Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Fertility-Sparing Treatment for Early-Stage Cervical Cancer ≥ 2 cm: Can One Still Effectively Become a Mother? A Systematic Review of Fertility Outcomes

Fertility-Sparing Treatment for Early-Stage Cervical Cancer ≥ 2 cm: Can One Still Effectively... Ann Surg Oncol https://doi.org/10.1245/s10434-023-13542-z REVIEW ARTICLE – GYNECOLOGIC ONCOLOGY Fertility‑Sparing Treatment for Early‑Stage Cervical Cancer ≥ 2 cm: Can One Still Effectively Become a Mother? A Systematic Review of Fertility Outcomes Carlo Ronsini, MD , M. C. Solazzo, MD, R. Molitierno, MD, P. De Franciscis, MD, F. Pasanisi, MD, L. Cobellis, MD, and N. Colacurci, MD Department of Woman, Child and General and Specialized Surgery, University of Campania “Luigi Vanvitelli”, Naples, Italy ABSTRACT Conclusion. Fertility preservation in patients with ECC > Background. Fertility-sparing treatments (FSTs) have 2 cm is challenging. The endpoint for evaluating the best played a crucial role in the management of early-stage cervi- treatment should include oncological and fertility outcomes cal cancer (ECC); however, there is currently no standard of together. From this prospective, NACT followed by less radi- care for women with ECC ≥ 2 cm who wish to preserve their cal surgery could be a reasonable compromise. fertility. The current orientation of the scientific commu- nity comprises upfront surgical techniques and neoadjuvant Keywords Cervical cancer · Fertility sparing treatment · chemotherapy (NACT) followed by minor surgery such us Trachelectomy · Birth rat · Pre-term rate · Pregnancy rate conization. However these approaches are not standardized. This systematic review aimed to collect the evidence in the literature regarding the obstetric outcomes of the different Cervical cancer is the fourth most common malignancy techniques for applying FSTs in ECC ≥ 2 cm. in women worldwide. Almost 40% of women with cervical Methods. A systematic review was performed in September cancer are diagnosed between the ages of 20 and 44 years, 2022 using the Pubmed and Scopus databases, from the date with the disease confined to the cervix in approximately 46% of the first publication. We included all studies containing of cases. On the other hand, the average age of a woman at data regarding pregnancy, birth, and preterm rates. r fi st pregnancy is increasing, making it common for patients Results. Fifteen studies fulfilled the inclusion criteria, and to be diagnosed with early-stage cervical carcinoma (ECC) 352 patients were analyzed regarding fertility outcomes. who have not yet completed their reproductive expectations. Surgery-based FST showed the pregnancy rate (22%), birth Therefore, fertility-sparing treatments (FSTs) have been rate (11%), and preterm rate (10%). Papers regarding FST considered an alternative to the ‘standard’ radical hyster- using the NACT approach showed a pregnancy rate of 44%, ectomy to preserve women’s fertility and quality of life. with a birth rate of 45% in patients who managed to get ECC management is controversial, depending on the tumor pregnant. The preterm rate amounted to 44%, and pregnancy stage and other risk factors such as tumor size, histotype, rates and birth rates were significantly different between the grade, and lymphovascular invasion. Radical trachelectomy two groups (p < 0.001). (RT) combined with pelvic lymphadenectomy (PLND) is the treatment of choice for women with stage 1B1 cervical cancer < 2 cm who wish to preserve their fertility. RT may © The Author(s) 2023 be performed vaginally, abdominally, or laparoscopically/ robotically. Reviews have conr fi med that vaginal RT (VRT) First Received: 10 January 2023 Accepted: 9 April 2023 is an oncologically safe option for this type of patient and have shown that 80% of women can conceive after VRT. On the other hand, tumor size ≥ 2 cm is an area in which there C. Ronsini, MD is less concordance in the literature and less standardiza- e-mail: carlo.ronsini@unicampania.it; tion of techniques. Essentially, two approaches are offered carlo.ronsini90@gmail.com Vol.:(0123456789) C. Ronsini et al. to these women: surgical FST and neoadjuvant chemo- the number of patients who attempted to conceive after therapy (NACT) followed by conization FST. In a previous treatment, pregnancy rate, birth rate, and preterm rate, were review, we have remarked on the significant heterogeneity extracted. The pregnancy rate was defined as the ratio of present in the clinical management of FST of ECC ≥ 2 cm, patients with at least one pregnancy and the total number focusing mainly on oncological outcomes. However, once of patients who attempted to conceive. The birth rate was oncological safety is demonstrated, it should be crucial to defined as the ratio of live-birth deliveries to the total num- deeply understand the impact those two approaches have on ber of patients who attempted to become pregnant; a prema- fertility outcomes. The purpose of this review was to com- ture delivery was defined as a delivery < 37 weeks’ gestation pare the rates of pregnancy, live births, and preterm rates (WG). The preterm rate was defined as the ratio of premature for women with ECC ≥ 2 cm treated with surgical FST or deliveries to the total number of pregnancies resulting in live NACT approaches. births; however, this activity was hindered by different cri- teria across papers and a diffused lack of information. Four studies did not specifically report the number of attempted MATERIAL AND METHODS conceptions, and in these cases, the authors considered the total number of patients who underwent successful FST. The methods for this study were specified a priori based on the recommendations reported in the Preferred Report- Chi-square tests were used to compare continuous variables. ing Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The study was registered in the Quality Assessment PROSPERO database for meta-analysis, with protocol num- ber CRD42022329253. We assessed the quality of the included studies using the Newcastle–Ottawa Scale (NOS). This assessment scale uses Search Method three broad factors (selection, comparability, and exposure), with the scores ranging from 0 (lowest quality) to 8 (best We performed a systematic search for articles regarding quality). Two authors (MR and MLV) independently rated the quality of the studies. Any disagreements were subse- fertility outcomes in FST of ECC ≥ 2 cm in the Pubmed and Scopus Databases in September 2022, from the date of the quently resolved by discussion or consultation with a third author (CR). The NOS scale is reported in the electronic first publication We