Did you know that cancer treatments can affect the fertility of men, women, and children? Fertility preservation methods are most effective when used before cancer treatments begin.
Preserving fertility in patients who have cancer
By S Samuel Kim, MD, published 5/11.
Fertility preservation is a significant issue among women of reproductive age who have cancer.
Over the past 25 years, advances in cancer treatment have led to improved long-term survival rates among both adult and pediatric cancer patients. The 5-year relative survival rate for childhood cancers is now higher than 75% and almost 95% for Hodgkin's disease in particular. Currently, more than 11 million individuals in the United States are living with cancer, and approximately 450,000 cancer survivors are of reproductive age. Furthermore, 4% to 5% of newly diagnosed cancer patients are younger than 35 years. After skin cancer (including both squamous and basal cell carcinoma), breast cancer is the most common cancer among women in the United States. Between 5% and 7% of cases of invasive breast cancer - approximately 11,000 cases per year - are diagnosed in women younger than 40 years of age. These epidemiologic data underscore the importance of survivorship issues in cancer patients, particularly those of reproductive age.
As the number of long-term cancer survivors increases, fertility has become an important quality-of-life issue among young women with the disease. Unfortunately, the gonads are susceptible to cytotoxic cancer treatment, in particular, to alkylating agents and radiation. Many women diagnosed with cancer at a young age must undergo chemotherapy, which may result in premature ovarian failure and subsequent infertility. Premature ovarian failure after chemotherapy may be associated with the type of chemotherapeutic agents, the cumulative dose of the cytotoxic drugs, and the patient's age, but other factors must be considered as well.
Although most women of reproductive age wish to preserve fertility, they fail to receive adequate information about fertility preservation. In a Web-based survey of young women diagnosed with breast cancer, Partridge and colleagues demonstrated that only half of all respondents felt that their concerns about fertility had been addressed adequately at the time of diagnosis. In 2006, the American Society of Clinical Oncology published guidelines recommending that oncologists discuss fertility issues with patients of childbearing age, and that they refer these women to reproductive specialists and psychosocial service providers, as needed. Nevertheless, fewer than half of all US physicians are following those guidelines. Failure to discuss fertility may provoke future feelings of grief and regret in patients; therefore, it is important for healthcare professionals to address fertility-related issues, including fertility preservation options, prior to initiating gonadotoxic cancer treatment.
Figure 1. Fertility preservation options in female cancer patients
Currently available fertility preservation options include the use of gonadotropin-releasing hormone (GnRH) agonists, controlled ovarian hyperstimulation with cryopreservation of mature oocytes or embryos, cryopreservation of immature oocytes or in vitro maturation followed by cryopreservation of mature oocytes, and cryopreservation of ovarian tissue. Of note, most of these options are still considered to be experimental, except for embryo cryopreservation. Additional options include donor egg in vitro fertilization, surrogacy, and adoption (Figure 1).
These fertility preservation options are also applicable to patients with other medical conditions that require gonadotoxic chemotherapy and/or radiotherapy, such as systemic lupus erythematosus and microscopic polyangiitis. Furthermore, young patients with sickle cell anemia or other bone marrow pathologies who require hemato-poietic stem cell transplantation should consult with a healthcare professional about fertility preservation prior to treatment.
Until these fertility preservation options are no longer considered controversial, their possible societal implications will remain a subject of debate. As the number of women who delay childbirth because of education and career rises, however, we can predict an increase in the demand for fertility preservation among this population in the future.
Hormonal protection with GnRH agonists
Whether GnRH agonists protect ovarian function from chemotherapy-induced gonadotoxicity remains controversial. The results of published studies are neither consistent nor convincing because of suboptimal study designs and inadequate sample sizes. A recent systemic review and meta-analysis of 11 prospective, controlled studies (8 nonrandomized, 3 randomized) with a primary endpoint of no sign of premature ovarian failure after treatment showed that GnRH agonist cotreatment during chemotherapy can protect ovarian function (odds ratio, 10.57; 95% Confidence Interval, 5.22 - 21.39). It is worth noting, however, that the results of this meta-analysis are influenced by nonrandomized studies.
