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Originally published as JCO Early Release 10.1200/JCO.2006.06.5888 on May 1 2006 © 2006 American Society of Clinical Oncology.
American Society of Clinical Oncology Recommendations on Fertility Preservation in Cancer Patients
From the Dana-Farber Cancer Institute, Boston, MA; Fertility Preservation Program, Center for Reproductive Medicine and Fertility, Weill Medical College, Cornell University; Fertile Hope, New York, NY; Oncology/Hematology Care, Crestview Hills, KY; American Society of Clinical Oncology, Alexandria, VA; Yale University Fertility Center, New Haven, CT; M.D. Anderson Cancer Center, Houston, TX; and the Royal Hospital for Sick Children, Edinburgh, Scotland, UK Address reprint requests to Kutluk Oktay, MD, The Center for Reproductive Medicine and Infertility, Cornell University, 505 E 70th St, HT-340, New York, NY 10021; e-mail: guidelines{at}asco.org
PURPOSE: To develop guidance to practicing oncologists about available fertility preservation methods and related issues in people treated for cancer. METHODS: An expert panel and a writing committee were formed. The questions to be addressed by the guideline were determined, and a systematic review of the literature from 1987 to 2005 was performed, and included a search of online databases and consultation with content experts. RESULTS: The literature review found many cohort studies, case series, and case reports, but relatively few randomized or definitive trials examining the success and impact of fertility preservation methods in people with cancer. Fertility preservation methods are used infrequently in people with cancer. RECOMMENDATIONS: As part of education and informed consent before cancer therapy, oncologists should address the possibility of infertility with patients treated during their reproductive years and be prepared to discuss possible fertility preservation options or refer appropriate and interested patients to reproductive specialists. Clinician judgment should be employed in the timing of raising this issue, but discussion at the earliest possible opportunity is encouraged. Sperm and embryo cryopreservation are considered standard practice and are widely available; other available fertility preservation methods should be considered investigational and be performed in centers with the necessary expertise. CONCLUSION: Fertility preservation is often possible in people undergoing treatment for cancer. To preserve the full range of options, fertility preservation approaches should be considered as early as possible during treatment planning.
The diagnosis and treatment of cancer often poses a threat to fertility. Methods of fertility preservation are evolving quickly, yet little has been published in the medical oncology literature regarding this topic. Studies suggest that the ability to have biological children is of great importance to many people. Any oncologist seeing reproductive-aged patients for consideration of cancer therapy should be addressing potential treatment-related infertility with them or, in the case of children, with their parents. Yet, studies suggest that many oncologists either do not discuss the possibility of treatment-related infertility or do so suboptimally. Teaching in many fellowship programs covers sperm banking and techniques such as oophoropexy,1 while little information is provided concerning other methods of fertility preservation. The purpose of this guideline is to review the literature pertaining to fertility preservation options for men, women, and children undergoing cancer treatment, and to give guidance to oncologists about these issues. The focus is restricted to interventions aimed at fertility preservation; the guidelines do not address methods of fertility restoration after completion of cancer treatment nor the risks of assisted reproductive techniques, except those unique to cancer patients. The risks of pregnancy to parents and offspring after cancer treatment are reviewed only insofar as they might affect a person’s desire to pursue fertility preservation methods before or during active cancer treatment.
