Optimizing Reproductive Options for Young Women with Cervical Cancer

Abstract

Cervical cancer is one of the leading causes of mortality in women of reproductive age. In recent years, the development of preventive and therapeutic strategies has significantly increased survival rates. While this represents an important medical achievement, it has also raised a major social issue regarding the need to ensure an adequate quality of life for surviving patients. Many of these women are left without their reproductive capacity at an age when their desire for motherhood has not yet been fulfilled. Infertility or subfertility in cancer survivors is actually a growing problem, complicated by the current trend of increasingly delaying pregnancy. The psychological effects of this issue can be devastating, sometimes even more so than the cancer diagnosis itself. Although today fertility-sparing surgeries can ensure excellent reproductive outcomes with minimal oncological risk, obstetric sequelae remain significant, and affected women often require specialized care pathways. Additionally, adequate counselling is still not provided to all patients who cannot access fertility-sparing treatments and who find themselves without hope. Reproductive medicine is therefore facing the modern challenge of offering concrete options to help these patients realize their desire for motherhood. The aim of this article is to provide an overview of the therapeutic options available to young women facing an early- or later-stage diagnosis of cervical cancer.

1. Introduction

The burden of cancers diagnosed in young women represents a significant issue both medically and socially. In recent years, the incidence of cancer in patients aged 15 to 40 has slightly increased (approximately 0.3% annually), and 3% of cancers affect women under 40 years old [1]. A substantial portion of these cases is made up of gynecological cancers, with breast cancer, cervical cancer, endometrial cancer, and lastly ovarian cancer, being the most common [2,3]. Fortunately, mortality from these cancers continues to decline, mainly thanks to prevention and early diagnosis, resulting in a five-year survival rate of over 80% for young women aged 15–44 [4]. In addition to posing a medical challenge, these cancers have a significant economic and social impact because they affect women during their reproductive years. As a result, many women face a difficult and often long journey toward parenthood [5]. In recent years, reproductive medicine has increasingly focused on fertility preservation in both oncology and non-oncology patients to provide a viable solution to their desire for motherhood. Oncological treatments can impair reproductive function for several reasons. The ovaries are particularly sensitive to both radiation and chemotherapy. The extent of damage depends on the type of therapy and the dose used, and harmful effects may occur immediately after treatment or years later [6,7]. The main indicators of ovarian reserve are AMH and AFC. Several studies have demonstrated that both serve as useful predictors of ovarian reserve loss in cancer patients who have survived chemotherapy [8,9]. Additionally, a recent meta-analysis showed that cancer itself, independent of oncological treatment, negatively impacts fertility, leading to a significant reduction in both AFC and AMH levels in cancer patients compared to a control group [10]. One possible explanation could be the systemic effects of cancer, including increased levels of stress hormones, enhanced catabolism, and immune system dysregulation, which in turn impact folliculogenesis [11]. In this context, cervical cancer is particularly significant due to its high incidence (an estimated 2500 new diagnoses in Italy reported for the year 2022, making it one of the most frequent malignancies in young women [12]), and because oncological treatments are often radical. Common treatments for cervical cancer include radical hysterectomy, vaginal brachytherapy, and/or pelvic chemo–radiotherapy, all of which have a significant impact on fertility [13,14]. Cervical cancer is frequently diagnosed in young patients, often before they have fulfilled their desire for motherhood. Most cervical cancers (approximately 80–90%) are squamous cell carcinomas (SCC), arising from cells in the ectocervix. Most of the remaining cases are adenocarcinomas (ADC), which originate in the glandular cells of the endocervix. Other types are extremely rare. SCC is generally HPV-related and is the subtype with a more favourable prognosis (with a 5-year survival rate in early stages of around 90%). Cervical cancer screening through the Pap test makes early diagnosis possible, allowing for timely intervention. SCC responds more favourably to chemo- and radiotherapy. ADC, on the other hand, has a poorer prognosis for two main reasons: first, early diagnosis is challenging (the Pap test sometimes fails to detect it due to its endocervical location); second, it shows limited response to adjuvant therapies. In the case of HPV-related ADC, the prognosis is better [15,16]. The high survival rate associated with cervical cancer means that many patients return to their daily lives, making future reproductive counselling and, where possible, access to fertility-sparing treatments essential. The Fédération Internationale de Gynécologie et d’Obstétrique (FIGO) recommends a fertility-sparing approach for all women planning a future pregnancy, given that literature shows good reproductive outcomes without compromising oncological safety, but this approach is only feasible in the earlier stages of the disease [13,17]. Therefore, prevention and treatment of precancerous lesions, along with the research and development of new therapeutic strategies for patients with more advanced stages of the disease, are crucial. The goal of this review is to provide an overview of the management and opportunities for fertility preservation in patients with cervical cancer, from the initial HPV infection to the more advanced stages of the disease.

