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- 1. Fertility Preservation for Breast Oncology Patients Patricia McShane MD University of Colorado Hospital Reproductive Endocrinology and Infertility
- 9. Â
- 10. Female fertility with age from Carcio and Rosenthal
- 15. Relative Infertility Risks by Cancer Therapy Note: Risk depends on dose, duration of treatment, and age of patient. Also, chemotherapy and radiation may contribute individuals risks, and a combination may be additive. Risk Adjuvant Therapies High Risk Whole abdominal or pelvic radiation doses >6 Gy in adult women Whole abdominal or pelvic radiation doses >10 Gy in postpubertal girls Total body irradiation (TBI) Cranial/brain irradiation >40 Gy CMF, CEF, or CAF x 6 cycles in women >40 years Cyclophosphamide 5 g/m2 in women >40 years Cyclophosphamide 7.5 g/m2 in girls <20 years Alkylating chemotherapy (e.g., cyclophosphamide, busulfan, melaphan) conditioning for transplant Any alkylating agent (e.g., cyclophosphamide, ifosfamide, busulfan, BCNU [carmustine], CCNU [lomustine]) + TBI or pelvic radiation Protocols containing procarbazine: MOPP, MVPP, COPP, ChlVPP, ChlVPP/EVA, BEACOPP, MOPP/ABVD, COPP/ ABVD Moderate Risk Whole abdomina or pelvic radiation 5 to <10 Gy in postpubertal girls Spinal radiation doses >25 Gy CMF, CEF, or CAF x 6 cycles in women 30â39 years AC in women >40 years Low Risk AC in women 30â39 years CMF, CEF, or CAF x 6 cycles in women <30 years Nonalkylating chemotherapy: ABVD, CHOP, COP AC No Risk Radioactive iodine MF Vincristine Unknown Risk Paclitaxel, docetaxel (taxanes used in AC protocols) Oxaliplatin Irinotecan Bevacizumab Cetuximab Trastuzumab Erlotinib Imatinib
- 25. Basic Steps for Freezing Embryos and Oocytes Menstruation Stimulate Ovaries Oocyte Retrieval Inseminate oocytes Freeze oocytes Freeze Embryos Embryo Cryopreservation Oocyte Vitrification
- 28. IVF, Embryo Implantation Rate SART 2009
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- 34. Fertility Preservation Options for Breast Oncology Patients: Comparison Chart GnRH Suppression Ovarian Transposition Embryo Cyropreservation Oocyte Vitrification Cryopreservation of ovarian cortical tissue Aspiration of immature oocytes? Established/ Experimental Established Established Established (?) Experimental, IRB protocol required Experimental, IRB protocol required Success for fertility preservation Moderate Successful for targeted radiation Successful, if sufficient oocytes retrieved Successful, if sufficient oocytes retrieved Only few live births so far Very experimental Time Delay No No Yes, 2-6 weeks Yes, 2-6 weeks No No Advantages Outpatient procedure Does not require partner; may be preferred by individuals with objections to embryo freezing No time delay No time delay Dis-advantages Not suitable if risk of ovarian metastases; experiem Very experimental; must be conducted under IRB protocol
- 37. Discussing Fertility Preservation with your patients
- 42. Ethical and legal considerations
- 43. Having Children after Cancer
- 44. Using Frozen Embryos and Oocytes Asses uterus and hormone levels Thaw embryos or oocytes Implant Embryos Inseminate Oocytes: IVF or ICSI Implant Embryos
- 53. Â
Editor's Notes
- 1) Women who undergo chemotherapy or radiation during their reproductive years face a 40-80% chance of losing their fertility, and male cancer patients have a 30-75% risk. The actual risk depends on patient age and quantity and type of cancer therapy. ( Quinn 2007) 2) **Include statistic from study about survivors not remembering discussing risk of infertility and fertility preservation before therapy
- 1) Of the 1.5 million people diagnosed with cancer in 2010 in the United States, about 10% are younger than 45 years old. Jensen 2007 In the specific case of invasive breast cancer, 5-7% of women diagnosed are under 40 years old, most between the ages of 30 and 40. Kim 2011 Additional Notes: Kim article: â Less than 10% of women who develop invasive breast cancer under age 40 have children postdiagnosis (3-5), despite survey results suggesting about half desire to do so (6) and observational studies that do not indicate an increased risk of relapse or death for women who become pregnant after a breast cancer diagnosis (7-9). Receipt of cytotoxic chemotherapy is a major factor in the low rate of live births after a diagnosis of breast cancer.â Woodruff: âBreast cancer is the most prevalent cancer to affect women. Although the likelihood of developing this cancer increases with age, about 1 in 3 women are premenopausal at the time of diagnosis.â â Fortunately, cancer related mortality for breast cancer has decreased dramatically such that with modern management, most women with this diagnosis can expect to live long, productive lives.â
- 1) Studies indicate an information deficit regarding the current technologies and best practice guidelines as well as patient eligibility, the cost of treatment, timing with cancer therapy, and the oncologistâs role in fertility preservation discussion.