Estimating the Risk of Infertility After Treatment for Cancer Male and female fertility may be transiently or permanently affected by cancer treatment or only become manifest later in women through premature ovarian failure. The panel wishes to emphasize that female fertility may be compromised despite maintenance or resumption of cyclic menses. Regular menstruation does not guarantee normal fertility as any decrease in ovulatory reserve may result in a lower chance of subsequent conception and higher risk of early menopause. Even if women are initially fertile after cancer treatment, the duration of their fertility may be shortened by premature menopause. An estimated 1,372,910 people were diagnosed with cancer in 2005, of whom 4% (approximately 55,000) are under the age of 35.2 The most common cancers diagnosed in people under the age of 40 years are breast cancer, melanoma, cervical cancer, non-Hodgkin’s lymphoma, and leukemia.3 The Panel recognizes that a table of all common cancer treatments with their associated risks of infertility is desirable. However, available data are poor and heterogeneous, so summarization was felt to be beyond the scope of this guideline. However, Tables 1 3A and 2, and several additional references4-12 illustrate the range of risks associated with several cancer therapies. The Panel noted that most of the available literature quantifying infertility risks reports rates of azoospermia and amenorrhea, though these are surrogate measures of infertility. In men and women, the greatest risks associated with chemotherapy involve the alkylating agents (particularly cyclophosphamide, ifosfamide, nitrosoureas, chlorambucil, melphalan, busulfan, and procarbazine). Total-body irradiation as used in myeloablative stem-cell transplantation is highly associated with infertility, while lesser doses or limited radiation fields have less gonadal toxicity.13,14 Several agents are associated with a low or no risk of infertility: methotrexate, fluorouracil, vincristine, bleomycin, and dactinomycin. There are little human data available for the newer agents such as taxanes. Given the paucity of data regarding rates of male and female infertility following most current cancer treatments and the large number of patient factors that influence fertility, oncologists may have difficulty providing precise guidance to patients about their risks for infertility.
Questions The committee addressed the following clinical questions:
Practice Guidelines Practice guidelines are systematically developed statements to assist practitioners and patients in making decisions about appropriate health care for specific clinical circumstances. Attributes of good guidelines include validity, reliability, reproducibility, clinical applicability, clinical flexibility, clarity, multidisciplinary process, review of evidence, and documentation. Guidelines may be useful in producing better care and decreasing cost. Specifically, utilization of clinical guidelines may provide the following:
In formulating recommendations for fertility preservation options, ASCO considered these tenets of guideline development, emphasizing review of data from appropriately conducted and analyzed clinical trials. However, it is important to note that guidelines cannot always account for individual variation among patients. Guidelines are not intended to supplant physician judgment with respect to particular patients or special clinical situations and cannot be considered inclusive of all proper methods of care or exclusive of other treatments reasonably directed at obtaining the same result. (Accordingly, ASCO considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in light of each patient’s individual circumstances. In addition, these guidelines describe the use of procedures and therapies in clinical practice; they cannot be assumed to apply to the use of these interventions performed in the context of clinical trials, given that clinical studies are designed to evaluate or validate innovative approaches in a disease for which improved staging and treatment is needed. In that guideline development involves a review and synthesis of the latest literature, a practice guideline also serves to identify important questions and settings for further research.)
Panel Composition The ASCO Health Services Committee (HSC) convened an Expert Panel consisting of experts in clinical medicine and research relevant to fertility preservation in cancer patients, including adult and pediatric oncology, obstetrics-gynecology, andrology, reproductive endocrinology and infertility, health services research, psychosocial oncology, and bioethics. A patient representative was also part of the Panel. Panel members are listed in the Appendix.
Literature Review and Analysis Articles were selected for inclusion in the systematic review of the evidence if they met the following criteria: (1) the study discussed a fertility intervention and reported primary data; and (2) the study population consisted of cancer patients scheduled for or undergoing cancer treatments that threaten fertility (other populations could be considered where data were lacking in cancer patients). Articles were excluded from further consideration if they did not report specifically on a fertility intervention and did not report primary data. However, due to the limited nature of the data in many areas, the Panel made an a priori decision to also retain high-quality reviews or background papers, and these articles were described as such in the coding process. An initial article abstract screen was performed by ASCO staff. The ASCO Panel reviewed all remaining potentially relevant abstracts identified in the original literature searches to select studies pertinent to its deliberations. Two Panel members independently reviewed each abstract for its relevance to the clinical questions, and disagreements were resolved by third-party review. Full text articles were then reviewed for all selected abstracts. The Panel designed a coding sheet to complete the review of identified potentially relevant studies, and the Co-Chairs assigned each Panel member a subset of articles to review. Data were extracted on the source of the threat to fertility, the intervention being considered, the outcomes assessed, the number of patients and types of cancer, and study design. Primary outcomes of interest included pregnancies and live births, but the following were also considered: fertility maintenance; resumption/maintenance of menses; number of oocytes recovered; number of embryos recovered; fertilization rates; and in vitro fertilization (IVF) outcome. Also considered were the risks associated with the fertility intervention, quality of life, patient and/or family satisfaction, patient education or increased awareness, and economic evaluation (eg, cost-effectiveness, cost utility).
