Introduction
A significant proportion of reproductive-aged women are affected by a breast or gynecologic cancer diagnosis in the United States. In 2019 there will be an estimated 268,600 new cases of invasive breast cancers with 15% occur under the age of 45. The percentages for newly diagnosed uterine, ovarian, and cervical cancers under the age of 45 are 6.5%, 12%, and 36.5%, respectively. Over the last several decades the number of women having their first child after the age of 35 has increased. In addition to reproductive aging and cancer treatments, fertility concerns have become more prevalent and complicated for women diagnosed with cancer. This population is faced with difficult considerations: their new cancer diagnosis, treatment options, prognosis, and impact on future fertility. Standard treatment for these cancers, in particular, gynecologic malignancies results in the removal and ablation of the reproductive organs, and the importance of preserving fertility has become more apparent. Health-care providers need to be familiar with fertility options and provide timely and appropriate referrals.
Treatment for cancer often consists of a combination of surgery, chemotherapy, and radiotherapy. Alkylating agents, platinum derivatives, taxanes, anthracyclines, and antimetabolites are the most commonly used antineoplastic drugs for breast and gynecologic cancers. However, these treatments can harm healthy tissues and organs. Following chemotherapy and radiotherapy women are at increased risk of premature ovarian failure and early menopause. The extent of the impact on the reproductive organs, particularly the ovaries, depends on several factors, including age of diagnosis, cumulative dose of chemotherapy, radiation, and type of chemotherapy. When abdominal and pelvic radiation doses are kept to less than 4 Gy, there does not appear to be an impact on ovarian or uterine function. Among chemotherapy treatments, alkylating agents such as cyclophosphamide pose the highest risk for ovarian toxicity and infertility. A chemotherapy combination containing cyclophosphamide is often used in the management of breast cancer. It is rarely used in the upfront management of gynecologic malignancies. The preferred regimen for the management of gynecologic cancers consists of a platinum and taxane doublet. Clinical trials have demonstrated that these agents pose relatively moderate-to-low risk for infertility.
To preserve fertility while treating gynecological cancers requires the use of techniques that have been proven to have efficacious oncologic outcomes while preserving fertility. There are several fertility techniques such as ovarian transposition, in vitro fertilization, oocyte freezing, and cryopreservation of ovarian tissue that have been evaluated. The patient and her partner should be informed of these options by a fertility specialist who specializes in oncofertility.
Organ-sparing surgical treatment aimed at preserving the uterus and at least one ovary has gained acceptance in the management of early stage gynecological cancers in selected patients of childbearing age. The aim is to preserve the functionality of the reproductive organs by reducing the radicality of the surgical procedure, thereby allowing the possibility of a future pregnancy. The option of fertility-sparing surgical treatment is reserved only for selected cases that are defined by the stage, histology, grade, and prognostic factors of the disease.
How Does Cancer Therapy Affect Fertility?
Female fertility refers to the ability of a woman to become pregnant and bear a child. At the time of birth a female’s ovaries contain hundreds of thousands to one million eggs or oocytes. Eggs grow and mature inside of ovaries within fluid-filled sacs known as follicles. Upon the onset of menarche, several immature oocytes are released from the ovaries. Usually, only one egg will dominate in growth and become a mature oocyte. The mature oocyte is released from the ovary into the fallopian tube through a process called ovulation. The mature oocyte is then either fertilized by sperm to create an embryo or if sperm does not fertilize the egg, the egg breaks down and menstruation will occur. Over a lifetime, approximately 1% of all oocytes are ovulated. This process occurs with every month’s menstrual cycle until menopause takes place and accounts for the natural decline in a female’s ovarian reserve.
Follicles or oocytes that are not fully developed are vulnerable in the setting of anticancer treatment. The damages imposed on the gametes by such treatment manifest as short-term or long-term infertility. Gynecological surgery impacts a patient directly due to removal of part, or all, of the female reproductive system. In addition, gynecological surgeries performed to treat cancers could result in scar tissue formation, making it challenging for female patients to carry a pregnancy to term. Chemotherapy and radiotherapy have a direct gonadotoxic effect by destructing ovarian follicles or damaging the DNA of existing oocytes that impact normal ovulatory function and the ability to become pregnant, respectively. Finally, antihormone therapies used to treat breast cancer patients have both direct and indirect consequences to fertility and ovarian function.
