Abstract
Background
Fertility preservation (FP) is an infrequently addressed issue for young adults with primary brain tumors. Given the improved prognosis and enhanced technology in reproductive medicine, more primary brain tumor patients see procreation as feasible, making the discussion of FP increasingly important. The goals of this study were to describe patients who received FP counseling by a fertility nurse specialist (FNS) and determine which sociodemographic and disease-related factors predict acceptance of referral to a reproductive specialist.
Methods
Institutional review board-approved retrospective review of primary brain tumor patients, ages 18 to 45, who were referred for FP counseling with a FNS from 2009 to 2013.
Results
Seventy patients were referred for FP counseling: 38 men, 32 women, with a median age of 32 years and median KPS of 90. Eighty-nine percent had gliomas; 58% grade III, 17% grade IV. Sixty-seven percent were referred for counseling at initial diagnosis. Of those referred, 73% accepted referral to a sperm bank (87% of men) or reproductive endocrinologist (56% of women). Patients were more likely to accept referral if they had no prior children (P = .048). There was no statistically significant difference in referral acceptance by age, race/ethnicity, marital status, religion, or tumor grade. After treatment, 3 men conceived naturally, 2 men conceived using banked sperm, and 2 women conceived naturally.
Conclusions
Despite the historically poor prognosis of patients with primary brain tumors, there is significant interest in FP among these patients, particularly if they have no prior children. Clinicians should develop strategies to incorporate FP counseling into practice.
Keywords: fertility, fertility preservation, primary brain tumor, young adult
Fertility preservation is a well-recognized but infrequently addressed clinical issue for young adults facing cancer therapy, particularly if they have a brain tumor. The American Society of Clinical Oncology (ASCO) recommends that healthcare providers discuss treatment-related fertility risks and fertility preservation (FP) options with all patients of reproductive age as early as possible in the treatment course and refer those who are interested to reproductive specialists.1,2 Receiving counseling about fertility before cancer treatment significanty reduces long-term regret about FP decisions and improves quality of life after treatment in women of reproductive age.3 However, initiating these discussions with patients who have poor prognoses or advanced disease, such as patients with primary brain tumors, can be challenging for or seem inappropriate to many oncologists.4
Patients with primary brain tumors are at risk for infertility because of the potential damaging effects on the hypothalamic-pituitary axis by tumor infiltration, cranial surgery, and radiotherapy.5,6 In addition, chemotherapy, particularly alkylating agents such as temozolomide, commonly used in the treatment of primary brain tumors, can impair sperm production in men or deplete the pool of ovarian oocytes in women.5,7 However, despite these potential risks, there are few data about fertility outcomes in brain tumor patients. Case reports of both men and women who have produced healthy children after treatment with temozolomide and radiotherapy have been published, but no large, population-based studies have been performed.8,9
Given the risk of treatment-induced infertility, patients wih primary brain tumors should be counseled regarding FP. However, despite ASCO recommendations, neuro-oncologists may be reluctant to discuss it with brain tumor patients given their presumed shortened life expectancy, fear of delaying treatment, and concern about sending mixed messages to patients about their prognosis.4 In addition, there have been small series and case reports that suggest possible glioma progression during pregnancy,10,11 which may inhibit clinicians from discussing FP with their female patients, in particular.
Advances in the diagnosis and treatment of primary brain tumors have led to significant periods of disease control, particularly for young adults with low-grade gliomas. Given the improved prognosis and enhanced technology in reproductive medicine, more young adults with primary brain tumors see future family building as feasible, making the discussion of FP increasingly important.
To address this emerging need, in 2009, Memorial Sloan Kettering Cancer Center (MSKCC), a large urban NCI-designated comprehensive cancer center, established a Cancer and Fertility Program led by a fertility nurse specialist (FNS). The FNS provides clinicians with education, resources, and assistance to support them in informing patients about the effects of treatment on fertility and FP options, and in making referrals to reproductive specialists. The FNS is also available to provide education and counseling to patients who want more detailed information, and to facilitate referrals and coordinate care as needed.
The goals of this study were to (i) describe characteristics of the primary brain tumor patients who received fertility counseling by the FNS, (ii) determine which patients accepted referral to a reproductive specialist (i.e, sperm bank for men and reproductive endocrinologist for women), (iii) identify sociodemographic or disease-related factors that could predict acceptance of referral to a reproductive specialist, and (iv) report reproductive outcomes in those patients for whom data were available.
