Abstract
Purpose: To compare long-term outcomes of gynecologic cancer patients who pursued controlled ovarian hyperstimulation (COH) for fertility preservation (FP) with those who did not.
Methods: Retrospective cohort, COH, and health outcomes in gynecologic cancer patients; data were analyzed by chi-square test, t-tests, and logistic regression.
Results: Ninety patients with a gynecologic malignancy contacted the FP patient navigator: 45.6% (n = 41) had ovarian cancer, 25.6% (n = 23) endometrial cancer, 18.9% (n = 17) cervical cancer, 5.6% (n = 5) uterine cancer, and 4.4% (n = 4) multiple gynecologic cancers. From this cohort, 32 underwent COH, 43 did not, and 18 pursued ovarian tissue cryopreservation (OTC; 3 patients had both COH and OTC). Median age and type of cancer were not significantly different between the groups. COH patients had a range of 1–35 oocytes retrieved. Days to next cancer treatment in the COH group was 36 days; for those who declined COH, it was 22 days (not significant [NS], p > 0.05). There were two recurrences reported in the stimulation group and four in the no stimulation group (NS). Five deaths were reported, two in the stimulation group, none in the no stimulation group, and three in the OTC group (NS); 34% (n = 11) COH patients returned to use cryopreserved specimens, of which 45% (n = 5) had a live birth.
Conclusion: Although time to next treatment was longer in the group of patients who underwent COH, this did not reach statistical significance. It appears that in selected patients with GYN malignancies, COH for oocyte or embryo cryopreservation is safe, with reasonable stimulation outcomes and no difference in long-term outcomes.
Keywords: fertility preservation, gynecologic cancer, IVF, oncofertility
Introduction
Gynecologic malignancies comprise ∼16% of female cancer diagnoses and traditionally require treatment modalities such as radiotherapy, chemotherapy, or radical surgery that damage a woman's reproductive capacity.1 Most of these patients are unaware of how treatment impacts future fertility, or their options for fertility preservation (FP). Contrarily, once patients are fully informed, a large majority desire FP before their treatment.2–6 This deficit in counseling is also disproportionally prevalent for women diagnosed with gynecologic compared with nongynecologic cancers for reasons incompletely studied.6 As women are living longer after their cancer diagnoses, future fertility is increasingly a quality-of-life issue and profoundly affects the survivorship experience.7,8
With this growing, underserved gynecologic cancer population, physicians and health care providers are changing their approach for health care management and FP awareness. The American Society for Reproductive Medicine and the American Society of Clinical Oncology have established guidelines for health care teams caring for gynecologic cancer survivors, which include discussions on the impact of cancer treatments on future fertility and liberal referrals to reproductive specialists.9 This is particularly pertinent for patients with gynecologic cancers because not only are their reproductive organs the nidus of disease but also the treatments are often highly gonadotoxic.
For over 10 years, the Reproductive Endocrinology and Infertility division of Northwestern Memorial Hospital has been providing FP consultations and treatments for women diagnosed with gynecologic cancers. Before undergoing chemotherapy or radiation therapy treatments, patients can choose controlled ovarian hyperstimulation (COH) for oocyte/embryo preservation or ovarian tissue cryopreservation (OTC).10–12 This has provided hundreds of women who were recently diagnosed with cancer the ability to receive consultations about their FP options, resulting in a subgroup of women pursuing FP.
