
UK study of 7 women on AI.
Serum E2, FSH, LH measured at baseline the 2, 4 7-10 and
12 weeks later.
Specific assay for postmenopausal LOW levels
Serum levels rose from baseline of <5pmol/l consistent
with AI therapy to a mean of 72 pmol/l at 2 weeks, by
week 4 this had decreased to <35 pmol/l in the majority
of women
Conclusion: Vagifem significantly raises systemic estradiol
levels at least in the short term. This may reverse the
estradiol suppression achieved by AI in women with
Breast Cancer and is contraindicated.
Current Overview of the Management of Urological
Atrophy in Women with Breast Cancer
Pruthi S, Simon JA, Early AP. Breast J. 2011 Jul-Aug;17(4):403-8. doi: 10.1111/j.1524-4741.2011.01089.x. Epub 2011 Jun 6
Local Estrogen Therapy and Risk of Breast Cancer Recurrence among
Hormone Treated Patients: A Nested Case Control Study
LeRay I., Dell’aniello S. et al Breast Cancer Res Treat 2012;135:603

Design
– Impact of vaginal estrogen on recurrence risk was evaluated among 917 women
with BC recurrence (cases) who were compared to women with BC in remission
(controls)
–
–
–

Matched for age and initial endocrine treatment
Rate of vaginal estrogen use was low (<3%)
Most frequent local estrogen: cream and tablets
Results
– Rate of concomitant vaginal estrogen use with endocrine therapy was similar with
cases and controls ( 2.1% versus 2.8% respectively) suggesting that
concomitant use is not associated with an increased risk of recurrence ( (RR
0.97)
– The rate of sequential se of vaginal estrogen following completion of endocrine
therapy was also similar ( 0.25 in cases and controls) suggesting there was no in
risk in the risk of recurrence
Dew et al: Conclusions






Cohort: N=1472
– HRT: 342 (23%)
– Local vaginal estrogens: 69 (4.7%)
 Tablets, cream
Diagnosis to treatment: 5.25 years ( 0-20 years)
Median time of use: 1 year
Median follow-up: 5.5 years
Deaths: 11.5% entire population
– 6% in local vaginal estrogen users
Study was underpowered for definitive data outcomes
Topical vaginal estrogen usage appears not to increase risk of recurrent
breast cancer
Dew et al. 2003. Climacteric. 2003;6:45-52.
39
Important New Studies

Goldfarb et al (SABC 2012) n=26
– BC Stage 1-3 on AI; 10mcg 17B-estradiol
– Median change in estradiol from baseline to wk 12 was 0.2 with
a range from -3.0 to 14.6
– Only 5/26 (19%) had sporatic elevation in E2 outside
menopausal range
– Clinical significance of the systemic E2 absorption is unknown
and warrants further study
– Impression:
 Elevations in E2 are rare and brief, data does not support the
routine monitoring of E2 levels
 Improvements in sexual function is not associated with an elevation
of E2 levels

Melisko et al ( SABC 2012) N=29
– Vaginal Testosterone 1% 0.5g qd (15) Vs. Estring 2mg (14) in BC pt on AI
– Preliminary Data
 Both effective to tx vaginal dryness
 Neither have met criteria for stoping
 Modest and mostly transient elevations of E2 have occurred, more often and only
persistent in the Test arm
 Accrual continues

Wills et al ( J of Onc Pract 2012 8:(3): 144-148) N=24
– Postmenopausal women with ER(+) BC or at high risk for BC who were taking an AI or
a SERM. (Estring VS 25mcg-17B estradiol tablets) on VE for 90 days
– VE Ring: E2 levels pre insertion and 12 weeks post insertion were significantly greater
than controls (p<0.001)
– VE Tablets: E2 levels pre insertion were NOT significantly different than controls
(p=0.48) and post insertion levels were 76 pmol/L higher than pre insertion
– Preinsertion levels for pt on VE tablets were not elevated compared with those of
controls suggesting that E2 elevations with this preparation may not be continuously
sustained
Low Dose Vaginal Estrogen Treatment

Breast cancer survivors may possibly use minimally absorbed
local vaginal estrogens products like the ring (Estring ®) and
tablets (Vagifem ®) and Conjugated Equine Estrogen
(Premarin Vaginal Cream) ® Estradiol cream (estrace ®)
– with very little systemic escape. OFF LABEL!
Kendal et al (2006): increased E2 level in BC patients on
Vagifem ®
 Surgical oncologists, medical oncologists, gynecologists and
patients will often disagree about safety
 NAMS and OBGYN advocate personalized and individualized
plans
 Formulate management plan

