Fertility preserving options in patients with gynecologic malignancies




A proportion of reproductive age women are affected by gynecologic malignancies. This patient population is faced with difficult decisions, related to their cancer care and treatment, as well as future childbearing potential. Therefore, it is important for gynecologists to be familiar with fertility sparing management options in patients with cervical, ovarian, and endometrial cancer. In addition to understanding the surgical approaches available, providers should be able to counsel patients regarding their eligibility for and the indications and limitations of fertility sparing therapy for gynecologic cancer, allowing for appropriate referrals. A comprehensive PUBMED literature search was conducted using the key words “fertility preservation,” “cervical cancer,” “endometrial cancer,” “ovarian cancer,” “borderline tumor of the ovary,” “germ cell tumor,” “obstetrical outcomes,” “chemotherapy,” and “radiation.” The following review summarizes fertility sparing options for patients with cervical, ovarian and endometrial cancer, with an emphasis on appropriate patient selection, oncologic, and obstetric outcomes.


Traditionally, surgical management for the treatment of gynecologic cancer is viewed as a “sterilizing” procedure, given the common removal of the adnexa and uterus. Consequently, younger patients faced with this diagnoses are concerned about cure and fertility, particularly those that have not yet completed childbearing.


It is anticipated that there will be 1,529,560 new cancers diagnosed in 2010 with 569,000 deaths. Of these malignancies, 83,750 will affect the female genital tract, with an estimated 27,710 deaths. Fifteen to 21% of affected women will be less than 40 years of age at the time of diagnosis. This population of patients may have disease identified at an early stage and could potentially be cured, with fertility preservation being a priority at the time of disease diagnosis. Furthermore, we have seen a continuous trend in developed nations of delayed childbearing, which will result in an increase proportion of women diagnosed with a gynecologic cancer before their first pregnancy.


Unfortunately, fertility-sparing options may not be offered to appropriate patients for various reasons, including lack of knowledge, unfamiliarity with the recommended surgical procedure, or concern over compromised cancer outcome. Alternately, patients facing a new cancer diagnosis may not be emotionally ready to discuss the complex risks and benefits surrounding this decision.


This review will describe the available evidence for fertility preservation in patients with cervical, ovarian, and endometrial cancer. Appropriate patient selection, surgical options, and related obstetric outcomes will be covered.


Cervical cancer


It is projected that there will be 12,200 new cases of cervical cancer diagnosed in the United States in 2010, with 4210 deaths. More than 1800 of these patients will be under the age of 40 years and potentially desire fertility preservation.


The standard surgical treatment for patients with International Federation of Gynecology and Obstetrics (FIGO) stage I-IIA cervical cancer is radical hysterectomy. However, selected patients with early-stage squamous cell carcinoma of the cervix may be potential candidates for fertility preserving surgical interventions. Microinvasion (FIGO stage IA1), defined as less than 3 mm of stromal invasion, may be safely managed with cervical conization or large loop excision of the transformation zone (LLETZ). These patients have a 0.8% risk of lymph node metastasis in the absence of lymph vascular space invasion (LVSI). Diakomanolis et al also described the use of laser CO 2 conization. Seventy-three women underwent laser CO 2 conization with no recurrences after a mean follow-up of 54 months. Our groups recommended criteria for conservative management based on review of the literature include: (1) a negative endocervical curettage at completion of the procedure; (2) absence of LVSI (the risk of tumor recurrence increases from 3.2% to 9.7% with LVSI); and (3) a negative endocervical margin, given 10% risk of more extensive disease in individuals with positive margins at completion of biopsy. In patients who meet the above criteria, the risk of disease recurrence is less than 0.5%.


Unlike squamous cell lesions, adenocarcinoma is a glandular lesion and is considered multifocal, with up to 13% of patients having foci of disease separated by ≥2 mm of stromal mucosa. Furthermore, the complex architecture of endocervical glands, with invagination, branching, and tunnel formation makes determination of depth of invasion problematic. Bisseling et al performed a retrospective review of the treatment of cervical microinvasive adenocarcinoma, in which 16 patients with stage IA1 disease were managed with conization. Over an average follow-up period of 72 months there were no documented recurrences. In addition, McHale et al investigated survival and fertility outcomes in patients with adenocarcinoma in situ and those with microinvasive disease between 1985 and 1996. Twenty of 41 women with adenocarcinoma in situ underwent cervical conization. In the 5 patients with positive margins, 2 recurred and 1 developed invasive disease. Four of 20 women with stage IA lesions underwent cervical conization to preserve fertility, with no evidence of recurrence at 5 years follow-up. If fertility preserving options are used in patients with squamous lesions or adenocarcinoma, it is essential to have satisfactory margins free of disease.


