Fertility In Cancer Patients Treatment

Email: enquiry@medicyatra.com

Fertility In Cancer Patients

22-06 2012

Copyright @ Forever Medic


The speaker declares that specific brand-name medications and/or
off-label, non-FDA-approved uses are discussed in the lecture.

• Letrozole or tamoxifen for ovarian stimulation

• 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 Investigational fertility
preservation technique*
Male: Female: • ryopreservation of
C
spermcryopreservation embryocryopreservation testicular or ovarian tissue
conservative gynecologic surgery • ryopreservation ofoocytes
C
oophoropexy • Ovarian suppression
*Clinical trial participation
encouraged
www.asco.org (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; cis-
platin
– 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 sperm-
intracytoplasmic 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
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Pvt. Ltd


Risk of amenorrhea is related to
age and treatment

Copyright @ Forever(Goodwin et al., J Clin Oncol 1999)
Medic


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
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 23-47 80-89
TAC x 6 51
AC x 4, T x 4 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)
Copyright @ Foreveret al., Breast Cancer Res Treat 2006)
(Abusief Medic

Effects of Paclitaxel, Dose Density, and
Trastuzumab on CRA
Variable Odds 95% CI p-value
ratio*
Chemotherapy AC-T 1.27 0.70-2.32 0.61
AC 1.00 Referent --
Regimen DD 1.30 0.66-2.57 0.56
q3wk 1.00 Referent --
Trastuzumab AC-TH 0.49 0.21-1.17 0.11
AC 1.00 Referent --
Tamoxifen yes 2.14 1.16-3.97 0.02
no 1.00 Referent --
Age at diagnosis 1.39 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@ Forever Medicand Sterility, In Press)
Copyright al., Fertility


Ovarian Reserve in Survivors
Compared to Controls
Survivors (n=20) Controls (n=20) P-value
Antral Follicle 5.2 11.3 0.0042
Count (AFC)
Anti-Mullerian 0.57 1.77 0.0004
Hormone
(AMH)
Follicle 11.56 8.04 0.02
Stimulating
Hormone
Inhibin B (InB) 24.3 46.6 0.02
Estradiol (E2) 126.0 38.8 0.14
Prospective studies are needed to determine the predictive value of these
tests for pregnancy after Copyright @ Forever Medic
chemotherapy
(Ruddy et al., Fertility and Sterility, In Press)

Age of Menopause Among Women Who Email: enquiry@medicyatra.com

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)


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:

triptorelin vs control
6 months: 44% vs 60%,
12 months 83% vs 79%
(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 Control group
35/39 resumed menses 13/39 resumed menses

27 resumed spontaneous ovulation Medic in control group
Copyright @ Forever vs. 10
(Badawy et al., Fertility and Sterility, in Press)


Ongoing Study: SWOG 0230
“POEMS”II, IIIA
Premenopausal Stage I,
ER-/PR- Breast Cancer Under age 50

CALGB 40401 Randomization Stratification:
ECOG S0230 n=416 Age
IBCSG 34-05 Chemotherapy

Standard cyclophosphamide Standard cyclophosphamide
Containing (neo)adjuvant Containing (neo)adjuvant
chemotherapy 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 hormone-
sensitive cancer

• Natural cycle IVF has low yield
(Oktay et al, JCO, 2005; Partridge & Winer, JCO 2005)

Comparison of Cycle Characteristics and Embryo Yield Among Tam-
IVF (12 patients) TamFSH-IVF (seven patients), and Letrozole-IVF
(11 patients) Patients (Oktay et al, JCO, 2005)

Tam-IVF TamFSH-IVF Letrozole-IVF av bv
Variable (a) (b) (c) b avc c
Age, years 36.6 ± 1.6 38.3 ± 1.9 38.5 ± 1 NS NS NS
Baseline FSH, mU/ 9.4 ± 1.5 9.4 ± 1.5 6.2 ± 1.1 NS NS NS
mL
PeakE2, pg/mL 419 ± 39 1,182 ± 271 380 ± 57 <. > .05 <.
05 05
Total follicles, No. 2 ± 0.3 6±1 7.8 ± 0.9 <. <. >.
01 001 05
Follicle > 17 mm, 1.2 ± 0.1 2.6 ± 0.4 3.2 ± 0.4 <. <. >.
No. 05 001 05
Total oocytes, No. 1.7 ± 0.3 6.9 ± 1.1 12.3 ± 2.5 <. <. >.
05 001 05
Mature oocytes, 1.5 ± 0.3 5.1 ± 1.1 8.5 ± 1.6 <. <. >.
No. 05 001 05
Total embryos, No. 1.3 ± 0.2
Copyright @ Forever Medic ± 0.8
3.8 ± 0.8 5.3 <. <. >.
05 001 05

Tamoxifen or aromataseEmail: enquiry@medicyatra.com
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



• 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
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• 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)@ Forever Medic
Copyright


• 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




• 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
Copyright @ Forever Medic al, Nat Med 1997;3:1228-32)
(Perez G, et


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


Fertility In Cancer Patients Treatment

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