–
–
–
–
Monitor estradiol levels
Evaluate abnormal bleeding
Try alternatives first?
Know your personal comfort zone
42
In Development for Menopausal VVA
Drug Name
Drug Category
Pharma Sponsor
Synthetic CE- A Cream
Bijuiva
Estrogen
Teva Inc.,
Current
Development
NDA
Ospemifene Tablets
(Osphena)
SERM
Quatrx Inc.,
Shionogi
Pharmaceuticals
APPROVED!!!
BZA/CEE Tablets
STEAR
TSEC
Pfizer
Pharmaceuticals
APROVED !!!
DHEA Vaginal Ovules
(Prasterone)
Androgenic Precursor
Endoceutics Inc
Bayer
Phase III
Lasofoxifene
(Fablyn)
SERM
Ligand Pharmaceuticals
Pfizer Inc
NDA Status Unclear
EMEA- Approved
Seala
SERM
BioNovo
Phase I-II
Tamoxifen
(vaginal inserts)
SERM
Pear Tree Pharmaceuticals
Phase I-II
BZA/CEE- Bazedoxifene+ conjugated equine estrogen
SERM: Selective estrogen receptor modulator
STEAR: Selective tissue estrogenic activity regulator
TSEC: Tissue Selective Estrogen Complex
Topical Testosterone for Breast Cancer Patients with Vaginal Atrophy Related to
Aromatase Inhibitors: A Phase I/II Study.
Witherby S, Johnson J, Demers L, Mount S, Littenberg B, Maclean CD, Wood M, Muss H.
Providence, Rhode Island, USA;
Abstract Purpose. Controversy exists about whether vaginal estrogens interfere with the efficacy
of aromatase inhibitors (AIs) in breast cancer patients. With the greater incidence of vaginal
atrophy in patients on AIs, a safe and effective nonestrogen therapy is necessary. We
hypothesized that vaginal testosterone cream could safely treat vaginal atrophy in women on AIs.
Methods. Twenty-one postmenopausal breast cancer patients on AIs with symptoms of vaginal
atrophy were treated with testosterone cream applied to the vaginal epithelium daily for 28 days.
Ten women received a dose of 300 μ g, 10 received 150 μ g, and one was not evaluable.
Estradiol levels, testosterone levels, symptoms of vaginal atrophy, and gynecologic examinations
with pH and vaginal cytology were compared before and after therapy.
Results. Estradiol levels remained suppressed after treatment to <8 pg/mL. Mean total
symptom scores improved from 2.0 to 0.7 after treatment (p < .001) and remained improved 1
month thereafter (p = .003). Dyspareunia (p = .0014) and vaginal dryness (p <.001) improved. The
median vaginal pH decreased from 5.5 to 5.0 (p = .028). The median maturation index rose from
20% to 40% (p < .001). Although improvement in total symptom score was similar for both doses
(-1.3 for 300 μ g, -0.8 for 150 μ g; p = .37), only the 300-μ g dose was associated with improved
pH and maturation values.
Conclusions. A 4-week course of vaginal testosterone was associated with improved signs and
symptoms of vaginal atrophy related to AI therapy without increasing estradiol or testosterone
levels. Longer-term trials are warranted
Intravaginal DHEA
(Vaginorm/Prasterone ®)

Labrie et al
– Journal of Steroid Biochemistry and Molecular
Biology 111 (2008) 178-194

Treatment
– One ovule of DHEA 0.0%, 0.5%, 1.0% or 1.8%
– 7 days vaginal PH was significantly decreased
– Serum Estradiol and Testosterone remained within normal
postmenopausal values at all DHEA values
– DHEA permits rapid effects for local beneficial effects against
vaginal atrophy, without changes in estradiol thus avoiding the
increased risk of breast cancer associated with the current
intravaginal or systemic estrogenic formulations
Labrie et al. Menopause vol 16 no 5 907-922
Ospemifene (Osphena)






First and Only oral non estrogen for the
treatment of moderate to severe dyspareunia a
symtptom of VVA due to menopause
2010 RCT Stage III: SERM ospemifene
– Quatrix Inc/ Shionogi Inc
827 women randomized either 30, 60 mg or placebo for 12 weeks
60 mg was shown to be effective, well tolerated for vaginal dryness and
dyspareunia
No proliferative effect on endometrium
Side effect: 8 % hot flashes
– 0.7% severe in 60mg group
– one participant (0.4%) in the 60 mg group discontinued because of
hot flashes.
–