Patients who undergo a cervical cone biopsy or LLETZ for fertility preserving purposes should understand the potential attendant obstetric risk of preterm delivery. A metaanalysis published in 2006 by Kyrgiou et al, reported obstetric outcomes pooled from 27 evaluable studies. Cold knife cone was significantly associated with preterm delivery (relative risk [RR], 2.59; 95% confidence interval [CI], 1.80–3.72) and low birthweight (RR, 2.53; 95% CI, 1.19–5.36). LLETZ was also significantly associated with preterm delivery and low birthweight (RR, 1.70; 95% CI, 1.24–2.35 and RR, 1.82; 95% CI, 1.09–3.06, respectively). More recently, a large retrospective study was performed evaluating 241,701 women delivering singleton pregnancies. In this population, no increased risk of preterm delivery was seen in women who had undergone a LLETZ before the index pregnancy.


Patients with greater than 3 mm of stromal invasion, defined as having FIGO stage IA2-IB1 disease, have a 7% risk of nodal metastasis, and definitive surgical treatment includes pelvic lymphadenectomy. For this group of patients, the fertility preserving option is a radical trachelectomy (RT), which includes resection of the entire cervix and surrounding parametria, and can be performed vaginally, abdominally, laparoscopically, and robotic assisted. First described by Dargent in 1987 in France, the vaginal radical trachelectomy (VRT) is preceded by a laparoscopic bilateral pelvic lymphadenectomy. Technically, the VRT is performed by dividing the uterus proximal to the cervical isthmus, and suturing the uterus to the vagina. Intraoperative frozen section should be used on both the endocervical margin and nodal tissue, with completion radical hysterectomy if tumor extends to within 5 mm of the margin. It is our recommendation that all patients offered this intervention satisfy 5 main criteria: (1) desiring preservation of fertility; (2) compliant with follow-up; (3) squamous cell carcinoma or adenocarcinoma with exclusion of undifferentiated and clear cell histologies; (4) FIGO stage IA1 with LVSI or stage IA2-IB1 lesion ≤2 cm; and (5) no evidence of pelvic lymph node metastasis. The overall complication rate for VRT of 2.5%, and the 4% recurrence and death rate are similar to those for traditional abdominal radical hysterectomy. The 2010 National Comprehensive Cancer Network (NCCN) Guidelines support cervical conization for the treatment of stage IA1 cervical cancer with negative margins, as well as RT plus pelvic lymph node dissection in patients desiring fertility preservation.


In addition to the vaginal approach, both abdominal and robotic assisted RTs have been described. The abdominal approach, used in patients with distorted vaginal anatomy, larger lesions or in centers where the vaginal approach is not mastered has been described with favorable outcomes. Ungár et al performed the procedure on 30 patients with stage IA2-IB2 disease with no recurrences after a median follow-up of 47 months. Other authors support the use of the abdominal approach, reporting larger parametrial margins. The robotic assisted RT was recently reviewed by Ramirez et al. Four patients underwent successful robotic assisted RT, with no intraoperative complications and no disease recurrence, with a median follow-up of 105 days. The median operative time was 339.5 minutes, with a median console time of 282.5 minutes, which the authors report as similar to published data for vaginal and abdominal approaches. We recommend that the initial surveillance of patients after RT include Papanicolaou smear with high-risk human papilloma virus (HR HPV) testing every 3 months. As described by Feratovic et al, physicians should have an understanding that the alteration in anatomy postoperatively may result in glandular cells appearing in cytology specimens, with misdiagnosis of atypical glandular cells of undetermined significance.


A comprehensive review of the literature regarding obstetric outcomes in patients undergoing RT is shown in Table 1 . A total of 582 patients, represented in 10 studies, had 257 pregnancies with a 64% live birth rate. There were 23 recurrences and 12 deaths. Patients should understand that pregnancies after RT are complicated by preterm delivery and miscarriage, with first and second trimester loss rates as high as 19% and 9.5%, respectively. Thus, referral to a Maternal-Fetal Medicine specialist for consultation before surgery may be warranted in this patient population.



TABLE 1

Oncologic and obstetric outcomes in patients with cervical cancer after radical trachelectomy
























































































Author Patients Pregnancies Live births Recurrences Deaths
Shepherd et al 123 55 28 5 4
Dargent et al 96 55 36 4 3
Burnett et al 21 3 2 0 0
Bernardini et al 80 22 18 7 4
Plante et al 72 50 36 2 1
Schlaerth et al 10 4 2 0 0
Schneider et al 36 7 4 1 0
Boss et al 19 2 2 0 0
Ungár et al 30 3 2 0 0
Mathevet et al 95 56 34 4 0
Total 582 257 (44%) 164 (64%) 23 (3.9%) 12 (0.2%)

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Jun 5, 2017 | Posted by in GYNECOLOGY | Comments Off on Fertility preserving options in patients with gynecologic malignancies

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