Fertility In Cancer Patients
Ann H. Partridge, M.D., M.P.H.,
Dana-Farber Cancer Institute,
Harvard Medical School
Boston, MA
April 21, 2009
The speaker declares no conflict of interest
with the topic presented in the lecture.
The speaker declares that specific brand-name medications and/or
off-label, non-FDA-approved uses are discussed in the lecture.
1) Letrozole or tamoxifen for ovarian stimulation
2) I will attempt to avoid bias by discussing the published
research in this area only and limitations of it
Cancer and Future Fertility
• Patients of reproductive age often find prospect of
infertility one of the most difficult components of
their disease and treatment
• Oncology providers focus on survival
• Can be difficult to assess who is interested in
future fertility
Fertility after cancer poses
challenging medical issues and
emotional consequences
• Surveys of cancer survivors have identified
an increased risk of emotional distress in
those who become infertile because of their
treatment
• Long-term quality of life is affected by
unresolved grief and depression
Fertility Concerns Common
• 57% of women age 40 and younger at
diagnosis of breast cancer recalled concerns
about fertility
• 29% reported that infertility concerns
influenced treatment decisions
(Partridge et al., JCO 2004)
Providers May Neglect to Discuss
Fertility
• Only 68% of women age 50 or younger at
diagnosis of breast cancer recalled
physician discussion of early menopause
• 34% of women recalled discussion of
infertility risk
(Duffy et al., JCO 2005)
American Society of Clinical Oncology
Recommendations on Fertility Preservation in People
Treated for Cancer
• Assessment of risk for infertility
• Communication with patient
•Patient at risk for treatment -induced infertility
•Patient interested in fertility preservation options
Refer to specialist with expertise in fertility preservation methods
Eligible for proven fertility preservation method
Male:
sperm cryopreservation
www.asco.org
Female:
embryo cryopreservation
conservative gynecologic surgery
oophoropexy
Investigational fertility
preservation technique*
•Cryopreservation of
testicular or ovarian tissue
•Cryopreservation of oocytes
•Ovarian suppression
*Clinical trial participation
encouraged
(Lee et al., J Clin Onc; 2006)
American Society of Clinical Oncology
Recommendations on Fertility Preservation in People
Treated for Cancer
• Assessment of risk for infertility
• Communication with patient
•Patient at risk for treatment -induced infertility
•Patient interested in fertility preservation options
Refer to specialist with expertise in fertility preservation methods
Eligible for proven fertility preservation method
Male:
sperm cryopreservation
www.asco.org
Female:
embryo cryopreservation
conservative gynecologic surgery
oophoropexy
Investigational fertility
preservation technique*
•Cryopreservation of
testicular or ovarian tissue
•Cryopreservation of oocytes
•Ovarian suppression
*Clinical trial participation
encouraged
(Lee et al., J Clin Onc; 2006)
Risk of Infertility in Men
• Male infertility can result from:
–
–
–
–
Disease
Anatomic problems
Primary or secondary hormonal insufficiency
Damage or depletion of the germinal stem cells
• The effects of chemotherapy or radiotherapy
include compromised sperm number, motility,
morphology, and DNA integrity
• Azospermia typically surrogate for infertility
All Cancer Treatments Are not Equal
• Alkylating agents appear to be most gonadotoxic; cisplatin
– cumulative dose important
• Radiation is very damaging:
– >=2.5 Gy to testis area results in prolonged azospermia
– External beam to field that includes ovaries
Men Have Sperm Banking!
• Sperm cryopreservation
– involves freezing and banking sperm collected through
masturbation, rectal electroejacualtion, testicular
aspiration or post-masturbation urine
– If patient sick or with certain cancers (e.g., testicular
cancer and Hodgkins)- sperm quality may be poor prior
to treatment
– Many patients have to start chemotherapy soon enough
to limit the number of ejaculates
– Still reasonable to make every effort to bank spermintracytoplasmic sperm injection (ICSI) allows the
successful freezing and future use of small sample
Other “Options” for Men
• Hormonal Gonadoprotection (e.g. GnRH analogs)
– The efficacy of gonadoprotection through hormonal
manipulations has only been evaluated in very small
studies in male cancer patients
– Evidence suggests hormonal therapy in men is not
successful in preserving fertility when highly sterilizing
chemotherapy is given
• Potential future options (not tested in humans yet)
– Testicular tissue cryopreservation or reimplantation
– Testis grafting with maturation in SCID mice
Risk of Infertility in Women
• Female fertility can be compromised by
any treatment that:
– Decreases the number of primordial
follicles
– Affects hormonal balance
– Interferes with the functioning of the
ovaries, fallopian tubes, uterus or cervix.