Bachman et al. Menopause: 17:3:: 480-486
Interesting: Ospemifene and 4-hydroxyospemifene effectively prevent
and treat breast cancer in Mtag.TG Transgenic Mouse.
–
Burich et al Menopause 19:1: 96-103
Tissue Selective Estrogen Complex
TSEC ( AKA STEAR) pair a selective estrogen receptor
modulator (SERM) with 1 or more estrogens to provide
clinical results based on their blend of tissue selective
activities. APRROVED AS DUOVIV ® STAY TUNED!!!

The ideal TSEC maintains the positive benefits of
estrogens on vasomotor symptoms, vulvar/vaginal
atrophy (VVA) and bone without stimulatory effects on
the uterus and breast

The first TSEC in clinical development pairs Bazedoxifene
(BZA) a SERM with a unique endometrial profile with
conjugated estrogens.
–
Goldfischer et al 2008 ISSWSH 2008
Neogyn ® Vulvar Soothing Cream

Cutaneous Lysate of cultured fetal fibroblasts

More than 100 cytokines, growth factors, inflammatory interleukins
IL-1RA, IL-4 and IL-10.

In clinical studies improvement in symptoms of atrophy as well as
for vulvar pain disorders (vulvodynia,lichen sclerosus)

Don’t forget the VUVLA
Treatment Tools






Lifestyle modification
Diet/exercise
Modify medications
Structured sexual tasks
Vibrators/dilators
Sexual
enhancers/accessories






Moisiturizers/lubricants
Behavioral techniques
Mindfulness
Therapy
Relaxation exercises
Acupuncture
49
Pharmacological Agents

Hormones
Tibolone
 Bremelanotide
 Lybrydo/Lybridos
 Femprox
 Flibanserin

– Estradiol
– Testosterone
PD5 inhibitors
Local Treatment
for atrophy
 BZA/CEE
 Osphefene
 Estriol


50
Treatment Paradigm
Alternative
Medicine
Behavior
Modification
Structured
Sexual
Tasks
Treat
Systemic
Illnesses
Sexual
Device
Sexual
Pharmacology
Treatment
Evaluate
medications
Patient
And
Partner
Education
Consultations
Psycho
therapy
Pain
management
51
A Tale of Recovery
Flibanserin
 Novel, non‐hormonal therapy that works on key sexual pathways in the brain
 Over 10,000 women studied in trials to date
 Once daily pill taken at bedtime
 Demonstrated efficacy on measurements of desire, distress and satisfying sexual events (SSEs)
 Well tolerated safety profile. Most common side effects –
dizziness, nausea, fatigue and somnolence
 Flibanserin acquired by Sprout Pharmaceuticals from Boehringer Ingelheim
 Re‐submission to FDA with 14 new trials and a validation study scheduled for 2013
Flibanserin: Structure
Mechanism of ACTION





