20. Family planning – Cervical Carcinoma

In patients with squamous cell carcinoma or adenocarcinoma of the cervix in FIGO stages IA1 L1 V0, IA2 V0, or IB1 and IIA1 V0 ≤ 2 cm and who wish to have children, radical cervicectomy with permanent cerclage is a fertility-preserving procedure [765]. Histopathological evidence of tumor-free pelvic lymph nodes is a prerequisite for this form of treatment. Neuroendocrine cervical carcinomas are frequently associated with recurrence, distant metastases, and low 5-year survival rates, and are therefore not suitable for radical vaginal cervicectomy (see section 8.6.2).

The adequate oncological safety of radical vaginal cervicectomy (RVC) in comparison with radical hysterectomy has been confirmed in several retrospective studies [766], [767]. Radical abdominal cervicectomy (RAC) may lead to a larger parametrial width in comparison with RVC [768]. However, parametrial infiltration is observed in only 0.4–0.6% of cases in cervical carcinomas less than 2 cm with N0 L0 V0 and stromal infiltrations less than 10 mm [319], [769]. It therefore remains questionable whether the length of the resected parametria plays a decisive role in these stages and whether radiotherapy offers any advantages over simple cervicectomy or conization. Various smaller studies of simple trachelectomy or conization have reported a low overall recurrence rate [770], [771].

Pregnancy rates after radical cervicectomy for cervical cancer vary from 24% to 66% in the literature [772], [773]. This is due to the different techniques used in the analyses and the numbers of women who actually hope to become pregnant after radical cervicectomy. According to Speiser et al. [772], the pregnancy rate after RVC is not significantly different in comparison with patients without previous surgery. Fifty of 76 women who sought pregnancy after RVC became pregnant (65.8%). In a systematic review by Bentivegna et al. [773], the fertility and live birth rates in 2777 patients with 944 pregnancies after radical cervicectomy were 55% and 70%, respectively. The live birth rate did not differ relative to the cervicectomy technique used (RVC 67% [308/460], RAC 68% [120/175], and 78% [50/649] with robot-assisted cervicectomy).

The main risk after radical cervicectomy is an increased rate of miscarriage and preterm delivery due to premature membrane rupture in chorioamnionitis. The risk of preterm delivery is 26.6–57%, with a significantly higher risk after RAC [773]. After radical cervicectomy, there is an increased risk of ascending infection and cervical insufficiency during pregnancy, with a risk of miscarriage or preterm delivery, due to the shortened cervix. Cervical stenosis occurs in 15% of cases, with problems of hematometra and also impaired fertility [774], [775].

In FIGO stages IA1 and IA2 without risk factors, conization with cervical curettage or simple cervicectomy can also be performed. The pregnancy rates are 71–75%, with an increased risk of second-trimester miscarriage in comparison with the general population (6% vs 1.6%) [770]. The rate of preterm birth appears to be much lower after conization/simple cervicectomy in comparison with radical cervicectomy. In a meta-analysis of 347 women, the risk of preterm birth was 6.8% (1.5–15.5%) vs. 26.6% (19.6–34.2%) [766].

For FIGO stage IB1 cervical carcinoma that is ≥ 2 cm, the use of neoadjuvant chemotherapy (NACT) followed by conization or cervicectomy with pelvic lymphadenectomy for organ preservation is increasingly being investigated. An analysis by Pareja et al. [776] included 394 patients with cervical carcinomas 2–4 cm in size and radical cervicectomy. The recurrence rate after RAC was 3.8% relative to all sizes and 6% for tumors larger than 2 cm, while after radical vaginal cervicectomy it was 4.2% (including all tumor sizes) and 17% for tumors larger than 2 cm, and after neoadjuvant chemotherapy followed by radical cervicectomy it was 7.6%. The highest pregnancy rates were achieved after neoadjuvant chemotherapy and radical cervicectomy (NACT+RT 30.7% vs. RVC 24% vs. RAC 16.2% [776]). In a systematic review by Bentivegna et al, pregnancy rates of 49% (22/61) were achieved after NACT and conization and 38% (39/61) after radical cervicectomy. It was also found that the preterm delivery rate was lower in patients with NACT than after RVC or RAC (11/71 [15%] vs. 113/285 [39%] and 59 /104 [57%], respectively; P [Committee, Ontario Guidelines Advisory et al. 2008]. Neoadjuvant chemotherapy combined with fertility-preserving surgery (conization/simple cervicectomy or radical cervicectomy ) for cervical carcinoma 2–4 cm in diameter is not currently standard, with case numbers that are still low and a lack of long-term follow-up data. However, the method may be discussed as an experimental procedure in individual cases in women who hope to have children.