Despite the newly implemented guidelines and recommendations to receive counseling for FP, patients are concerned that delaying treatment will worsen outcomes and that FP treatment itself may impact their disease progression; this fear is a large deterrent for women against pursuing FP.13 At this time, although there are limited data on the long-term effects of performing COH for FP before cancer treatment or its impact on survival or recurrence, most data appear reassuring in terms of long-term cancer-free survival.2,3,11,14–17 Similarly, when patients are appropriately selected for OTC, there is a potentially minimal risk of reintroducing malignant cells with transplantation11,18; indeed, OTC is a particularly appealing option for women who cannot wait for ovulation induction given the aggressive nature of their malignancies.19,20
The aims of this study are to quantify the delay to cancer treatment experienced by patients who elected to undergo COH for gynecologic cancers and to determine whether there is an association between COH for FP and cancer recurrence and/or mortality. We also tracked pregnancy rates after treatment in the patient groups that did and did not pursue COH. Additionally, we examined the barriers and reasons cited for why patients did not decide to proceed with COH. We hypothesize that the minimal delay in gynecologic cancer treatment endured by reproductive-aged patients for FP will not result in increased cancer recurrence or mortality and that FP may be adopted as a safe and effective component of patients' treatment course to increase future quality-of-life and reproductive options.
Methods
Study population
This is a retrospective study that was approved by the Northwestern IRB. Subjects were identified from our FP patient navigator's (PN) patient log. Specifically, we examined women who had been diagnosed with gynecologic cancers and contacted the FP PN at Northwestern Memorial Hospital from January 2007 through December 2017, regardless of whether they ultimately elected to undergo COH; we also included a subset of patients who obtained OTC. Subjects were excluded from the examined cohort if they presented for noncancer-related FP or for reasons other than FP, were older than 45 years at the time of PN consultation as in vitro fertilization (IVF) would not be an option, initially met with the FP PN with a diagnosis of cancer recurrence, or had chemotherapy treatment before PN consultation. Patients with recurrent cancer at presentation were excluded because our main end point was cancer recurrence. Both recurrent cancer diagnosis and recent chemotherapy from COH outcomes were excluded because the history of chemotherapy could directly affect COH outcomes and therefore could be a confounder. Patients for whom PN consultation to next cancer treatment was >100 days were also excluded because we felt that the decision to pursue or to not pursue COH would not have impacted their cancer care. However, these patients were included in analyses of cancer recurrence, mortality, and stimulation outcomes.
For every patient examined, data on gynecologic cancer diagnosis, staging (if available), treatment history, date of initial consultation with the FP PN, subsequent cancer treatment dates (surgery, chemotherapy, and tamoxifen), cancer relapse (defined as recurrence of same primary cancer type), and mortality were collected. Patient mortalities were identified using medical records as well as obituaries. Pregnancy outcomes were also recorded. Cancer recurrence and mortality data were collected from oncology and pathology notes. Pregnancy information, both spontaneous and as a result of using cryopreserved gametes, was also collected.
Patients who underwent a COH cycle were grouped by whether they underwent a cycle-specific (CS) or random-start (RS) protocol. COH outcome data were collected, as well as gamete disposition preferences, future pregnancy data, and last encounter date with a Northwestern provider.
Controlled ovarian hyperstimulation
Our protocol has been documented in previous studies.21,22 Briefly, COH was started using recombinant follicle-stimulating hormone with or without urinary menotropins, with dosage based on age and ovarian reserve measurements. While many clinics coadminister letrozole or other aromatase inhibitors (AIs) during COH as a precaution to counteract the increase in serum estradiol (E2) for hormone-sensitive cancers,23–25 our practice does not believe that the short-term, elevated serum E2 levels would increase chances of cancer recurrence.17 Our practice has increasingly included more RS protocols, allowing patients who desire to begin stimulation immediately the ability to do so. For the CS protocol, gonadotropins were initiated on the third day of menses, whereas for the RS protocol, gonadotropins were initiated at any point in the menstrual cycle. Response to medication was evaluated with regular ultrasound examinations and E2 measurements, with gonadotropin dosage adjusted accordingly. For a CS protocol, once the leading follicle grew to at least 12 mm in diameter or E2 reached 300 pg/mL, the patient began a daily injection of gonadotropin-releasing hormone antagonist to prevent ovulation. For RS, the antagonist was started once the new lead follicle grew to at least 12 mm. As per our institutional IVF protocol for all patients, when at least two follicles measured at least 16 mm in diameter, final follicular maturation was triggered by an injection of human chorionic gonadotropin and oocyte retrieval was performed 36 hours later. Slow cooling was used at our clinic for oocyte cryopreservation until 2008, when vitrification became the standard protocol. Our clinic does not prescribe letrozole or other AIs or selective estrogen receptor modulators during stimulation for patients with hormone-sensitive cancers, including breast cancer.