Serotonin may have a role in HSDD by acting as a sexual satiety signal.
Serotonergic agents (e.g. SSRIs) inhibit desire, arousal, and orgasm.
Flibanserin is a 5‐HT1A receptor agonist which could have pro‐sexual effects.
Stimulating the serotonin 5‐HT2A receptor has been associated with decreased sexual behavior (male rodents).
Flibanserin is a 5‐HT2A antagonist which might have pro‐sexual effects.
Borsini F, Evans K, Jason K, et. al. Pharmacology of flibanserin. CNS Drug Rev. 2002;8(2):117-42.
FLIBANSERIN’S MECHANISM OF ACTION
Flibanserin
5-HT
+
+
---
--
Testosterone
X-
σ receptors
Estrogen
+
+
+
+/-
+
+
+
+
Desire
+
+
--
Prolactin
Oxytocin
Subjective
Excitement
+
+
+
+
Progesterone
Melanocortins
+
Dopamine (DA)
+
+
-X -Flibanserin
-5-HT
X -Norepinephrine (NE)
Orgasm
Adapted from Clayton A, Hamilton D.
Psychiatr Clin N Am. 2010;33:323-338.
Pivotal Study Endpoints
Primary Endpoints
Change from baseline to the final visit period in the monthly frequency of Satisfying Sexual Events (SSEs)
Desire score as measured by eDiary (511.71 and .75) or FSFI‐d (511.147 and .130)
Secondary Endpoints
Female Sexual Function Index (FSFI) desire items (511.71 and .75)
Female Sexual Distress Scale‐ Revised total score and Item 13 (FSDS item 13)
Other Endpoints
Female Sexual Function Index (FSFI) total score
Patient Global Impression (PGI) of improvement
Patient benefit evaluation responder endpoint
eDiary Distress
eDiary Desire day
CHANGE FROM BASELINE FOR SATISFYING SEXUAL EVENTS (SSE) –
STUDY 511.147
**
**
**
**
**
*
* p= 0.033; ** p < 0.0001 for difference between placebo and flibanserin M. Katz, L. DeRogatis, R. Ackerman, P. et. al. Efficacy of flibanserin in women with Hypoactive
Sexual Desire Disorder: results from the BEGONIA trial. J Sex Med (in press).
CHANGE FROM BASELINE FOR FSFI‐
DESIRE DOMAIN (FSFI‐d) –
STUDY 511.147
**
**
**
*
* p = 0.0002; ** p < 0.0001 difference between placebo and flibanserin M. Katz, L. DeRogatis, R. Ackerman, P. et. al. Efficacy of flibanserin in women with Hypoactive
Sexual Desire Disorder: results from the BEGONIA trial. J Sex Med (in press).
Consistent Efficacy: 4 different US Phase III Clinical Trials*
RATE OF FIRST ONSET OF MOST COMMON
SIDE EFFECTS – ALL TRIALS*
16
14
12
% of subjects
10
8
Placebo
Flibanserin 100 mg qhs
6
4
2
0
Week 1
W eek 2
Week 3
W eek 4
*Somnolence, fatigue, or sedation in phase III placebo
controlled trials (%)
Data on file Sprout Pharmaceuticals.
60
Flibanserin
Summary & Conclusions
Consistently demonstrated safety and efficacy Large scale trials in more than 10,000 women
Fourteen new trials and one validation study Only compound for FSD in Phase III clinical study
To be re‐submitted to FDA in 2013
Femprox
RCT Stage III trial of topical alprostadil 0.4% cream with a skin penetration enhancer (DDAIP) an ester of N, N dimethylalanine and dodecanol
 900 mg dose showed statistically significant and clinically relevant improvements in primary and secondary efficacy outcomes

– Primary endpoint: arousal success (yes to #3 of Female Sexual encounter profile )
– Secondary endpoints: FSFI and Global Assessment Questionaire and Sexual Distress Scale.
–
Goldstein et al J Sex Med 2012 9: supl 1 22
Lybrido and Lybridos




Lybrido combines testosterone
with a phosphodiesterase
inhibitor (PDE5 inhibitor)
Lybrido is designed for women
with HSDD and low motivation,
relatively insensitive system for
sexual cues.
Testosterone is believed to
improve desire, whereas the
PDE5 inhibitor works to
increase genital sensitivity.
Administered sublingually, the
time of peak concentration of
the PDE5 inhibitor coincides
with the 4-hour delay in
behavioral effect of the
testosterone.




Lybridos combines
testosterone with a 5HT(1A)
agonist (buspirone).
Designed for women with
HSDD who have sexual
inhibition.
Testosterone increases sexual
motivation and buspirone
counters the sexual inhibition.
Administration of Lybridos is
sublingual and the timeframe
for the pharmacological effects
of the buspirone coincide with
the behavioral window for
testosterone administration.3,4
Bremelanotide




Melanocortin receptor 4 agonist
(MCR4 agonist) for treatment of
HSDD and/or FSAD.
Was initially delivered as a
nasal spray and Phase II adverse effects on BP.
The drug reformulated in a lower
dose for SQ injection.
Phase IIb study is completed in
premenopausal women with
HSDD and or FSAD
Results:
1.25 and 1.75 mg SC was effective in decreasing distress, increasing arousal and desire and increasing the number of SSE with robust dose response and consistency of effect across all key endpoints.
1.Stephen B. Levine, MD;1 Candace Brown, MSN, PharmD;2 Eileen Palace, PhD;3 Steven Fischkoff, MD;4 Christine Schnorrbusch, Phase 2B.,
Bremelanotide Study in Pre and Post Menopausal Women with Female Sexual Arousal Disorder BS4. Poster Presentation.
ACOG Annual Meeting. Annual Clinical Meeting. New Orleans LA. Poster 56. May 2008.
Do you have any questions concerning infertility and
parenthood after cancer?
Many of your cancer patients are
at risk for infertility due to
treatment……..
A patient seen in General Gynecology recently
said….. I was never given any information
concerning infertility and sexuality at any
point in my treatment, I think this is
malpractice.
Parenthood Options after Cancer