2. HPV Infection and Precancerous Lesions in Fertility-Aged Women

2.1. HPV Infection and Pregnancy

While the majority of HPV cases resolve on their own within 1–2 years, persistent HPV infection is still a significant concern, as it has been consistently associated with the development of various malignancies, included cervical cancer. Furthermore, recent studies indicate that HPV infection may also have a negative impact on pregnancy. The immune system undergoes significant changes during pregnancy, which arguably promotes the persistence of HPV. This increased risk of pregnancy complications among HPV-positive women without cervical lesions includes preterm birth, miscarriage, pregnancy-induced hypertensive disorders, intrauterine growth restriction, low birth weight, premature rupture of membranes (PROM), and fetal death [18]. Therefore, it is important to counteract HPV infection in order to optimize pregnancy outcomes and improve fetal survival and well-being. A recent meta-analysis comprising 36 studies investigated the link between maternal HPV infection and adverse pregnancy outcomes. The findings demonstrated a significant correlation between HPV and both preterm birth and preterm premature rupture of membranes. However, there was a low association with intrauterine growth restriction, low birth weight, and fetal death. No significant association was found for spontaneous abortion and pregnancy-induced hypertensive disorders [19]. Further results were found in another meta-analysis that involved 14 studies with 7008 women. A significant association was found between preterm delivery and HPV infection. However, no significant association was found when separately examining high-risk HPV-infected women or women infected with HPV 16 or 18 in terms of preterm delivery. Additionally, no significant association was found between spontaneous abortion and HPV infection [20]. Another meta-analysis included 7 studies involving 45,603 patients, with 22,799 in the control group and 22,799 in the HPV infection group. The results showed that HPV infection increased the probability of premature delivery and PROM (all p-values were less than 0.05, and the difference was statistically significant) [21]. Although numerous studies are conducted on this topic, data are still controversial and, to date, HPV does not appear to be a particularly concerning infectious disease for pregnant women. More prospective large cohort studies are needed to prove a causative relationship between maternal infection and serious neonatal outcome [22]. Scientific evidence showing that HPV does not cause pregnancy complications could be a further motivation for HPV vaccination.

2.2. Precancerous Lesions Before and During Pregnancy

During the early months of pregnancy, patients undergo HPV testing and/or Pap smears, which may yield positive results. Several studies have been conducted to evaluate the optimal management strategies for the expectant mother and the fetus. The treatment of precancerous lesions was the subject of a meta-analysis, which showed that cold knife conization was the procedure most associated with severe pregnancy complications. Cryotherapy and laser ablation, on the other hand, appear to be the safest. Moreover, large loop excision of the transformation zone was not found to be risk-free [23]. A meta-analysis, which includes 71 studies, shows that cervical intraepithelial neoplasia (CIN) is an independent risk for prematurity that is increased by excisional and ablative treatments [24]. The frequency and severity of adverse sequelae increase with increasing cone depth and are higher for excision than for ablation. These findings are confirmed in another study which showed that all excisional surgical procedures to treat CIN present similar obstetric complications, but not serious neonatal outcomes. Caution is recommended in treating young women with mild cervical abnormalities [25]. The diagnosis and treatment of CIN in pregnant women appears to be complex due to the variety of colposcopic findings and there are not sufficient studies indicating a treatment strategy. The American Society for Colposcopy and Cervical Pathology recently released guidelines on how to assess abnormal Papanicolaou test results and manage CIN in pregnant patients [26]. Many techniques traditionally recommended for evaluating abnormal cervical cytology and treating CIN in non-pregnant women, such as colposcopy, cervical biopsy, and electrosurgical excision, could be applied to pregnant patients with important exceptions. The modification of cervical vasculature and the risk of premature rupture of membranes in pregnancy are the main challenge for the diagnosis and treatment of CIN during pregnancy [27]. Colposcopy remains the first diagnostic choice, with good accuracy (89.9%), especially when performed by experienced operators. The progression rate is low in pregnant women (3.9%) and the transformation into invasive cancer is almost zero. Regression or persistence of lesions does not appear to be related to neonatal factors. Vaginal delivery appears to promote regression of lesions [28]. For this reason, pregnant women with CIN should choose vaginal delivery first. For these reasons, treatment should be postponed until the postpartum period. Another meta-analysis confirmed the above-mentioned findings, as it was observed that the progression rate of CIN lesions remained very low (1%), with the majority of lesions classified as CIN 3 regressing [29]. However, the risk of progression to invasive cancer is not completely eliminated; therefore HPV infection during pregnancy always deserves important follow-ups.