Although the purported protective effects of GnRH agonist therapy will remain uncertain until current ongoing, large, prospective, randomized studies have been completed, GnRH cotreatment may be a viable option for fertility preservation among patients undergoing chemotherapy, especially when other treatments have failed or are limited. Whereas the duration of most GnRH agonist cotreatment is less than 6 months, long-term use of this therapy has been associated with osteoporosis, even among younger cancer patients.
Embryo cryopreservation
Embryo cryopreservation is a clinically established technology. According to a 2008 report by the Society for Assisted Reproductive Technology, the current live birth rate per transfer using frozen-thawed embryos is 35.6% in US women younger than 35 years. The process of embryo cryopreservation normally takes 2 to 5 weeks, and requires controlled ovarian stimulation with gonadotropins, oocyte retrieval, and in vitro fertilization. Hence, the practice may not be applicable to all patients with cancer, especially those who require immediate treatment. Furthermore, gonadotropins increase peak estradiol levels, which may be contraindicated in patients with hormone-dependent cancers such as estrogen receptor - positive breast cancer.
In patients with breast cancer, an alternative strategy is the use of tamoxifen or letrozole to stimulate follicular growth; however, this process does not generate sufficient numbers of follicles for embryo cryopreservation. To make this method practical, a treatment protocol that comprises low-dose gonadotropin in combination with tamoxifen or letrozole has been developed. Although it is too early to determine the safety and efficacy of this protocol in women with breast cancer, the results are encouraging. In postpubertal cancer patients, embryo cryopreservation should be considered if there is adequate time for ovarian stimulation and if a partner or sperm donor is available.
Oocyte cryopreservation
Oocyte cryopreservation is an alternative to embryo storage, and is ideal for women who do not have a partner and do not want to use donor sperm. In this procedure, the patient undergoes controlled ovarian stimulation and egg retrieval; however, oocyte cryopreservation does not require in vitro fertilization. Thus, the detailed process of embryo creation is not required.
More than 1,000 healthy babies have been born worldwide through the process of oocyte cryopreservation. Although it is still considered experimental in the United States, current live birth rates from a series of frozen-thawed oocytes are comparable to those in frozen-thawed embryo transfer cycles. It is important to note that there was no apparent increase in the rate of congenital anomalies among oocyte cryopreservation infants compared with those born using natural conception, although it is too premature to conclude the safety of this technology.
Mature oocytes can be cryopreserved by either slow freezing or vitrification. Vitrification can minimize ice crystal formation and potentially decrease ultrastructural damage. Indeed, many studies have reported significantly enhanced clinical pregnancy rates with embryos resulting from vitrified oocytes. When data from 1998 to 2008 are analyzed, the oocyte survival rate was higher in the vitrified group (81%) compared with the slow-frozen group (68%) and the fertilization rate (pronuclear embryo) was 79% in the vitrified group and 73% in the slow-frozen group. The live birth rates per embryo transfer were 34% and 14% in the vitrified and slow-frozen groups, respectively.
Ovarian tissue cryopreservation
Ovarian tissue cryopreservation is an emerging technology for fertility preservation, and it may be the only option for prepubertal girls or for those who cannot delay cancer treatment or who are unwilling to undergo ovarian stimulation. This technology is still in its early stage, however, with limited experience to date. Several advantages of this strategy have been suggested: It can permanently store abundant immature oocytes for future use; it can be effective not only for restoring fertility but also for restoring endocrine function with ovarian tissue transplantation; it does not delay cancer treatment; and it does not increase serum hormone levels. However, the patient must understand that this is an invasive procedure and that surgical complications can occur. In addition, ovarian tissue cryopreservation is currently an experimental procedure. The ovary is usually harvested using laparoscopic surgery. The harvested ovary is then processed into thin slices of ovarian tissue (approximately 5 mm x 5 mm x 1 mm) prior to freezing.