Natural Decline of Oocytes with Age
(Lobo, NEJM 2005)
Chemotherapy-related Amenorrhea
• CRA may be permanent or temporary
• CRA is an imperfect surrogate for menopause
and infertility
• Accurate assessment of ovarian function has
implications for
– family planning, contraception
– treatment in hormone sensitive tumors
– other survivorship concerns
Risk of amenorrhea is related to
age and treatment
(Goodwin et al., J Clin Oncol 1999)
Ovarian Failure Risk with Cancer Treatments
• High risk:
– Total body irradiation, high dose
cyclophosphamide, chlorambucil, melphalan,
busulfan, nitrogen mustard, procarbazine
• Intermediate risk:
– Cisplatin, carboplatin, doxorubicin
• Low or no risk:
– Methotrexate, 5-fluorouracil, vincristine,
vinblastine, bleomycin, actinomycin
• Unknown risk:
– Taxanes, oxaliplatin, irinotecan, monoclonal
antibodies, Tyrosine kinase inhibitors
(Sonmezer and Oktay, Hum Reprod Update, 2004)
Risk of Chemotherapy-Related Amenorrhea
with Common Breast Cancer Regimens
% women with amenorrhea
Treatment
Age <30
Age 30-40
Age>40
None
~0
<5
20-25
AC x 4
--
13
57-63
CMF x 6
19
31-38
76-96
CAF/CEF x 6
TAC x 6
AC x 4, T x 4
23-47
80-89
51
38 (15% age <40)
(Goodwin et al., JCO 1999; Burstein, H. J. et al. NEJM 2000; Nabholtz et al., ASCO 2002;
Parulekar et al., JCO 2005; Fornier et al., Cancer 2005; Petrek et al, JCO 2006)
Effects of Newer Treatments: Paclitaxel,
Dose Density, and Trastuzumab on CRA
• Premenopausal women who received adjuvant
chemotherapy
• N=451
• Age at diagnosis, mean:
42 years (range 25-55)
• Follow-up, mean:
34 months (range 6-93)
(Abusief et al., Breast Cancer Res Treat 2006)
Effects of Paclitaxel, Dose Density, and
Trastuzumab on CRA
Variable
Chemotherapy AC-T
AC
Regimen
DD
q3wk
Trastuzumab
AC-TH
AC
Tamoxifen
Age at diagnosis
yes
no
Odds
ratio*
95% CI
p-value
1.27
1.00
1.30
1.00
0.70-2.32
Referent
0.66-2.57
Referent
0.61
-0.56
--
0.49
1.00
2.14
0.21-1.17
Referent
1.16-3.97
0.11
-0.02
1.00
1.39
Referent
1.30-1.49
-<0.0001
(Abusief et al., Breast Cancer Res Treat 2006)
Issues for Women Who
Remain Premenopausal
• Will a woman be less fertile, even if she
continues to menstruate?
• Will a woman go through menopause
earlier (“delayed, premature menopause”)
Ovarian Reserve in Women Who Remain
Premenopausal After Chemotherapy For
Early Stage Breast Cancer
• 20 breast cancer survivors who remained
premenopausal after chemotherapy
• 20 age, gravidity-matched controls
• Day 2-4 of cycle, measured ovarian reserve
(Ruddy et al., Fertility and Sterility, In Press)
Ovarian Reserve in Survivors
Compared to Controls
Survivors (n=20) Controls (n=20) P-value
Antral Follicle
Count (AFC)
5.2
11.3
0.0042
Anti-Mullerian
Hormone
(AMH)
0.57
1.77
0.0004
Follicle
Stimulating
Hormone
11.56
8.04
0.02
46.6
38.8
0.02
0.14
Inhibin B (InB) 24.3
Estradiol (E2)
126.0
Prospective studies are needed to determine the predictive value of these
tests for pregnancy after chemotherapy
(Ruddy et al., Fertility and Sterility, In Press)
Age of Menopause Among Women Who
Remain Premenopausal Following
Treatment for Early Breast Cancer
• Long-term data from the International Breast Cancer
Study Group (IBCSG) Trials V and VI
• Included women who had reported menses in months
12-24 after diagnosis
• N= 767 women
– 540 women randomized to PeCT (1 cycle CMF) or No CT
– 227 randomized to CMF x 6 or 7
(Partridge et al, Eur J Ca 2007)
Age at Menopause by Age at
Treatment and Treatment Group
Not clear that these data apply to women treated with
more modern regimens
(Partridge et al, Eur J Ca 2007)
Effects of Endocrine Therapy
• Adjuvant endocrine therapy for breast
cancer (tamoxifen or ovarian suppression)
does not appear to cause permanent
amenorrhea or infertility
• BUT… endocrine therapy usually entails
years of treatment when pregnancy
contraindicated, and aging during that time
compromises fertility
Fertility Preservation Considerations
for Women with Cancer
The obvious: weigh the “necessity” of
systemic therapy
Options for Fertility Preservation
in Women- Anatomic Fixes
• Pelvic shielding during radiation
• Ovarian Transposition
– surgical repositioning of ovaries away from the radiation field
• Conservative Gynecologic Surgery (Radical
Trachelectomy)
– surgical removal of the cervix while preserving the uterus
Other Options for Preserving
Fertility for Women with Cancer
•
Ovarian suppression (LHRH agonists) during treatment
•
Cryopreservation of embryos
•
Cryopreservation of ovarian tissue
•
Cryopreservation of oocytes
•
Pharmaceutical protection with anti-apoptotic agents (eg.