Methods
This was an IRB-approved retrospective review of primary brain tumor patients, ages 18 to 45, who received counseling with the FNS at MSKCC between 2009 and 2013. Factors that could influence the likelihood of acceptance of a referral to a reproductive specialist such as gender, race/ethnicity, Karnofsky Performance Score (KPS), marital status, prior children, religion, tumor histology, and tumor grade were selected a priori and evaluated. Fisher's exact test was used to calculate P values for categorical variables and a t-test was used to calculate P values for continuous variables.
Results
Patient Population
Between 2009 and 2013 there were 960 unique patients with primary brain tumors between the ages of 18 and 45 evaluated in the Neurology Department of MSKCC. Any of these patients were eligible for referral to the FNS for fertility counseling by the patient's neuro-oncologist. As awareness of the Cancer and Fertility Program grew, there was a trend toward increasing numbers of referrals to the FNS each year (Fig. 1). Seventy patients (7%) received formal FP counseling with the FNS during this time. The number of additional patients who were offered counseling with the FNS and declined is unknown.
Fig. 1.
Primary brain tumor patients who received counseling by the fertility nurse specialist by year.
Characteristics of Patients who Received Fertility Counseling
There were 38 men and 32 women who were referred to the FNS. The median age of the patients was 32 and the median KPS was 90 (range 70–100) (Table 1). Forty-six percent of patients were married at the time of referral, 79% had no prior children, and 54% identified with a formal religion. The most common tumor histology was glioma (89%), 75% of which were malignant (58% WHO Grade III, 17% WHO Grade IV). For patients with malignant gliomas, the most commonly planned tumor-directed therapy was focal brain radiotherapy (∼54–60 Gy in 30 fractions) with concurrent temozolomide (75 mg/m2) followed by adjuvant temozolomide for a minimum of 12 months. Other tumor types represented in the sample included central nervous system lymphoma, ependymoma, meningioma, and pineoblastoma. Sixty-six percent of patients were referred to the FNS for counseling at initial diagnosis and 34% at tumor progression. Of the 23 patients referred at tumor progression, 10 had not received any prior adjuvant treatment, and 4 had received radiotherapy, but no prior chemotherapy.
Table 1.
Characteristics of patients who received counseling by the fertility nurse specialist
| All (n = 70) | Men (n = 38) | Women (n = 32) | ||||
|---|---|---|---|---|---|---|
| Median age at referral, years | 32 | 31.5 | 32.5 | |||
| Age range, years | 18–45 | 18–45 | 20–44 | |||
| Median KPS (range) | 90 (70–100) | 90 (70–100) | 90 (70–100) | |||
| Race/Ethnicity | ||||||
| Caucasian | 55 | 79% | 28 | 74% | 27 | 84% |
| African-American | 1 | 1% | 0 | 0% | 1 | 3% |
| Hispanic | 4 | 6% | 3 | 8% | 1 | 3% |
| Asian | 7 | 10% | 5 | 13% | 2 | 7% |
| Unknown | 3 | 4% | 2 | 5% | 1 | 3% |
| Histology | ||||||
| Glioma | 62 | 89% | 34 | 90% | 28 | 88% |
| Oligodendro-glioma subtype | 16 | 26% | 6 | 18% | 10 | 36% |
| CNS lymphoma | 2 | 3% | 2 | 5% | 0 | 0 |
| Ependymoma | 3 | 4% | 2 | 5% | 1 | 3% |
| Meningioma | 1 | 1% | 0 | 0% | 1 | 3% |
| Other/Unknown | 2 | 3% | 0 | 0% | 2 | 6% |
| Tumor grade | ||||||
| WHO I | 1 | 1% | 1 | 3% | 0 | 0 |
| WHO II | 12 | 17% | 3 | 8% | 9 | 28% |
| WHO III | 40 | 58% | 25 | 66% | 15 | 46% |
| WHO IV | 12 | 17% | 7 | 18% | 5 | 16% |
| No pathology | 5 | 7% | 2 | 5% | 3 | 10% |
| Time of referral | ||||||
| Prior to adjuvant treatment | 55 | 79% | 28 | 74% | 27 | 84% |
| After initiation of adjuvant treatment | 13 | 18% | 9 | 24% | 4 | 13% |
| Unknown | 2 | 3% | 1 | 2% | 1 | 3% |
| Marital status | ||||||
| Married | 32 | 46% | 15 | 39% | 17 | 53% |
| Single | 27 | 38% | 17 | 45% | 10 | 31% |