2.3. HPV Vaccines for Prevention and Therapy of Cervical Cancer in Pregnancy

The human papillomavirus (HPV) vaccine is recommended for all girls and women 9 to 26 years of age [30]. Currently, four HPV vaccines are available for the prevention of HPV infection and associated conditions, including bivalent (Cervarix and Cecolin), quadrivalent (Gardasil), and nonavalent (Gardasil-9) vaccines. Additionally, a new 14-valent recombinant vaccine is in development which will cover the 9 strains already included in Gardasil-9, along with 5 additional types (HPV-35, -39, -51, -56, and -59). Overall, HPV vaccines demonstrate adequate immunogenicity and a high safety profile with minimal side effects in the general population [31]. Some women have been inadvertently vaccinated during pregnancy, but there is still limited data available regarding the safety of the HPV vaccine during pregnancy. The safety of these vaccines has already been extensively demonstrated in clinical trials and post-licensure studies. However, monitoring for rare adverse events or associations with potential autoimmune manifestations is still ongoing in pregnant women [32,33,34]. A crucial aspect of monitoring the HPV vaccination process is evaluating vaccine coverage data based on the year of birth and the number of doses administered. Furthermore, it is important to maintain individual vaccination records to enable future correlation between the incidence of HPV-related diseases and the vaccination status of individuals. HPV vaccination during pregnancy was not associated with a significantly higher risk of adverse pregnancy outcomes compared to no exposure. The rates of spontaneous abortions and major birth defects were not higher than those in the unexposed population. Although no adverse effects have been recorded, the HPV vaccine is not yet recommended at this time [35]. As for immunostimulants, which are often used to support the healing process, we do not have data confirming their safety during pregnancy, and therefore they are currently contraindicated. Despite this, it has been shown that the use of HPV vaccines in cases of active infection or after excisional surgical treatment prevents recurrences. Therefore, HPV vaccination as a complementary approach, either prior to or following surgical treatment, can serve as an efficient and straightforward strategy to reduce the risk of cervical lesion relapse or cervical cancer in women infected with HPV who are planning a pregnancy. In accordance with these findings, the HPV FASTER protocol aligns perfectly with the goal of preventing HPV infection following fertility-preserving treatment. This approach recommends offering the HPV vaccine to women between the ages of 9 and 45, or even up to 50 years old, regardless of their HPV infection status [36]. As a result, the vaccine can be administered to women after undergoing fertility-sparing procedures for precancerous and cancerous cervical lesions [37]. The SPERANZA project is the first prospective published experience evaluating the clinical effectiveness of the HPV vaccine in reducing post-surgical recurrent disease in women treated for cervical high-grade squamous intraepithelial lesion or HSIL (CIN2+) and microinvasive cervical cancer (FIGO stage IA1. All women enrolled in a case–control case group received post-LEEP (loop electrosurgical excision procedure) quadrivalent HPV vaccination, while the control group was submitted to follow-up alone. Follow-up was performed with an HPV test, colposcopy, and cytology. The primary objective was the incidence of recurrent CIN2+ at least one year post-surgery. Results show that the vaccine does not have a therapeutic effect but underlines its role as an adjuvant to surgical treatment. The clinical implications of this strategy may influence the post-treatment management of HPV diseases [38]. Subsequently, another study demonstrated that adjuvant HPV immunization with prophylactic vaccines after a LEEP conization or preventive surgery in patients with CIN—2 lesions or more—was associated with a significant reduction in HPV 16–18 relapses [39]. These findings encourage the use of HPV vaccination as an additional simple and effective method to prevent recurrent infections or cervical cancer in HPV-positive women after fertility-sparing surgery (FSS) [37,40,41]. Therapeutic vaccines represent a promising and innovative future development and have been the subject of research for several years. Some of these have reached phase two and three of clinical trials, but currently none are available for clinical use [37,42,43,44]. In conclusion, the possibility of an increased risk of miscarriage caused by HPV vaccination during the periconceptional or gestational period cannot be completely excluded. It would be appropriate to carry out new clinical trials that demonstrate the correlation between HPV vaccination and spontaneous abortion and HPV vaccination and fertility-sparing.