- McShane script: Prior to consideration of fertility preservation, it is useful to review the basic requirements for conception. These include viable sperm, reasonable oocyte (egg) quality, and a normal endometrial cavity which can gestate the pregnancy. The normal semen analysis per WHO standards is 20 million/cc with a volume of 1-5 ccâs, 50% or greater motility, and 40% normal forms. However, it is certainly possible to achieve pregnancy with lesser sperm quality although assisted reproduction may be required.
- McShane script: One of the least well recognized facts of fertility is the decline in female fertility with age. The monthly chance of conception may be close to 30% in non-contracepting couple where the female ages in the early 20âs. This drops to level of < 5% per month in women age 40 and over and is almost zero by age 45 with rare exceptions. This may vary from woman to woman depending on lifestyle and genetics. Presence of normal monthly menses does not necessarily reflect the impairment of ovarian reserve which has occurred with normal aging. In fact most women in their forties will have fairly regular menses but extremely low monthly fecundability, or the chance of pregnancy.
- 1) This number will already be significantly lower by puberty, at approximately 300,000 primordial follicles. By menopause, only around 1000 germ cells will remain.
- McShane script: Certainly cancer chemotherapy may impair ovarian reserve even after one course. So it is recommended that indicators of ovarian reserve be tested prior to active attempts at fertility preservation for cancer patients. Anti-mullerian hormone levels can be performed anytime during a womanâs cycle. Follicle stimulation hormone and estradiol levels on day two to four of the cycle as well as antral follicle count may also be informative. A good option is to initiate the basic testing while awaiting a referral to a reproductive endocrinologist for interpretation of the results and consideration of various fertility preservation options. Additional Notes: â Since there is significant variation in fertility with age, the clinical assessment of a womanâs âovarian reserveâ typically involves not just age but also changes in the release of pituitary follicle-stimulating hormone FSH and corresponding production of estradiol and inhibin B by granulosa cells with ovarian follicles.â (Woodruff 2007)
- 1) Even if menses resume following cancer therapy, the patientâs ovarian reserve may be greatly reduced and she may be at risk for premature ovarian failure. Patients may have the opportunity to freeze remaining oocytes.
