Fertility-Sparing Treatment for Early-Stage Cervical, Ovarian, and Endometrial Malignancies

Abstract

Approximately 20% of gynecologic malignancies are diagnosed in reproductive-age women, and standard-of-care surgical treatment often precludes future fertility. In early-stage disease, shared decision making about fertility-sparing medical and surgical approaches may give well-selected patients the opportunity to pursue their family-building goals without compromising long-term survival. While future fertility is an important consideration for young women with cancer, rates of fertility-sparing procedures remain low. Moreover, as data on pregnancy rates and outcomes after fertility-sparing treatments are limited, it is challenging to counsel patients on realistic expectations. This review examines the critical oncologic outcomes of fertility-sparing approaches in early-stage gynecologic malignancies, and highlights pregnancy outcomes in this population.

Precis

Fertility-sparing approaches are important to discuss with appropriate reproductive-age patients being treated for a gynecologic malignancy.

Introduction

Of the 113,520 women estimated to receive a diagnosis of female genital tract cancer in 2020, 21% will be younger than 40.¹ The American Society of Clinical Oncology (ASCO) has defined fertility as a key survivorship issue since 2006. The most recent guidelines from ASCO² and the American Society of Reproductive Medicine (ASRM)³ urge oncologists to discuss fertility options before treatment commences as part of informed consent to cancer therapy. However, in 2016, only 5.5% of reproductive-age women with lung, breast, colorectal, or cervical cancer in the United States were evaluated for fertility preservation, and only 4.6% of those patients underwent a fertility-preserving procedure.⁴ Moreover, geographic location,^5-8 socioeconomic status,⁹ race,^7,10 age,^7,8 level of education,¹¹ and insurance¹² have all been shown to affect access to reproductive specialists or surgeons offering fertility-sparing procedures; as a result, fertility is not only a central survivorship concern but also a health equity issue for young women with cancer and their physicians. The objectives of this Clinical Expert Series review are to discuss the ideal candidate for fertility-sparing treatment, review surgical and medical approaches to fertility sparing and their oncologic outcomes, then discuss surveillance, and conclude with a summary of pregnancy outcomes.

Who is an appropriate candidate for fertility-sparing treatment?

Table 1 lists National Comprehensive Cancer Network (NCCN) guidelines for fertility-sparing treatment for women with cervical, ovarian, and endometrial cancer.

Table 1.

NCCN Guidelines for Fertility-sparing Surgery by Cancer Site

Site and Histology	Stage and/or Tumor Features	Procedure
Cervical Cancer18
Squamous cell carcinoma, adenocarcinoma and adenosquamous carcinoma only	IA1 without LVSI	Cone biopsy with negative margins. If margins positive repeat cone biopsy or perform trachelectomy
	IA1 with LVSI, IA2	Cone biopsy with negative margins (if margins positive repeat cone biopsy or perform trachelectomy) + pelvic lymph node dissection (consider SLN mapping). Or radical trachelectomy + pelvic lymph node dissection (consider SLN mapping)
	IB1, select IB2***	Radical trachelectomy + pelvic lymph node dissection +/− para-aortic lymph node dissection (consider SLN mapping)
Ovarian Cancer24
Epithelial ovarian cancer	IA/IC*	USO + comprehensive surgical staging
	IB	BSO + comprehensive surgical staging
Malignant sex cord-stromal	IA/IC**	USO + comprehensive surgical staging
Malignant germ cell tumors	Regardless of stage	USO + comprehensive surgical staging
Uterine Cancer71
Endometrioid adenocarcinoma only	Well-differentiated (grade 1)	Continuous progestin-based therapy: megestrol, medroxyprogesterone, levonorgestrel-releasing intrauterine device. Requires endometrial evaluation every 3-6 months: • If complete response by 6 months, encourage conception. • If cancer present at 6-12 months, proceed with total hysterectomy with staging.
	Disease limited to endometrium on MRI or TVUS (less preferred)
	Absence of suspicious metastatic disease on imaging
	No contraindications to medical therapy or pregnancy

USO, unilateral salpingo-oophorectomy; BSO, bilateral salpingo-oophorectomy; TVUS, transvaginal ultrasound; SLN, sentinel lymph node.

^*Not recommended for clear cell carcinoma.

^**Completion surgery should be considered after childbearing is finished.

