A nationwide survey of oncologists regarding treatment-related infertility and fertility preservation in female cancer patients

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1 A nationwide survey of oncologists regarding treatment-related infertility and fertility preservation in female cancer patients Eric J. Forman, M.D., a Carey K. Anders, M.D., b and Millie A. Behera, M.D. a a Department of Obstetrics and Gynecology, Duke University Medical Center, Durham; b Department of Medicine, University of North Carolina, Chapel Hill, North Carolina Objective: To survey oncologists regarding their knowledge and practice patterns concerning fertility preservation for female cancer patients. Design: An online survey was sent to oncologists at cancer centers ranked by U.S. News & World Report. Setting: Oncologists who treat women of reproductive age at academic medical centers. Patient(s): None. Intervention(s): None. Main Outcome Measure(s): Counseling and referral practices of oncologists regarding fertility risks among young women with cancer. Results: Most (95%) of the 249 responding oncologists routinely discuss a treatment s impact on fertility; 1,701 surveys were sent. Although 82% have referred patients to reproductive endocrinologists, more than half rarely refer. When planning treatment, 3 rarely consider a woman s desire for fertility. Gynecologic oncologists were more likely to routinely consider fertility compared with other oncologists (93% vs. ). Gynecologic oncologists also were more likely to provide a less effective regimen to better preserve fertility (61% vs. 37%). Most oncologists (86%) would be willing to sacrifice less than a 5% reduction in disease-free survival if a regimen offered better fertility outcomes; 36% felt patients would be willing to sacrifice >5%. Conclusion(s): Although most oncologists at academic medical centers discuss the risk of infertility with female patients, referrals to reproductive endocrinologists are rare. Gynecologic oncologists may be more likely than others to consider modifying treatment to preserve fertility. According to oncologists, patients may be willing to sacrifice more in survival than they would. (Fertil Steril Ò 2010;94: Ó2010 by American Society for Reproductive Medicine.) Key Words: Fertility preservation, oncofertility, survey, infertility, cancer, oncologists In recent years there has been a heightened interest in improving the quality of life of cancer survivors. Fertility is one area that has received significant attention. It is estimated that up to 52,000 women under age 40 are diagnosed with cancer each year (1). Meanwhile, the average age of first childbirth has been steadily increasing, from 21.4 in 1970 to 25.0 in 2001, according to the Centers for Disease Control and Prevention. These trends, coupled with improving survival rates from various forms of cancer, have led to an increasing number of women with cancer with an interest in future fertility. These trends also led to the recognition of oncofertility, a movement that is dedicated to preserving fertility for cancer survivors (2). Although certain types of cancer treatment, for example, totalbody irradiation or high doses of alkylating agents, are more likely to result in infertility via premature ovarian failure, advances in reproductive medicine provide some hope for the preservation of fertility after treatment. In vitro fertilization with embryo cryopreservation is an established technique that, in certain cases, can be performed before gonadotoxic therapy. Techniques such as oocyte cryopreservation, ovarian tissue cryopreservation, and ovarian suppression with gonadotropin-releasing hormone (GnRH) agonists are available at Received July 25, 2009; revised September 24, 2009; accepted October 5, 2009; published online November 27, E.J.F. has nothing to disclose. C.K.A. has nothing to disclose. M.A.B. is a speaker and investigator for Insightec. Reprint requests: Eric J. Forman, M.D., Duke University Medical Center, Box 3616, Durham, NC (FAX: ; eric. forman@duke.edu). some centers. The American Society of Clinical Oncology (ASCO) and the American Society for Reproductive Medicine (ASRM) have recommended that the impact of cancer treatments on fertility be addressed with all cancer patients of reproductive age, and that options for fertility preservation, such as embryo cryopreservation, be discussed routinely (3, 4). Despite these strong recommendations, surveys have shown that many patients with cancer do not recall having had a discussion related to fertility before treatment. There have been several published surveys of patients on the topic, but knowledge is limited regarding oncologists practice patterns related to treatment-related infertility and fertility preservation options. Prior surveys of oncologists had focused on pediatric patients and sperm cryopreservation in men with cancer (5 7). We previously published results of a pilot survey of oncologists at a single academic institution, specifically