- *Do we want to tailor this chart for breast cancer? *I assume we can reproduce this chart, just as Savemyfertility.org did from the American Society of Clinical Oncology, Note: Risk depends on dose, duration of treatment, and age of patient. Also, chemotherapy and radiation may contribute individuals risks, and a combination may be additive. Additional Notes: Kim: âThe akylating agent, cyclophosphamide, is one of the oldest and most effective drugs used in adjuvant therapy for breast cancer but is also one of the most potent in reducing ovarian follicular reserve. A woman who takes the equivalent of 2.4-3 g/m 2 of cyclophosphamide over 12-16 weeks can count on adding an approximate 10 years to her ovarian reproductive age of 1.5-3.0 years per cycle.â Woodruff: âRadiation therapy to the pelvis can have a significant direct negative impact on ovarian function. As with chemotherapy, the extent of damage not only depends on the age of the woman but also on radiation dose and field of treatment. Doses as low as 4-6 Gy in adults and 10-20 Gy in children can lead to irreversible decrease in ovarian function with some experiencing ovarian failureâ. -The uterus can also be damaged; a decrease in uterine cavity volume or uterine blood flow may result. -Non-pelvic irradiation can also negatively impact fertility. For example, cerebral irradiation may disrupt central hypothalmic-pituitary hormonal regulation of ovarian function. - âFortunately, conventional therapies such as ovulation induction with gonadotropin injections or in vitro fertilization and embryo transfer usually suffice to restore fertility.â Woodruff: âA clear example regarding the major impact of age is provided by the study of Goldhirsch et al. [16], in which premenopausal women undergoing classic 6-month cyclophosphamide, methotrexate, and fluorouracil (CME) adjuvant chemotherapy for breast cancer were studied and found to have a 33% risk of amenorrhea if under 40 years and an 81% risk if older.â Chart Source: http://savemyfertility.org/pocket-guides/fertility-preservation-women-diagnosed-cancer Table adapted from the 2006 American Society of Clinical Oncology recommendations on fertility preservation in cancer patients; Fertile Hope. Cancer and Fertility: Fast Facts for Reproductive Professionals; and Meirow D, et al. Clin Obstet Gynecol. 2010;53:727-739. CMF=cyclophosphamide/methotrexate/fluorouracil âą CEF=cyclophosphamide/epirubicin/fluorouracill âą CAF=cyclophosphamide/adriamycin (doxorubicin)/fluorouracill âą MOPP=mechlorethamine/oncovin (vincristine)/procarbazine/prednisonel âą MVPP=mechlorethamine/vinblastine/procarbazine/prednisolonel âą COPP=cyclophosphamide/oncovin/procarbazine/prednisonel âą ChlVPP=chlorambucil/vinblastine/procarbazine/prednisolonel âą EVA=etoposide/vinblastine/adriamycinl âą BEACOPP=bleomycin/etoposide/adriamycin/cyclophosphamide/oncovin/procarbazine/prednisonel âą ABVD=adriamycin/bleomycin/vinblastine/dacarbazinel âą AC=adriamycin/cyclophosphamidel âą CHOP= cyclophosphamide/hydroxydaunomycin/oncovin/prednisonel âą COP=cyclophosphamide/oncovin/prednisonel âą MF=methotrexate/5-fluorouracil
- 1) Rates of amenorrhea range from 13% to 62% in women 30 to 40 years of age and 57% to 96% in women over 40. Additional Notes: Kim: âEven women who regain menses after cytotoxic chemotherapy +/- antihormonal therapy are likely to have undergone significant follicle depletion and reproductive aging of 10 years or more (16-19). Kimâ âThe primary determinants of chemotherapy-induced amenorrhea and/or loss of fertiltiy are age of the women at the time of chemotherapy, dose and number of cycles of akylating agent received, and to a lesser extent exposure to anthracyclines, taxanes, and platinum analogs.â Kim: âAmenorrhea is likely to be permanent in 90% of women over 40 and 95% of women over 45 (50-53)
- Additional Notes: Woodruff: The time required for oocyte maturation with ovulation induction is generally about 2 weeks from the onset of menses. Hence, if the decision to undergo conventional IVF and embryo freezing is made much after day 3 of the menstrual cycle, the day of menstrual cycle by when ovulation induction is usually initiated, the patient will have to wait until the onset of the next menstrual period prior to initiating ovulation induction. ASCO Guidelines: âThere are little human data available for the newer agents such as taxanes.
- Directly from Kim: âChemotherapy regimens can usually be altered somewhat to reduce gonadotoxciity. For example, for luminal B tumors, three cycles of FEC followed by three cycles of docetaxel provides similar chemotherapeutic efficacy as six cycles of FEC with less ovarian damage due to reduced amount of alkylating agent (54). For most Her-2+ tumors, preliminary evidence suggests that taxane and carboplatin are as effective as anthracycline, cyclophosphamide, and taxane combinations, completely avoid cyclophosphamide, and are probably not as likely to result in sterility (55,56). Triple negative âŠâŠâŠ.read more
- *Which apply to breast cancer? Did I miss any for breast cancer? Additional Notes: ASCO Guidelines: âFertility preservation options in females depend on the patientâs age, type of treatment, diagnosis, whether she has a partner, the available time, and the potential that cancer has metastasized to her ovaries.â
- McShane script For many years, ovarian suppression of cycling patients with depo Lupron has been tried to potentially modify the gonadal toxicity of chemotherapy. It appears that there is in fact a modest affect of this strategy on ovarian reserve but the effect is not as robust as one would like. The injections are expensive, and do result in hot flashes. Long term Depo Lupron use has been associated with osteoporosis. This concern is made more complex by the ultimate use of selective estrogen receptor modulators, or SERMâs, in breast cancer patients. Note: In ASCO guidelines (2006), says GnRH suppression should only be done in clinical trials. Is this still true or no?