| In a relationship | 11 | 16% | 6 | 16% | 5 | 16% |
| Prior children | ||||||
| 0 | 55 | 79% | 33 | 87% | 22 | 69% |
| 1 | 10 | 14% | 3 | 8% | 7 | 22% |
| 2 | 5 | 7% | 2 | 5% | 3 | 9% |
| Religion | ||||||
| Christian | 13 | 19% | 6 | 16% | 7 | 23% |
| Catholic | 18 | 26% | 9 | 24% | 9 | 28% |
| Jewish | 4 | 6% | 3 | 8% | 1 | 3% |
| Muslim | 1 | 1% | 0 | 0% | 1 | 3% |
| Hindu | 2 | 3% | 2 | 5% | 0 | 0 |
| Other/Unknown | 1 | 1% | 0 | 0 | 1 | 3% |
| No religion specified | 31 | 44% | 18 | 47% | 13 | 40% |
Of the brain tumor patients in this age group who were not referred to the FNS and for whom data was available, the median age at evaluation at MSKCC was 35, 61% were married, and 69% identified with a formal religion. Glioma was the most common tumor histology (86%). Standardized information regarding KPS and prior children was not available for these patients.
Characteristics of Patients who Accepted Referral to a Reproductive Specialist
Of the 70 patients who received FNS counseling, 51 (73%) accepted referral to a reproductive specialist (Table 2). Thirty-three (87%) of the men went to a sperm back and 18 (56%) of the women met with a reproductive endocrinologist. There was no statistically significant difference in referral acceptance by age (P = .37), KPS (P = .43), race/ethnicity (P = .75), marital status (P = .58), religion (P = .79), or tumor grade (P = 1.0). Men and women were more likely to accept referral to a reproductive specialist if they had no prior children (P = .048). Ninety-one percent of men and 72% of women with no prior children accepted referral for sperm banking and reproductive endocrinology, respectively.
Table 2.
Characteristics of patients by acceptance of referral to reproductive specialist
| Accepted Referral (n = 51) | Declined Referral (n = 19) | |||
|---|---|---|---|---|
| Median age | 32 | 35 | ||
| Sex | ||||
| Men | 33 | 5 | ||
| Women | 18 | 14 | ||
| Median KPS (range) | ||||
| 90 (70–100) | 90 (70–100) | |||
| Race/Ethnicity | ||||
| Caucasian | 41 | 80% | 14 | 73% |
| African-American | 0 | 0% | 1 | 5% |
| Hispanic | 2 | 4% | 2 | 11% |
| Asian | 5 | 10% | 2 | 11% |
| Unknown | 3 | 6% | 0 | 0% |
| Histology | ||||
| Glioma | 45 | 88% | 17 | |
| Oligodendro-glioma subtype | 10 | 22% | 6 | 89% |
| CNS lymphoma | 2 | 4% | 0 | 35% |
| Meningioma | 1 | 2% | 0 | 0% |
| Ependymoma | 1 | 2% | 2 | 0% |
| Other/Unknown | 2 | 4% | 0 | 11% |
| Tumor Grade | ||||
| WHO I | 1 | 2% | 0 | 0% |
| WHO II | 8 | 16% | 4 | 0% |
| WHO III | 30 | 58% | 10 | 21% |
| WHO IV | 8 | 16% | 5 | 53% |
| Unknown/NA | 4 | 8% | 0 | 26% |
| Time of referral | ||||
| Prior to initiation of adjuvant treatment | 42 | 82% | 14 | 74% |
| After initiation of adjuvant treatment | 7 | 14% | 5 | 26% |
| Unknown | 2 | 4% | 0 | 0% |
| Marital status | ||||
| Married | 21 | 41% | 11 | 58% |
| Single | 21 | 41% | 6 | 32% |
| In a relationship | 9 | 18% | 2 | 10% |
| Prior children | ||||
| 0 | 43 | 84% | 12 | 63% |
| 1 | 6 | 12% | 4 | 21% |
| 2 | 2 | 4% | 3 | 16% |
| Religion | ||||
| Christian | 7 | 14% | 6 | 32% |
| Catholic | 15 | 29% | 3 | 16% |
| Jewish | 4 | 8% | 0 | 0% |
| Hindu | 2 | 4% | 0 | 0% |
| Muslim | 0 | 0% | 1 | 5% |
| Other/Unknown | 1 | 2% | 0 | 0% |
| No religion specified | 22 | 43% | 9 | 47% |
Reproductive Outcomes
Five men in our sample conceived children after treatment; three men conceived naturally after undergoing tumor-directed treatment with resection, radiation, and chemotherapy, and two conceived with banked sperm. Of the patients who used banked sperm for conception, one had developed azoospermia after treatment with 6 cycles of temozolomide followed by thiotepa, busulfan, and autologous stem cell transplant, and the other desired conception while undergoing active treatment with temozolomide. The 6 children conceived by these 5 patients are healthy to the best of our knowledge.