Ovarian tissue cryopreservation
As described by our previous studies, women undergoing oophorectomy for either a cancerous or a benign ovarian lesion are candidates for OTC.26–29 While COH may not be feasible for patients who cannot risk delaying cancer treatment or prepubertal females, OTC with retransplantation in the future may potentially restore endocrine function and fertility.30 At the moment, this form of FP is experimental and the efficacy has not been thoroughly studied.31
During surgery, the standard surgical technique was used for either complete or partial oophorectomy depending on case-specific variables. The resulting specimen was immediately stored under sterile conditions in an insulated container at 0–5°C and transported fresh to pathology where the ovarian tissue was sectioned for gross and microscopic examination to ensure the presence of follicles and ovarian tissue normality. The slow-freeze technique was used to cryopreserve at least six pieces of ovarian cortex measuring, at the minimum, 5 × 20 × 1 mm each. All patients who underwent OTC obtained intraoperative infectious disease testing, and ovarian tissue processing occurred within 1 hour of surgical removal.
Statistical methods
Categorical data were analyzed by the chi-square test and continuous data were analyzed by t-test. Subsequently, linear and logistic regression analyses were performed to adjust for potentially confounding variables. Statistical analyses were performed with SPSS IBM Statistics 25.0 for Windows (SPSS, Chicago, IL). All p values were two-sided, and a p value of <0.05 was considered statistically significant.
Results
Demographics
A total of 90 gynecologic cancer patients were included in the analysis, in which 29 (32.2%) proceeded with COH for FP before initiating their next cancer treatment (Tables 1 and 2), 14 (15.6%) proceeded with OTC, and 4 (4.4%) proceeded with COH, followed by OTC. Of these patients, three obtained COH at Northwestern and were included in our analysis. Our final cohort of patients who pursued COH at Northwestern before initiating cancer treatment was thus 32.
Table 1.
Demographic Characteristics from Women with Gynecologic Cancer Who Did and Did Not Pursue Fertility Preservation
| Initiated ovarian stimulation | Did not initiate ovarian stimulation | Underwent OTC | |
|---|---|---|---|
| No. of subjects (n) | 32 | 43 | 18 |
| Age, median (range) | 32.96 (15.40–44.24) | 33.97 (20.48–43.72) | 33.44 (27.17–38.90) |
| BMI, median (range) | 26.51 (19.05–61.27) | 26.44 (18.75–51.75) | 23.17 (17.40–45.53) |
| Gravidity, median (range) | 0 (0–1) | 0 (0–5) | 0 (0–2) |
| Parity, median (range) | 0 (0–1) | 0 (0–4) | 0 (0–2) |
| Gynecologic cancer diagnosis (n) | |||
| Ovarian | 12 | 22 | 7 |
| Endometrial | 7 | 11 | 8 |
| Uterine | 3 | 2 | 0 |
| Cervical | 7 | 8 | 2 |
| Multiple | 3 | 0 | 1 |
No significant differences were observed between subjects who did and did not initiate ovarian stimulation; n = 3 patients initiated ovarian stimulation, followed by OTC.
BMI, body–mass index; OTC, ovarian tissue cryopreservation.
Table 2.
Demographic Characteristics from Women with Gynecologic Cancer Who Did and Did Not Pursue Ovarian Stimulation for Fertility Preservation
| Initiated ovarian stimulation (n = 32) | Did not initiate ovarian stimulation (n = 43) | |
|---|---|---|
| Age at PN consultation (years), median (range) | 32.96 (15.40–44.24) | 33.97 (20.48–43.72) |
| BMI, median (range) | 26.51 (19.05–61.27) | 26.44 (18.75–51.75) |
| Gravidity, median (range) | 0 (0–1) | 0 (0–5) |
| Parity, median (range) | 0 (0–1) | 0 (0–4) |
| Gynecologic cancer diagnosis (n) | ||
| Ovarian | 12 | 22 |
| Endometrial | 7 | 11 |
| Uterine | 3 | 2 |
| Cervical | 7 | 8 |
| Multiple | 3 | 0 |
| Days until next cancer treatment after PN consultationa (days), median (range) | 36 (21–64) | 22 (1–85) |
| Length of follow-up (days), median (range) | 1623 (314–3934) | 2547 (384–4165) |
No significant differences were observed between groups.