made no restrictions on country, and considered only studies published in the English-language. supplementary material. Search terms used were ‘fertility sparing’ and ‘cervical neo- plasm’ for each database. RESULTS Study Selection Study Characteristics Study selection was made independently by MCS and CR, From database screening, 1614 studies were selected. and in case of discrepancies, CR decided on the inclusion or After removing records with no full text, duplicates, and exclusion of a study. Inclusion criteria were (1) studies that wrong study designs, 23 studies were suitable for eligibility, included patients with ECC ≥ 2 cm; (2) studies that reported of which 15 matched the inclusion criteria and were included at least one outcome of interest (pregnancy rate, birth rate, in the systematic review. Overall, the publication years of preterm rate); and (3) original peer-reviewed articles. We the studies ranged from 2013 to 2021. The basic characteris- excluded non-original studies, preclinical trials, animal tri- tics of the included studies (first author, year of publication, als, abstract-only publications, and articles in languages country, study design, study range [years], and the number other than English. If possible, the authors of studies that of participants) are described in Table 1. were only published as congress abstracts were contacted via email and asked to provide the relevant data. The selected Outcomes studies and the reasons for exclusion are reported in Fig. 1. All included studies were assessed regarding any potential A total of 395 patients were included in this review. Six conflicts of interest. of the 15 selected studies presented data regarding fertility outcomes in surgical FST, while the remaining nine studies Data Extraction and Analysis presented data on FST with the use of NACT. No studies reported data from a direct comparison between these two MCS and MR extracted data for all relevant series and FSTs. The overall pregnancy, birth, and preterm rates for the case reports. Data on the surgical approach to tumors (sur- surgical FST procedures were 22.2, 11.1, and 10%, respec- gical-FST or NACT-FST) and fertility outcomes, such as tively. Furthermore, in the NACT group, the pregnancy rate Fertility‑Sparing Treatment for Early‑Stage Cervical …       Records identified through Records identified through Pub Med searching Scopus searching (n = 374 ) (n = 1240 ) Records excluded by Records title Records title Records excluded by selection from title screened screened selection from title (n =36) (n =14) (n=338) (n=1226) Articles abstracts Articles abstracts screened screened (n = 25) (n = 10) Articles after duplicates removed (n =31) Full-text articles assessed for eligibility Insufficient data (n=8) (n =23) Studies included in qualitative synthesis (n = 15 ) FIG. 1 PRISMA flow diagram. PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses amounted to 44%, and data showed birth and preterm rates The live birth rate was 12.5%; data regarding the preterm of 45.5 and 43.9%, respectively. Pregnancy and birth rates rate are not available. were significantly higher in the NACT group (pregnancy rate Deng et al. enrolled 45 patients with stage IB1 cervical 22.2% vs. 44.4%, p = 0.0016; birth rate 11.1% vs. 45.5%, cancer who had tumors larger than 2 cm treated with ART p < 0.001). On the contrary, preterm births were more fre- guided by the sentinel lymph node biopsy (SNLB) proce- quent in NACT patients (10% vs. 43.9%, p = 0.047). The dure. After a follow-up period of 45 months, 19 patients fertility outcomes of two groups are summarized in Table 2. tried to conceive (42.2%) and five succeeded, for a total of five pregnancies after surgery (pregnancy rate 26.32%). Of Surgical Fertility‑Sparing Treatment (FST) Outcomes these five pregnancies, one was a term delivery (birth rate 5%, preterm rate 0%), one was a mid-trimester miscarriage, Cao et al. performed a retrospective comparison between and three were first-trimester miscarriages. vaginal and abdominal trachelectomy in ECC. A total of Guo et al. investigated the oncological safety of ART 48 patients with ECC > 2 cm were recruited—24 in the compared with radical hysterectomy. Seventy-five patients VRT group and 24 in the abdominal RT (ART) group. In a with ECC > 2 cm were recruited and agreed to ART. The mean follow-up period of 20 months, independently from follow-up time was 70 months. During this period, 29 the technique used, only 24 patients attempted to conceive, women tried to conceive (38.6 %), resulting in five preg - three of whom had a pregnancy (pregnancy rate 12.5 %). nancies (pregnancy rate 17.2%). Among these pregnancies, Eligibility Identification Included Screening C. Ronsini et al. TABLE 1 Study characteristics Study, year Country Study design Study year FIGO stage No. of partici- pants Cao et al. China Prospective, case-control, multicentric 2003–2012 IB1 48 De Vincenzo et al. Italy Retrospective, observational, monocentric 2014–2018 IB2 9 Deng et al. China Retrospective, observational, monocentric – IB1 > 2 cm^ 45 Guo et al. China Retrospective, observational, monocentric 2003–2016 IB1 > 2 cm^ 75 Lanowska et al. Germany Retrospective, observational, monocentric 2006–2013 IB1 > 2 cm^ 20 IB2 Li et al. China Retrospective, observational, 2004–2013 IB1 > 2 cm^ 55 monocentric Lintner et al. Hungary Retrospective, observational, 1999–2006 IB1 > 2 cm^ 31 UK multicentric IB2 USA Lu et al. China Retrospective, observational, monocentric 2005–2012 IB1 > 2 cm^ 7 Marchiole et al. France Retrospective, observational, monocentric 2007–2017 IB1 > 2 cm^ 19 IB2 IIA1 > 2 cm^ Rendón et al. Colombia Retrospective, observational, monocentric 2009–2019 IB1 >2 cm^ 23 IB2^ IIA1 > 2 cm^ Robova et al. Czech Republic Retrospective, observational, 2005–2013 IB1 > 2 cm^ 20 monocentric IB2^ Salihi et al. Belgium Retrospective, observational, 2004–2013 IB1 > 2 cm^ 5 monocentric IB2^ Tesfai et al. Netherlands Retrospective, observational, monocentric 2006–2018 IB–IIA^ 15 Wethington et al. USA Retrospective, observational, monocentric 2001–2011 IB1 9 Zusterzeel et al. Netherlands Retrospective, observational, monocentric 2009–2018 IB2 14 FIGO International Federation of Gynecology and Obstetrics TABLE 2 Surgical FST and NACT fertility outcomes the delivery of a healthy neonate (pregnancy rate 42.8% and birth rate 42.8%)—one at 28 weeks’ gestation (preterm rate Outcomes Surgical FST NACT p. 33.3%) and two at term. Pregnancy rate 22.2 (20) 44.4 (40) 0.0016 Wethington et al. reported a case series of nine patients Birth rate 11.1 (10) 45.5 (41) 0.00001 treated with both abdominal and laparoscopic trachelec- Preterm