While there were 18 women who were evaluated by reproductive endocrinologists, FP procedures could not be confirmed for all of these patients. At least 7 women underwent oocyte cryopreservation and 1 woman underwent embryo cryopreservation. At least 1 patient considered ovarian tissue preservation. To date, no women in this sample have conceived children from cryopreserved oocytes or embryos. Of the 18 women who accepted referral to a reproductive endocrinologist, 14 are alive, 1 is deceased, and the vital statuses of 3 women are unknown.
In our study population, 2 women with primary brain tumors naturally conceived children without the use of reproductive technology. Prior to conception, 1 patient underwent surgical resection and focal radiation therapy without chemotherapy for her brain tumor and the other was treated with surgical resection. Neither patient received chemotherapy prior to conception.
Discussion
Despite the ASCO guidelines highlighting the importance of discussing FP with all patients of reproductive age prior to starting cancer treatment that may impair fertility, there are persistent challenges in ensuring patients receive this information. This is particularly true for patients with poor prognoses. At our institution, the overall percentage of patients with primary brain tumors who were referred for counseling with the FNS was low, 7%, a trend that has been documented previously in the systemic cancer population. Prior studies performed in the broader cancer patient population confirm that less than half of patients receive adequate information regarding FP prior to initiation of treatment.12 Physicians commonly state that lack of knowledge about FP, uncertainty about the success of FP, limited time for discussion, fear that FP will delay treatment, and concern that patients may not be able to afford FP procedures are barriers to having discussions with patients about FP. Furthermore, many oncologists feel that discussions of FP are inappropriate for patients with advanced disease, poor prognoses, and functional limitations.12,13 While our study did not assess physician attitudes about FP discussions, we suspect that physicians selectively offer fertility counseling to patients who are more likely to have a longer survival from their brain tumors and are in a better position to function as a parent, as supported by the fact that all patients in our study who were referred to the FNS had a KPS of at least 70 and median KPS was 90. Also, of the patients referred to the FNS, 79% had no children, which suggests that neuro-oncologists may be more likely to discuss FP with patients who have not started a family prior to diagnosis.
The percentage of patients receiving FNS counseling increased from 2% in 2009 to 17% in 2013, which is based on the annual denominator of patients evaluated at the institution. The FNS has helped to educate physicians about FP and has provided patients with dedicated time and resources to fully understand FP options. The FNS also expedites referrals to sperm banks or reproductive endocrinologists so that FP is feasible without requiring a delay in treatment. A growing understanding among our neuro-oncologists of the role the FNS can play in facilitating FP discussions may also explain this increase over time. While the FNS is a valuable resource for physicians and patients, if a neuro-oncologist feels equipped with the appropriate knowledge of FP options and procedures, he or she may proceed with direct referral of a patient for FP without interim consultation with the FNS.
Limited data were available on the reasons the other 890 primary brain tumor patients in this age group did not receive counseling, so it could not be determined if this was because the risk of infertility was not discussed by the neuro-oncologist, the patient was offered and declined the counseling, or pursued fertility preservation independently such as going directly to a sperm bank after discussion with the neuro-oncologist.