3. Reproductive Options in Early Stages of Cervical Cancer

3.1. Fertility-Sparing Surgery (FSS)

Early cervical cancer encloses a wide spectrum of conditions, ranging from clinically undetectable microinvasive cancer to large, voluminous cancers. The standard treatment, even for early stages, consists of a destructive surgery with a radical hysterectomy and lymphadenectomy [13,14]. However, in certain cases, fertility preservation is feasible and should be considered during treatment planning for reproductive-aged women, especially for those who wish to maintain their fertility [15]. For microinvasive tumours (stage IA1 FIGO) conservative surgery might be proposed to all patients who require the preservation of their fertility, since many studies have now demonstrated that there is no difference in survival rates between conization and hysterectomy [17,45,46]: (Figure 1). In the context of early-stage cervical cancer, the differentiation between SCC and ADC does indeed play a role in treatment considerations and outcomes. However, for early-stage disease (typically classified as stage I or sometimes stage II), the prognosis and potential for fertility-preserving treatments can be similar between these two histological types, under certain conditions. In a recent multicentre study, the feasibility of conservative surgery was evaluated in a selected group of patients affected by FIGO stage IA2-IB1 cervical carcinoma. Other inclusion criteria were as follows: any grade of SCC or ADC (grade 1 or 2 only); tumour size < 2 cm; no lymphovascular space invasion; depth of invasion < 10 mm; negative imaging for metastatic disease; and negative conization margins. Patients who desired fertility preservation were treated with conization followed by a sentinel lymph node biopsy and/or full pelvic lymph node dissection. A 5% rate of lymph node positivity and a 2.5% rate of disease recurrence were observed. After an average follow-up of approximately 36 months, the disease recurrence rate was 3.5%. The authors, therefore, concluded that a reasonably safe conservative treatment can be offered to these groups of patients [47]. The CONTESSA/NEOCON-F multi-centre study aims to demonstrate the feasibility of conservative surgery to preserve fertility in patients with tumours measuring 2–4 cm in diameter (FIGO stage IB2) without lymphovascular disease after neoadjuvant chemotherapy (NACT). Results are expected by 2025 [48]. The available results regarding tumours larger than 2 cm, although encouraging, are still limited and in these patients, and fertility-sparing surgery (FSS) is still considered experimental [49,50]. Regarding the best surgical approach in terms of safety and reproductive outcomes, no particular approach has emerged as superior. Bentivegna et al. evaluated six different types of surgical procedures: Dargent’s procedure; simple trachelectomy or cone resection; NACT with conservative surgery; and laparotomic, laparoscopic, and robot-assisted abdominal radical trachelectomy. All these techniques demonstrated optimal fertility outcomes and were also contingent upon the expertise of the surgical team. However, the most favourable results were observed in patients with good prognostic factors, such as small tumour sizes, minimal or absent lymphovascular space involvement, and negative surgical margins. For these patients, conventional surgery alone is appropriate, given the low risk of recurrence [51].

3.2. Reproductive and Obstetrics Outcomes After FSS in Cervical Cancer

Reproductive outcomes in patients undergoing conservative surgeries are optimal. Several studies reported encouraging results [52]. Nezhat et al. evaluated fertility rates in a large number of patients undergoing FSS for early-stage cervical cancer (FIGO stage IA1-IB1). They found that the average clinical pregnancy rate was 55.4%. Among surgical approaches, radical vaginal trachelectomy demonstrated the highest clinical pregnancy rate of 67.5%. The risk of recurrence and cancer-related death was very low (3.2% and 0.6%, respectively) after a median follow-up of 39.7 months [53]. Another study found that among 149 treated with the robot, 81 pregnancies and 76 live births were obtained. However, only 54% of these delivered at term. The risk of recurrence was 6% [54]. The abdominal approach, on the other hand, is the most invasive and has the worst reproductive outcomes. In fact, in a 13-year study, Kasuga obtained the following results: the pregnancy rate for women attempting to conceive after abdominal radical trachelectomy was 44% (48 out of 109), after a mean duration of 3 years. The majority of these pregnancies were achieved through fertility treatments (in vitro fertilization-embryo transfer, or intrauterine insemination) [55]. On the other hand, a minimal/non-invasive procedure could lead to the best reproductive outcomes. Tsaousidis et al. investigated reproductive outcomes in 23 women who underwent large conization, a fertility-preserving procedure that is potentially safer and less invasive than radical trachelectomy. All women who tried to conceive were able to do so, with the majority achieving pregnancy naturally. During the follow-up period (ranging from 2.6 to 8 years), no cases of cervical cancer recurrence were reported [56]. These data confirmed that optimal management should be able to find a balance between oncological safety and cancer treatment outcomes, on one hand, and reproductive ability and pregnancy outcomes on the other. A more invasive approach can lead to several obstetric pathologies, all of which are reported as frequent complications in these patients, from cervical incompetence to intrauterine infections and preterm premature rupture of membranes (PPROM) [57]. There are several possible strategies to minimize these complications and improve pregnancy outcomes. Following trachelectomy, it is recommended to use antibiotic prophylaxis during pregnancy to reduce the risk of infection and PPROM [58,59]. Progesterone supplementation via the vaginal route should be the main strategy for preventing preterm birth in all women following trachelectomy. For patients with very a short residual cervix, cervical cerclage should be appropriate, along with routine cervicometry assessment, and the use of tocolytics and corticosteroids as needed [60,61].