rate 10 (1) 43.9 (18) 0.047 tomy (LRT) and robotic trachelectomy (RRT). In a median follow-up period of 40 months, two women tried to conceive FST fertility-sparing treatment, NACT neoadjuvant chemotherapy (22.2%), one of whom had a pregnancy (pregnancy rate 50%), but none of them delivered (birth rate and pregnancy there were two live births (birth rate 6.9%); the preterm rate rate 0%). Overall, surgical FST techniques showed a preg- nancy rate of between 12.5 and 50%, a birth rate between 0 was not estimated. Li et al. conducted a retrospective review of the onco- and 42.8%, and a preterm rate of between 0 and 33.3%. The follow-up period ranged from 20 to 90 months on average. logical, surgical, and obstetric outcomes of patients undergo- ing ART for ECC ≥ 2 cm. A total of 55 patients preserved The overall results, derived from recalculation of all the mentioned studies, reported a pregnancy rate of 22.2%, birth their fertility potential. In a mean follow-up period of 30.2 months, nine patients tried to conceive (16.3%); three were rate of 11.1%, and preterm birth of 10%. These results are summarized in Table 3. successful (33%) but there was only one live birth (birth rate 11%). Neoadjuvant Chemotherapy FST Outcomes Lintner et al. reported 30 patients with ECC > 2 cm treated with ART plus PLND. These authors reported a In their retrospective observational study, De Vincenzo median follow-up time of 90 months, during which eight women tried to conceive (23.3%). Three pregnancies led to et  al. published data on nine patients treated with three Fertility‑Sparing Treatment for Early‑Stage Cervical …       TABLE 3 Surgical FST Attempted to Pregnancy Birth rate [% (n)] Preterm rate [% (n)] Mean FUP outcomes conceive/ rate [% (n)] (months) all patients [n/N (%)] Cao et al. 24/48 (50) 12.5 (3) 12.5 (3) NR 20 Deng et al. 19/45 (42.2) 26.32 (5) 5 (1) 0 45 11 a Guo et al. 29/75 (38.6) 17.2 (5) 6.9 (2) NR 70 Li et al. 9/55 (16.3) 33 (3) 11 (1) 0 30.2 14 b Lintner et al. 7/30 (23.3) 42.8 (3) 42.8 (3) 33.3 (1) 90 Wethington et al. 2/9 (22.2) 50 (1) 0 0 44 Total 90/262 (34.3) 22.2 (20) 11.1 (10) 10 (1) FST fertility-sparing treatment, FUP follow-up, NR not reported Five women had eight pregnancies Three women had four pregnancies cycles of cisplatin and paclitaxel q21 and then treated After a median follow-up period of 47 months, seven women with cold-knife conization. Among the nine patients, only delivered 11 babies and three women delivered twice (preg- three patients tried to conceive and two became pregnant, nancy rate 43.5%). There were four term deliveries, seven both spontaneously (pregnancy rate and birth rate 66.6%). preterm births (preterm rate 63.3%), and an ongoing preg- One patient underwent a cesarean section at 34 weeks 3 nancy at 18 weeks. days because of preterm premature rupture of membranes In 2014, Robova et al. reported on data regarding fertil- (PROMs). The other woman was subjected to a cesarean sec- ity outcomes from 20 patients treated with different types tion at 37 weeks and 2 days because of PROMs and maternal of NACT followed by vaginal simple trachelectomy plus request (preterm rate 50%). Both babies were in good condi- laparoscopic lymphadenectomy. Fertility-sparing procedure tion. The third patient reported several unsuccessful attempts was performed in all patients, with a pregnancy rate of 50%; to become pregnant, likely due a reported cervical stenosis. eight women delivered 10 babies, and four premature deliv- Lanowska et  al. reported on the experience of 20 eries (preterm rate 40%). patients treated with NACT followed by VRT. Seven of 20 A subanalysis of the paper by Salihi et al. showed data patients tried to become pregnant and seven pregnancies from five patients with ECC ≥ 2 cm. In this group, only one occurred in five women, with a pregnancy rate of 71.4% pregnancy occurred, with a birth rate of 20%. and a birth rate of 57.4%. One ectopic pregnancy and one Tesfai et al. presented a series of 19 women treated with miscarriage occurred. All four babies were born by cesar- ART after neoadjuvant chemotherapy. Three of 15 patients ean delivery and two premature deliveries occurred due to with a successful ART became pregnant and had eight premature rupture of the membranes and vaginal bleeding, spontaneous pregnancies (pregnancy rate 20%) during the respectively (preterm rate 50%). median follow-up period of 73 months. All women delivered Marchiole et  al. presented a series of seven patients at full term via cesarean section (birth rate 40%). One patient treated with three or four cycles of cisplatin + paclitaxel + terminated two pregnancies due to non-medical reasons. ifosfamide with a VRT of completion. The pregnancy rate Finally, Zusterzeel et al. evaluated fertility outcomes was 50%. Three women had eight pregnancies; four first in a series of 14 women treated with NACT followed by trimester miscarriages and one therapeutic abortion at 18 VRT and PLND. In a median follow-up period of 50 months, weeks occurred, with a birth rate of 17.6%. All three babies seven women tried to conceive (50%), resulting in four were born prematurely by cesarean delivery (preterm rate patients having six pregnancies, including two first-trimester 100%). miscarriages and three live births born at term. The birth rate Lu et al. successfully treated six women who under- was 42.8% and the preterm rate was 0%. went NACT followed by total LRT. In a median follow-up The overall results, derived from recalculation of all the of 66 months, four women attempted to conceive and two mentioned studies, reported a pregnancy rate of 44%, birth succeeded (pregnancy rate 50%). One patient had a miscar- rate of 45.5%, and preterm birth rate of 43.9%. In a median riage in the first trimester and the other patient underwent a follow-up period of between 23 and 73 months, the applica- cesarean section due to PROMs. The authors reported a birth tion of NACT schemes in 90 patients resulted in 40 pregnan- rate of 25% and a preterm rate of 100%. cies, 41 live births, and 18 preterm deliveries. These results Rendón et al. reported on 23 patients treated with dif- are summarized in Table  4. Substratification by surgical ferent chemotherapy regimens combined with conization. approach after NACT showed a pregnancy rate of 41.9%, C. Ronsini et al. TABLE 4 NACT fertility outcomes Attempted to conceive/all Pregnancy rate Birth rate [% (n)] Preterm rate [% (n)] Mean patients [n/N (%)] [% (n)] FUP (months) De Vincenzo et al. 3/9 (33.3) 66.6 (2) 66.6 (2) 50 (1) 37 12 a Lanowska et al. 7/20 (35) 71.4 (5) 57.1 (4) 50(2) 23 16 b Marchiole et al. 6/17 (28.3) 50 (3) 17.6 (3) 100(3) NR Lu