n = 20 patients not included: n = 8 patients >100 days, n = 10 patients had cancer surgery and no chemotherapy before meeting with the PN, and n = 2 patients missing the next treatment date.
PN, patient navigator.
Median age at time of contact with the PN was 32.96 years (range: 15.40–44.24 years) for COH patients and 33.97 years (range: 20.48–43.72 years) for patients who declined COH (not significant [NS], p > 0.05) (Tables 1 and 2). Overall, there was no significant difference in whether a patient underwent COH or not based on the type of gynecologic cancer (Tables 3 and 4). The median number of days to cancer treatment after consulting the PN was 36 (range: 21–64 days) in the COH group and 22 (range: 1–85 days) in the group that declined COH (NS) (Tables 1 and 2). Of note, we also ran the analysis, including patients who required more than 100 days for their next cancer treatment after meeting with the PN (n = 8), which resulted in no significant difference; the median number of days to cancer treatment after consulting the PN in the COH group was 50 (range: 21–256 days) and 21 in the no COH group (range: 1–118 days) (NS). Twenty-eight patients underwent a CS protocol and four underwent an RS protocol, showing similar outcomes (Table 5).
Table 3.
Cancer Staging from Women with Gynecologic Cancer
| Cancer type | Cancer staging | Initiated ovarian stimulation (n = 29) | Did not undergo ovarian stimulation (n = 43) | OTC (n = 14) |
|---|---|---|---|---|
| Ovarian cancer | Unstaged | 0 | 0 | 0 |
| Stage I | 9 | 11 | 2 | |
| Stage II | 1 | 4 | 0 | |
| Stage III | 2 | 6 | 5 | |
| Stage IV | 0 | 1 | 0 | |
| Total | 12 | 22 | 7 | |
| Endometrial cancer | Unstaged | 1 | 3 | 0 |
| Stage I | 5 | 8 | 2 | |
| Stage II | 0 | 0 | 0 | |
| Stage III | 1 | 0 | 1 | |
| Stage IV | 0 | 0 | 2 | |
| Total | 7 | 11 | 6 | |
| Uterine cancer | Unstaged | 1 | 0 | 0 |
| Stage I | 1 | 0 | 0 | |
| Stage II | 1 | 0 | 0 | |
| Stage III | 0 | 0 | 0 | |
| Stage IV | 0 | 2 | 0 | |
| Total | 3 | 2 | 0 | |
| Cervical cancer | Unstaged | 0 | 0 | 0 |
| Stage I | 6 | 4 | 1 | |
| Stage II | 1 | 2 | 1 | |
| Stage III | 0 | 0 | 0 | |
| Stage IV | 0 | 2 | 0 | |
| Total | 7 | 8 | 2 |
No significant differences were observed between subjects who did and did not initiate ovarian stimulation; n = 4 patients not included with multiple gynecologic cancers: n = 3 endometrial and ovarian, n = 1 endocervix; n = 3 patients had ovarian stimulation, followed by OTC.
Table 4.
Ovarian Cancer Diagnoses by Cell Type
| Ovarian cancer type | Initiated ovarian stimulation | Did not initiate ovarian stimulation | OTC |
|---|---|---|---|
| Epithelial | 12 | 17 | 7 |
| Germ cell | 1 | 2 | 0 |
| Stromal cell | 0 | 2 | 0 |
| Small cell carcinoma | 1 | 0 | 0 |
| Ovarian sarcoma | 0 | 1 | 0 |
| Total | 14 | 22 | 7 |
No significant differences were observed between groups.