Sphingosine-1-phosphate)
•
Oocyte donation and gestational surrogacy
Ovarian Sensitivity to Chemotherapy
Normal premenopausal ovary
Low level recruitment of primordial follicles
Cytotoxic chemotherapy
Oocyte toxicity
Decreased estradiol
Increased FSH
Increased follicular recruitment
More oocytes at risk
Ovarian Sensitivity to Chemotherapy
Normal premenopausal ovary
Low level recruitment of primordial follicles
Cytotoxic chemotherapy
Oocyte toxicity
Decreased estradiol
Increased FSH
GnRHa
Increased follicular recruitment
More oocytes at risk
Summary of Phase II Trials
and Case Series
• GnRH agonist coadministration with chemotherapy is
associated with high rates of resumption of menses
after chemotherapy
• Successful pregnancies have occurred following
chemotherapy with GnRHa
• Lack of randomized data
– Uncontrolled studies tended to have young patient
populations
A randomized trial using the GnRH agonist
(triptorelin) during chemotherapy
•N=49 (12-month f/u on 42 patients, and 18 month on 34 patients)
•Median age 39 years, range 21–43
•Median time to return of menses
Triptorelin arm:
6.1 months (range 1–19)
Control arm:
4.7 months (range 0–22) (p=0.79)
•Menstruation resumed post chemotherapy in the respective
groups as follows:
6 months:
12 months
18 months
triptorelin vs control
44% vs 60%,
83% vs 79%
88% vs 84%
(R. Ismail-Khan et al. ASCO 2008)
Gonadotropin-releasing hormone agonists for
prevention of chemotherapy-induced ovarian
damage: prospective randomized study
•N=80
•Age range 18-40
•Menstruation resumed post chemotherapy (3-8 months)
in the respective groups as follows:
GnRHa group
35/39 resumed menses
Control group
13/39 resumed menses
27 resumed spontaneous ovulation vs. 10 in control group
(Badawy et al., Fertility and Sterility, in Press)
Ongoing Study: SWOG 0230
“POEMS”
Premenopausal Stage I, II, IIIA
ER-/PR- Breast Cancer Under age 50
CALGB 40401
ECOG S0230
IBCSG 34-05
Randomization
n=416
Standard cyclophosphamide
Containing (neo)adjuvant
chemotherapy
Stratification:
Age
Chemotherapy
Standard cyclophosphamide
Containing (neo)adjuvant
chemotherapy
Plus monthly goserelin
IVF/Embryo Cryo
Cryopreservation of Embryos
• Standardly available: 20-30% pregnancy rate per transfer
of 2-3 embryos
• Requires medical stability, time, and partner/sperm,
adequate ovarian reserve
• Expensive, ethically problematic if patient dies
• Requires ovarian stimulation prior to systemic breast
cancer treatment- concerning in patients with hormonesensitive cancer
• Natural cycle IVF has low yield
(Oktay et al, JCO, 2005; Partridge & Winer, JCO 2005)
Comparison of Cycle Characteristics and Embryo Yield Among TamIVF (12 patients) TamFSH-IVF (seven patients), and Letrozole-IVF
(11 patients) Patients (Oktay et al, JCO, 2005)
Tam-IVF
(a)
TamFSH-IVF
(b)
Letrozole-IVF
(c)
av
b
avc
bv
c
36.6 ± 1.6
9.4 ± 1.5
38.3 ± 1.9
9.4 ± 1.5
38.5 ± 1
6.2 ± 1.1
NS
NS
NS
NS
NS
NS
419 ± 39
1,182 ± 271
380 ± 57
> .05
Total follicles, No.
2 ± 0.3
6±1
7.8 ± 0.9
Follicle > 17 mm,
No.
Total oocytes, No.