et al. 4/7 (54.1) 50 (2) 25 (1) 100 (1) 66 17 c Rendón et al. NR/23 43.5 (10) 47.8 (11) 63.6 (7) 47 18 d Robova et al., 2014 NR/20 50 (10) 50 (10) 40 (4) 42 Salihi et al. NR/5 20 (1) 20 (1) 0 58 20 e Tesfai et al. NR/15 20 (3) 40 (6) 0 73 22 f Zusterzeel et al. 7/14 (50) 57.1 (4) 42.8 (3) 0 50 Total 90/130 (69.2) 44.4 (40) 45.5 (41) 43.9 (18) FST fertility-sparing treatment, NACT neoadjuvant chemotherapy, FUP follow-up, NR not reported Five women had seven pregnancies Three women had eight pregnancies Seven women delivered 11 babies, three women delivered twice Eight women delivered 10 babies Three women had eight pregnancies Four women had six pregnancies Four studies did not specifically report the number of attempted conceptions; in these cases, the authors considered the total number of patients who underwent successful FST TABLE 5 NACT fertility outcomes by surgical approach preserving fertility remains a crucial challenge to gyneco- logical oncologists. Tumor size is an important prognostic Outcomes Cone VRT LRT ART factor to outline the ideal candidate for FSTs and leads to Pregnancy rate 41.9 (13/31) 55.0 (22/40) 50.0 (2/4) 20.0 (3/15) a clinical approach. In fact, National Comprehensive Can- Birth rate 45.1 (14/31) 50.0 (20/40) 50.0 (2/4) 40.0 (6/15) cer Network (NCCN) guidelines recommend fertility- Preterm rate 61.5 (8/13) 36.0 (9/25) 25.0 (1/4) 0 (0/6) sparing surgery as an option for reproductive-aged women with stage IB1 disease, and emphasize that this approach is Data are expressed as % (n/N) most validated in lesions < 2 cm in size. To date, this group NACT neoadjuvant chemotherapy, VRT vaginal radical trachelectomy, of patients can benefit from several surgical techniques to LRT laparoscopic trachelectomy, ART abdominal radical trachelec- maintain their reproductive potential. These methods include tomy 15 women delivered 21 babies a simple conization to RT with and without lymphadenec- 25,26 tomy, according to general indications for ECC. RT has evolved significantly over the years and several different approaches are available: vaginally, abdominally, or lapa- a birth rate of 45.1%, and a preterm rate of 61.5% for coni- zation; 55.0, 50.0, and 36.0% for VRT, respectively; 50.0, roscopically/robotically. When several procedures seem to offer the same oncologic outcomes, it is crucial to find 50.0, and 25.0% for minimally invasive RT, respectively; and 20.0, 40.0, and 0% for ART, respectively. These results are an acceptable compromise between the best choice of cure and fertility results. VRT or conization/simple trachelectomy summarized in Table 5. have shown encouraging results regarding safety and preg- 2,25 nancy rate. Much more debatable is which strategy to DISCUSSION adopt in the case of ECC ≥ 2 cm. In these patients, VRT is contraindicated due to the high risk of recurrence and Cervical cancer still represents one of the most frequently two main strategies have been proposed: abdominal surgical diagnosed cancers worldwide and the fourth leading cause FST or NACT FST. In a previous review, our group col- of cancer death in women. In the two most recent dec- lected the literature evidence regarding managing this type ades, there has been an increase in patients in their child- of patient, focusing on oncological outcomes. The results of bearing years diagnosed with ECCs due to the widespread this work ended in extremely heterogeneous data that reflect use of cervical cancer screening programs. In this scenario, Fertility‑Sparing Treatment for Early‑Stage Cervical …       current clinical practice. Nevertheless, approaches limited to to minimize gonadotoxic damage using gonadotropin- minimally invasive or vaginal techniques seem to show the releasing hormone (GnRH) agonists that decrease the risk 5 33 highest recurrence rate (RR) and ART seems to be a safer of premature ovarian failure (POF). Unfortunately, none option, according to recent evidence from the LACC trial. of the studies in the literature provided information regard- On the other hand, some literature reported that despite this ing the use of these treatment regimens, which should be oncological safety, ART proved to result in worse pregnancy considered the optimum to ensure the best chance of pre- results. In the reported series, surgical FST showed a preg- serving patients’ fertility. While less radical surgery is a 8 34 nancy rate of between 12.5 and 50%, and only Cao et al. definite trend for ECC < 2 cm, supported by a poor risk published data on fertility outcomes in patients treated with of parametria spr ead in patients with tumors > 2 cm could ART or VRT. The authors confirmed that RR was higher in be a risky strategy. Conceptually, in selected patients treated the VRT group (p = 0.040), and in four of seven recurrences, with NACT, chemotherapy responders with no residual dis- the recurrent sites after VRT were found to be located in the eases, less radical surgery could be a reasonable approach parametrical tissue. Hence, ART could be a safe option for to improve obstetric outcomes once negative lymph node patients with ECC > 2 cm, but this result does not mean it status has been assessed. This leads to another controversial is the best choice to preserve fertility potential. Obstetric point related to NACT and fertility preservation—the time results in ART FST were not encouraging, with a pregnancy of lymphadenectomy. Some authors prefer to perform lym- 29 9,12,18,19,36 rate of 20%. Our results agree, showing pregnancy and phadenectomy before administering chemotherapy, birth rates of 22 and 11%, respectively. excluding node-positive patients from NACT because of the Several factors can affect fertility after ART. First, a high risk of recurrence. On the other hand, post-NACT stag- higher risk of adhesion or a higher frequency of septic ing could have advantages in terms of no delays in treatment morbidities linked to an abdominal approach. The lower initiation and the possibility to sterilize lymph node micro- fertility rate after a laparotomic RT could also be related to metastasis in patients who would otherwise be excluded 14–16 greater disruption of pelvic nerve innervations and abnor- from the procedure. malities of the fallopian tubes. In addition, ART is usually Similarly, in patients with ECC ≥ 2 cm, the modalities of performed with ligation of the uterine arteries that theo- lymphadenectomy are also controversial. Despite the high retically impact on fertility. Nevertheless, a subanalysis risk of lymph node metastasis, using the sentinel lymph conducted by Bentivegna et al. of 735 cases showed that node (SLN) could minimize the risks of lymphadenectomy- 37,38 