- McShane script: If the patient has a partner, the use of in vitro fertilization (IVF) with embryo cryopreservation is the most established technique for fertility preservation prior to extensive chemotherapy. The major issue with this approach is that the timing must be synchronized with the womanâs menstrual cycle. The IVF process requires approximately two weeks of intensive medication and monitoring which begins with the womanâs menstrual period. This in many cases involves a delay of therapy which is of concern to both patients and their oncologist. Prior to the IVF cycle, the partnerâs semen analysis, determination of ovarian reserve as well as TSH (thyroid stimulating hormone), and prolactin serum levels should be obtained. Ideally, the resulting embryos would be replaced in the womanâs own uterus after cancer therapy. This requires normal uterine configuration, but gestational carrier can be used if the uterus is not normal or if assessing uterine status would further delay therapy.
- McShane script: The foundation of successful IVF is the recruitment of multiple oocytes since human reproduction is inherently inefficient. The goal of an IVF cycle is usually retrieval of 10 or 15 oocytes which results in the generation of 3 to 5 good quality embryos after insemination and culture.
- If we like flow charts, we could include them and add additional script: â On day 3 of the menstrual cycle, patients begin 12 days of hormone stimulating medicationsâŠâŠ.Following retrieval, oocytes can be immediately vitrified or inseminated and frozen as embryosâŠ..â
- McShane Script: There has been some concern about the risk of stimulating tumor growth especially in estrogen receptor positive tumors since ovarian stimulation which is required in order to generate multiple oocytes. The current approach for hormonally dependent cancer is to use gonadotropins FSH and comibination FSH/LH with letrozole (Femara), an aromatase inhibitor which does not raise estradiol levels in circulation as much as the typical gonadotropin stimulation. Other short term risks of the therapy include low risk to the surgical complications from the transvaginal oocyte retrieval as well as ovarian hyperstimulation syndrome which is typically no more than mild in the case of a woman who is not conceiving during the stimulation cycle. The long term risks of stimulation are less well known and are likely modified by the use of SERMs. These include possible increase in ovarian cancer. Additional Notes: Kamen and McShane: âIn 167 women undergoing ovarian stimulation with gonadotropins, mean maximum serum estradiol values reached 605 pg/mL and on days 6 to 10, progesterone level averaged 46ng/mL. This compares with an average preovulatory estradiol level of 250 pg/mL and progesterone value of 8.9 ng/mL during a normal menstrual cycle.â Missing citation: âBecause estrogen exposure is a risk factor for breast cancer, several studies have investigated whether ovarian stimulation leads to increased risk of this disease. But studies have shown a non-significant increase. -Cohort of 3375 women treated with IVF; non-significant increase in breast cancer incidence after 8.1 years of follow-up; women over 40, however, were at increased risk -however, studies thus far have less than 10 years of follow-up Available studies, despite limited, are reassuring Nonetheless Letrozole or Tamoxifen are recommended to be used during ovarian stimulation before chemotherapy to lower peak estradiol levelsâ Kim: âAlthough tamoxifen or letrozole can induce ovulation or stimulate follicular growth, it does not generate enough follicles for embryo cryopreservation. To make it a more practical method, use of low-dose gonadotropin in combination with tamoxifen or letrozole has been attempted with good results (73). â In terms of peak E2 levels, ovarian stimulation with letrozole plus gonadotropin resulted in a much lower levels compared with tamoxifen plus a gonadotropin. Moreover, when letrozole plus gonadotropin is used for COS, recurrence rates of breast cancer do not appear to be increased at 2 years of follow-up.