1.2 ± 0.1
2.6 ± 0.4
3.2 ± 0.4
1.7 ± 0.3
6.9 ± 1.1
12.3 ± 2.5
Mature oocytes,
No.
Total embryos, No.
1.5 ± 0.3
5.1 ± 1.1
8.5 ± 1.6
1.3 ± 0.2
3.8 ± 0.8
5.3 ± 0.8
<
.05
<
.01
<
.05
<
.05
<
.05
<
.05
<
.05
>
.05
>
.05
>
.05
>
.05
>
.05
Variable
Age, years
Baseline FSH,
mU/mL
PeakE2, pg/mL
<
.001
<
.001
<
.001
<
.001
<
.001
Tamoxifen or aromatase inhibitor
stimulation protocols for IVF
• Increase embryo yield, lower E2 levels
with Letrozole, blockage of receptors
with Tamoxifen
– Unclear if mitigates potential risk
• Preliminary safety data available
• Number of babies resulting from such
strategies that would have not been born
otherwise remains unclear
(Oktay et al, JCO 2005; Partridge & Winer, JCO 2005; Oktay et al., JCO 2008)
Oocyte Cryopreservation
• Requires time and stimulation prior to treatment
• No requirement for sperm, less ethical concern
• Experimental- approximately 2% pregnancy rate
per thawed oocyte
Oocyte Cryopreservation
• Technically difficult
• MII oocytes: extremely sensitive to
temperature changes
• Crystal formation can cause
cytoplasmic damage
• Cryoprotectants
– depolymerize meiotic spindle
– cause aneuploidy
• Hardening of zona pellucida
– barrier to fertilization
Cryopreservation of
Ovarian Tissue
• Requires surgical procedure to remove ovary or
piece of ovary
• May increase risk of infertility in low risk
situation
• Potential for reintroduction of malignant cells at
reimplantation
• Highly experimental- few babies born to date
Ovarian Cryopreservation
• Ovarian cortex is frozen in thin slices
• Primordial follicles are less sensitive to
cryodamage because of
– low metabolic rate
– absence of zona pellucida
– high surface-volume ratio
Ovarian Cryopreservation
• Resumption of endocrine function has been
reported after orthotopic and heterotopic
transplantation
• Embryo was generated from oocytes
retrieved from sc transplanted ovarian tissue
• Two live births reported after orthotopic
transplantation of frozen-banked ovarian
tissue in lymphoma survivors
Ovarian Cryopreservation
• Heterotopic tranplantation technique:
– Optimal site unknown
– Most have been to arm or forearm (or suprapubic
area)
- No need for abdominal surgery
- Easy monitoring of follicular dvelopment
- Easy removal if necessary
(Oktay K, et al, JAMA, 2001;286:1490-3)
Ovarian Cryopreservation
• Xenotransplantation:
– Has been shown feasible in several animal
models into immunodeficient mice
– Concerns:
• Retroviruses, prions
• Abnormal oocyte development
• Abnormal chromatin patterns
– Benefits:
• Easier to repeat grafting if needed
• Easier access for IVF
Ovarian Cryopreservation
• Transplanting complete, intact ovary:
– Has been demonstrated in rats and sheep
– Recently demonstrated in human, but high risk
for ischemia-reperfusion injury
– No pregnancy demonstrated
(Bedaiwy M, et al, Hum Reprod, 2006)
Sphingosine-1-Phosphate
• Apoptotic inhibitor
– blocks pro-apoptotic messenger:
ceramide (early messenger that signals
apoptosis in response to stress)
– shown to be beneficial in mice when
injected into ovarian bursa sac prior to
radiation
– has not been evaluated in humans
(Perez G, et al, Nat Med 1997;3:1228-32)
Safety and Timing of Pregnancy
after Cancer
• Conventional wisdom is to wait until patient gets
through the period of highest risk recurrence
– Receive optimal therapy (endocrine therapy may be
prolonged)
• No data to suggest harm in pregnancy sooner
• No evidence for increased risk of disease recurrence
associated with most fertility preservation methods and
pregnancy- little data!
• Aside from hereditary genetic syndromes and in-utero
exposure to chemotherapy, no evidence for increased
risk of cancer or abnormality in progeny
Conclusions: Fertility Concerns in
Cancer Survivors
• Very complex and difficult issues
• Limited available data
• Patient preferences critical in some
settings
• Managing expectations often necessary
Conclusions: Fertility Concerns in
Cancer Survivors (cont.)
• Address fertility issues up front; include
fertility concerns in the risk-benefit
analysis
– Refer to fertility specialists early
• In the event of pregnancy, consider “high
risk” obstetrics management
Resources
• ASCO www.asco.org
• Fertile Hope www.fertilehope.org
• Lance Armstrong Foundation
www.livestrong.org