4. Reproductive Options in Advanced Stages of Cervical Cancer

Cervical cancer represents the fourth most common cancer affecting women, and its socio-economic impact is devastating [62]. Although screening and vaccination programmes, and the refinement of new surgical and medical procedures, are improving diagnostic capacity and oncological outcomes, cervical cancer still represents a threat, not only to women’s health, but also to their fertility: in 2019, in the United States, the hysterectomy-adjusted incidence of cervical cancer in females in reproductive age ranged from 0.08 per 100,000 (<24 years) to 18.54 per 100,000 (45–49 years) [63]. Most women who undergo radical surgery during their reproductive years experience depression due to the inability to conceive. Given that fertility-sparing options in cervical cancer can be offered to patients with cervical carcinoma staged below IB1 according to FIGO staging, it is necessary to explore the alternatives for those who are in a more advanced stage of the disease (Figure 2). It is essential to provide appropriate pre-surgical counselling to all women with advanced-stage cervical cancer. In recent years, gynecological surgery has made significant strides, offering patients both therapeutic and preventive options aimed at preserving female fertility. Unfortunately, the various therapeutic alternatives for fertility preservation in these patients are limited and often available only in a few specialized centres across the country.

Furthermore, advanced stage cervical cancers often require oncological treatments that have direct detrimental effects on fertility.

While radiotherapy damage pathways are better defined and depend on the response of irradiated tissues to radiation, the use of chemotherapy multidrug regimens represents an important limitation in the establishment of the influence that each of these agents can exert on ovarian function and fertility [64].

It has been theorized that chemotherapy can have two distinct effects on ovarian function: the first occurs during treatment, depends on the decline of the growing follicles population, and results in a clinically manifest amenorrhea, while the second one is delayed but strictly related to the first one, since it depends on the number of primordial follicles that will physiologically be selected to replenish the body of follicles damaged during treatment, and will manifest in premature ovarian failure, whose clinical manifestation will be as much premature as the extent of the involvement of primary follicles during cytotoxic treatment [65].

A further mechanism that may lead to a decline in ovarian function is the effect that some of these chemotherapeutic agents exert on ovarian vascularization and stromal tissue [66].

Cisplatin, and other platinum-based compounds, forms intra- and interstrand DNA cross-links, thus activating cellular checkpoints and consequent apoptosis [67,68]. It seems that these compounds can also impair cellular activities and functions by targeting nuclear and cytoplasmic proteins [66,67,68,69].

Data regarding the ovarian toxicity of platinum-based compounds on human models are still lacking and mostly conflicting, but these agents are still considered moderately toxic, given the evidence of their negative impact on ovarian reserves in animal models, especially on immature oocytes and primordial follicles [70,71]. This represents one of the main differences with ovarian toxicity induced by taxanes: their effects on ovarian function seem to be transient, primarily due to the relative insensitivity of primordial follicles to these agents [72].

Bevacizumab also appears to contribute to reduced female fertility, although there are clear limitations to studying its effects, primarily due to its consistent use in combination with other antineoplastic agents and the relative scarcity of studies on human models. Animal studies, however, have demonstrated a reduction in the weight of the ovaries and uterus, as well as disruptions in menstrual cycles, related to its use [73].

Moreover, immune checkpoint inhibitors, such as pembrolizumab, may also play a role in this context, albeit indirectly, as they are associated with immune-mediated endocrine side effects, such as hypothyroidism and hypophysitis, which can impact fertility [74].

As previously mentioned, radiotherapy can impair female fertility at multiple levels, depending on the irradiation field of the treatment. At the ovarian level, radiation-induced damage appears to primarily affect oocytes (even though these cells are arrested at the diplotene stage of the first meiotic division), contrary to the principle that cells with higher replication rates are typically more sensitive [73].

Additionally, radiation exposure, particularly during pediatric age, appears to impair uterine vascularization, reduce uterine volume and elasticity, and induce endometrial atrophy followed by fibrosis [63,75,76].

4.1. Neoadjuvant Chemotherapy

NACT followed by FSS (with or without lymphadenectomy) could represent an option for patients with FIGO 2018 IB1-IB2 stage cervical cancer: by medically decreasing the size of the bulky tumour, patients could have access to fertility-sparing surgical procedures. The CONTESSA trial, a prospective multi-centre trial is currently investigating the outcomes of NACT (platinum-based chemotherapy with Placitaxel) followed by FSS for premenopausal women diagnosed with stage IB2 cervical canceer: primary objectives are the feasibility of FSS in this type of patient and discovery of the rate of functionality in uteruses, defined as success of FSS procedures and no adjuvant therapy [50]. The safety and success of NACT followed by FSS in patients with IB1-IB2 cervical cancer has already been studied in a small but promising systematic review by Gwatcham et al., with a reported complete pathologic response in 39.5% of the cases and full-term delivery in 69.4% of the patients included in the study (n = 114) [64].