^***Has been most validated for tumors less or equal to 2 cm.

Cervical Cancer

An estimated 13,800 new cases of cervical cancer will be diagnosed in 2020 in the United States.¹³ Fertility-sparing treatment is important to consider, as 43% of patients with cervical cancer will be diagnosed before age 45. Early-stage cervical cancer is often curable,^14,15 although the risk of recurrence following primary treatment increases with large tumor size, nodal metastases, and specific histological type.^16,17 Thus, ASCO² and NCCN guidelines¹⁸ suggest that fertility-sparing surgery should be restricted to low-risk, reproductive-age patients defined as those with International Federation of Gynecology and Obstetrics (FIGO 2018) stage IA1 to IB2 with low-risk histology (squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma). Patients should be counseled about increased risk of recurrence with high-risk features such as larger tumor size. For example, a systematic review of 1,364 patients with node-negative disease who underwent fertility-sparing surgery found a recurrence rate of 17% in patients with (FIGO 2009) stage IB1 >2 cm compared with only 4% in stage IB1 <2 cm.¹⁹ In addition, it has been reported that while women with tumors >2 cm can technically undergo a trachelectomy, 20-40% will require adjuvant treatment that could compromise fertility.^20,21 A recent multi-institutional retrospective study from the Japan Society of Gynecologic Oncology compared “ideal candidates” for fertility-sparing surgery (defined as those with low-risk histology, tumor size <2 cm, no nodal metastases, no deep invasion) with “less ideal candidates” (those not meeting criteria). They reported a fourfold increased risk of recurrence for “less ideal candidates”. Women who only had one risk factor had survival equivalent to that of the ideal candidates, potentially defining an intermediate group for whom fertility-sparing surgery is safe.

Ovarian Cancer

Although ovarian cancer is most commonly diagnosed among postmenopausal women, approximately 12% of patients will receive a diagnosis in their reproductive years,²² and rates of fertility-sparing surgery are increasing.^7,23 NCCN guidelines advise that conservation of at least the uterus and one or both ovaries can be considered for patients with apparent early-stage disease and/or low-risk tumors who wish to preserve fertility.²⁴ For example, ovarian germ cell tumors commonly occur in reproductive-age women, and whenever feasible, fertility-sparing surgery is considered standard^24-26 because these tumors are extremely chemosensitive.²⁷ In addition, fertility-sparing surgery is possible for a high percentage of young patients with sex cord-stromal tumors as approximately 57% are diagnosed at stage IA, and have a favorable prognosis.²⁸ Approximately one third of adult granulosa cell tumors (the most common ovarian sex cord stromal tumor)²⁹ are diagnosed during the reproductive years, 97% are stage I,³⁰ and there is no convincing evidence to suggest that fertility-sparing surgery compromises outcomes. ^31-33

Reproductive-age women with epithelial ovarian cancer are more likely to present with early-stage disease³⁴ which is associated with excellent prognosis.²² Fertility sparing in early-stage epithelial ovarian cancer is generally accepted as a safe option,^35,36 as demonstrated by a large retrospective cohort study where fertility-sparing surgery was not associated with worse overall survival.²³ However, there is controversy surrounding early-stage epithelial ovarian cancer with stage IC disease or having high risk features such as grade 3 or clear cell histology. For example, a study using Surveillance, Epidemiology, and End Results (SEER) data demonstrated that stage IC serous and clear cell carcinoma were associated with worse overall survival.²³ Furthermore, a meta-analysis including 545 patients³⁷ and a Japanese multi-institutional study raised concerns regarding the safety of fertility conservation in women with grade 3 tumors.³⁸ Other multi-institutional studies, however, did not find that fertility-sparing surgery affected oncologic outcomes even among women with high-risk features such as stage IC disease⁷, clear cell histology^7,39, or high pathologic grade.⁷ Currently, the NCCN guidelines do not recommend fertility-sparing surgery for any patients with clear cell carcinoma.²⁴

Borderline ovarian tumors typically present in younger women and at earlier stages and have a much better prognosis. Approximately one third of borderline tumors occur in women younger than 40, ⁴⁰ and conservative surgery is an acceptable option for women who wish to preserve fertility. While recurrence rates for fertility-sparing surgery are approximately 13-30%, the majority of the recurrences are of borderline histology, particularly for serous borderline tumors,⁴¹ and do not appreciably affect survival. In a meta-analysis of 120 studies, the pooled malignant recurrence rate was 1.6%, with a death rate of 0.5%. ⁴²