the infundibulopelvic and ovarian vessels could supply the related morbidity and provide information on the pres- vascular network of the uterine corpus, allowing a pregnancy ence or absence of micrometastases by ultrastaging. The to be achieved. An innovative approach that can extend upstream intent would be to identify patients with positive the possibility of an FST in women with ECC > 2 cm was lymph nodes to exclude them from the FST pathway, regard- NACT. In this work, we reported the fertility results of 90 less of the ART or NACT approach. Therefore, we believe patients treated with NACT followed by surgical proce- systematic or SLN-limited lymphadenectomy should pre- dures (simple conization, ART, or VRT). The pregnancy cede FST and be part of the standard diagnostic pathway of and birth rates were higher compared with those observed patients with ECC ≥ 2 cm. after an upfront RT, i.e. 44 and 45% versus 22% and 11 Another consideration to be made relates to the pregnancy (p < 0.001). Furthermore, it should be pointed out that in rate. No studies, regardless of approach, have reported on the NACT group, some authors reported high pregnancy whether or not patients were directed to specialized in vitro and birth rates in patients with the use of conization or VRT fertilization (IVF) centers. Cancer patients, all the more so 9,17 after NACT. if they have undergone NACT cycles, need to be assisted in This is easily understood if we focus on the surgical their procreation journey. On the other hand, patients should implications on fertility. The use of NACT is conceived to be framed from a fertility point of view before being referred minimize surgical aggressiveness. Combining NACT with to FST. None of the reported studies performed an anti-mul- ART means adding the surgical impact of pelvic anatomy to lerian hormone (AMH) assay prior to FST. Currently, the chemotherapeutic damage to the ovaries. However, patients main guidelines give 40 years of age as the limit to FST, treated with simple conization or VRT did not present opti- which may not reflect the patient’s reproductive capacity at mal fertility outcomes. This finding can be partly explained all. This biased view of the problem is perhaps related to by considering that the leading cause of obstetrical failure is the specifics of individual teams, which, dealing primarily related to cervical stenosis, lack of cervical mucus, and the with oncologic pathology, may need to be more trained in length of the cervix or isthmus. On the other hand, the gon- obstetrics and medically assisted procreation issues. There- adotoxicity exerted by chemotherapy should be mentioned. fore, FST treatments should be multidisciplinary. Drugs such as platinum and paclitaxel are considered at Finally, it is worth considering that in this review, the intermediate risk of gonadotoxicity. There are strategies overall birth rate of 14.4 % is related to a preterm rate of C. Ronsini et al. 37%. In particular, premature delivery is often caused by obstetric care, and mode of delivery. All three confounders 9,12,15 PROM, likely caused by clinical or subclinical chorio- have implications in fertility outcomes. amnionitis. Hence, although the fertility outcome is prom- ising, premature birth or first-trimester fetal loss remains CONCLUSION a main problem. The main explanation is likely related to a shortened cervix length and potential exposure of the Fertility-sparing treatment in patients with ECC ≥ 2 cm amniotic membrane to the bacteria of the vagina, which remains a challenge, especially considering the significant can lead to an increase in infections. The literature reported heterogeneity in clinical management. This becomes even several strategies to decrease this risk, such as prophylactic more challenging when the point of evaluation in best treat- 10,14 41 cerclage and the Saling procedure, a total occlusion of ments should include oncological and obstetrical outcomes the uteri cervix using vaginal mucosa. Vice versa, consider- together. Nevertheless, NACT followed by minimally inva- ing cerclage might result in bladder irritation, pelvic infec- sive surgery seems to be a reasonable compromise, from an 42,43 tion, and stenosis, some groups abandoned performing obstetrical point of view. Still, standardization of treatments a prophylactic cerclage and preferred to monitor the length remains a distant goal due to the many factors involved in 44,45 of the cervix during pregnancy using T VU and placed evaluating these patients. Moreover, guidelines on the man- a cerclage when necessary. However, a routine cerclage agement of pregnancy after FST are lacking and future stud- during ART may justify the lower percentage of preterm ies are needed to investigate the best strategy to reduce the births in the surgical group of patients, even if the low num- high risk of preterm delivery and PROMs. ber of births makes it obligatory to look at these data with skepticism. SUPPLEMENTARY INFORMATION The online version con- tains supplementary material available at https:// doi. or g/ 10. 1245/ Undeniable is that when a pregnancy occurs in women s10434- 023- 13542-z. who underwent an FST, this pregnancy is at high risk. A standardized follow-up modality should be applied to AUTHOR CONTRIBUTIONS CR: Conceptualization and meth- improve obstetrical outcomes in pregnant women after FST. odology. MCS: Data curation and writing – original draft. RM: Data In addition, it is interesting to note that considering only curation. FP: Data curation. LC: Review and editing. PdF: Review and editing. NC: Validation. series with available data, only 35% of women who com- pleted FST tried to conceive during follow-up. In their work, FUNDING Open access funding provided by Università degli Studi Carter et al. showed that many women who have undergone della Campania Luigi Vanvitelli within the CRUI-CARE Agreement. an RT experience distress that persists for up 6 months No specific funding was disclosed. in terms of sexual disorders. In fact, pregnancy concerns DISCLOSURE Carlo Ronsini, Maria Cristina Solazzo, Rossella appear to increase after FST, leading to lower fertility out- Molitierno, Pasquale de Franciscis, Francesca Pasanisi, Luigi Cobel- comes. However, studies investigating factors that affect a lis, and Nicola Colacurci have made no disclosures. women’s choice to conceive are lacking, underestimating a crucial aspect of the physical and emotional impact on OPEN ACCESS This article is licensed under a Creative Commons patients undergoing FST. Future studies in this area are Attribution 4.0 International License, which permits use, sharing, adap- needed to offer