4.2. Drug-Induced Ovarian Suppression

Neo-adjuvant/adjuvant chemotherapy and/or radiotherapy treatment represents the standard treatment for advanced stages of cervical cancer. Their cytotoxic effects have an important role in reducing ovarian reserve and function and impairing fertility in patients undergoing these kinds of treatments. In the literature, there is a growing interest in the co-treatment of Gonadotropin-releasing Hormone (GnRH) analogues with chemoradiotherapy and/or radiotherapy, considering the former as a chemoprotective agent [77]. The rationale of the use of this drug as a chemoprotective agent lays on the observation that gonadotocixity is lower in prepuberal girls than in adult women [78], and on their multiple beneficial effects: (1) a reduction in ovarian cellular turnover as a result of the suppression of gonadotropic stimulation of the ovarian tissue, and consequent reduction in cellular disruptions caused by gonadotoxic treatment [79], (2) a reduction in ovarian blood flow and vascular permeability, reducing the volume of gonadotoxic agents that reach the ovarian tissue [80], and (3) an increase in the expression of anti-apoptotic molecules in ovarian germ-line stem cells [79]. Due to the lack of data concerning the effectiveness of GnRH antagonists as chemoprotective agents in gynecological cancer in human models [77], they should be regarded as second-line agents, considering GnRH agonists as the treatment of choice. Combination of GnRH antagonists and agonists as fertility preservation treatment have only been investigated in experimental animal models, showing promising results, such as the prevention of the flare-up effect related to GnRH agonists [81,82]. A recent meta-analysis considering 579 cervical cancer patients who underwent co-treatment taking GnRH analogues during standard chemotherapy regimens (Paclitaxel and Cisplatin) showed a significant protective effect on ovarian function [83]. Given the conflicting data on the efficacy of GnRHa on fertility preservation, their use should be considered in addition to other fertility-sparing approaches, or when other FS options are not available, or in urgent cases [81,82,83,84].

4.3. Ovarian Transposition

In early stages, cervical cancer with nodal, vaginal margins or parametrial involvement or a combination of negative prognostic factors, and in locally advanced disease, radiation therapy (both external beam radiation therapy and brachytherapy) represents an essential treatment option [85]. The EBRT dose currently used for the treatment of cervical cancer inevitably causes ovarian failure [86], so patients eligible for radiation treatment could benefit of ovarian transposition in order to preserve their function. This procedure consists of transposing the gonads above the pelvic brim, making sure to avoid impairment of gonadal vascularization by torsion or tension of gonadal vessels [87]. An important concern related to this kind of fertility-sparing procedure is the risk of ovarian metastasis of cervical cancer. A recent meta-analysis by Fan et al. involving 18,389 patients diagnosed with cervical cancer stages IA-IIB reported that the main risk factors for ovarian metastases were the size of the tumour (using a cut-off of 4 cm diameter, with an incidence of 0.74% among patients with <4 cm tumours, up to 1.93% for tumour >4 cm), older age, pelvic lymph node and/or parametrial involvement, invasion of the corpus uteri, lymphovascular space involvement and histologic type (OR 3.89 for adenocarcinoma) [88]. According to a more recent but smaller meta-analysis by Laios et al., involving 1160 women undergoing ovarian transposition alone (OT alone) or ovarian transposition before radiation therapy (OT + RT), 9% of the women in the OT alone group lost ovarian function, versus 39% of patients in the OT + RT group, while 1% of women in the OT alone group were diagnosed with ovarian metastases, versus no cases in the OR + RT group [89]. The results of these studies are in line with the concept that ovarian transposition may be considered as a fertility-sparing procedure in patients eligible for radiation treatment for cervical cancer, but should be offered after a thorough evaluation of risk factors for ovarian metastasis and adequate counselling concerning the risk of losing ovarian function related to the surgical procedure itself.