Endometrial cancer

The majority of women who receive a diagnosis of endometrial cancer are postmenopausal, with only approximately 6% of patients diagnosed before age 45.⁴³ Although fertility-sparing techniques preclude accurate surgical staging, the Society of Gynecologic Oncology (SGO) and the NCCN describe an ideal candidate for fertility sparing treatment as a woman strongly desiring fertility, with a well-differentiated (grade 1) tumor, no evidence of myometrial invasion (stage IA), no contraindications for medical management, and accepting the risks of nonstandard treatment.⁴⁴ Beyond tumor factors, counseling about fertility-sparing should include a realistic assessment of the patient’s ability to conceive spontaneously in the context of common underlying factors such as chronic anovulation or polycystic ovarian syndrome, and the feasibility and cost of accessing assisted reproductive technologies.⁴⁵ Further discussion of studies involving patient selection appears in the hormonal treatment section.

Fertility-sparing surgical approaches

Cervical conization and trachelectomy

Among reproductive-age women with early-stage cervical cancer, the type of surgical management depends on the clinical presentation and tumor characteristics,⁴⁶ including stage, tumor size, depth of invasion, histology, and presence of lymphovascular space invasion. Uterine-preserving surgical options include cervical conization, simple trachelectomy, or radical trachelectomy. Microinvasive stage IA1 cervical cancer can be treated with fertility-sparing conization. FIGO 2018 stage IA2-IB1 cervical cancer can be treated with a radical trachelectomy (vaginal, laparoscopic, abdominal, or robot assisted) with pelvic lymph node assessment.⁴⁷ Although minimally invasive radical hysterectomy for early-stage cervical cancer seems to confer worse prognosis compared with open surgery,^48,49 there is limited evidence to suggest that these findings also apply to fertility-sparing procedures such as radical trachelectomy. Patients should be counseled that findings during surgery and at pathologic examination may require changes to initial treatment plans that can lead to infertility. Prior to fertility-sparing surgery, magnetic resonance imaging (MRI) of the pelvis is indicated for all patients who have a macroscopic tumor to assess for tumor size, lymphatic spread, and extension beyond the cervix.

There are promising but limited data regarding neoadjuvant chemotherapy followed by fertility-sparing surgery in premenopausal women with tumors measuring >2 cm to <4 cm who wish to preserve their childbearing potential. The Cervical Cancer Treated with Neoadjuvant Chemotherapy Followed by Fertility-sparing Surgery (CoNteSSa) trial (NCT04016389), ⁵⁰ a single-arm multi-center phase II study, will provide further information regarding the safety of this strategy.

Post-operative complications after fertility-sparing treatment for cervical cancer, such as cervical stenosis and Asherman syndrome, can negatively affect fertility.^51,52 For example, a retrospective study reporting incidence rates of cervical stenosis after radical trachelectomy found that 14 of 15 patients developed cervical stenosis when a device (Foley catheter or tailed intrauterine device) was not placed in the cavity.⁵³ Management of post-operative complications may include cervical dilation with or without stent placement for stenosis and/or hysteroscopic lysis of adhesions for intrauterine adhesions.

Ovarian preservation in gynecological cancers

Although cervical cancers rarely metastasize to the ovaries, and limited retrospective studies have suggested that ovarian preservation in young women with early-stage cervical cancer is safe, there is no guideline-based consensus regarding the indication for ovarian removal versus ovarian preservation in this population. The proportion of cases presenting with ovarian metastases at the time of surgery ranges from 0.6 to 1.5%. Cervical adenocarcinomas are somewhat more likely to metastasize to the ovaries than squamous cell carcinomas: 2% versus 0.4%, respectively.⁵⁴ A population-based study of stage I cervical cancer by Matsuo et al.⁵⁵ suggested that ovarian conservation decreases all-cause mortality, including death resulting from cardiovascular and other chronic diseases. In women with cervical cancer who desire ovarian preservation but require radiation therapy, ovarian transposition, or surgically fixing the ovaries out of the radiation field, may protect the ovaries from the deleterious effects of radiation. ⁵⁶