Systemic Treatments: Chemotherapy, Targeted Therapy and Immunotherapy, Antihormonal Therapy
Chemotherapy
Chemotherapy targets all cells in the body that divide quickly. Many cells in our bodies are quickly dividing, including the gametes. When these cells are damaged by the cytotoxic effects of chemotherapy, infertility could occur. The exact impact that a chemotherapy agent has on future fertility is almost impossible to predict. This is especially true for patients receiving multiple chemotherapy agents to treat cancer. There are some risk factors that are used to help health-care providers predict the risk that agents pose to fertility; however, these are only meant to be used a guide. These risk factors include the patient’s age at the time she receives her treatment, the drug used, and the dose.
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Age: Since younger female patients have more eggs in their reserve, they have a higher chance of retaining fertility throughout the cytotoxic damage from chemotherapy. Women who are treated for cancer before they are 35 have the best chance of becoming pregnant after treatment.
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Drug: Some drugs are more likely to impact fertility than others. Alkylating agents and conditioning chemotherapies in preparation for bone marrow transplants are considered to pose the highest risk to future fertility. However, the exact degree to which fertility may be impacted in the future is very difficult to predict. This is especially true when treating patient with multiple chemotherapy agents.
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Dose: Higher doses and longer duration of the chemotherapy have greater potential negative impact on fertility.
Targeted Therapy and Immunotherapy
Some targeted therapy may cause ovarian failure, however, there is limited research available regarding other targeted treatments and immuno-therapies on fertility.
Antihormonal Therapy
Endocrine therapy, or antihormone therapy, is a common treatment for patients with hormone-sensitive tumors. Although hormone therapy may not impact fertility directly, many patients are prescribed these medications for anywhere from 5 to 10 years consecutively. Due the natural decline of ovarian reserve over time, the patient’s age at the completion of therapy could make it increasingly difficult to achieve pregnancy. In addition, patients are advised to avoid pregnancy during the time that they are taking antihormone therapy because the medication poses a high risk of birth defect to a developing fetus. It is important to educate patients that menstruation may be irregular or cease while on treatment. However, it may still be possible to become pregnant. For this reason, birth control should be implemented to prevent pregnancy.
Radiation Therapy
Damage to fertility due to radiation therapy depends on the dose of radiation, the area of the body treated, and the woman’s age at time she is receiving treatment. Radiation directed at the ovaries threatens the health of oocytes as they are considered sensitive to radiation therapy. Radiation directed at the uterus could lead to decreased uterine volume and endometrial atrophy. Total body radiation also poses high risk to future fertility.
Age: Younger women are likely to have a higher ovarian reserve and, as a result, are less likely to enter permanent menopause at the time of therapy.
Dose: A dose of only 5 or 6 Gy can cause ovarian failure in a woman over 40, but doses 14–20 Gy can cause ovarian failure in women under 35.
Location: Radiation therapy to the abdomen or pelvis can cause harm to the female reproductive organs. Radiation directed at the uterus and/or cervix could result in the inability to carry a pregnancy to term, a higher risk for miscarriage, preterm labor, and low birth weight babies.
Radiation therapy to the brain can also disrupt fertility. The pituitary gland is responsible for regulation of the hormones luteinizing hormone (LH) and Follicle-stimuating hormone (FSH), which control ovulation. When the pituitary gland is in the field of brain radiation therapy, there is a risk that normal hormonal function, hence, ovulatory function is disrupted that can lead to infertility.
Options for Fertility Preservation
A referral to a reproductive endocrinologist (RE) is appropriate for any female patient that is at risk for future infertility as a result of cancer treatment. If the patient is interested in fertility preservation, all measures must be taken prior to the start of her cancer treatment and as soon as possible after initial diagnosis in an effort to delay the start of treatment as some fertility-sparing measures take 2–4 weeks. A patient that may need gynecological surgery may be candidates for fertility-sparing surgery. Egg or embryo cryopreservation is the standard of care for fertility preservation in female patients. At this time, ovarian suppression and ovarian tissue cryopreservation are fertility-sparing options that are considered to be experimental.