focusing on women with cancer (8). That survey demonstrated that although oncologists universally recognized the importance of counseling regarding fertility preservation, referrals to reproductive endocrinologists were rare. Herein we present results of a nationwide survey of oncologists at academic medical centers to assess their practice patterns regarding fertility preservation in women with cancer. MATERIALS AND METHODS Based on results from our pilot survey, a 29-item survey was developed. The study was reviewed and exempted by the institutional review board at Duke University. A database of 1,701 oncologists was created by searching publicly available addresses from oncology departments at the top Fertility and Sterility â Vol. 94, No. 5, October /$36.00 Copyright ª2010 American Society for Reproductive Medicine, Published by Elsevier Inc. doi: /j.fertnstert

2 TABLE 1 FIGURE 1 Demographics. Number Percent How often do you refer patients to a reproductive endocrinologist or obstetrician/gynecologist who specializes in fertility? Total surveys sent 1,701 Responses Specialty Gynecologic Oncology Medical Oncology Pediatric Oncology Radiation Oncology Surgical Oncology Other Experience, y Still in fellowship < > Age, y > Gender Male Female Number of premenopausal women treated with chemotherapy yearly None < > Number of premenopausal women treated with radiotherapy yearly None < > cancer hospitals as ranked by U.S. News & World Report. Surveys were sent via on three occasions from October 2007 through January Data were collected and analyzed using Survey Monkey (Portland, OR), an online survey tool. Statistical analysis was performed by Duke Research on Research with SPSS version 13 for Windows, using Pearson chi-square test and Fisher s exact test. A value of P<.05 was considered significant. Primary variables included answers to the questions, How often do you discuss the impact a female patient s condition and/or treatment will have on her future fertility?, How often do you refer patients to a reproductive endocrinologist or obstetrician/gynecologist who specializes in fertility?, How often do you consider a patient s desire for future fertility when planning her treatment regimen for cancer?, and Are you ever willing to provide a less effective treatment regimen in order to attempt to preserve a woman s fertility? Multiple selections were listed as reasons for those who did not always discuss fertility or refer their patients. Additional questions addressed demographic factors, appropriate time intervals for referrals to be seen, knowledge of gonadotoxic regimens, and fertility-preservation options. Question types included yes/no, true/false, multiple choice, fourpoint Likert scale (always, usually, rarely, never). Number of Physicians % 43.3% 33.2% Never Rarely Usually Always Reported Frequency 5.8% RESULTS The response rate was 15% (249/1,701), with nearly half being medical oncologists. At least 103 addresses were incorrect or undeliverable, 38 recipients were away or not accepting s, and 24 recipients opted out. Responses were not obtained from 1,249 recipients for unknown reasons. Table 1 summarizes the demographics of the respondents. Overall, 95% of oncologists report that they routinely (always or usually) discuss the impact a female patient s condition and/or treatment will have on her fertility with no significant differences by gender, age, experience level, or specialty. Reasons listed for not discussing infertility included poor prognosis (3), need to initiate therapy in 1 to 2 weeks (22%), patient already has a child (1), poor success of fertility preservation options (8%), too young to have children (7%), limited knowledge of fertility risks (6%), lack of availability of reproductive services (5%), cost of fertility preservation is prohibitive (4%), patient is a lesbian (2%), patient is not married (1%). Referrals to reproductive endocrinologists are routinely made 39% of the time, whereas 18% of oncologists never refer their patients (Fig. 1). These rates did not vary significantly by gender, age, experience level, or specialty. The most common cited reasons for not referring included lack of patient interest in fertility preservation (38%), lack of time because of emergent need to start therapy (28%), and poor prognosis for future fertility (6%). When referrals are made, however, oncologists expect their patients to be seen in an expedited fashion, with 94% expecting referrals to be completed within a week. Reproductive endocrinology services are available within the same facility according to 78% of respondents and within 25 miles for an additional 2. When planning treatment, 33% always, 34% usually, and 3 rarely consider a woman s desire for fertility, with no differences based on provider gender or experience level. Gynecologic oncologists were more likely to routinely consider fertility compared with other oncologists (93% vs., P<.001). Gynecologic oncologists also were more likely to provide a less effective regimen in an attempt to better preserve fertility (61% vs. 37%, P¼.008). Oncologists who treat more female patients, such as those who specialize in breast cancer, were more likely to consider less effective regimens when compared with leukemia Fertility and Sterility â 1653