Consensus Development Based on Evidence
Guideline and Conflict of Interest
Revision Dates
Literature Search Preliminary searches identified 1,675 potential articles. The initial abstract screen performed by ASCO staff eliminated 807 abstracts that failed to meet any of the inclusion criteria. The ASCO Panel conducted dual independent review of all remaining 868 potentially relevant abstracts identified in the original systematic review. The Panel eliminated 463 abstracts at this stage of the review; the remaining 405 articles were reviewed in full for the interventions and outcomes described above. One hundred twenty-nine articles that did not report primary data on a fertility preserving intervention were excluded from further consideration. Two hundred thirty-three articles met the inclusion criteria, and an additional 43 articles met the a priori criteria as supplementary studies or reviews. A meta-analysis was not performed because the studies were judged to be too small and heterogeneous for meaningful quantitative synthesis. Cohort studies or case series were identified in embryo and oocyte cryopreservation, ovarian tissue preservation, conservative surgical treatment of tumors, ovarian transposition (during radiotherapy), trachelectomy, sperm banking, rectal electroejaculation, hormonal manipulation, intracytoplasmic sperm injection, and testicular sperm extraction. Case reports were available for the other methods of fertility preservation. Of the outcomes assessed, 111 studies reported on pregnancies, live births, or IVF outcome. Of these 111 studies, the majority were case series or case reports.
Limitations of the Literature Little is known about the emotional impact of infertility or utilization of fertility preservation options on cohorts that are diverse in ethnicity and socioeconomic status, groups that face even greater barriers to fertility preservation.15,16 The Panel encourages additional well-designed studies evaluating methods of fertility preservation in people with cancer to help answer these questions. However, the Panel also notes that the traditional gold standard of randomized, controlled, and blinded therapeutic studies may not be possible in this area.
I. Are Cancer Patients Interested in Fertility Preservation Interventions?
Surveys of cancer survivors have identified an increased risk of emotional distress in those who become infertile because of their treatment.19,20,25-28 These studies mirror what has been observed in infertile noncancer populations where research clearly shows that long-term quality of life is affected by unresolved grief and depression,16 as well as reduced life satisfaction and increased anxiety.29-31 Some evidence suggests that patients may choose a less efficacious treatment strategy in order to avoid greater toxicity and long-term complications. For example, if given a choice, young women with early-stage breast cancer may choose a less toxic regimen of chemotherapy even if it confers slightly less protection from recurrence.27 Parents may also be interested in fertility preservation on behalf of their children with cancer. Impaired future fertility is difficult for children to understand, but potentially traumatic to them as adults. Use of established methods of fertility preservation (semen cryopreservation and embryo freezing) in postpubertal minor children requires patient assent and parental consent. Unfortunately, the modalities that are available to prepubertal children to preserve their fertility are limited by patients’ sexual immaturity and are essentially experimental. Efforts to preserve fertility of children using experimental methods should only be attempted under institutional review board (IRB)–approved protocols, where proper attainment of informed consent from a legally authorized representative(s) (ie, parent[s] or guardian[s]) and of childhood assent can be ensured.32-34 It has been suggested that to overcome some of the practical obstacles involved in studying experimental fertility preservation in children, the consent process should be performed in two stages.35-36 The decision to harvest gametes would be made at the time of cancer treatment, and consent for the procedure would rely on parents/guardians. The decision of how to use the gametes after they have been isolated could be made at a future point by the patient. Then, the adult patient would be better able to express personal preferences about the handling of the tissue.
