Access to Infertility Care and Utilization of a Regional Fertility Preservation Program for Cancer Patients

Background. Fertility preservation (FP) prior to gonadotoxic cancer treatment is underutilized in the United States (US) due to limited access to care. Objective. We aimed to determine the utilization of a regional FP program in an underserved region in the Southeast US. Methods. We performed an institutional review board-approved retrospective cohort study of patients enrolled in the FP program at an academic tertiary medical center from 2014 to 2018. Results. Sixtynine reproductive age patients were enrolled in the FP program, including 29 men and 40 women between 20 and 49 years of age. Cancer diagnoses among the enrolled patients included hematologic (n = 34), breast (n = 14), testicular (n = 11), reproductive tract (n = 7), and gastrointestinal (n = 3) malignancies. Patients with reproductive tract malignancies were found to have approximately 9.7 times greater odds of proceeding with FP than patients with hematologic malignancies (P < .05). Conclusion. Utilization of a regional FP program should be considered to increase access to care to this critical resource for patients desiring future family building. Patients with hematologic malignancy may face unique barriers to FP.


Introduction
Approximately 5,000 adolescents aged 15 to 19 and 60,000 adults aged 20 to 39 are diagnosed with cancer every year in the United States (US) [1]. Fortunately, overall survival rates are improving, and the vast majority survive cancer. In 2008-2014, 84.6% of adolescent cancer patients achieved 5-year remission [1,2]. Cancer treatments, however, may be gonadotoxic and impair fertility. Female cancer survivors, for instance, have an approximately 38% lower chance of pregnancy compared with the general population [3]. The gonadotoxic effect of cancer treatment depends on patient age, type of chemotherapy, radiation, or surgery, and duration of treatment. Alkylating agents such as cyclophosphamide and alkylating-like agents such as cisplatin or carboplatin are highly detrimental to primordial and pre-antral/antral follicles, granulosa cells, and spermatogonia [4]. Gonadotoxicity is increased when chemotherapy is combined with abdominal, pelvic, or testicular radiation [5]. Treatment may even necessitate the removal of one or both ovaries or testes.
There are established methods of fertility preservation (FP) for male and female cancer patients before cancer treatment. For female patients, FP options include embryo or oocyte cryopreservation, ovarian transposition, fertilitysparing surgery, and ovarian tissue cryopreservation. Embryo cryopreservation is the most well-studied FP method for women. Standard protocols for ovarian stimulation require two to six weeks. "Random start" protocols can be initiated at any time during the menstrual cycle and have been shown to decrease the time to starting cancer treatment and are as effective in oocyte retrieval as conventional protocols [6]. Oocyte cryopreservation is suitable for female patients without a male partner or sperm donor. However, oocyte and embryo cryopreservation does not protect ovaries against radiation damage, so the patient may still be at risk of post-treatment ovarian insufficiency. Other methods such as ovarian chemoprotection utilizing GnRH agonists during chemotherapy may be helpful if cryopreservation is not feasible or as an adjunct to reduce the probability of chemotherapy-induced ovarian insufficiency; however the efficacy of GnRH agonist therapy is not yet proven [7]. Ovarian tissue cryopreservation (OTC) is the only FP option available to prepubertal children and is no longer considered experimental [8]. Ovarian tissue transposition carries the risk of transplanting malignant cells after re-grafting. Ovarian transposition or oophoropexy can be utilized in patients undergoing abdominal or pelvic radiation. For male patients, FP options include semen cryopreservation and gonadal shielding from radiation [5].
Physician counseling of potential fertility outcomes is critical. Unfortunately, the gonadotoxic effects of cancer therapy may be under-appreciated. One study showed that only 9% of patients received information about the fertility risk of cancer treatments or FP options, at a cancer center in the US [9]. Guidelines set by several organizations, including the American Society of Clinical Oncology (ASCO) and the American Academy of Pediatrics (AAP), encourage FP counseling and early referral to reproductive endocrinology [7]. Lack of FP counseling can be a source of significant distress for cancer survivors. Regarding the risk or reality of infertility, patients have reported feelings of depression, anxiety, and intense psychological distress [10,11]. In a study of female cancer survivors who were not counseled about potential infertility risk, those who later experienced infertility reported feelings consistent with post-traumatic stress disorder [11]. Surveys of adolescents have shown that they value parenthood in the future, even if it is not a short-term goal for them [12,13]. Even for those patients who did not pursue FP after counseling, they report better quality of life and less distress about infertility risk [14].
This study's FP or "oncofertility" program was established to meet these needs of cancer patients in an underserved region in the Southeast US. While FP can profoundly impact patients' lives, little is known about which patients pursue FP or which FP methods are preferred over other management, particularly among patients with limited access to care. In this study, we aim to answer these questions by assessing the utilization of a regional FP program within a multidisciplinary health care system.

Materials and methods
This was an institutional board review-approved retrospective cohort study at a university tertiary care facility in the state of Georgia, US. Waiver of informed consent was obtained. A retrospective chart review was performed of patients enrolled in the FP program between September 2014 and May 2018. The FP program of this study, which was established in September 2014, is the first formal oncofertility program in the area. Patients were counseled about the risk of cancer treatment on fertility and available FP options. If they elected for FP, they underwent a treatment method that was tailored to their clinical scenario. Chart review was performed to identify characteristics of the study population. The primary outcome assessed was whether patients pursued FP. Secondary outcomes were to examine whether the decision for FP correlated with characteristics such as demographics, malignancy type, whether the patients were seen on an inpatient versus outpatient status, or specific FP methods. Live birth outcomes were also examined. Statistical analysis of whether patients pursued FP was performed using logistical regression models in STATA with a P -value < .05 to determine statistical significance. De-identified data can be provided upon request.