A key finding in our study was the significant interest in FP among our sample of patients. Of those patients who received counseling by the FNS, the majority (73%) accepted referral to a reproductive specialist. This may illustrate the value of providing in-depth information about options to aid in decision-making. Men were more likely to accept referral to a sperm bank (87%) than women to a reproductive endocrinologist (56%), likely related to the relative ease of sperm banking as compared with the more complicated, invasive, and expensive procedures of oocyte, embryo, and ovarian tissue preservation in women. Also, given the potential risk of pregnancy on brain tumor growth,11,14 women may be more reluctant to become pregnant, thus affecting their decisions about whether to pursue FP procedures. However, surrogacy remains an option for such women who desire a biologic child.
The only other statistically significant sociodemographic predictor of accepting referral to a reproductive specialist aside from male gender was having no prior children, which has been previously demonstrated among female patients in the broader cancer population.15 In our study, both men and women without prior children were more likely to accept referral to the reproductive specialist (P = .048). However, having prior children did not exclude interest in FP as 8 patients with prior children proceeded with the referral to a reproductive specialist. Thus, clinicians cannot assume that FP is unimportant to a young patient who is already a parent.
In a published study of 199 women with newly diagnosed primary gynecologic, breast, gastrointestinal, or hematologic cancer, the average age of those receiving FP counseling was significantly younger than those who did not receive formal counseling, 31.5 versus 34 years.15 In our study, the average age of patients accepting referral to a reproductive specialist was 32 and of those who declined the referral was 35, suggesting more interest in younger patients; however, this difference was not statistically significant (P = .37), perhaps due to our small sample size. In the same study of newly diagnosed women with cancer, a significantly higher percentage of Caucasian women received FP counseling as compared with African-American, Hispanic, and Asian women (26.3%, 17.6%, 0%, and 13.3%, respectively).15 In the general population, there is a disproportionately low representation of African-American women undergoing assisted reproductive technology.16 The patients in our study were predominantly Caucasian (79%) and there was no statistically significant difference in acceptance of reproductive specialist by race (P = .75), but the population of non-Caucasian patients was quite small.
With respect to social factors, neither marital status nor affiliation with a traditional religious group predicted patient interest in pursuing fertility preservation. In our study population, 83% of Catholics and 100% of Jews and Hindus elected to pursue referral to a reproductive specialist after consultation with the FNS; however, our sample size was too small to determine whether these were significant trends. Because no significant differences were noted in age, race, marital status, religion, or tumor grade between those patients who accepted referral to a reproductive specialist and those who did not, clinicians cannot predict which patients are most interested in pursuing FP.
In our study, 5 men and 2 women conceived children. Two children were conceived with sperm banked prior to initiation of treatment and, to our knowledge, no women in this sample have conceived children from cryopreserved oocytes or embryos to date. Due to the relatively short duration of follow-up in this study, we do not know how many more children, if any, will be conceived from the preserved specimens that have been collected from these patients. We also do not know of any children that have been conceived posthumously from preserved specimens as these outcomes would not be documented in the patient's medical record.
This study has a number of limitations. The sample was drawn from a single institution, the number of patients analyzed was small, and limited data were available about the young primary brain tumor patients who did not receive FNS counseling. We also did not have data on financial factors, which may influence patient decisions about FP. In addition, data on FP decisions were not available for all patients, and follow-up in regard to reproductive outcomes was short-term. However, our data do emphasize the level of interest and the desire to pursue FP in a subset of young patients with primary brain tumors, including those with a malignant histology.
We hope to clarify reproductive outcomes in this patient population in a prospective study so that further information regarding the feasibility of conception after treatment, effect of conception on brain tumor biology, and determination of the utilization of banked fertility specimens may be obtained. Having data available on this subject will help clinicians to counsel brain tumor patients appropriately, allowing patients to make informed decisions about FP.
Conclusion
Given the significant interest in FP in young patients with primary brain tumors, clinicians must develop strategies to incorporate FP counseling into their practices. Our study demonstrates that there are few sociodemographic and clinical predictors of patient interest in FP and that primary brain tumor patients of reproductive age should be offered FP counseling regardless of gender, race/ethnicity, marital status, prior children, religion, tumor type, and tumor grade. Further investigation into clinician referral patterns, patient satisfaction with information provided about fertility, and outcomes of FP with respect to children conceived is necessary as this retrospective study highlights the many gaps in our knowledge that only prospective studies will clarify.
Funding
This research was funded in part through the NIH /NCI Cancer Center Support Grant P30 CA008748.
Conflict of interest statement. The authors have no conflicts of interest to declare.
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