4.4. Cryopreservation (Oocytes, Embryos, and Ovarian Tissue)

Considering that all the aforementioned treatments are not free of risks and contraindications, young patients seeking fertility preservation should be counselled regarding available ART options concerning oocyte cryopreservation, embryo cryopreservation, or ovarian tissue cryopreservation prior to gonadotoxic treatment. Controlled ovarian stimulation (COS), achieved with gonadotropins, is a crucial step for the success of these procedures, which also depends on the viability of oocytes recovered after the stimulation [90,91]. COS and consequent oocyte or embryo retrieval should be performed before gonadotoxic treatment, and can have a “random start”, not considering the menstrual cycle, without compromising fertilization rates in emergency settings [92]. A recent study conducted on 68 cancer patients, 33 of whom had a diagnosis of cervical cancer, reported that one in four women of the population enrolled returned to claim their cryopreserved eggs/embryos (mean time of return 36 months, min value 16 months-max value 85 months). Among them, the successful live birth rate reported was 58.8% [93]. However, cervical cancer patients often require urgent NACT protocols, thus having insufficient time to induce COS and oocyte maturation [94]. Furthermore, patients should be informed about the risk of potentially causing cancer spread during oocyte pick-up [94]. Another available option, especially for women who cannot delay urgent treatment, is represented by ovarian tissue cortex cryopreservation: a novel technique, successfully performed for the first time in 2000 by Oktay et al. in a human model [95], consisting of retrieving ovarian tissue, freezing it, and then thawing it in order to transplant it back after gonadotoxic therapy [96]. The thawed tissue can be transplanted back either via orthotopic methods (ovary, beneath the pelvic sidewall peritoneum or beneath the fallopian tube) or heterotopic methods (subcutaneously into lower abdomen or forearm, subperitoneal, between breast tissue and pectoralis muscle) [97], while considering orthotopic ovarian transplantation as the primary choice, as this method more easily allows spontaneous conception (potentially restoring the physiological microenvironment for follicular development) [98]. A 2022 meta-analysis by Diaz et al., including 21 studies for analysis of ovarian orthotopic transplantation outcomes with a total of 92 patients, reported pregnancy rates up to 81.3% and live birth rates up to 56.3%, depending on ovarian tissue processing and freezing methods, with a mean time of ovarian hormone restoration from tissue transplantation of 3.88 months [99], while in another systematic review and meta-analysis considering 735 women the pooled rate for pregnancies was 37% and live birth rate was 28%, with a median time for the graft function of 2.5 years [100]. However, this technique holds the aforementioned risk of ovarian recurrence and/or metastasis, especially in high-risk cancers or when risk factors are identified [101].

4.5. Uterine Transplantation (UTx)

It is evident that the main issue, beyond the restoration of reproductive capacity related to gametes, is the presence or absence of the uterus. In countries where surrogacy is permitted, cryopreservation is considered the first choice for women with advanced-stage cervical cancer. In countries where surrogacy is not allowed, UTx remains the only alternative. Before 2014, when the first birth from a transplanted uterus occurred, infertility associated with the iatrogenic absence of the organ was considered incurable. Since 2014, various births following UTx have been reported in the literature, mainly in patients with Rokitansky–Küster–Hauser syndrome [102]. Thanks to the pioneering work initiated by the DUETS (Dallas Uterus Transplantation Study) in 2016, uterus transplantation has evolved from an experimental study into a well-defined surgical procedure, aimed at allowing women with absolute uterine infertility to carry one or more pregnancies. Once gestation is achieved, the uterus is removed. The success of this intervention should not be measured in terms of the survival of the transplanted organ, but rather in the possibility of enabling a woman without a uterus (due to iatrogenic or congenital reasons) to carry a pregnancy. Uterine function generally restores within 4–6 weeks post-transplant, and embryo transfer can be performed starting from 3 to 6 months. Delivery is obtained by cesarian section performed between 36 and 38 weeks [103]. A 2019 review concerning the outcomes from the first 45 cases of UTx reported eighteen live births, but numerous surgical complications, with more than 25% of grafts being removed because of complications, and one in ten donors requiring surgical repair [104]. Although both the technical success and live birth rates following UTx are promising, to date only a small number of the estimated one million women globally affected by uterine infertility factor have benefited from this procedure [105]. Numerous limitations currently prevent this surgical procedure from becoming standard clinical practice. First and foremost, finding a suitable donor remains challenging [106]. Uterine transplants from both deceased and living donors have been reported in the literature, but legislation in many countries restricts living organ donation, especially as this is not a “life-saving transplant.” Where it is legally permitted, ethical considerations persist, involving the donor, the recipient, and even the potential child. To address these issues, the “Montreal Criteria” were established in 2012 by a team of experts to provide guidance on managing the primary ethical concerns, with the goal of supporting reproductive specialists globally. These criteria outline specific characteristics that both the donor and recipient must meet to be considered suitable candidates for UTx and assess the risk–benefit ratio to determine whether the procedure is appropriate [107]. Beyond ethical concerns, there are additional medical and surgical considerations. The transplanted uterus must be suitable to achieve pregnancy through IVF, which must be managed in highly specialized centres and ideally completed within a year of the uterine transplant to minimize prolonged immunosuppressive treatments. Natural conception is not possible due to tubal devascularization during the procedure. Consequently, the donor should be premenopausal or, at most, within 5 years post-menopause, should have previously given birth, and should not have comorbidities, recurrent miscarriages, or uterine scars, including those from cesarian sections [108]. Furthermore, as with all transplants, a key exclusion criterion is ABO blood group incompatibility and the presence of specific antibodies against the donor’s human leukocyte antigens. Lastly, the surgery itself is high-risk, with a serious complication rate of 32.4% for recipients. Complications include rejection, hypoxic and/or thrombotic vascular issues, infections, and vesicovaginal fistulas or strictures. Donors also face risks, including fistulas, urinary tract injury, pyelonephritis, bowel obstruction, acute anemia, and vaginal cuff dehiscence [109].