Bilateral salpingo-oophorectomy is part of the standard of care for the surgical management of women with ovarian and endometrial cancer; however, some reproductive-age women may be candidates for ovarian preservation. In most early-stage epithelial ovarian cancers, it is likely safe to preserve the contralateral unaffected ovary. In the case of unilateral borderline ovarian tumors, it is important to consider the oncologic outcomes of cystectomy versus oophorectomy as an ovarian conservation procedure. Although ovarian cystectomy seems to be associated with increased risk of recurrence compared with oophorectomy in some retrospective studies,^41,57 many investigators combine oophorectomy and cystectomy in their analyses of “fertility-sparing surgery”, making this question difficult to answer with high quality data. In a retrospective comparison of 143 patients with stage I borderline tumors treated with a salpingo-oophorectomy and 47 who underwent a cystectomy, 7% versus 23% recurred with a second borderline tumor respectively. The malignant recurrence rate in this study, however was low at 1%.⁵⁸ NCCN guidelines recommend a unilateral salpingo-oophorectomy over cystectomy for unilateral borderline tumors and a bilateral salpingo-oophorectomy for bilateral borderline tumors. Given the low malignant recurrence rate, it is reasonable to consider an oophorectomy on one side and cystectomy on the other or bilateral cystectomies (a very conservative approach) for patients with bilateral borderline tumors who desire future fertility. ⁵⁹

Among reproductive-age women with endometrial cancer, recognition of the implications of ovarian preservation given the risk of synchronous ovarian cancer or metastasis to the ovaries, facilitates shared decision-making. ⁶⁰ A growing body of literature supports the oncologic safety of ovarian conservation in young women with endometrial cancer. ⁶¹ In a study from the National Cancer Database, Wright et al. identified a cohort of 15,648 young women with low-grade early-stage endometrial cancer and found that ovarian conservation did not adversely affect survival.⁶² Furthermore, the Korean Gynecologic Oncology group demonstrated that among women with stage I-II endometrial cancer, ovarian conservation had no effect on rates of recurrence or survival.⁶³ In a population-based study using the SEER database, Matsuo et al. identified 86,005 women who underwent surgical staging for low-grade stage I endometrioid adenocarcinoma between 1983 and 2012. ⁶⁰ In this population, ovarian conservation was associated with improved long-term overall survival, specifically from cardiovascular disease.

Finally, young patients should be assessed for their potential risk of having developed endometrial, ovarian, or endometrial and ovarian cancers as a result of Lynch syndrome, because the safety of fertility preservation in the setting of genetic cancer syndromes is unknown.

Medical approaches to fertility sparing

Gonadotropin-releasing hormone agonists

Gonadotropin-releasing hormone (GnRH) agonists are hypothesized to achieve “ovarian quiescence” and thus provide ovarian protection during chemotherapy. Other proposed theories for GnRH mechanism of action include decreased utero-ovarian perfusion, increased production of sphingosine-1-phosphate, and protection of possible germinative stem cells. ⁶⁴ Randomized trials have been conducted primarily in patients with breast cancer receiving chemotherapy, with conflicting results (Appendix 1). A study in patients with lymphoma was the only one not to define premature ovarian failure using menstrual history, which is acknowledged as a poor proxy for fertility. This study demonstrated that after a median follow-up of 5 years, GnRH was not efficacious in preventing premature ovarian failure or improving pregnancy rates.⁶⁵ A limitation of these trials is that few evaluated live birth rate as an endpoint, which is most relevant in establishing the role of GnRH agonist therapy in fertility preservation. Meta-analyses have shown favorable effects of GnRH on ovarian suppression during chemotherapy, ^66,67 but such pooled analyses suffer from the same methodologic concerns. Given the conflicting results, ASCO does not consider GnRH agonists as a proven fertility-preservation method.²