these women more complete and personal- tation, distribution and reproduction in any medium or format, as long ized counseling before treatments. as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes Fertility outcomes should only be considered in light were made. The images or other third party material in this article are of the comparable oncological safety of the different tech- included in the article’s Creative Commons licence, unless indicated niques. This could be the truth for ART and NACT, as previ- otherwise in a credit line to the material. If material is not included in ously published by our group. the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will The strengths of this study lie in its systematic nature and need to obtain permission directly from the copyright holder. To view a rigor of the research, collecting the largest number of FSTs copy of this licence, visit http://cr eativ ecommons. or g/licen ses/ b y/4.0/ . in patients with ECC >2 and adding the most possible infor- mation on obstetrical outcomes. However, the main weak- ness of the study is that most of the analyzed series focused REFERENCES on oncological outcomes, and only some of them detailed the total number of patients wishing to become pregnant, as 1. Quinn MA, Benedet JL, Odicino F, et al. carcinoma of the cervix well as every detail about each pregnancy. It almost seems uteri. Int J Gynaecol Obstet. 2006;95(Suppl 1):S43–103. that fertility outcomes have always been regarded as sec- 2. Plante M, Gregoire J, Renaud MC, Roy M. The vaginal radical trachelectomy: an update of a series of 125 cases and 106 preg- ondary to oncological outcomes. This is understandable nancies. Gynecol Oncol. 2011;121(2):290–7. https://d oi.o rg/1 0. in the hierarchy of these concepts, but makes it difficult to 1016/j. ygyno. 2010. 12. 345. obtain standardized information on the mode of conception, Fertility‑Sparing Treatment for Early‑Stage Cervical …       3. van Kol KGG, Vergeldt TFM, Bekkers RLM. Abdominal radical 17. Rendón GJ, Lopez Blanco A, Aragona A, et al. Oncological and trachelectomy versus chemotherapy followed by vaginal radical obstetrical outcomes after neo-adjuvant chemotherapy followed trachelectomy in stage 1B2 (FIGO 2018) cervical cancer. A sys- by fertility-sparing surgery in patients with cervical cancer ≥2 tematic review on fertility and recurrence rates. Gynecol Oncol. cm. Int J Gynecol Cancer. 2021;31(3):462–7. https://doi. or g/10. 2019;155(3):515–21. https:// doi. org/ 10. 1016/j. ygyno. 2019. 09. 1136/ ijgc- 2020- 002076. 025. 18. Robova H, Halaska MJ, Pluta M, et al. Oncological and preg- 4. Nezhat C, Roman RA, Rambhatla A, Nezhat F. Reproduc- nancy outcomes after high-dose density neoadjuvant chemo- tive and oncologic outcomes after fertility-sparing surgery for therapy and fertility-sparing surgery in cervical cancer. Gynecol early stage cervical cancer: a systematic review. Fertil Steril. Oncol. 2014;135(2):213–6. https:// doi. or g/ 10. 1016/j. y gyno. 2020;113(4):685–703. https:// doi. org/ 10. 1016/j. fertn stert. 2020. 2014. 08. 021. 02. 003. 19. Salihi R, Leunen K, van Limbergen E, Moerman P, Neven P, 5. Ronsini C, Solazzo MC, Bizzarri N, et al. Fertility-sparing treat- Vergote I. Neoadjuvant chemotherapy followed by large cone ment for early-stage cervical cancer ≥ 2 cm: a problem with resection as fertility-sparing therapy in stage IB cervical cancer. a thousand nuances—a systematic review of oncological out- Gynecol Oncol. 2015;139(3):447–51. https:// doi. org/ 10. 1016/j. comes. Ann Surg Oncol. 2022;29(13):8346–58. https:// doi. org/ ygyno. 2015. 05. 043. 10. 1245/ s10434- 022- 12436-w. 20. Tesfai FM, Kroep JR, Gaarenstroom K, et al. Fertility-sparing 6. Page MJ, Moher D, Bossuyt PM, et al. PRISMA 2020 explana- surgery of cervical cancer > 2 cm (International Federation of tion and elaboration: updated guidance and exemplars for report- Gynecology and Obstetrics 2009 stage IB1-IIA) after neoadju- ing systematic reviews. BMJ. 2021;372:n160. https://doi. or g/10. vant chemotherapy. Int J Gynecol Cancer. 2020;30(1):115–21. 1136/ bmj. n160.https:// doi. org/ 10. 1136/ ijgc- 2019- 000647. 7. Kansagara D, O’Neil M, Zakher B, Motu’apuaka M, Paynter 21. Wethington SL, Sonoda Y, Park KJ, et al. Expanding the indica- R, et al. Quality Assessment Criteria for Observational Stud- tions for radical trachelectomy a report on 29 patients with stage ies, Based on the Newcastle-Ottawa Scale. 2017. Available at: IB1 tumors measuring 2 to 4 centimeters. Int J Gynecol Cancer. https://www .ncbi. nlm. nih. go v/book s/NBK47 6448/ t able/appc. t4 . 2013;23(6):1092–8. https:// doi. or g/ 10. 1097/ IGC. 0b013 e3182 Accessed 27 Mar 2022. 96034e. 8. Cao DY, Yang JX, Wu XH, et al. Comparisons of vaginal and 22. Zusterzeel PLM, Aarts JWM, Pol FJM, Ottevanger PB, van abdominal radical trachelectomy for early-stage cervical can- Ham MAPC. Neoadjuvant chemotherapy followed by vagi- cer: preliminary results of a multi-center research in China. Br nal radical trachelectomy as fertility-preserving treatment for J Cancer. 2013;109(11):2778–82. https:// doi. org/ 10. 1038/ bjc. patients with FIGO 2018 stage 1B2 cervical cancer. Oncolo‑ 2013. 656. gist. 2020;25(7):e1051–9. https://doi. or g/10. 1634/ t heoncolog is t. 9. de Vincenzo R, Ricci C, Fanfani F, et al. Neoadjuvant chemo-2020- 0063. therapy followed by conization in stage IB2–IIA1 cervical cancer 23. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: larger than 2 cm: a pilot study. Fertil Steril. 2021;115(1):148–56. GLOBOCAN estimates of incidence and mortality worldwide for https:// doi. org/ 10. 1016/j. fertn stert. 2020. 07. 006. 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209– 10. Deng X, Zhang Y, Li D, et al. Abdominal radical trachelectomy 49. https:// doi. org/ 10. 3322/ caac. 21660. guided by sentinel lymph node biopsy for stage IB1 cervical 24. Koh WJ, Abu-Rustum NR, Bean S, et al. Cervical cancer, version cancer with tumors > 2 Cm. Oncotarget. 2017;8(2):3422–9. 3.2019, NCCN clinical practice guidelines in oncology. J Natl 11. Guo J, Zhang Y, Chen X, Sun L, Chen K, Sheng X. Surgical and Compr Cancer Netw. 2019;17(1):64–84. https://doi. or g/10. 6004/ oncologic outcomes of radical abdominal trachelectomy versus jnccn. 2019. 0001. hysterectomy for stage IA2-IB1 cervical cancer. J Minim Inva‑ 25. Plante M. Evolution in fertility-preserving options for early- sive Gynecol. 2019;26(3):484–91. https://d oi.o rg/1 0.1 016/j.j mig. stage cervical cancer: radical trachelectomy, simple trache- 2018. 06. 006. lectomy, neoadjuvant chemotherapy. Int J Gynecol Cancer. 12. Lanowska M, Mangler M, Speiser D, et al. Radical vaginal tra- 2013;23(6):982–9. https:// doi. or g/ 10. 