â Jensen: With letrozole, significantly lower peak estradiol levels and a nearly 50% reduction in gonadotropin requirement compared with age-matched controls (cancer-free) undergoing in vitro fertilization. â Azim et al prospectively compared 79 women with breast cancer who underwent ovarian stimulation plus letrozole with 136 women with breast cancer who did not undergo ovarian stimulation before cancer treatmentâŠsimilar in age and stage of disease as well as risks of calculated relapse and mortalityâŠmedian follow-up of 23 months in the ovarian stimulation group and 33 months for controlsâŠno difference in noted recurrence or survival. The authors concluded that ovarian stimulation with gonadotropins and letrozole is unlikely to cuase significantly increased risk of recurrence, althought they acknowledged that a longer follow-up is needed.â 1) Kamen 2009 : Using letrozole or tamoxifen concurrent with FSH have not shown higher cancer recurrence rates in initial studies Letrozole has been demostrated to produce lower peak estradiol levels with an equal number of oocytes harvested compared with the use of FSH alone in women undergoing IVF. Tamoxifen demonstrated similar peak estradiol levels but fewer oocytes when compared to FSH-only cycles Tamoxifen is an antagonist of estrogen receptors Letrozole is an aromatase inhibitor, and prevents aromatase from producing estrogen by competitive inhibition ASCO Guidelines: âShort term breast cancer recurrence rates after ovarian stimulation using letrozole or tamoxifen concurrent with follicle stimulating hormone (FSH) administration have been compared with nonrandomized controls and no increase in cancer recurrence has been noted in these initial studies. Only a small percentage of cancer survivors have yet returned to utilize their embryos but the initial pregnancy rates are encouraging. Nevertheless, long-term follow-up with a larger number of patients is needed to evaluate the safety and efficacy of this approach.â
- McShane Script: If the patient does not have a male partner or if she desires to cryopreserve her oocytes rather than embryos, oocyte preservation via vitrification has become a viable alternative in recent years. The classicial approach to embryo cryopreservation did not work well for oocytes but fortunately, a newer approach has evolved in the last several years which appears to be very viable and can be used for social indications or oocyte donation as well as oncofertility. To generate multiple oocytes for retrieval, the time requirement and the time within the menstrual cycle are the same as for an IVF cycle. The risks short term of the stimulation, retrieval and possible ovarian hyperstimulation syndrome are the same. Given that vitrification is a newer procedure, the risk to the offspring at this time is relatively unknown. Additional Notes: Kim: âVitrification is a solidification of liquid by an extreme elevation in viscosity while rapid cooling takes place and eliminates ice crystal formation and growthâ Dr. Kondapolli: oocyte turned into glass Jensen: âRecent technological advances have now improved oocyte cryopreservation such that oocytes can survive the freezing or vitrification process approximately 50% to 60% of the time, with fertilization rates of 60% to 70% with use of intracytoplasmic sperm injection.
- McShane Script: Cryopreservation of ovarian cortical tissue which would require a laparoscopic approach is an experimental process. This could be done immediately, independent of the womanâs menstrual cycle but does involve the risk of laparoscopy and general anesthesia. The ultimate replacement of the cortical strips or maturation of the oocytes from the cortical strips after thawing has been successful in a small number of cases worldwide. **To what detail should we describe these procedures?
- ASCO Guidelines: â To offset this relatively large loss [due to ischemia], typically the cortex from an entire ovary is cryopreserved in adults.â â Ovarian cryopreservation and transplantation procedures should only be performed in centers with the necessary expertise under IRB-approved protocols that include follow-up for recurrent cancer.
- In ovarian cortical tissue cryopreservation, Basic stepsâŠ..