Progestins

Progestins are the mainstay of fertility-sparing treatment in young patients with endometrial cancer, ⁴⁴ and the rate of progestin utilization appears to be increasing.^68,69 The most frequently studied⁷⁰ methods of progestin administration, and those recommended by NCCN⁷¹ and SGO⁴⁴ for fertility-sparing treatment, are oral medroxyprogesterone (MPA), megestrol acetate (MA), and the levonorgestrel-releasing intra-uterine device (LNG-IUD). There is no consensus regarding the optimal duration of treatment and preferred regimen.^72,73 In two systematic reviews including patients with both atypical hyperplasia and stage I endometrial cancer receiving a variety of progestin-containing regimens, hormonal therapy achieved a reasonable complete response rate of 71-78%, with about one-third of patients achieving pregnancy.^70,74 In the earlier of these meta-analyses, Gunderson and colleagues showed that despite the reassuring response rate, the durable complete response rate was only 53% (over 39 months). In addition, this result was more pronounced for patients with hyperplasia compared with carcinoma (66% vs. 48%). Even among those who initially responded, 23% with hyperplasia and 35% with carcinoma experienced a recurrence. There are limited data indicating that recurrences can be treated with a second course of hormonal therapy.⁷⁵

There are conflicting data regarding long-term survival after progestin therapy for endometrial cancer. For example, Greenwald and colleagues⁷⁶ reported no differences in all-cause mortality after 15 years of follow-up between patients who received progestin therapy and those who underwent primary surgery. Importantly, however, when the analysis was limited to endometrial cancer–specific deaths as defined by SEER, there was a clear increase in mortality associated with hormonal therapy. Only when broadening the definition of cancer-specific survival did they find that the groups had equivalent survival. Moreover, a recent population-level analysis using the National Cancer Database found an increased risk of cancer-specific mortality among young patients with endometrial cancer who received fertility-sparing treatment.⁶⁸ Thus, while these data suggest that fertility-preserving treatment with progestins should be approached with caution, it remains an important option in appropriately selected well-informed patients.

Levonorgestrel-releasing intrauterine device:

The most common LNG-IUD releases 20 mcg of progestin daily and is less well-studied than oral progestins for the purpose of fertility sparing management. Response rates are superior in atypical hyperplasia compared with endometrial cancer.⁷⁷ In a retrospective study, a complete response occurred in 80% of women with grade 1 and 75% of those with grade 2 endometrial cancer, although the sample size was small.⁷⁷ Only 39% (n=19) of patients who achieved a complete response attempted to conceive, and 73% were successful. The recurrence rate in this study was high at 41%, although the authors reported that the majority of recurrences occurred in women who removed the LNG-IUD. In a prospective evaluation of 21 patients with stage IA grade 1-2 endometrial cancer⁷⁸ who wished to preserve their fertility, participants underwent hysteroscopic resection of the lesion followed by LNG-IUD for 6 months. After 3 months, 18 patients (86%) had a complete response lasting a median of 85 months.

Combination therapy:

A meta-analysis including 1,038 women found higher pooled response rates in women using both the LNG-IUD and oral progestins compared to LNG-IUD and oral progestins alone (87% vs 76% and 71%, respectively). ⁷⁴ Notably, this study pooled a variety of oral progestin regimens, making the results difficult to generalize. A prospective phase II trial from Japan⁷⁹ using the LNG-IUD with MPA found a more modest complete response rate of 37% among 35 patients at 6 months. These authors recommended continuing the regimen for at least 9-12 months.

Recently, the addition of metformin to progestin therapy has shown promise. Epidemiologic studies demonstrated that metformin use is associated with improved survival in patients with endometrial cancer.^80,81 Metformin exerts its antineoplastic activity through activation of multiple signaling pathways controlling cell metabolism⁸² and possible disruption of estrogen mediated endometrial proliferation.⁸³ A recent study of 150 patients with endometrial cancer or hyperplasia demonstrated that those randomized to MA plus metformin had higher 16-week complete response rate than those randomized to MA alone (34% vs 21% respectively).⁸⁴ In a prospective study, 63 patients received 400 mg of MPA and 750-2250 mg of metformin daily until conception. Ninety-seven percent achieved a complete response within 18 months, with a 13% relapse rate during 57 months of follow-up. Thirty-one patients who desired conception underwent in-vitro fertilization (IVF) and embryo transfer ; 19 (61%) were able to conceive and 14 (45%) delivered a living child.⁸⁵ The ongoing Improving the Treatment for Women with Early Stage Cancer of the Uterus (feMME) trial (NCT01686126), a phase II randomized 3-arm trial of LNG-IUD alone, with metformin, or with a weight loss intervention to assess rates of complete pathologic response, will provide more insight into the added value of metformin to the LNG-IUD. Finally, a pilot randomized controlled trial (B-FiERCE, NCT 04008563) of referral to bariatric surgery with a LNG-IUD vs LNG-IUD alone will assess whether the addition of bariatric surgery is an acceptable and feasible option for obese women with endometrial cancer and atypical hyperplasia.