Table 5.
Controlled Ovarian Hyperstimulation Cycle Characteristics of Gynecologic Cancer Patients Who Underwent a Cycle-Specific Protocol Versus Random-Start Protocol and Completed an Oocyte Retrieval
| Stimulation measures (n = 32a) | Cycle specific (n = 28) | Random start (n = 4) |
|---|---|---|
| Age, years | ||
| Median (range) | 33.00 (15.40–44.24) | 30.39 (19.24–34.90) |
| BMI | ||
| Median (range) | 24.53 (19.51–61.27) | 28.84 (19.05–38.97) |
| AMH (ng/mL) | ||
| Median (range) | 1.58 (0.29–10.30) | 1.59 (1.03–2.23) |
| Peak estradiol (pg/mL) | ||
| Median (range) | 1367 (109–3186) | 1227 (814–3705) |
| No. of days of stimulation | ||
| Median (range) | 10 (6–16) | 10 (10–11) |
| Total FSH dosage | ||
| Median (range) | 2137 (300–5850) | 2250 (1500–4350) |
| Total HMG dosage | ||
| Median (range) | 1013 (0–2100) | 825 (750–1650) |
| Total no. of oocytes retrieved | ||
| Median (range) | 9 (1–35) | 13 (9–17) |
| No. of mature oocytes | ||
| Median (range) | 7 (1–28) | 8 (6–15) |
| No. of oocytes cryopreserved | n = 11 | n = 3 |
| Median (range) | 6 (1–3) | 8 (8–17) |
| No. of embryos cryopreserved | n = 16 | n = 1 |
| Median (range) | 6 (1–14) | 13 |
| No. of both embryos and oocytes cryopreserved | n = 1 Oocytes: 8 Embryos: 8 | n = 0 |
| No. of days to next cancer treatment (after PN meeting)a | n = 16 | n = 3 |
| Median (range) | 38 (21–64) | 24 (21–28) |
n = 7 > 100 days until next treatment, n = 2 were missing the next treatment date, n = 4 had surgery before meeting with the PN and no chemotherapy and were not included in this analysis.
AMH, anti-Müllerian hormone; FSH, follicle-stimulating hormone; HMG, human menotropin gonadotropin; PN, patient navigator.
Of the 43 patients (57.3%) who did not undergo COH, the primary reasons cited were not following up with the PN after the initial meeting (7 patients, 16.3%) and not enough time to start a stimulation cycle before initiating cancer treatment (6 patients, 14.0%). Other reasons for declining COH included 5 (11.6%) patients who were not interested, 3 (7.0%) found COH cost-prohibitive, 3 (7.0%) lived elsewhere, 2 (4.7%) were medically ineligible, 2 (4.7%) did not undergo gonadotoxic cancer treatment that would necessitate FP, and 1 (2.3%) had already banked the embryos (Fig. 1). There was no reason documented for declining COH in 14 patients (32.6%).
FIG. 1.
Noted reasons for patients declining FP. n = 14 patients did not have any noted reason for declining FP. FP, fertility preservation.
Gynecological cancer outcomes
Median follow-up time is reported in Tables 1 and 2. Recurrence in cancer was detected in 2 (6.3%) patients who underwent COH and 4 (9.3%) patients who declined COH. Mortality was reported in 2 (6.3%) patients who underwent COH and 0 patients who declined COH. Among OTC recipients, mortality was reported in 3 (16.7%) patients.
Ovarian stimulation
Complete stimulation information was available for analysis for 32 patients who elected COH. Median peak E2 was 1329 pg/mL (range: 109–3705 pg/mL). A total of 28 underwent a CS protocol and 4 underwent an RS protocol. There were similar outcomes between the two stimulation protocols regarding demographics and cycle-related outcomes (Table 5).