3 FIGURE 2 Estimated Risk of Permanent Amenorrhea in 32-Year-Old Woman with Breast Cancer. Risk quoted in Lee et al., CMF (cy clophosphamide, methotrexate, 5-fluorouracil) x 6 cy cles A C (doxorubicin, cy clophosphamide) x 4 cy cles 1 High Risk (>8) Intermediate Risk (20-8) Lo we r Risk (<2) AS CO Ri sk Ca te go ry specialists (63% vs. 31%, P¼.01), who have a mixed patient population. Only 9% of pediatric oncologists would be willing to consider less effective regimens, compared with 48% of all other oncologists (P<.001). Nearly half (48%) of oncologists would be willing to sacrifice 1% to 5% of disease-free survival in a potentially curable cancer if a treatment offered better fertility outcomes, with 38% willing to sacrifice less than 1%; 42% felt their patients would be willing to sacrifice 1% to 5% survival, and 35% felt they would sacrifice greater than 5% (P<.05). More than 9 of oncologists stated that they were very knowledgeable or aware of fertility preservation options, specifically embryo, oocyte, and ovarian tissue cryopreservation and pretreatment with GnRH agonists. Yet this knowledge does not seem to have been gained by personal experience, as only 17% have experience with embryo cryopreservation, the most established technique. Interestingly, 22% report personal experience with GnRH agonists, a technique that is considered investigational. When ascribing risk of gonadotoxicity from specific regimens, there were gaps in knowledge. Hypothetic cases were devised using risk categories described in the published recommendations of the American Society of Clinical Oncology (3). Oncologists were asked to ascribe a risk of permanent amenorrhea in an otherwise healthy 32-year-old woman diagnosed with breast cancer after four cycles of AC (doxorubicin, cyclophosphamide). Although the estimated risk per ASCO guidelines is less than 2, only 36% of responders categorized risk correctly. Although the risk of permanent amenorrhea following CMF (cyclophosphamide, methotrexate, 5-fluorouracil) is 2 to 8 for an otherwise healthy 32-year-old woman, 62% of responders classified risk appropriately (Fig. 2). Discrepancies in risk assignment were also observed when predicting permanent amenorrhea in a slightly older 42-year-old woman. Although the rates of permanent amenorrhea are 2 to 8 and greater than 8 for AC and CMF, respectively, only 54% and 52% assigned the correct risk category (Fig. 3). Both AC and CMF regimens contain an alkylating agent, which was correctly identified as the most gonadotoxic class of chemotherapeutics by 82% of respondents. Finally, although ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) for Hodgkin s disease is considered a lower risk regimen with less than 2 chance of permanent amenorrhea, two-thirds of respondents incorrectly categorized it as an intermediate- or high-risk regimen (Fig. 4). The vast majority (97%) of respondents agreed with ASCO and ASRM guidelines that oncologists have a responsibility to inform patients about the risk that cancer treatment may affect fertility. There seems to be broad interest in further education on this topic, with 75% of respondents expressing interest in attending future seminars on fertility preservation in female cancer patients. DISCUSSION This study represents the first published survey of oncologists from centers across the country that specifically focuses on current knowledge and practices regarding treatment-related infertility and fertility preservation in women. Similar to the results of a previous pilot survey, most oncologists routinely discuss these issues; however, referrals to reproductive specialists are not the norm. Further research is indicated to elucidate the barriers to referrals, especially because fertility experts were usually located within the same academic center. The finding that different specialties are more likely to consider fertility and potentially alter their regimens also raises questions. Are there differences in training among the specialties that produce these differences? Or are clinicians who treat more women, such as gynecologic oncologists and those who specialize in breast cancer, more attuned to the wishes of female patients? Pediatric oncologists were significantly less likely to alter their treatment regimens. This is not surprising, as proven techniques such as embryo cryopreservation are not available to prepubertal females. Additionally, pediatric oncologists and parents may prioritize long-term survival more than adults Forman et al. Survey of oncologists on fertility preservation Vol. 94, No. 5, October 2010