Post-treatment surveillance

Cervical cancer

Close follow-up after fertility-sparing surgery for cervical cancer is essential. For tumors less than 2 cm the risk of recurrence is less than 5%. Most recurrences are localized to the neo-cervix, followed by the parametrium or pelvic sidewall. Anatomical changes after radical trachelectomy such as a short neo-cervix and narrow cervical canal can make follow-up examinations challenging. Despite these challenges, protocols for the follow-up of these patients have not been well established. Pap tests in combination with HPV testing and colposcopy as indicated should identify the majority of relapses in these patients.⁸⁶

Ovarian cancer

Regular follow-up, initially every 3 months, with pelvic examination and CA-125 can reliably detect disease recurrence in women with ovarian cancer, including women who have undergone fertility-sparing surgery. Patients with stage I epithelial ovarian cancer, early-stage sex-cord stromal tumors, and malignant ovarian germ cell tumors have excellent prognosis and are unlikely to recur.^25,28,34 Patients with borderline tumors who undergo fertility sparing surgery, however, have up to a 30% chance of recurrence, though the incidence of malignant transformation is low.^41,42,57 In an unselected population of reproductive age women, the likelihood of diagnosing an ovarian mass on ultrasound ranges from to 8% to 35%^87-89 and the most common finding is a simple cyst.⁸⁹ In women with a history of fertility sparing surgery, the pre-test probability that a new adnexal mass is malignant is, of course, higher and the decision to proceed with surgery requires balancing the risk of continued surveillance of a suspicious mass with the likelihood of conception. The presence of benign ovarian pathology in reproductive age women may also increase their CA-125, further complicating interpretation of imaging findings.

Endometrial cancer

The optimal follow-up schedule for women receiving hormonal treatment for endometrial cancer is unknown, and the follow-up should be individualized based on baseline risk factors, associated symptoms, and response to treatment. Given the risk of endometrial cancer progression, some institutional protocols recommend office endometrial biopsy (can be performed with an IUD in place) every 3-6 months, until two consecutive negative biopsies are obtained, after which sampling frequency is reduced. If a complete response is noted, then conception should be encouraged. Until pregnancy is achieved, close follow-up and endometrial sampling every 6 months is also advisable to detect an early recurrence.^90,91 After patients complete childbearing, clinicians should discuss definitive hysterectomy, as long-term recurrences have been observed.⁹² For patients with persistent carcinoma after 3 to 6 months, including lack of any pathologic demonstration of progestin effect, increasing the dose of oral progestin can be considered.⁹³ If a patient was treated initially with an LNG-IUD alone, an oral progestin can be added. In women with persistent disease after 6-12 months of treatment, proceeding to definitive surgical management with hysterectomy and staging is recommended.

When should patients attempt pregnancy?

Women who want to have children after a cancer diagnosis face difficult decisions about pregnancy timing. The data for timing of pregnancy after gynecologic malignancy are sparse. For patients with cervical cancer, timing should be individualized based on the presence of risk factors for recurrence such as stage, tumor size, LVSI, histology, as well as type of surgery. It is important to allow for appropriate recovery following surgery and for enough follow-up time to be reassured that the cancer is not quickly relapsing.

In patients with ovarian cancer, it is important to consider whether or not chemotherapy was administered. A recent population-based study using data from three state cancer registries found that women who conceived more than 1 year after chemotherapy had the same risk of having a preterm infant or a low birthweight infants women without a history of cancer.⁹⁴ Women who conceived less than 1 year after starting chemotherapy, however, experienced twice the risk of a preterm birth and low birth weight [Relative Risk (RR) 1.9, 95% CI 1.3-2.7 and RR 2.0, 95% CI 1.4-3.0 respectively]. While waiting 12 months following completion of chemotherapy may be advantageous, the likelihood of successful pregnancy declines with age.