II. What Is the Quality of Evidence Supporting Current and Forthcoming Options for Preservation of Fertility in Males?
Sperm cryopreservation. Due to recent advances in IVF technology and sperm banking procedures, even men with extremely reduced sperm count and motility are candidates for sperm cryopreservation. It is strongly recommended that sperm be collected before initiation of cancer therapy because the quality of the sample and sperm DNA integrity may be compromised even after a single treatment session.37,38 In addition, depending on the type of cancer—particularly testicular cancer and Hodgkin’s lymphoma39—and the overall condition of the patient, sperm quality may be poor even in patients who have not yet started treatment.37,38,40,41 Many patients have to start chemotherapy immediately or soon enough to limit the number of ejaculates to one or two samples. Even in these instances, it is reasonable to make every effort to bank sperm38 since recent progress in andrology laboratories and in the use of assisted reproductive techniques, particularly the technique of intracytoplasmic sperm injection (ICSI) allows the successful freezing and future use of a very limited amount of sperm. There are case reports and small case series of successful collection of sperm from a postmasturbation urine sample, rectal electroejaculation under anesthesia,42,43 and testicular sperm aspiration,44 but these are uncommon and/or investigational methods. Oncologists should make every effort to discuss sperm banking with appropriate patients,38,45-47 though a recent survey48 suggests that oncologists lack knowledge about recent advances in assisted reproductive techniques. Sperm cryopreservation in boys and young men involves additional considerations. Spermarche, the production of sperm, occurs at approximately 13 to 14 years, but once sperm are present, the patient’s age does not seem to affect quality of sperm produced.49 However, prepubertal boys have not yet developed gametes, and collection of semen through masturbation in adolescents may be compromised by embarrassment and issues of informed consent. For example, one study suggested adolescent boys may be more successful if a parent does not accompany them to the sperm bank.50 Hormonal gonadoprotection. The efficacy of gonadoprotection through hormonal manipulations has only been evaluated in very small studies in cancer patients. Hormonal therapy in men is not successful in preserving fertility when highly sterilizing chemotherapy is given,51,52 nor did it speed recovery of spermatogenesis in 18 men after nonsterilizing treatment compared to concurrent controls.53,54 Based on observations in rats, a small prospective study evaluated the effects of hypothalamic-pituitary-gonadal suppression plus testosterone in seven men rendered azoospermic after chemotherapy or radiation treatment for childhood cancer. No recovery of spermatogenesis was seen after 12 weeks of suppression.55 In contrast, a very small study evaluating testosterone in men without cancer treated with cyclophosphamide for glomerulonephritis suggested some benefit.56 Other methods to preserve male fertility. Other methods, such as testicular tissue cryopreservation and reimplantation57 or grafting of human testicular tissue to SCID mice to facilitate spermatogenesis,58,59 remain experimental and have not been tested in humans. Of note, such approaches are also the only methods of fertility preservation potentially available to prepubertal boys. Other considerations of fertility preservation options in males. Epidemiological studies confirm that most young male patients with cancer are not referred for sperm banking.12,37,38 Reasons for this apparent underutilization are likely multifactorial. Physicians may not discuss or emphasize opportunities to preserve fertility before treatment.60 Psychological, logistic and financial constraints on patients may further limit sperm banking. Men may be traumatized about their diagnosis or lack interest in fertility preservation at the time of diagnosis. However, two recent surveys suggest that for men who desire future children, lack of timely information is the most common reason for not banking sperm.19,20 Responsibility for organizing an appointment with the cryopreservation laboratory often falls to the patient. Most insurance companies in the United States do not cover sperm cryopreservation. However, even in the United Kingdom, where the national health system subsidizes sperm banking for young cancer patients, many young men are not given referrals.61 Even when sperm is banked, most studies suggest that a minority (up to 30%, but < 10% in most cohorts) of men return to use their stored specimens.41,62-64 Storage fees are rarely a reason that men have cryopreserved semen destroyed.65 In the absence of a heritable cancer syndrome, there is no evidence that a prior history of cancer increases the rate of congenital abnormalities or cancer in a man’s offspring.66 However, recent studies suggest the sperm of untreated men with cancer may have poor DNA integrity even before treatment.67,68 Small studies suggest transient higher rates of aneuploidy after chemotherapy and radiotherapy,69-71 though DNA integrity of sperm seemed similar to age-matched controls in one cohort of pediatric cancer survivors.72 Men should be advised of a possible, not yet quantifiable, higher risk of genetic damage in sperm stored after diagnosis of cancer or initiation of cancer therapy. In noncancer populations, there is no evidence of an increased risk of adverse outcomes if cryopreserved rather than fresh sperm are used for assisted reproductive techniques. Intracytoplasmic sperm injection (ICSI) allows successful fertilization with a single sperm but has raised concerns about the health of offspring conceived by this method. Although no studies have shown an increased rate of adverse outcomes compared with traditional in vitro fertilization techniques (both may be associated with a higher rate of major birth defects than unassisted conception),73 the technique is relatively new, and long-term follow-up of progeny is recommended.74,75
Fertility preservation options in females depend on the patient’s age, type of treatment, diagnosis, whether she has a partner, the time available and the potential that cancer has metastasized to her ovaries.76 The panel reviewed the available information supporting embryo and oocyte cryopreservation (with or without hormonal stimulation), ovarian tissue cryopreservation, ovarian suppression, ovarian transposition, and trachelectomy. Conservative surgical and radiation therapy approaches to specific cancers are also available but are not discussed further. Table 5 summarizes the options for fertility preservation in females. The Panel notes that due to requirements for scheduling and procedures, some interventions may entail a delay in cancer treatment and wishes to emphasize that early referral to a subspecialist can minimize this delay.