Fertility-Sparing Surgery
In this section the role of fertility-sparing surgery and nonsurgical treatment is discussed for endometrial, cervical, and ovarian cancers.
Endometrial Cancer
Endometrial cancer is the most common gynecologic malignancy in the United States. The standard-of-care treatment is total hysterectomy and bilateral salpingo-oophorectomy (BSO), with selective use of sentinel lymph node (SLN) mapping or pelvic and/or para-aortic lymph node dissection when appropriate, depending on the risk factors and apparent cancer staging. Approximately 14% of the affected women with the disease will be of the childbearing age. The fertility-preserving (FP) treatment for patients with endometrial cancer is currently limited to hormonal treatment. The ideal candidate for FP treatment is a person with (1) grade 1 (well differentiated) tumor on dilation and curettage, (2) absence of lymphovascular space invasion (LVSI) on adequate curettage specimen, (3) no myometrial invasion on magnetic resonance imaging or ultrasound, and (4) no evidence of suspicious or metastatic disease on imaging.
Currently, for patients with endometrial cancer, treatments involve the use of progesterone either orally or delivered by levonorgestrel-releasing intrauterine device (IUD). Megestrol acetate (160 mg daily or 80 mg bis in die (BID)) or medroxyprogesterone acetate (600 mg daily) are the two most commonly used oral regimens. Levonorgestrel-releasing intrauterine system is the only progesterone containing IUD that has been studied in endometrial cancer patients. Prospective studies have shown that levonorgestrel-releasing IUD is associated with greater regression of histology, lower relapse rates, and lower rates of hysterectomy. Metaanalysis on quality-of-life data showed superiority of levonorgestrel releasing compared to oral progesterone, with reduced weight gain, sleep disorders, headaches, and mood disorders. It is recommended to provide continuous treatment for 3 months, followed by reevaluation with hysteroscopy and/or endometrial sampling.
Relapse can occur in up to 50% of cases, but a second cycle of progesterone treatment has been associated with good response rate in up to 89% of patients. Women who experience a remission are encouraged to pursue immediate conception. Timely referral to a RE is crucial to minimize the time to conception, as these patients tend to have other factors that may contribute to infertility such as obesity, polycystic ovary syndrome, and advancing age. The use of metformin has also demonstrated in improve outcomes in women with endometrial cancer. A metaanalysis demonstrated that the oncologic outcomes were 81% (regression rate) with obstetrical outcomes of 47% (live births). Following completion of childbearing, women are recommended to undergo definitive hysterectomy.
Cervical Cancer
Cervical cancer is the second most common gynecologic malignancy in the United States, with an estimated 13,240 new cases and 4170 deaths in the year 2018. Forty-three percent of patients diagnosed with cervical cancer are under the age of 45 and potentially desire to preserve fertility. Traditionally, the treatment for early, cervical cancer that is defined as stage I–IIA disease is radical hysterectomy. Microinvasion disease defined as International Federation of Gynecology and Obstetrics (FIGO) stage IA1 with <3 mm stromal invasion can be managed with conization, either a loop electrosurgical excisional procedure (LEEP) or a cold knife cone (CKC) biopsy.
Candidates for a fertility-sparing option include women with clinically early stage cervical cancer. Those with stage IA1 disease (microinvasion) are appropriate candidates for CKC if there is no evidence of LVSI, negative endocervical curetting after excision, and negative endocervical margins. If the patient meets all of the criteria defined earlier, the risk of recurrence is <0.5%.
In the absence of margin status, patients with stage IA1 and negative LVSI have recurrence rate of approximately 7%, with over 80% of the recurrences occurring within the first 36 months. Hence, close follow-up is paramount, and patients should be counseled to undergo definitive surgical management as soon as childbearing is complete. The LVSI status is an important prognostic factor for lymph node involvement, recurrence risk, and overall survival.