1097/ IGC. 0b013 e3182 chelectomy after laparoscopic staging and neoadjuvant chemo- 95906b. therapy in women with early-stage cervical cancer over 2 cm: 26. Bentivegna E, Gouy S, Maulard A, Chargari C, Leary A, Morice oncologic, fertility, and neonatal outcome in a series of 20 P. Oncological outcomes after fertility-sparing surgery for cervi- patients. Int J Gynecol Cancer. 2014;24(3):586–93. https:// doi. cal cancer: a systematic review. Lancet Oncol. 2016;17(6):e240– org/ 10. 1097/ IGC. 00000 00000 000080. 53. https:// doi. org/ 10. 1016/ S1470- 2045(16) 30032-8. 13. Li J, Wu X, Li X, Ju X. Abdominal radical trachelectomy: is it 27. Covens A, Rosen B, Murphy J, et al. How important is removal safe for IB1 cervical cancer with tumors ≥ 2 cm. Gynecol Oncol. of the parametrium at surgery for carcinoma of the cervix? 2013;131(1):87–92. https:// doi. or g/ 10. 1016/j. y gyno. 2013. 07. Gynecol Oncol. 2002;84(1):145–9. https://doi. or g/10. 1006/ gyno. 079.2001. 6493. 14. Lintner B, Saso S, Tarnai L, et al. Use of abdominal radical tra- 28. Di Donato V, Caruso G, Sassu CM, et al. Fertility-sparing sur- chelectomy to treat cervical cancer greater than 2 cm in diameter. gery for women with stage I cervical cancer of 4 cm or larger: a Int J Gynecol Cancer. 2013;23(6):1065–70. https:// doi. org/ 10. systematic review. J Gynecol Oncol. 2021;32(6):e83. https://doi. 1097/ IGC. 0b013 e3182 95fb41.org/ 10. 3802/ jgo. 2021. 32. e83. 15. Lu Q, Zhang Y, Wang S, et al. Neoadjuvant intra-arterial chem- 29. Canis MJ, Triopon G, Daraï E, et al. Adhesion prevention after otherapy followed by total laparoscopic radical trachelectomy myomectomy by laparotomy: a prospective multicenter compara- in stage IB1 cervical cancer. Fertil Steril. 2014;101(3):812–7. tive randomized single-blind study with second-look laparos- TM https:// doi. org/ 10. 1016/j. fertn stert. 2013. 12. 001. copy to assess the effectiveness of PREVADH . Eur J Obstet 16. Marchiolè P, Ferraioli D, Moran E, et  al. NACT and laparo- Gynecol Reprod Biol. 2014;178:42–7. https://doi. or g/10. 1016/j. scopic-assisted radical vaginal trachelectomy in young patients ejogrb. 2014. 03. 020. with large (2–5 cm) high risk cervical cancers: safety and obstet- 30. Donnez J. CO laser laparoscopy in infertile women with endo- rical outcome. Surg Oncol. 2018;27(2):236–44. https:// doi. org/ metriosis and women with adnexal adhesions. Fertil Steril. 10. 1016/j. suronc. 2018. 04. 006. 1987;48(3):390–4. h tt p s: / / d oi . o r g / 1 0. 1 01 6/ S 00 15 - 0 28 2 (1 6 ) 59404-7. C. Ronsini et al. 31. Bentivegna E, Maulard A, Pautier P, Chargari C, Gouy S, Morice the detection of sentinel lymph node metastasis in endome- P. Fertility results and pregnancy outcomes after conservative trial cancer patients: a retrospective cohort comparison. Int J treatment of cervical cancer: a systematic review of the litera- Gynecol Cancer. 2020;30(3):372–7. https:// doi. or g/ 10. 1136/ ture. Fertil Steril. 2016;106(5):1195-1211.e5. https://do i.o rg/1 0. ijgc- 2019- 000937. 1016/j. fertn stert. 2016. 06. 032. 40. Boss EA, van Golde RJT, Beerendonk CCM, Massuger LFAG. 32. Plante M. Evolution in fertility-preserving options for early-stage Pregnancy after radical trachelectomy: a real option? Gynecol cervical cancer. Int J Gynecol Cancer. 2013;23(6):982–9. https:// Oncol. 2005;99(3):S152–6. https:// doi. or g/ 10. 1016/j. y gyno. doi. org/ 10. 1097/ IGC. 0b013 e3182 95906b.2005. 07. 071. 33. Sonmezer M, Oktay K. Fertility preservation in young women 41. Saling E. Prevention of habitual abortion and prematurity undergoing breast cancer therapy. Oncologist. 2006;11(5):422– by early total occlusion of the external os uteri. Eur J Obstet 34. https:// doi. org/ 10. 1634/ theon colog ist. 11-5- 422. Gynecol Reprod Biol. 1984;17(2–3):165–70. https:// doi. org/ 10. 34. Badawy A, Elnashar A, El-Ashry M, Shahat M. Gonadotropin-1016/ 0028- 2243(84) 90140-0. releasing hormone agonists for prevention of chemotherapy- 42. Plante M, Renaud MC, Roy M. Radical vaginal trachelectomy: induced ovarian damage: prospective randomized study. Fertil a fertility-preserving option for young women with early stage Steril. 2009;91(3):694–7. https:// doi. or g/ 10. 1016/j. fer tn s ter t. cervical cancer. Gynecol Oncol. 2005;99(3):S143–6. https://doi. 2007. 12. 044.org/ 10. 1016/j. ygyno. 2005. 07. 067. 35. Lanowska M, Morawietz L, Sikora A, et al. Prevalence of lymph 43. Pareja FR, Ramirez PT, Borrero FM, Angel CG. Abdominal radi- nodes in the parametrium of radical vaginal trachelectomy (RVT) cal trachelectomy for invasive cervical cancer: a case series and specimen. Gynecol Oncol. 2011;121(2):298–302. https://doi. or g/ literature review. Gynecol Oncol. 2008;111(3):555–60. https:// 10. 1016/j. ygyno. 2011. 01. 011.doi. org/ 10. 1016/j. ygyno. 2008. 07. 019. 36. Vercellino GF, Piek JMJ, Schneider A, et al. Laparoscopic lymph 44. Bouchard-Fortier G, Reade CJ, Covens A. Non-radical surgery node dissection should be performed before fertility preserv- for small early-stage cervical cancer. Is it time? Gynecol Oncol. ing treatment of patients with cervical cancer. Gynecol Oncol. 2014;132(3):624–7. https:// doi. or g/ 10. 1016/j. y gyno. 2014. 01. 2012;126(3):325–9. https:// doi. or g/ 10. 1016/j. y gyno. 2012. 05. 037. 033. 45. Kasuga Y, Miyakoshi K, Nishio H, et al. Mid-trimester residual 37. Restaino S, Ronsini C, Finelli A, Perrone E, Scambia G, Fanfani cervical length and the risk of preterm birth in pregnancies after F. Role of blue dye for sentinel lymph node detection in early abdominal radical trachelectomy: a retrospective analysis. BJOG. endometrial cancer. Gynecol Surg. 2017;14(1):23. https:// doi. 2017;124(11):1729–35. https:// doi. or g/ 10. 1111/ 1471- 0528. org/ 10. 1186/ s10397- 017- 1026-0. 14688. 38. Ronsini C, de Franciscis P, Carotenuto RM, Pasanisi F, Cobellis L, Colacurci N. The oncological implication of sentinel lymph Publisher’s Note Springer Nature remains neutral with regard to node in early cervical cancer: a meta-analysis of oncological jurisdictional claims in published maps and institutional affiliations. outcomes and type of recurrences. Medicina. 2022;58(11):1539. https:// doi. org/ 10. 3390/ medic ina58 111539. 39. Fanfani F, Monterossi G, di Meo ML, et  al. Standard ultra- staging compared to one-step nucleic acid amplification for http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Annals of Surgical Oncology Springer Journals

Fertility-Sparing Treatment for Early-Stage Cervical Cancer ≥ 2 cm: Can One Still Effectively Become a Mother? A Systematic Review of Fertility Outcomes

Loading next page...