Pregnancy is often encouraged as soon as possible after successful treatment of endometrial cancer for two reasons: the changes in endogenous estrogen and progesterone during pregnancy are likely protective, and the exact duration of response to hormonal therapy is unknown, but may be as low as 12-24 months.^70,72,95 However, for patients requiring ovarian stimulation with gonadotropins, there is concern that spiking serum estradiol levels can precipitate a recurrence. Ultimately, pregnancy timing is a complex and difficult to study, as it depends on a multitude of individual patient factors and is best considered in a multi-disciplinary setting.

Pregnancy Outcomes of Fertility-Sparing Management

Women who consider and pursue fertility-sparing treatment for early gynecologic cancers should be thoroughly counseled on pregnancy risks and outcomes associated with their treatment. However, providing accurate data on pregnancy and live birth rates is difficult because studies often include heterogeneous treatment modalities. Additionally, it is important to use caution when interpreting pregnancy and live birth rates based on attempted pregnancies, as there may be significant clinical reasons why a patient who opted for fertility-sparing surgery did not attempt to conceive later, including disease recurrence. Moreover, many studies do not distinguish between women who were unable to conceive and those who chose not to attempt pregnancy. Finally, it is unclear in many studies whether conceptions were spontaneous or were achieved with the use of assisted reproductive technologies. A summary of live-births rates after fertility-sparing treatment is given in table 2.

Table 2.

Proportion of recurrences and live-births after fertility-sparing treatment from select studies^*

	Recurrence (%)	Live-births (%)
Cervical Cancer <2 cm	4%19	67%-70% (38% premature)19,46
Cervical Cancer >2cm	17%19
Epithelial Ovarian Cancer	11%35,36	78%-96%25,96
Non-epithelial Ovarian Cancer**	3%-15%33	86%-95%26,32
Borderline tumor	13-30% (LMP) 41,42,57; 1.6% (malignant)42
Endometrial Cancer	35%70	20%-47%70,74,96,99

^*Proportions obtained from systematic reviews when available

^**Includes germ cell tumors, and sex-cord stromal tumors

LMP, low malignant potential

Cervical Cancer

The majority of women undergoing fertility-sparing treatment for early-stage cervical cancer can expect to have a live birth; however, there is a significantly increased risk of preterm labor and birth, and it is unclear whether surgical approach influences this risk. In a systematic review of 2,777 patients treated with various fertility-sparing procedures (including conization, simple trachelectomy, vaginal radical trachelectomy, abdominal radical trachelectomy, and minimally invasive radical trachelectomy) the reported live birth rate was 70% and the prematurity rate was 38%.¹⁹ Although there were no differences in live birth rates among these approaches, the prematurity rates were significantly lower in women who had a simple trachelectomy/cone resection and neoadjuvant chemotherapy followed by fertility-sparing surgery, compared to other conservative surgeries. As expected, most second-trimester fetal losses and premature deliveries were due to premature rupture of membranes. The high rate of premature delivery among these patients highlights the importance of preconceptual counseling by maternal-fetal medicine subspecialists.

Ovarian Cancer

Most reproductive-age women with germ cell tumors who receive chemotherapy in addition to fertility-sparing treatment can expect to conceive spontaneously; in fact, amenorrhea rates after completion of fertility-sparing surgery and chemotherapy have been reported to be less than 3%.⁹⁶ A review of 658 patients found that among women who attempted conception after fertility-sparing surgery the rate of pregnancy ranged from 66% to 95%,²⁵ which is consistent with other studies. ^26,32

There is limited information regarding obstetric outcomes of women with epithelial ovarian cancer who undergo fertility-sparing surgery; however, it seems that there is a high successful conception rate of 66% to 100%, suggesting no significant detriment as a result of fertility-sparing surgery.⁹⁷ In one of the largest reviews published to date, Eskander et al.⁹⁶ found that among 328 women who underwent fertility-conserving surgery reported in the literature, there were 119 pregnancies and a 96% live birth rate. The pregnancy rate among patients with borderline tumors of the ovary is similar.⁹⁸