Embryo disposition decisions and pregnancy outcomes following cancer treatment
We found that 72% of patients who underwent COH had contact with a Northwestern provider within the past year. Eleven of 32 COH patients (34%) returned to use cryopreserved specimens—8 patients who had cryopreserved embryos and 3 patients who had cryopreserved oocytes. Of the patients who returned to use cryopreserved oocytes or embryos, 5/11 (45%) had a live birth, including two sets of twins; additionally, there is one patient who is currently pregnant. Two patients had two live births. A gestational carrier was used in 7 of the 11 returning patients (64%), all of which had hysterectomies as a part of cancer treatment. None of the 32 COH patients experienced a live birth from a spontaneous pregnancy, whereas 6/43 (14%) patients who did not elect COH had a live birth, including two sets of twins. Median time from oocyte retrieval date to return to use cryopreserved specimens was 488 days (range 181–2190 days). There were no differences in age or anti-Müllerian hormone between patients who returned to use their gametes and those who did not. For oocyte/embryo disposition elected at the time of cryopreservation, 46.9% preferred to donate to a person of their choosing, 43.8% donated to research, and the rest preferred to discard their eggs or embryos. Disposition preferences were not noted for OTC patients.
Conclusion
This study compared the long-term outcomes in patients with gynecologic cancers who pursued FP and those who did not. Of the 90 gynecologic cancer patients in the study, 32 (35.6%) proceeded with COH for FP at our clinic before initiating their cancer treatment and 18 (20.0%) underwent OTC. Both the stimulation group and the nonstimulation group contained patients with the diagnosis of ovarian, endometrial, uterine, or cervical cancer. Compared with patients who did not elect COH, cancer patients who had COH for FP had an ∼2-week delay to initiation of cancer treatment, which in our study was not statistically significant. There was no significant difference in cancer recurrence and mortality between the patients who elected COH and those who did not. Additionally, of the patients who elected to pursue COH, there was no significant difference in IVF outcomes between the RS and CS protocols. However, we did find that the RS group experienced a slightly shorter delay to treatment at a median of 24 days to next cancer treatment (range 21–28 days), compared with the CS group's 38 days (range 21–64 days; p = NS). Of the patients who pursued COH for FP, 11 of the 32 (34%) returned to use their cryopreserved specimens, with 6 successfully giving birth and 2 more currently pregnant. Additionally, 7 of the 11 women who returned to use their cryopreserved specimens had hysterectomies as part of their treatment, and 6 of those women were able to use gestational carriers to have children. Although none of the patients who pursued COH experienced a live birth from a spontaneous pregnancy, 6 of the 43 patients who did not pursue COH went on to experience spontaneous pregnancy.
As women are living longer after cancer diagnoses, FP should no longer be an afterthought in discussions about survivorship. Quality-of-life surveys have consistently shown that most young women with cancer diagnosis view future fertility as a major concern.7,8 Governing bodies, including the American Society of Clinical Oncology, American Society for Reproductive Medicine, and American College of Obstetricians and Gynecologists, have all published clinical opinions recommending pre-treatment counseling on FP and stressed the importance of early referrals, if desired, to reproductive specialists for discussions on potential FP options.32–34 Indeed, one main reason for cancer patients not undergoing COH in our cohort was not enough time before initiating treatment (Fig. 1). Use of the RS IVF protocol would thus help to ameliorate this concern and minimize delay to initiating fertility treatment; our results are consistent with those described in the literature of not finding differences in outcomes between RS and conventional CS protocols or in the median number of days to cancer treatment after consulting with a PN.7
Other reasons why patients chose to forego FP at Northwestern include lack of follow-up with a PN, lack of interest, and cost. However, we do not have data documented for a third of patients. These are consistent with prior qualitative research suggesting that arguments against FP include a patient's prioritization of obtaining cancer treatments before FP and her ethical and religious reservations.5 Similarly, a systematic review of factors affecting patient's FP decisions revealed three main barriers: knowledge deficits, psychosocial/clinical concerns, and social/structural factors such as resource and economic limitations.35 This economic barrier may be even less influential in the future for our patients since Illinois recently passed state-mandated insurance coverage of FP for cancer patients (HB 2617); however, the majority of states do not have such legislation. Even before this law, however, Illinois is one of the few states with state-mandated fertility coverage. The presence of our PNs also helps to close the information gap for patients during this stressful time, so lack of follow-up with PNs is not surprisingly a reason for patients to decline FP.