Results
A total of 69 patients, including 40 females and 29 males, utilized the FP program. The average age of females was 28.8 ± 5.9 years and males 28.6 ± 6.4 years. About threefourths of patients were seen on an outpatient basis. Majority of cancer diagnoses were hematologic (n = 34), followed by breast (n = 14), testicular (n = 11), reproductive tract (n = 7), and gastrointestinal (n = 3) (Figure 1).
Female patients underwent medical ovarian suppression (n = 17), embryo or oocyte cryopreservation (n = 12), ovarian transposition (n = 1), or combined methods (n = 4), and six patients declined to proceed with treatment. Of note, OTC was not offered to subjects as it was an experimental method of FP at the time of the study. Fifteen male patients underwent successful semen cryopreservation, while three patients had unsuccessful attempts (two patients had azoospermia, and one patient was unable to collect a specimen), and 11 declined treatment (Figures 2 and 3). An informal survey of reasons for declining FP included health status, financial burden or time limitations. In total, 34 female and 15 male patients pursued FP, and four live births resulted.  Statistical analysis using logistical regression models showed that patients with reproductive tract malignancies had 9.7 times greater odds of proceeding with FP than patients with hematologic malignancies (P < .05). Other demographic variables and diagnoses did not significantly predict whether patients pursued FP (Table 1).

Discussion
Our study investigated which patients pursued FP, as this was not well known in our study population or the literature. Although all patients included in the study were counseled on FP, we found that patients with reproductive tract malignancies were more likely to proceed with FP methods than patients with hematologic malignancies. This result is consistent with previous studies that have found that the likelihood of receiving FP counseling was associated with a cancer diagnosis and that the proportion of patients with gynecologic cancers who were counseled was significantly higher than those with nongynecologic cancer [10].
Despite patients with hematologic malignancies comprising nearly half of our study population, they had significantly lower odds of proceeding with FP, suggesting there are barriers specific to this patient population. Patients with acute leukemia or lymphoma may require emergent therapy and may be unable to delay treatment for even a week needed to perform emergent in vitro fertilization [15]. In the context of an accelerated timeline to treatment, these patients may not receive FP counseling or referrals to reproductive endocrinology. Furthermore, these patients may be too clinically unstable to undergo standard FP options at the time of diagnosis. Patients with hematologic malignancies may have myelosuppression and may be more predisposed to bleeding complications from oocyte retrieval, limiting opportunities for FP in some cases. Treatment of non-Hodgkin's lymphoma often requires gonadotoxic doses of cyclophosphamide [15]. These considerations all pose significant barriers to treatment, and the results of our study affirm that patients with hematologic malignancies face unique barriers to care. Patients in this study were not offered OTC due to its experimental nature at the time of the study; future research should examine outcomes for patients with hematologic malignancies who undergo OTC given the unique time and health limitations faced, and given that many FP options may not be available to these patients. As there are more than a million survivors of Hodgkin and non-Hodgkin's lymphoma in the US every year, and nearly a fifth are patients of reproductive age [15], this is a crucial population of patients that should be targeted for FP services to close the gap in access to FP care.
Limitations of this research include the retrospective nature of the study. There are inherent biases in the referral and counseling process that may confound the results. Research suggests that males receive more counseling [16,17] and referrals [18], and that women who already have children are less likely to receive referrals [9]. Although the patients in our study received referrals and counseling, we could not examine the referral rates for all patients diagnosed with cancer at our institution. This is an area of further research. It would be worthwhile to investigate whether higher referral rates for patients with certain cancer diagnoses may increase FP utilization. Access to FP may improve if referrals to reproductive endocrinology are routinely part of the cancer treatment process, with an established referral infrastructure in place [19]. Future directions in this research also include collecting data on the long-term outcomes in patients who received FP counseling and pursued an FP option. Another limitation of this study is the lack of data on specific reasons behind why patients proceed with FP. This could be a future avenue of research and provide direction for what aspects of FP counseling patients find most useful.
It should be noted that cost was a commonly cited reason why patients did not pursue FP. The study did take place in a state in which infertility care is not mandated. Further advocacy is necessary to overcome financial barriers to FP. Even if patients are adequately counseled and referred to RE on time, the cost of FP may be prohibitive. Most insurance companies, including Medicaid, do not cover the expenses of FP for cancer patients except in a few mandated states; thus, coverage remains elusive [20]. These barriers amount 4 Journal of Fertility Preservation to cancer patients' inability to protect their reproductive health, facing the risk of infertility after cancer treatment.

Conclusion
In conclusion, this study examines the utilization of FP services in an underserved region in the Southeastern US, and identifies patients with reproductive tract malignancies as a patient population likely to proceed with FP, relative to patients with hematologic malignancies. The study results demonstrate increased access to care in this underserved region, which did not have formal oncofertility services prior to initiation of the FP program. The utilization of the regional FP program should be considered to increase access to care to this critical resource for patients desiring future family building.
Funding This research was not supported by any funding.