Embryo cryopreservation. Embryo cryopreservation is considered an established fertility preservation method as it has routinely been used for storing surplus embryos after in vitro fertilization for infertility treatment. This approach typically requires approximately two weeks of ovarian stimulation with daily injections of follicle-stimulating hormone from the onset of menses. Follicle development is monitored by serial ultrasounds and blood tests. At the appropriate time, an injection of HCG is administered to start the ovulatory cascade, and oocytes are subsequently collected by ultrasound guided transvaginal needle aspiration under intravenous sedation. Oocytes are fertilized in vitro and cryopreserved after fertilization. Because stimulation must be started at the onset of menses and takes two weeks, a delay of 2 to 6 weeks in chemotherapy initiation may be required if reproductive specialists do not see women early in their menstrual cycle. Most 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. A partner or sperm donor is also required. Live birth rates after embryo cryopreservation depend on the patient’s age and the total number of embryos cryopreserved and may be lower than with fresh embryos. Oocyte collection can be performed without ovarian stimulation ("natural cycle-IVF") but the embryo yield is extremely low.77,78 For women with hormone-sensitive tumors,79 alternative hormonal stimulation approaches such as letrozole or tamoxifen have been developed to theoretically reduce the potential risk of estrogen exposure. Short term breast cancer recurrence rates after ovarian stimulation using letrozole or tamoxifen concurrent with follicle stimulating hormone (FSH) administration have been compared to nonrandomized controls and no increase in cancer recurrence rates has been noted in these initial studies.77,78 Only a small percentage of cancer survivors have yet returned to utilize their embryos but the initial pregnancy rates are encouraging.77,79 Nevertheless, long-term follow-up with a larger number of patients is needed to evaluate the safety and efficacy of this approach. The panel also notes that letrozole and tamoxifen should not be given to a woman after pregnancy is established.80,81 Recently, standard ovarian stimulation with coapplication of a progestin-releasing IUD has been reported to allow successful preservation of embryos in a patient with endometrial cancer.82
Oocyte cryopreservation.
Ovarian tissue cryopreservation. One concern with reimplanting ovarian tissue is the potential for reintroduction of cancer cells. In patients without evidence of systemic metastasis to other organs, the likelihood of occult ovarian metastasis appears to be low in the majority of cancers seen in young females,99,100 and there are no reports of cancer recurrence after ovarian transplantation although fewer than 20 procedures are reported thus far. Thus, ovarian tissue screening to detect malignant cells should be performed to minimize the risk of inadvertent transfer with the ovary. In patients with high risk of ovarian involvement, xenografting and ex vivo follicle growth are experimental but not yet practical possibilities.101 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.
Ovarian suppression. Anecdotally, because GnRH analogs are readily available, this strategy has been used widely without clear evidence for efficacy or full understanding of the potential risks and benefits, especially in women with hormone sensitive tumors. At this time, since there is insufficient evidence regarding the safety and effectiveness of GnRH analogs and other means of ovarian suppression on female fertility preservation, women interested in ovarian suppression for this purpose are encouraged to participate in clinical trials.