In cases of stage IA1 with positive LVSI, the recurrence risk increases up to 9%, and therefore a conization (with negative margins) with laparoscopic pelvic SLN mapping is a reasonable strategy. Patients who undergo a CKC or LEEP procedure are at a small but known increased risk of preterm delivery, premature rupture of membranes, and low birth weight. Adenocarcinoma in situ presents a more challenging clinical situation. Unlike the squamous cell lesions, adenocarcinoma is a glandular lesion and is considered multifocal. Up to 13% of patients have foci of the disease separated by 2-mm of stromal mucosa known as “skip lesions.” Bisseling et al. reported about 16 patients with stage IA1 disease who were managed with conization; and after 72 months none of the patients recurred.
For women with a stage IA2–IB1 cervical cancer, a FP radical trachelectomy (FPRT) is a reasonable option in selected cases. The FPRT procedure comprises three main steps, that is, dividing the uterus proximal to the cervical isthmus, excising the entire cervix and surrounding parametria, and then suturing the uterus to the vagina. Once tumor-free margins have been achieved, many surgeons insert a cerclage suture around the lower uterine segment, in anticipation of future pregnancy. Assessment for lymph node metastases is critical for any patient with>3 mm depth of invasion (i.e., >stage IA1) or other high-risk features (e.g., LVSI and high-risk histology) on a biopsy specimen. Frozen section may be utilized to assess for nodal metastases and positive surgical margins, in which case fertility-sparing surgery may be aborted, or the surgical procedure altered (e.g., complete ipsilateral pelvic and para-aortic lymphadenectomy). Candidates for an FPRT are (1) women desiring preservation of fertility, (2) are compliant with the expected follow-up, (3) have squamous cell or adenocarcinoma histology, (4) FIGO stage IA1 with LVSI or IA2/IB1 with tumor <2 cm in diameter, and (5) no evidence of pelvic lymph node metastases.
Patients with cervical tumors >2 cm have an increased risk of positive lymph nodes, deep infiltration, and LVSI. Selected centers offer FPRT for patients with lesions>2 cm via the abdominal approach that allows for a wider surgical margin. In the United States, most fertility-sparing procedures are performed via the abdominal approach due to surgeon preference and comfort. Cervical factors such as stenosis, short length, and the lack of mucus to facilitate sperm migration are considered the main causes of infertility after trachelectomy. Rob et al. noted that during trachelectomy at least 1 cm of cancer-free cervical stroma should be saved, as this increases the chance of pregnancy.
Bentivegna et al. performed a systematic review of the literature comparing these methods. A total of 2488 patients submitted to FP, and 944 ensuing pregnancies were analyzed. One hundred and six (4.2%) recurrences were reported. The overall fertility, live birth, and prematurity rates for these procedures were, respectively, 55%, 70%, and 38%. There was no difference between the live birth rates according to the five FP procedures, but abdominal RT had overall higher prematurity rate (57%) compared to conization (15%), vaginal RT (39%), and minimally invasive RT (50%).
Ovarian Cancer
Epithelial ovarian cancer accounts for approximately 80% of ovarian malignancies. Most patients present at advanced stages (III, IV) of the disease, and rarely prior to the age of 40 years. The borderline/low-malignant potential (LMP), stage I, and germ cell tumors are more common in women of reproductive ages.
Thirty-four percent of cases of borderline ovarian tumors occur in women less than 40 years of age. For the early stage disease, survival is estimated to be around 99%. Therefore the standard of care is fertility preservation if desired by the patient. Ovarian cystectomy is reasonable, but there could be approximately 30% risk of recurrence in the affected ovary. Unilateral salpingo-oophorectomy (USO) carries an approximately 8% risk of recurrence. If there is bilateral ovarian involvement and complete resection can be achieved, ovarian cystectomy is the treatment of choice. Surgeons must keep in mind that approximately 25% of the borderline tumors on frozen pathologic evaluation are upgraded to invasive on final pathologic assessments. About 20% of the patients may have noninvasive as well as invasive metastatic implants. Complete surgical staging (including exploration of the entire abdominal cavity, peritoneal washings, infracolic omentectomy, and multiple peritoneal biopsies) is essential.