For appropriately selected patients, studies report a 50%–80% success rate in conception after fertility treatments for patients treated conservatively for cervical cancer and over 60% in endometrial cancer and ovarian cancer.8 Our study similarly found a high success rate after fertility treatment, with a 45% live birth rate and a pregnancy rate of at least 66%. Notably, spontaneous pregnancy was common for ovarian cancer patients, in part, because the chemotherapy used does not have a large effect on fertility.36,37 This is consistent with our data, considering that all spontaneous pregnancies came from ovarian cancer patients. We also describe five pregnancies from gestational carriers, which are particularly relevant for patients who require treatments necessitating hysterectomy or pelvic radiation therapy.38 Because of the high likelihood of needing to use a gestational carrier, we do recommend performing the necessary FDA testing in this group of FP patients.39
Although we do not have pregnancies resulting from OTC in our cohort, delivery rates have been reported to be as high as 33% after ovarian autotransplantation.40 Given that oophorectomy is a standard part of recommended surgical management for many gynecologic cancers, it is reasonable to attempt OTC before surgery. This not only offers a future potential for natural conception but also a possibility of endogenous hormone production from the transplanted ovary for premenopausal women. However, tissue reimplantation is not always feasible for patients if there are concerns about reintroducing malignancies, and attempts have been made for in vitro follicle growth and maturation to circumvent this risk41; while pregnancy and live birth have been achieved in mice using in vitro techniques, they have not been successful in human subjects and remain major areas of research.19,20
Other common concerns for fertility treatments are the necessary hormonal injections and subsequent supraphysiological estrogen levels that could theoretically lead to estrogen-sensitive tumor stimulation32,33; these are particularly relevant for endometrial cancers. There is also a theoretical risk of tumor seeding from oocyte retrieval in patients with ovarian cancer, with inconclusive data regarding whether IVF increases cancer recurrence.37 However, our study supports the general findings in the literature that fertility treatments do not increase recurrence rates.8 Some protocols incorporate AIs (e.g., letrozole) or selective estrogen receptor modulators (e.g., tamoxifen) to circumvent this risk and have found no differences in stimulation outcome.7 In our practice, we do not feel that the short period of time in which the E2 levels are elevated would cause progression of cancer or an increase in cancer recurrence, therefore we do not incorporate estrogen modulators in our stimulation protocols.
While modest, our sample size is comparable with the size of other studies describing this patient population. However, one limitation of our study is the retrospective nature of the review. We were unable to determine whether patients obtained fertility or oncologic treatments outside of our institution. We also did not specifically examine pregnancy outcomes in our cohort, which would depend on the method of fertility-sparing treatment utilized. This is important for patients undergoing certain treatments such as trachelectomy for cervical cancer as there is an increased risk of preterm delivery from cervical insufficiency.8 Data on miscarriages in our population are also unavailable, although overall miscarriage rates for endometrial and ovarian cancer patients are comparable with the general population.8
Clear reproductive risk counseling for women diagnosed with gynecologic cancers cannot be understated and should be the standard of care for all patients. Providers should be open and frank in discussing a woman's range of options and provide early referral to specialists in FP if the patient is interested. From a societal perspective, there is fortunately also an increase, in the recent years, of legislation covering FP for cancer patients.7 Reassuringly, our study suggests that undergoing an FP consult does not delay treatment for a patient and conducting COH treatments does not increase recurrence rates. Alternatively, we present good pregnancy and live birth success rates, which are encouraging, as both cancer and fertility treatments are undergoing active advancements.
Author Disclosure Statement
No competing financial interests exist.
Funding Information
This study was supported by a Northwestern Memorial Foundation Evergreen Grant (to M.E.P.) and P50 HD076188 (M.E.P., PI: T. Woodruff).
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