Endometrial Cancer

Endometrial cancer patients who respond to hormonal therapy will often require fertility services to achieve pregnancy. A retrospective study using a nationally representative commercial claims database found that of 63 patients who had a live birth, 50% required fertility treatment.⁶⁹ Furthermore, patients were almost 6 times more likely to achieve a live birth if they also underwent fertility treatment versus attempting spontaneous conception. A meta-analysis of 1,038 women with endometrial cancer or atypical complex hyperplasia⁷⁴ demonstrated that, of 71% of women who had a response to progestin therapy, 34% became pregnant, but only 20% delivered a live infant. These results are consistent with a prior meta-analyses that reported a pregnancy rate of 35%,⁷⁰ but lower than previously reported live birth rates of 28-47%.^96,99 It is important to note that these results should be interpreted with caution as they are based on very few pregnancies, and the differences described above may reflect different populations with differing access to infertility treatments. In the meta-analysis by Wei et al.,⁷⁴ patients who responded to the LNG-IUD and LNG-IUD with progestin had pregnancy rates of 18% and 40% and live delivery rates of 14% and 35%, respectively. However, more recent retrospective reviews of patients using a LNG-IUD with or without progestins demonstrated much higher live birth rates (67-73%).^77,100

The importance of interdisciplinary care

Interdisciplinary, patient-centered care is integral to optimizing oncologic, fertility, and pregnancy outcomes in women with a history of early gynecologic cancer. Collaboration between gynecologic oncologists, reproductive endocrinologists, and maternal-fetal medicine specialists can facilitate and enhance treatment planning.

All women of reproductive-age with newly diagnosed, early-stage gynecologic cancer who are candidates for fertility-sparing therapies should be referred to reproductive specialists early during the course of treatment planning. Early referral allows the patient to learn about her fertility potential and factors that influence it, including age, ovarian reserve, reproductive history, and the fertility status of her intimate partner. Fertility preservation methods include oocyte or embryo cryopreservation and ovarian tissue cryopreservation, though the latter has a very limited role in gynecologic malignancies due to concerns for reintroducing malignancy with graft reimplantation in the future. Furthermore, it is important to be aware and review with patients that access to assisted reproductive technologies in the United States may be limited by cost and insurance coverage. ASRM estimates that an average IVF cycle costs $12,400¹⁰¹ and many women will require multiple IVF cycles to conceive. Moreover, with the exception of 16 states that have insurance coverage mandates for infertility or fertility preservation treatments through private insurers, there is no federally mandated insurance coverage for infertility care. Even when insurance plans provide treatment coverage, benefits vary greatly among different policies, and care is by no means free, limiting access to many women.¹⁰² Exploration of these factors can influence decision-making about oncologic treatment options, including whether a decision to pursue fertility-sparing management is appropriate. This shared decision making with patients also presents an opportunity for discussion of the possible fertility risks associated with treatments as well as alternative planning in the event conservative management is not successful, such as the decision to perform ovarian transposition at the time of an aborted trachelectomy, versus proceeding with egg or embryo freezing prior to chemoradiation in a woman with cervical cancer. Establishing a relationship with a reproductive specialist early on also facilitates post-treatment management.

Approximately 20% ¹⁰³ of women managed conservatively for cervical cancer and 50%⁶⁹ of women managed conservatively for endometrial cancer require some type of fertility treatment. Women with cervical cancer who have fertility-sparing surgery often experience neo-cervical stenosis, intrauterine adhesions, and secondary amenorrhea. Reproductive specialists can address these issues and provide fertility treatments including ovulation induction, intrauterine inseminations and IVF as needed. Patients can also be referred while undergoing fertility-sparing management with progestins for counseling and treatment planning so that the patient is ready to conceive immediately after hormonal therapy has concluded. Additionally, women who have completed their cancer treatment but do not currently desire pregnancy should also be considered for referral for fertility preservation if this was not addressed before treatment. Finally, in women without ovarian function after cancer treatment, utilization of donor oocytes is an option to achieve pregnancy.

Preconceptual counseling with a maternal-fetal medicine specialist is another important component of interdisciplinary care. Maternal–fetal medicine specialists can counsel patients on pregnancy outcomes associated with cancer treatment, provide anticipatory guidance about potential problems and complications that may occur during pregnancy, and formulate strategies for risk reduction. They can also make recommendations and help manage concurrent comorbidities to optimize health status prior to conception. For women who have had a trachelectomy, discussions and recommendations about cerclage placement, monitoring of neo-cervical length during pregnancy, and mode of delivery can be made. Women with endometrial cancer can benefit from counseling about the increased risk of pregnancy-induced hypertension, gestational diabetes, and other conditions as well as management of already present comorbid conditions.