- Additional Notes: Woodruff: âFreezing sections of ovarian cortex or freezing wither mature or immature oocytes, still have more limited availability, though with time and increased interest in these techniques both success and availability will increase.â
- See: http://savemyfertility.org/pocket-guides/fertility-preservation-women-diagnosed-cancer -Example of useful reference chart
- ASCO Guidelines: âAs with the other potential complications of cancer treatment, oncologists have a responsibility to inform patients about the risks that their cancer treatment will permanently impair fertility. Yet, recent surveys of male and female cancer survivors of reproductive age concur that at least half have no memory of a discussion of fertility at the time of their treatment dispositionâŠ.Even when patients do recall infertility discussions, many are dissatisfied with the quality and amount of information provided.â â Physicians may be prioritizing discussions about immediate or potentially life-threatening complications instead of discussing infertility. Data regarding the risks of infertility with various chemotherapy regimens are poor or nonexistent. Some physicians do not recognize the importance of fertility to cancer survivors or believe that the cost of fertility preservation interventions are prohibitiveâŠ.However, oncologists overestimated these costs and their deterrent effectâŠ[the examples they cite reference are in reference to sperm banking] â While professional organizations such as âŠ.. do provide patient information, patients may not be aware of these resources and able to access information in a timely fashion when confronted with a new diagnosis of cancer. In addition, a physicianâs recommendation is a very strong predictor of whether a man banks sperm, almost as influential as the patientâs desire for children in the future.â â Ideally, after referral, the decision about who is an appropriate candidate to attempt specific fertility preservation techniques could be rendered by a team, including a medical oncologist, reproductive endocrinologist, and a psychosocial provider â As long as the oncologist presents the options in enough detail for the patient to decide whether to seek consultation, the detailed counseling could be done by an infertility specialist.â â When referring patients, oncologists should remember that many methods are still investigationalâ -Should list which need to done in specialized centers working with IRB-approved consents. â One option the oncologist should routinely offer is a referral for psychological counseling when a man or woman has moderate to severe distress about potential infertility.
- Infertility treatments are usually not covered by insurance At Colorado Springs meeting, didnât we talk about if fertility perservation procedures are included as part of the prescribed cancer therapy, may be able to be covered? Quinn ( Oncologistsâ Views) : âThe majority of physicians, regardless of their program, reported little to no knowledge of clinic or specialists to refer patients to.â
- ASCO Guidelines: âMost insurance companies do not offer assisted reproductive techniques as benefits so this approach may be associated with high out-of-pocket costs for most women.
- ASCO Guidelines: âPotential legal issues, such as ownership of embryos and reproductive tissue in the event of a patientâs death, divorce or incapacity, should also be discussed by the reproductive specialist.
- **Include this topic briefly or no? To discuss with this slide: Assess uterus and hormones. Goal: mature endometrium Not all embryos and oocytes survive thaw Embryos and oocytes graded for quality Implantation rate per embryo a bit lower than fresh embryos Oocytes? Studies indicate no higher rate of birth defects But greater risk for low birth rate (other greater risks?) Additional notes: Woodruff: âAt the time of the patientâs choosing, embryos can be thawed and transferred into either the patientâs own uterus, providing that her uterus is viable for pregnancy, or that of another woman (gestational surrogate).
- Additional Notes: Kim: Becoming pregnancy after a diagnosis of breast cancer does not appear to resutl in worse outcomes in case-control studies or cohort studies (4,5,7,8). In fact, in several series, pregnancy after a daignosis of breast cancer appeared to result in reduced risk of relapse (7-9), particularly for women who waited for 2 years after diagnosis to conceive (9). Jensen: âCancer survivors often desire, yet fear pregnancy after cancer therapy, particularly that for hormone-responsive malignancies like breast cancer.â - âMultiple studies have shown that pregnancy after breast cancer treatment does not appear to adversely affect recurrence or survival. In particular a large population-bases student examined more than 10,000 women with primary breast cancer who were younger than 45 years at the time of diagnosis; only 371 had a full-term delivery after cancer treatment. A multivariate analysis including age at diagnosis, stage of disease, and pregnancy history before diagnosis showed that women who had a full-term pregnancy after cancer diagnosis had a reduced risk of dying (0.73; 95% confidence interval, 0.54-0.99) compared with other women with breast cancer. The author concluded that no evidence exists to suggest that pregnancy after breast cancer had a negative influence on prognosis.â Jensen: Patients express concern of birth defects; large studies of offsprings of cancer survivors have showed no statistically significant increase in childhood malignancies or genetic malformations.
- 1) These studies may be biased, as the healthiest patients are more likely to desire and achieve pregnancy, referred to as the âhealthy mother effectâ Kamen 2009 .