1)Natural Conception

2) Assisted Conception

Donor eggs

Donor sperm

Donor embryos

Third Party Reproduction
– Surrogacy
 Gestational versus Traditional
- Adoption
- Infant
- National and International
- Cancer friendly agencies
- Embryo

Child free living

Oocyte Cryopreservation
– No longer considered experiment
– Improved outcomes with vitrification
 Rapid freezing with liquid nitrogen and the oocyte is
solidified into a glass like structure
 No evidence of increased neonatal risks
 Implantation Rates 17%-41%
 Clinical Pregnancy Rates 36-65%
– Cobo et al 2010; Rienzi 2010

Embryo Cryopreservation
– Often considered gold standard
– Mature oocytes harvested
– ASRM and SART Guidelines

Invitro Oocyte Maturation
– Experimental
– Attractive to those who need urgent chemotherapy
– Lower implant rates, clinical pregnancy rates and live
birth rates versus IVF

Ovarian Tissue Cryopreservation
–
–
–
–
Prepubscent girls ( 6000 cancers girls aged:
Orthotopic reimplantation in the pelvic cavity
Heterotopic reimplantation outside
> 24 live births orthotopic /505 naturally conceived
70

Surgical Techniques
– Ovarian shielding
– Ovarian transposition
 Variable success
– 16-90% reduction
 Rodriguez et al 2012

Fertility Sparing Surgery
– Simple Oophorectomy for Borderline
– Radical trachelectomy
 212 case study, 66% achieved pregnancy, of those who were
pregnancy, 45% reached full term, 255 delivered between 28-36
weeks, and 5% delivered before 28 weeks
– Speiser et al 2011

Early Stage Endometrial Cancer
– 45 studies – 391 participants
– Complex atypical hyperplasia or Grade 1 adenocarcinoma treated with
progestin
– CAH response (66%)- repro outcome 41.2%
– Grade 1 response (48%)-repro outcome 34.8%
– 117 live births
 Gunderson et al 2012

Medical Suppression
– GNRH agonists prior to chemo
– Debatable efficacy
72
Ovarian Suppression
Embryo Freezing
Ovarian Shielding
Egg (Oocyte) Freezing
Embryo Freezing
Egg (Oocyte) Freezing
Ovarian Tissue Freezing
Ovarian Tissue Freezing
Donor Embryos
Ovarian Transposition
Donor Eggs
Radical Trachelectomy
Surrogacy
Adoption
Natural Conception
Using Frozen Embryos
Using Frozen Eggs
Using Frozen Ovarian
Tissue
Cycle of Cancer
• Early Diagnosis
• Less Aggressive
Treatment
• Same Outcome
• Pregnancy after
Diagnosis
• Pregnancy
During Diagnosis
• Preservation of
hormones
• Limited organ
Destruction
Cancer
Survivorship
Sexuality
Pregnancy
Fertility
• Preservation of
gonadal function
if feasible
74
Attention to Issues!
There are Needs to be Addressed!
Of 635 Japanese breast surgeons, 32% were consulted about sexual issues.1
“Although majority recognized importance of patients’ sexuality-related concerns, they did
not necessarily think that surgeons had a professional responsibility to deal with them.”
•Of 35 specialists in gynecologic/women’s cancers, 20% reported they had the time to discuss sexual
issues with their patients.2
“With little time for sensitive discussions on sexuality, fertility and intimacy issues, and
perceived lack of support once a problem has been identified, it is understandable why
physicians do not routinely discuss such issues with their patients.”
1. Takahasmi, et al. JCO 2006; 24:5763-68.
2. Wiggins, et al. J Psychosoc Onc 2007; 25:61-70.
The Business of
Survivorship Medicine
Healing is an Art
Medicine is Science
Healthcare is Business
Preceptorships and consultations are
available for you and your institution
Components
of
Cancer Care
Clinical
Excellence
Patient
Education
And
Support
Medical
Training
and
Education
Research
Conclusions
 ASK…
You cannot treat a problem if you do not know
that one exists… Menopausal issue, Sexuality and
other quality of life concerns are paramount.
 Know your own personal comfort zone and
level of expertise
 Get help, get trained and get formalized
 Refer when appropriate
Thank you for your kind attention
80