Fertility In Cancer Patients Treatment

Fertility In Cancer Patients

22-06 2012

Email: [email protected]

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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

Eligible for proven fertility preservation method

Male: Female:sperm cryopreservation embryo cryopreservation

conservative gynecologic surgeryoophoropexy

••

• Patient at risk for treatment- induced infertility • Patient interested in fertility preservation options

Refer to specialist with expertise in fertility preservation methods

Investigational fertilitypreservation technique*

•Cryopreservation of testicular or ovarian tissue

•Cryopreservation of oocytes• Ovarian suppression*Clinical trial participation encouraged




• Assessment of risk for infertility•Communication with patient


Refer to specialist with expertise in fertility preservation




www.asco.org (Lee et al., J Clin Onc; 2006)




American Society of Clinical Oncology Recommendations on Fertility Preservation in People

Treated for Cancer




••


Refer to specialist with expertise in fertility preservation methods







• Assessment of risk for infertility•Communication with patient





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




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

(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)

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)




Effects of Newer Treatments: Paclitaxel, Dose Density, and Trastuzumab on CRA

(Abusief et al., Breast Cancer Res Treat 2006)

• 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)




Effects of Paclitaxel, Dose Density, andTrastuzumab on CRA

(Abusief et al., Breast Cancer Res Treat 2006)

Variable Odds ratio*

95% CI p-value

Chemotherapy AC-T

AC

1.27 0.70-2.32 0.61

1.00 Referent --

Regimen DD

q3wk

1.30 0.66-2.57 0.56

1.00 Referent --

Trastuzumab AC-TH

AC

0.49 0.21-1.17 0.11

1.00 Referent --

Tamoxifen yes

no

2.14 1.16-3.97 0.02

1.00 Referent --

Age at diagnosis 1.39 1.30-1.49 <0.0001



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-valueAntral 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

Inhibin B (InB) 24.3 46.6 0.02Estradiol (E2) 126.0 38.8 0.14

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)



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 ovaryLow level recruitment of primordial follicles

Cytotoxic chemotherapy

Oocyte toxicity

Decreased estradiolIncreased FSH

Increased follicular recruitment

More oocytes at risk



Ovarian Sensitivity to Chemotherapy

Normal premenopausal ovaryLow level recruitment of primordial follicles

Cytotoxic chemotherapy

Oocyte toxicity

Decreased estradiolIncreased FSH

Increased follicular recruitment

More oocytes at risk

GnRHa



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 mensesTriptorelin 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 control6 months: 44% vs 60%, 12 months 83% vs 79% 18 months 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 Control group

35/39 resumed menses 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, IIIAER-/PR- Breast Cancer Under age 50

Randomizationn=416

Standard cyclophosphamideContaining (neo)adjuvant chemotherapy

Standard cyclophosphamideContaining (neo)adjuvant chemotherapyPlus monthly goserelin

Stratification: Age Chemotherapy

CALGB 40401ECOG S0230 IBCSG 34-05



IVF/Embryo CryoIVF/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)

VariableTam-IVF

(a)TamFSH-IVF

(b)Letrozole-IVF

(c)a v b a v c

b v c

Age, years 36.6 ± 1.6 38.3 ± 1.9 38.5 ± 1 NS NS NS

Baseline FSH, mU/mL

9.4 ± 1.5 9.4 ± 1.5 6.2 ± 1.1 NS NS NS

PeakE2, pg/mL 419 ± 39 1,182 ± 271 380 ± 57 < .0

5> .05 < .0

5Total follicles, No. 2 ± 0.3 6 ± 1 7.8 ± 0.9 < .0

1< .00

1> .0

5Follicle > 17 mm, No.

1.2 ± 0.1 2.6 ± 0.4 3.2 ± 0.4 < .05

< .001

> .05

Total oocytes, No. 1.7 ± 0.3 6.9 ± 1.1 12.3 ± 2.5 < .05

< .001

> .05

Mature oocytes, No.

1.5 ± 0.3 5.1 ± 1.1 8.5 ± 1.6 < .05

< .001

> .05

Total embryos, No. 1.3 ± 0.2 3.8 ± 0.8 5.3 ± 0.8 < .05

< .001

> .05



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)

(Oktay K, et al, JAMA, 2001;286:1490-3)

- No need for abdominal surgery

- Easy monitoring of follicular dvelopment

- Easy removal if necessary



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



Health & Medicine

Fertility In Cancer Patients Treatment