If radiochemotherapy is planned, ovariopexy is a measure that can preserve ovarian function in terms of both endocrine function and fertility (see Chapter 10, Radiotherapy). Radiotherapy has substantial effects on ovarian function. A radiation dosage of as little as 2 Gy to the ovaries (LD50) reduces follicular density by half [778]. The radiation effect on the ovaries is heavily age-dependent [779]. In 97.5% of women aged 30 years, a radiation dosage of 14.3 Gy leads to the complete elimination of ovarian function. Ovariopexy in young premenopausal patients before the start of radio(chemo)therapy, alongside modern techniques, can achieve a significant reduction in the ovarian dosage [780], [257]. Various surgical techniques have been described in the literature. Due to the inhomogeneity of the patient groups and the lack of prospective randomized studies, no reliable conclusions can be drawn in comparing the different techniques, although cranial transposition is probably the safest technique for reducing the radiation dose in pelvic irradiation. A meta-analysis including 32 publications and a total of 1189 patients reported a success rate of 80.8% (min. 17%, max. 95%) in relation to preserved ovarian function [781]. The height at which the ovaries are suspended is thought to be one of the strongest prognostic factors for preservation of ovarian function. The ovaries should be at least 2 cm above the iliac crest [782]. The risk of ovarian ischemia, which led to amenorrhea in 4% of the patients regardless of the radiation dosage, should be considered to have limited relevance in relation to the benefits of this treatment [783]. Although the overall effectiveness of ovarian transposition in preserving ovarian function is considered to be high, reports of pregnancy after radiotherapy for cervical cancer are rare [784]. Since ovariopexy usually requires complete separation of the adnexa from the uterus, assisted reproduction measures must be considered after the completion of oncologic therapy [785]. Reversing the procedure is technically difficult and is associated with a high risk of functional ovarian loss. In addition, irradiation of the uterus significantly reduces the chances of pregnancy. Organ doses to the uterus in excess of 45 Gy result in significant damage and often cause uterine infertility [786]. For women with uterine infertility (hysterectomy or uterine radiation damage) but with preserved ovarian function or cryopreserved oocytes beforehand, the option of surrogacy is available. However, surrogacy is prohibited in Germany under the Embryo Protection Law. An alternative for patients after hysterectomy is uterus transplantation. Worldwide, 13 healthy children have now been born after uterus transplantation [787], [788]. One patient underwent uterus transplantation after hysterectomy for cervical carcinoma and had two pregnancies [771]. Patients who have had organ transplantation are at increased risk of recurrence due to immunosuppression [774]. No data after uterus transplantation are available for patients in whom immunosuppressants were administered in a time-limited setting until explantation of the organ.

Prior to radiochemotherapy or neoadjuvant chemotherapy, fertility-preserving options include cryopreservation of oocytes and/or ovarian tissue.
Cryopreservation of fertilized and unfertilized oocytes is one of the established fertility protection measures in women. The success rate depends on the age at the time of cryopreservation and the underlying ovarian reserve. According to registry-based calculations, the chance of birth per stimulation and cryopreservation in women aged [Peppercorn, J. M. et al. 2011], [789]. A time window of about 2 weeks for hormonal stimulation with oocyte retrieval needs to be taken into account until the start of cytotoxic therapy.

Ovarian tissue cryopreservation is also an established method for restoring fertility after cancer treatment. The procedure can be performed at very short notice before cytotoxic therapy at any time in the cycle, and thus usually does not lead to any delay in oncological therapy. A total of over 120 births have been achieved worldwide after orthotopic transplantation of cryopreserved ovarian tissue [790], [791], [792], [793], [794]. The birth rate is currently about 30–35%. After radiotherapy of the uterus, a probably much lower pregnancy rate must be expected due to the uterine damage, although no figures on this are available. In addition, the risk of ovarian metastases must be taken into account during transplantation, since with autotransplantation of ovarian tissue there is a potential risk of causing a recurrence with the cryopreserved tissue. Ovarian metastases in early-stage cervical carcinoma without risk factors are rare, but the risk is significantly higher with adenocarcinoma than with squamous cell carcinoma (5.31% vs. 0.79% in stages IB–IIa ) [795].

For further information on the individual methods and success rates of fertility-protective measures, reference may be made to the consensus-based guideline on fertility preservation in oncological diseases (AWMF register no.: 015/082).