Traditionally, the management of invasive epithelial ovarian cancer (IEOC) includes hysterectomy, BSO, abdominal/pelvic washings, biopsies, and full lymphadenectomy. This is followed by adjuvant chemotherapy in all cases aside from completely staged, IA grade 1 and IB grade 1 lesions. However, in patients with well differentiated, encapsulated, unilateral lesions without adhesions or ascites, FP surgery may be a reasonable option. Surgical treatment of FP approaches includes (1) exploration, (2) USO, (3) pelvic and para-aortic lymphadenectomy, (4) omentectomy, (5) washings, and (6) peritoneal biopsies. Approximately 20% of the patients may have noninvasive or invasive implants. If the contralateral ovary appears grossly normal, the risk of occult malignancy is <3%. Therefore biopsy of a normal-appearing contralateral ovary should be avoided as this can result in diminished fertility either due to adhesion formation or diminished ovarian reserve. Of the 328 cases of fertility conserving surgery in the peer-reviewed literature, there were 119 pregnancies and a 96% live birth rate. Overall, the FP staging among the IEOC cases resulted in reasonable obstetrics outcomes (36% pregnancies, 87% live births) and oncologic outcomes (13% recurrences). Per Version 2.2018 of the NCCN guidelines (Ovarian Cancer), USO (preserving uterus and contralateral ovary) or BSO (preserving uterus) can be considered for patient whose disease appears early stage or low risk such as LMP, malignant germ cell, mucinous, or malignant sex cord-stromal tumors. Comprehensive surgical staging even in these cases remains necessary.
Oocyte or Embryo Cryopreservation
In order to achieve oocyte or embryo cryopreservation, patients must undergo the process of ovarian stimulation followed by egg retrieval with a RE. At the initial consultation the RE often orders laboratory studies to assess blood hormone levels and may perform a transvaginal ultrasound to visualize the ovaries and follicles. The laboratory studies in combination with the ultrasound can provide some guidance regarding the status of the patient’s ovarian reserve. If deemed an appropriate candidate for fertility preservation by the RE, the process of ovarian stimulation and egg retrieval is initiated.
Ovarian Stimulation
Female patients with normal ovarian function typically develop and mature one egg per month with each menstrual cycle. The goal of ovarian stimulations is to develop and mature the maximum amount of eggs available for cryopreservation. The patient is prescribed a series of hormone injections that stimulate the ovaries to develop and mature multiple eggs in a short time frame. The RE carefully regulates each hormone dose and monitors the patient’s follicular development via ultrasound scans and blood tests throughout this process. Special consideration is taken for patient with hormone-sensitive cancer in the setting of exogenous hormone treatments. In those particular cases the course of injections that the RE uses may be modified and/or oral antihormone therapy may be added during this time period. The total time for this process is approximately 2–4 weeks.
Oocyte Retrieval
Once the RE identifies that the eggs have reached full maturity, the next step includes a transvaginal egg retrieval. This is an outpatient procedure that is performed under conscious sedation or light anesthesia. The physician uses vaginal ultrasound to direct a needle through the vaginal wall to extract mature eggs from the ovarian follicles. The amount of eggs that each female can produce varies and is dependent on her ovarian reserve.
Once the eggs are extracted from the ovaries, the female can cryopreserve the oocytes. If she chooses to use these eggs in the future, they would have to be fertilized with sperm after thawing to create embryos that would then be transferred to her uterus. If she chooses to create an embryo at the time of egg retrieval, the mature egg would be fertilized with sperm and the resulting embryo will be frozen. Those embryos could then be thawed and transferred into the uterus when the patient is ready to become pregnant.
Ovarian Tissue Freezing
Although this measure is considered experimental, it may be the best option for patients who are not candidates for oocyte harvesting and cryopreservation because either the patient has not reached puberty or cannot delay the start of cancer treatment for 2–4 weeks due to the severity of her disease.
Ovarian tissue cryopreservation involves removal of all or part of one ovary prior to the start of cancer therapy. The ovarian cortex, or outer layer of the ovary that contains the eggs, is isolated and cryopreserved for future use. Once the ovarian tissue is removed and frozen, the intention is for the patient to initiate cancer treatment and achieve remission from her disease. Once the patient is ready to use her cryopreserved specimen, the thawed ovarian tissue is placed into her body. This is performed by transplanting the tissue either directly back in the pelvis or in a different part of the body. Once implanted, the ovarian tissue matures and produces oocytes. These oocytes can be harvested and collected by the same means as ovarian stimulation and oocyte harvesting as previously mentioned.