Ovarian transposition.
Conservative gynecologic surgery. In the treatment of other gynecologic malignancies, interventions to spare fertility have generally centered on doing less radical surgery and/or lower dose chemotherapy with the intent of sparing the reproductive organs as much as possible for subsequent fertility. Reports are generally limited in size and lack randomized controls. However, they reveal no obvious increased risk of disease recurrence in women treated with fertility sparing approaches. For example, in the two largest published series of 212 women with malignant ovarian germ cell tumors, fertility-sparing surgery with or without chemotherapy did not appear to substantially affect the risk of recurrence compared with historical controls.124,125
Other considerations of fertility preservation options in females. There is concern that instrumentation of the pelvis to perform fertility preservation maneuvers can result in local spread of disease. In one case report, a woman with cervical adenocarcinoma developed an abdominal wall metastasis at the site of trocar insertion for laparoscopy done for ovarian transposition for fertility preservation.138 It is unclear how often this occurs however.
Discuss infertility as a potential risk of therapy. As 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 disposition.19,20,23,139 The few studies of oncologists’ practices of discussing infertility confirm patients’ reports. In clinical practice many oncologists do not mention even proven techniques such as sperm banking.48,140,141 Even when patients do recall infertility discussions, many are dissatisfied with the quality and amount of information provided.27,141,142 Almost all these studies rely on retrospective self-reports from either oncologists or cancer survivors, and the role of recall bias cannot be ascertained. Patients who participate in survey research are usually self-selected, affluent, well-educated, Caucasians.19,20 Furthermore, the participation rates by physicians have been very low, often under 33%, so that it is unclear whether the results are generalizable.48,141 Studies document many reasons why oncologists do not discuss infertility with the frequency that they discuss other treatment related complications such as neutropenia and cardiopulmonary toxicity. 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 survivors143 or believe that the cost of fertility preservation interventions is prohibitive. For example, 51% of oncologists in a United States study believed that most men could not afford to bank sperm because of out-of-pocket costs.141 However, oncologists overestimated these costs48 and their deterrent effect; in a companion survey of young men, only 7% cited financial reasons for not banking sperm.19 Oncologists are also less likely to refer patients for sperm banking if the cancer prognosis is poor141,144 or they believe that patients would not be interested for other reasons. Physicians’ emotional discomfort with discussing fertility issues may also play a role141 along with lack of knowledge and time. While the Panel recommends discussion about risks of treatment-induced infertility at the earliest possible opportunity, the Panel recognizes that raising this issue at the first encounter or at the time of diagnosis may not always be practical or wise. Clinician judgment should be employed in the timing of raising this issue, with the goal of discussion and referral at the earliest possible opportunity. While professional organizations such as the American Society for Reproductive Medicine and patient advocacy organizations such as Fertile Hope,145 Lance Armstrong Foundation/Livestrong, and the Susan G. Komen Breast Cancer Foundation 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 physician’s recommendation is a very strong predictor of whether a man banks sperm, almost as influential as the patient’s desire for children in the future.19,146 This finding is reminiscent of the important influence of physician recommendations in promoting smoking cessation and cancer screening147,148 and suggests that physician encouragement affects patient interest in fertility preservation options. An algorithm for triaging fertility preservation referrals is presented in Figure 1, and suggested talking points are illustrated in Table 3. 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, all guided by written protocols which can be shared with patients.149 Patients, and parents of minors, should not be provided with unrealistic expectations about their cancer prognoses, the success rates of fertility preservation interventions or the cost of attempting to preserve fertility, and the option of declining fertility preservation interventions should also be discussed. Potential legal issues, such as ownership of embryos and reproductive tissue in the event of a patient’s death, divorce or incapacity, should also be discussed by the reproductive specialist.