The survival rate of follicles (mainly primordial follicles) after freezing and thawing is about 70% to 80%. The problem that arises is how to develop immature oocytes in stored ovarian tissue when the patient is ready to have a child. Although in the future immature oocytes will be developed entirely through in vitro culture, currently transplantation of frozen-thawed tissue in the patient's own body is the only realistic method for restoring fertility. To date, 15 healthy human babies have been born worldwide after transplantation of frozen-thawed ovarian tissue (including unpublished data).
The patient's age is a critical consideration because the likelihood of restoration of ovarian function and fertility is correlated closely with the number of follicles in the ovarian tissue that decline with age. Normally, cryopreservation of ovarian tissue is not recommended if a patient is older than 39 years of age or if her serum anti-Mullerian hormone level is < 0.4 ng/mL. Although the efficacy of this technology is still unknown, it appears promising when the number of live births associated with this technique is compared with the number associated with the use of transplantation. It is estimated that approximately 40 cases of transplantation of frozen-thawed ovarian tissue have been performed so far.
The safety of transplanting stored ovarian tissue is a crucial issue, as the risk for reintroduction of cancer cells exists with certain types of cancer. To date, more than 40 cases of ovarian transplantation have been performed in women with various cancers, including breast cancer, cervical cancer, non-Hodgkin's lymphoma, Hodgkin's lymphoma, and Ewing sarcoma, with no cases of cancer cell reintroduction reported after ovarian tissue transplantation in humans. Indeed, Kim and colleagues demonstrated the safety of transplanting human ovarian tissue from lymphoma patients using a xenotransplantation model. However, the detection of cancer cells in ovarian tissue taken at the time of harvest for cryopreservation has been reported. All patients with cancer who undergo ovarian transplantation should be counseled regarding the risk for cancer cell reintroduction, and reliable screening methods for detecting minimal residual disease in ovarian tissue must be further developed prior to the standard use of this technology.
Conclusion
Most patients with cancer who are of reproductive age perceive fertility as a critical issue and desire to preserve fertility. Options for preserving fertility in women with cancer include cryopreservation of embryos, oocytes, and ovarian tissue. It is important to counsel patients about fertility issues immediately after a diagnosis of cancer. If the patient desires to preserve fertility, the clinician should communicate with fertility specialists to facilitate timely referrals after a discussion with the patient of the currently known risks and benefits because in many cases the window of time between a cancer diagnosis and cancer treatment is narrow. Indeed, many young patients lose the opportunity to preserve fertility because of the lack of timely referrals and appropriate consultation.
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How can cancer affect fertility?________________
You may have heard that cancer can reduce fertility. While this is true for cancers that affect the reproductive organs, such as cancer of the uterus or testicles, other cancers may not directly cause infertility. In most cases, infertility is actually caused by the treatment for the cancer, such as chemotherapy or radiation, rather than the cancer itself. It is important to understand that while cancer treatments can be very effective, they can cause side effects that harm the ability to reproduce.
Remember: Concerns about fertility are valid and important, especially in planning for life after cancer. If you have been diagnosed with a cancer of the reproductive tract or you are concerned about the possible effect of cancer treatment on your future fertility, start by visiting the sections of this Web site that describe your options for preserving fertility before you begin treatment. This information may help you prepare to speak with your doctor about the options that are appropriate for and available to you.
Each patient is unique. The impact of a given treatment on fertility can vary and so can the time available before starting life saving treatments. Patient age, marital status, personal wishes, religious and cultural constraints and prognosis may all affect decision making. Fertility preservation treatments must be tailored to the individual circumstances and integrated with the treatment regimen. Close coordination between the treating physician and the reproductive endocrinologist is the key to preserving family-building options for your patients.
For more information, read the following options for women, men, and children or call the Oncofertility Consortium's Patient Navigator for Fertility Preservation: Annette Haggan, at 866-708-FERT (3378).