A number of pregnancies have come from using frozen tissue; however, this technique is considered investigational as implantation of previously frozen and thawed ovarian tissue may present a risk of reintroducing cancer into a patient in remission. Research on methods to perfect this technique is needed in order to determine its safety.
Ovarian Suppression
Ovarian suppression or gonado-protection may be another method to preserve fertility in some cases per ASCO guidelines. This is based on the theory that administering medication to temporarily shut down the ovaries can protect them from the gonadotoxic damage of chemotherapy. This can be done with long-acting hormone medications called gonadotropin-releasing hormone (GnRH) agonists. This method may help maintain fertility for some women, but the mechanism of action and efficacy remains a topic of research at this time. In addition, there is no evidence to suggest that using GnRH agonists help to improve rate of pregnancy. Since this treatment is considered experimental at this time, it should be done so in combination with other nonexperimental methods of fertility preservation if used. However, a recent metaanalysis suggests a statistically significant benefit for using GnRH agonists for the prevention of premature ovarian failure. The use of GnRH agonists should only be offered to patients when other standard-of-care methods to fertility preservation are not available.
Assessment of Ovarian Function After Therapy
Menstrual cycles can cease during or after treatment but have the potential to return. However, even if a woman’s menstrual cycle resumes after cancer treatment is completed, her fertility is still uncertain. Females that resume menses after treatment are still risk for early menopause. In the case the patient is interested in learning the status of her fertility postcancer treatment, she has the option to perform blood tests to measure hormone levels in the bloodstream. These blood tests are the best way to interpret the status of the ovarian reserve at the present time and can provide some guidance regarding the impact of the patient’s treatment on her fertility. Ovarian reserve test results should be analyzed by a RE at which point the patient would be counseled regarding treatment options based on the results.
Sexual Education During and Postcancer Treatment
Patients must be educated that it is not safe to become pregnant while on cancer treatment due to high risk of birth defects. It is recommended that patients use two forms of birth control to avoid pregnancy while on anticancer treatment. Once treatment is completed, it may be possible to attempt pregnancy naturally. However, pregnancy must be discussed with the patient’s oncology team as the timing of safe conception following cancer treatment is not clearly defined based on current research. Safe timing of pregnancy following cancer treatment is thought to anywhere from 6 months to 2 years.
It is common for cancer patients to question whether they are at an increased risk of conceiving a child with birth defects due to exposure of oocytes to anticancer therapy. Current evidence does not suggest that there is an increased rate of birth defects in children of cancer survivors. Particularly for breast cancer patients with hormone-positive tumors, there are concerns that pregnancy after cancer treatment could increase the risk of recurrence of the cancer; however at this time, studies suggest that pregnancy does not increase the chance of cancer recurrence.
Conclusion
It is the choice of the patient whether or not she should proceed with fertility preservation prior to the start of cancer treatment. Making a decision about whether or not to preserve fertility is influenced by many factors, including the importance of having a biological child, the likelihood of success in having a child from eggs collected, the patient’s acceptance of the uncertainties involved, and her financial resources. The role of the health-care provider is to provide patients with all resources regarding fertility preservation in order for the patient to make an independent, informed decision.
Discussion regarding infertility due to anticancer treatment and subsequent measures to preserve fertility is a multidisciplinary approach. All health-care providers in the oncology setting must be prepared to notify their patients that infertility is a potential risk associated with cancer therapy. This discussion should take place as soon as possible after initial cancer diagnosis is made and prior to the start of the patient’s oncological plan of care. Although many patients may not express interest in fertility preservation at the onset of diagnosis, evidence suggests that discussions about fertility are of great importance to cancer patients. In addition, studies suggest that patients can benefit from discussing fertility with providers at any phase of her cancer journey. Patients that express interest in fertility preservation or are ambivalent about the subject should be referred to a fertility expert as early as possible upon initial cancer diagnosis to assure that the patient has access to all possible fertility-sparing measures.
References
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