Answer basic questions about whether fertility preservation options decrease the chance of successful cancer treatment, increase the risk of maternal or perinatal complications, or compromise the health of offspring. There have been many published reports regarding parental outcome after interventions to spare fertility through cancer treatment and/or pregnancy following cancer. However, available studies are generally limited to case reports and small series. The few larger studies addressing these issues have generally been comprised of heterogeneous patient populations, retrospective in nature, with relatively short-term follow-up, and lacking randomized controls. Available data are reassuring, however, in that there is no clear increased risk to a survivor’s health from available interventions to preserve fertility or from subsequent pregnancy, beyond that of normal populations with similar comorbidities. In light of the long-term organ toxicity that may result from cancer and cancer therapy, pregnancy after cancer treatment may be complicated by an increased risk of organ impairment, especially of the heart, lungs, and uterus. For example, there is evidence that pregnancy may increase the risk of worsening cardiac ejection fraction in women treated with doxorubicin for childhood cancer,150 and uterine or total-body irradiation appears to increase the risk of miscarriage, prematurity and low birth weight.151-154 While several studies have revealed no evidence that use of cryopreserved sperm regardless of mode of extraction or fertilization technique has a detrimental effect on perinatal health of offspring or mother, the available data regarding the effects of female fertility sparing interventions on maternal or fetal perinatal health are limited. The major risk that has been recognized appears to be an increased risk of cervical incompetence, miscarriage, prematurity and low birth weight in women with lower gynecologic malignancies who have undergone conservative surgery such as trachelectomy for fertility preservation,122,155-157 and the health risks associated with a higher rate of multiple births after assisted reproductive technology. Short and long-term follow-up following fertility sparing interventions for women with cancer is warranted. At the present time, in light of concerns, women with a history of cancer and cancer treatment should be considered high risk for perinatal complications and would be prudent to seek specialized perinatal care. Aside from hereditary genetic syndromes, however, there is scant evidence that a history of cancer, cancer therapy, or fertility interventions increases the risk of problems in the progeny. Available studies including large registry studies have revealed no increased risk of genetic abnormalities, birth defects, or cancers, aside from hereditary syndromes, in the children of cancer survivors.72,152,158-161 Data regarding the effects of interventions to spare parental fertility on the health of the progeny are limited to case reports and small series with relatively short follow-up. At present, there does not appear to be a clear detrimental effect from any of the available fertility sparing interventions. However, patients should be encouraged to participate in registries and clinical studies as available to define further the safety of fertility preservation interventions and strategies.
As needed, refer patients to reproductive specialists and psychosocial providers. 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. Research on infertility patients has shown that structured, cognitive-behavioral counseling can reduce anxiety and depression.163-165 The American Society for Reproductive Medicine has both a Fertility Preservation Special Interest Group (http://www.asrm.org/Professionals/PG-SIG-Affiliated_Soc/fpsig/fpsig_index.html) and a Mental Health Professional Group (http://www.asrm.org/Professionals/PG-SIG-Affiliated_Soc/MHPG/index.html).
Consensus statements have also been developed by some professional societies, including the British Fertility Society (http://www.britishfertilitysociety.org.uk/practicepolicy/documents/fccpaper.pdf),166 the European Society of Human Reproduction and Embryology (ESHRE) Task Force (http://www.eshre.com), and the American Society for Reproductive Medicine.162,167 The Panel has evaluated the Guidelines produced by reproductive specialist societies and found them to be consistent with the ASCO guidelines.
Fertility preservation is often possible in people undergoing treatment for cancer. Broader application of fertility preservation methods is limited by several factors: lack of knowledge about the risk of infertility with current cancer treatments, failure to discuss and consider options before treatment, lack of insurance coverage for most procedures with consequent high out of pocket costs, and the investigational status of many fertility preservation methods. The Panel recommends that oncologists discuss at the earliest opportunity the possibility of infertility as a risk of cancer treatment, recognizing that in many cases, adequate data are not available to provide accurate predictions for any one individual. For patients at risk for infertility who are interested in evaluating their options for fertility preservation, referral to appropriate specialists as early as possible is recommended. People attempting fertility preservation in the context of cancer treatment are encouraged to enroll in clinical trials that will advance the state of knowledge. Figure 1 and Table 3 provide additional guidance to oncologists in initial discussions. Supplementary materials available for public use such as a summary of guidelines, slide set, and patient information may be found on ASCO’s Web site (http://www.asco.org).
Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed discription of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
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ABSTRACT
INTRODUCTION
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