These limitations make UTx a challenging option for cancer survivors, who may already be weakened by oncological treatments. Nonetheless, highlighting these issues is essential to encourage collective advancements that may render uterine transplant a realistic and accessible alternative in the future.

5. Discussion

Cervical cancer remains a condition with a still-significant incidence, especially among young women. Medical and surgical advancements have enabled both early-stage diagnosis and minimally invasive treatment, although unfortunately, these are not always possible. The surgical and medical treatment of cervical cancer can deprive a woman of her reproductive system or severely impair its function, effectively condemning her to the loss of any hope for future pregnancy, with enormous psychological and social impact. Therefore, in all stages of the disease, from active infection to more advanced stages, it is mandatory to provide adequate counselling to all reproductive-aged women and refer them to the most suitable centre based on the individual case. Indeed, a personalized approach, such as the possibility of FSS or oocyte cryopreservation, can preserve reproductive function and ensure the potential for future pregnancy. In cases of FSS, it is important to discuss with the patient the risk of cancer recurrence, which, although low, is still significant. For this reason, the specialist and the patient should plan the correct timing for pregnancy, which should ideally occur within two years post-surgery. Although obstetric outcomes are generally favourable, pregnancy complications among cancer survivors are significantly higher than in the general population and could sometimes be severe, such as miscarriage, preterm birth, or intrauterine fetal death. These complications must be well understood and managed to ensure optimal neonatal outcomes, although few studies have addressed these issues, particularly those aimed at clarifying the most appropriate timing and mode of delivery. This review aimed to summarize the main findings in the literature to ensure that all patients receive the best reproductive options. However, it also highlighted the lack of randomized studies with adequate sample sizes. Most of these studies are based on results from patients with very early stages (IA1-IB1 FIGO) of the disease. Further research is therefore needed to confirm the few, still partial data and to extend the possibility of FSS to stages IB2-IIA1. NACT performed to down-stage the disease before trachelectomy or conization is a viable option, but it should be preceded by the possibility of oocyte–ovarian cryopreservation to give true meaning to minimally invasive surgery with uterine preservation. The absence of guidelines on fertility-sparing practises has long led clinicians to forgo a standardized approach, depriving many patients of the opportunity to access these treatments. However, in recent months, the main international gynecological societies have published guidelines that clinicians can now refer to. This document is the result of multidisciplinary work by 25 experts in the field, coming from various specialties (e.g., gynecological oncology, oncofertility, reproductive surgery, endoscopy, imaging, conservative surgery, medical oncology, and histopathology) and aims to address key issues: to discuss indications and treatment methods for fertility-sparing surgery (FSS); to improve reproductive outcomes and establish a dedicated pathway in infertility management; and to standardize post-operative management for these patients [110]. We hope that this effort will lead clinicians to discuss these options with their patients before establishing the treatment plan. Where FSS is not feasible, and radical surgery or radiotherapy is necessary, it is important not to extinguish the hope of future pregnancy by informing the patient of the options of ovarian transposition, surrogacy, or, where surrogacy is not allowed, UTx. Where permitted, surrogacy can be an option, especially for patients who, before undergoing a hysterectomy, were able to perform cryopreservation or embryo preservation and thus may have the chance in the future of achieving a pregnancy with their own oocytes, but with a borrowed uterus. Data on this topic in the literature is very limited; however, the few available studies indicate that surrogacy is a growing phenomenon and that success rates are promising [111]. One final consideration concerns the issue of inequity in healthcare based on the socio-economic status or the geographic location of the patient. The preservation of fertility in patients with cervical cancer varies based on different social situations. Belonging to lower and middle social classes often means receiving impersonal and discontinuous treatment, where healthcare is focused on the disease rather than the value of preserving fertility. In contrast, patients from higher social classes have the necessary resources to face the risks of targeted and diverse oncological treatments, ensuring access to more individualized healthcare. Lower and middle social classes living in areas with greater social vulnerability may have limited opportunities to access care outside of their immediate residential county [112]. Geographically tailored efforts, along with socioculturally tailored efforts, are needed to help improve equity in cervical cancer care access. Despite the multiple therapeutic options discussed, not all young women with cervical cancer will be able to fulfil their desire for motherhood. Therefore, the best strategy, as in all fields of medicine, remains prevention.