Women:
During this process, a woman’s ovaries are first stimulated to mature multiple eggs, which are then removed and fertilized through in vitro fertilization (IVF) with sperm to create embryos. The embryos are then frozen for future use. The entire process can take up to one month. Watch an animation about embryo banking. This is a new technology that is starting to show good results but is still considered experimental. This process is exactly the same as described for embryo banking except that the eggs are NOT fertilized before freezing. This is a good option for single women who do not have a male partner and do not want to use donor sperm. The entire process can take up to one month. Read more information about egg banking. One entire ovary is removed surgically and the outer surface (cortex) which contains the eggs is frozen in strips for later use. Women who are survivors of some types of cancer can have pieces of the tissue thawed and transplanted back. A number of pregnancies have resulted from using this technique. Transplant is not safe following some types of cancer (e.g. leukemia) because of the risk of re-seeding the original cancer. The Oncofertility Consortium® is actively researching new ways to use this tissue. New techniques are still experimental but may be the best option for woman who must start their treatments immediately. Read more about ovarian tissue banking and watch an animation. Surgeons can move the ovaries away from the area receiving radiation therapy. The goal of the surgery is to move the ovaries within the pelvis where they can still function, but will be out of the way of harmful radiation. This technique will not protect against the effects of chemotherapy.
Men:
Sperm cells are collected and frozen for future use. Read more information about sperm banking. - Testicular tissue banking
Testicular tissue, including cells that produce sperm and sperm itself, is removed and frozen.
Children/Adolescents:
Young women are stimulated with fertility drugs to cause them to produce a number of eggs. The eggs are retrieved surgically and frozen for future use. This technique is still considered experimental, takes about a month to complete and requires multiple vaginal ultrasounds and a vaginal egg retrieval. Not all adolescents and their families will be comfortable with this procedure.
One entire ovary is removed surgically, the outer surface (cortex) which contains the eggs is removed and frozen in strips. Women who are survivors of some types of cancer can have pieces of the tissue thawed and transplanted back. A number of pregnancies have resulted from using this technique. Transplant is not safe following some types of cancer (e.g. leukemia) because of the risk of re-seeding the original cancer. The Oncofertility Consortium® is actively researching new ways to use this tissue. New techniques are still experimental but may be the best option for woman who must start their treatments immediately. Read more about out ovarian tissue freezing and watch an animation.
Sperm cells are collected and frozen for future use. Read more information about sperm banking. Watch a cancer survivor discuss banking sperm.
- Testicular tissue banking
Testicular tissue, including cells that produce sperm and sperm itself, is removed and frozen. Read more information here. The procedures listed above have varying risks and side effects. Some options may not be recommended for certain types of cancer or disease. There may also be treatments available that have a smaller risk of infertility. It is important to discuss these procedures with your physician and your insurance provider since they may be expensive and not covered by insurance.
Third party reproduction:
There are other parenthood options that are available to individuals who may not be able to conceive or carry their own biological children. These include:- Donor eggs
- Donor sperm
- Donor embryos
Eggs, sperm, or embryos provided by a known or anonymous donor.
Having another woman carry your child.
The Oncofertility Consortium® has compiled a list of adoption agencies that would like to work with cancer survivors.
- FERTLINE
The national fertility hotline was designed to provide patients and providers with oncofertility information tailored to each individual case. For immediate fertility preservation counseling, referral to a fertility center near you, and information on the financial and emotional aspects of treatment, call the Oncofertility Consortium's Patient Navigator, Annette Haggan, at 866-708-FERT (3378).
Supportive Oncology at Northwestern University
The Robert H. Lurie Comprehensive Cancer Center provides emotional and practical support for patients and their families during all stages of treatment and recovery and can connect you with information, resources, and counseling to help you manage the challenges of living with cancer.
A list of additional links to local and national cancer support groups and patient advocacy organizations is available at MyOncofertility.org
For information about fertility preservation or to get a referral to a fertilty preservation center near you, please call the FERTLINE! This resource is available to patients, families and health care professionals.
Visit MyOncofertility.org for more in depth information, educational materials and patient related videos.