4 FIGURE 3 Estimated Risk of Permanent Amenorrhea in 42-Year-Old Woman with Breast Cancer. Risk quoted in Lee et al., CMF (cy clophosphamide, methotrexate, 5-fluorouracil) x 6 cy cles A C (doxorubicin, cy clophosphamide) x 4 cy cles High Risk (>8) Intermediate Risk (20-8) Lo w er Risk (<2) ASCO Risk Category Our previous pilot survey indicated that physicians who had attended a seminar addressing fertility preservation in cancer patients may be more likely to alter treatment regimens to better preserve fertility (8). The current survey showed that oncologists have limited personal experience with fertility preservation techniques. It also highlighted possible confusion surrounding the risks of amenorrhea from specific chemotherapy regimens. It is encouraging that 75% of respondents to the current survey expressed interest in attending such an educational seminar. The results of this survey also suggest a difference in how clinicians and their patients view fertility after cancer. Although the most common reason cited for not referring patients was their lack of interest in fertility preservation, previous patient surveys indicate a strong interest in this area. One survey, for example, found that 73% of women with breast cancer were at least somewhat concerned about infertility after treatment (9). Beyond possible benefits on fertility, counseling on fertility preservation options may be important in helping patients cope with their condition and therapy. One study, for example, found that men who banked their sperm felt it was a positive factor in coping emotionally with cancer (10). Although 1 of oncologists cited having previous children as a reason not to discuss fertility, patient surveys indicate that women who already have children may be more distressed by infertility, as they may have a strong desire to complete their family or have a new partner (11). Although only listed by a small number of oncologists, sexual orientation, marital status, and age may not be valid reasons FIGURE 4 Estimated Risk of Permanent Amenorrhea in 34-Year-Old Woman with Hodgkin s Disease. Risk quoted in Lee et al., High Risk (>8) Intermediate Risk (20-8) AS CO Ri sk Ca te go ry Lo w er Risk (<2) A BVD (doxorubicin, bleomycin, vinblastine, dacarbazine) Fertility and Sterility â 1655

5 for deferring a discussion of the impact of treatment on fertility. Only 4% of respondents cited cost of reproductive services as a reason not to discuss risks. Oncologists who responded were willing to sacrifice less in survival than they thought their patients would to preserve fertility. There is some evidence in the literature that patients are willing to consider less aggressive regimens. One patient survey, for example, found that, 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 (9). Further research is indicated to clarify the reasons for this discrepancy. To date, there have been few surveys addressing oncologists knowledge and practices regarding fertility preservation. Two published surveys of oncologists focused on sperm cryopreservation for male cancer patients (6, 7). These surveys indicated that fewer than half routinely offered sperm banking, and only 26% were aware of intracytoplasmic sperm injection. Additionally, a survey conducted among pediatric oncology providers regarding fertility issues in pediatric cancer patients found that only 35% of providers currently consulted with reproductive specialists, whereas 93% indicated a desire to do so in the future (5). A recent study in the United Kingdom reviewed data forms for over 1,000 patients collected prospectively from pediatric oncologists (12). Although the effect of cancer treatments on fertility was discussed with 63% of patients regardless of gender, only 1% of newly diagnosed girls were referred to a reproductive specialist. Studies featuring interviews of pediatric and adult oncologists on their opinions regarding fertility preservation indicated that referrals for fertility preservation are not routinely made (13, 14). There are several limitations to the current study. Only clinicians at academic centers were surveyed, and their practices may not reflect practices in the community, especially in locations where reproductive services are not readily available. One could hypothesize that referrals to reproductive specialists might be even rarer in communities where these providers are less accessible. There may be reporting bias as answers were based entirely on the respondents recollection and not objective data from patient charts. Finally, there may be selection bias; perhaps clinicians with an interest in this area were more likely to respond. Nevertheless, this survey provides valuable insight into oncologists beliefs and practices. It provides compelling evidence that they agree with ASCO s recommendations and are interested in further education. Further research is necessary to identify barriers to referrals for fertility preservation and to encourage increased collaboration between oncologists and reproductive specialists. REFERENCES 1. 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