 
/lp/springer-journals/fertility-sparing-treatment-for-early-stage-cervical-cancer-2-cm-can-673bE5KoTh

References (46)

Publisher
Springer Journals
Copyright
Copyright © The Author(s) 2023
ISSN
1068-9265
eISSN
1534-4681
DOI
10.1245/s10434-023-13542-z
Publisher site
See Article on Publisher Site

Abstract

Ann Surg Oncol https://doi.org/10.1245/s10434-023-13542-z REVIEW ARTICLE – GYNECOLOGIC ONCOLOGY Fertility‑Sparing Treatment for Early‑Stage Cervical Cancer ≥ 2 cm: Can One Still Effectively Become a Mother? A Systematic Review of Fertility Outcomes Carlo Ronsini, MD , M. C. Solazzo, MD, R. Molitierno, MD, P. De Franciscis, MD, F. Pasanisi, MD, L. Cobellis, MD, and N. Colacurci, MD Department of Woman, Child and General and Specialized Surgery, University of Campania “Luigi Vanvitelli”, Naples, Italy ABSTRACT Conclusion. Fertility preservation in patients with ECC > Background. Fertility-sparing treatments (FSTs) have 2 cm is challenging. The endpoint for evaluating the best played a crucial role in the management of early-stage cervi- treatment should include oncological and fertility outcomes cal cancer (ECC); however, there is currently no standard of together. From this prospective, NACT followed by less radi- care for women with ECC ≥ 2 cm who wish to preserve their cal surgery could be a reasonable compromise. fertility. The current orientation of the scientific commu- nity comprises upfront surgical techniques and neoadjuvant Keywords Cervical cancer · Fertility sparing treatment · chemotherapy (NACT) followed by minor surgery such us Trachelectomy · Birth rat · Pre-term rate · Pregnancy rate conization. However these approaches are not standardized. This systematic review aimed to collect the evidence in the literature regarding the obstetric outcomes of the different Cervical cancer is the fourth most common malignancy techniques for applying FSTs in ECC ≥ 2 cm. in women worldwide. Almost 40% of women with cervical Methods. A systematic review was performed in September cancer are diagnosed between the ages of 20 and 44 years, 2022 using the Pubmed and Scopus databases, from the date with the disease confined to the cervix in approximately 46% of the first publication. We included all studies containing of cases. On the other hand, the average age of a woman at data regarding pregnancy, birth, and preterm rates. r fi st pregnancy is increasing, making it common for patients Results. Fifteen studies fulfilled the inclusion criteria, and to be diagnosed with early-stage cervical carcinoma (ECC) 352 patients were analyzed regarding fertility outcomes. who have not yet completed their reproductive expectations. Surgery-based FST showed the pregnancy rate (22%), birth Therefore, fertility-sparing treatments (FSTs) have been rate (11%), and preterm rate (10%). Papers regarding FST considered an alternative to the ‘standard’ radical hyster- using the NACT approach showed a pregnancy rate of 44%, ectomy to preserve women’s fertility and quality of life. with a birth rate of 45% in patients who managed to get ECC management is controversial, depending on the tumor pregnant. The preterm rate amounted to 44%, and pregnancy stage and other risk factors such as tumor size, histotype, rates and birth rates were significantly different between the grade, and lymphovascular invasion. Radical trachelectomy two groups (p < 0.001). (RT) combined with pelvic lymphadenectomy (PLND) is the treatment of choice for women with stage 1B1 cervical cancer < 2 cm who wish to preserve their fertility. RT may © The Author(s) 2023 be performed vaginally, abdominally, or laparoscopically/ robotically. Reviews have conr fi med that vaginal RT (VRT) First Received: 10 January 2023 Accepted: 9 April 2023 is an oncologically safe option for this type of patient and have shown that 80% of women can conceive after VRT. On the other hand, tumor size ≥ 2 cm is an area in which there C. Ronsini, MD is less concordance in the literature and less standardiza- e-mail: carlo.ronsini@unicampania.it; tion of techniques. Essentially, two approaches are offered carlo.ronsini90@gmail.com Vol.:(0123456789) C. Ronsini et al. to these women: surgical FST and neoadjuvant chemo- the number of patients who attempted to conceive after therapy (NACT) followed by conization FST. In a previous treatment, pregnancy rate, birth rate, and preterm rate, were review, we have remarked on the significant heterogeneity extracted. The pregnancy rate was defined as the ratio of present in the clinical management of FST of ECC ≥ 2 cm, patients with at least one pregnancy and the total number focusing mainly on oncological outcomes. However, once of patients who attempted to conceive. The birth rate was oncological safety is demonstrated, it should be crucial to defined as the ratio of live-birth deliveries to the total num- deeply understand the impact those two approaches have on ber of patients who attempted to become pregnant; a prema- fertility outcomes. The purpose of this review was to com- ture delivery was defined as a delivery < 37 weeks’ gestation pare the rates of pregnancy, live births, and preterm rates (WG). The preterm rate was defined as the ratio of premature for women with ECC ≥ 2 cm treated with surgical FST or deliveries to the total number of pregnancies resulting in live NACT approaches. births; however, this activity was hindered by different cri- teria across papers and a diffused lack of information. Four studies did not specifically report the number of attempted MATERIAL AND METHODS conceptions, and in these cases, the authors considered the total number of patients who underwent successful FST. The methods for this study were specified a priori based on the recommendations reported in the Preferred Report- Chi-square tests were used to compare continuous variables. ing Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The study was registered in the Quality Assessment PROSPERO database for meta-analysis, with protocol num- ber CRD42022329253. We assessed the quality of the included studies using the Newcastle–Ottawa Scale (NOS). This assessment scale uses Search Method three broad factors (selection, comparability, and exposure), with the scores ranging from 0 (lowest quality) to 8 (best We performed a systematic search for articles regarding quality). Two authors (MR and MLV) independently rated the quality of the studies. Any disagreements were subse- fertility outcomes in FST of ECC ≥ 2 cm in the Pubmed and Scopus Databases in September 2022, from the date of the quently resolved by discussion or consultation with a third author (CR). The NOS scale is reported in the electronic first publication We made no restrictions on country, and considered only studies published in the English-language. supplementary material. Search terms used were ‘fertility sparing’ and ‘cervical neo- plasm’ for each database. RESULTS Study Selection Study Characteristics Study selection was made independently by MCS and CR, From database screening, 1614 studies were selected. and in case of discrepancies, CR decided on the inclusion or After removing records with no full text, duplicates, and exclusion of a study. Inclusion criteria were (1) studies that wrong study designs, 23 studies were suitable for eligibility, included patients with ECC ≥ 2 cm; (2) studies that reported of which 15 matched the inclusion criteria and were included at least one outcome of interest (pregnancy rate, birth rate, in the systematic review. Overall, the publication years of preterm rate); and (3) original peer-reviewed articles. We the studies ranged from 2013 to 2021. The basic characteris- excluded non-original studies, preclinical trials, animal tri- tics of the included studies (first author, year of publication, als, abstract-only publications, and articles in languages country, study design, study range [years], and the number other than English. If possible, the authors of studies that of participants) are described in Table 1. were only published as congress abstracts were contacted via email and asked to provide the relevant data. The selected Outcomes studies and the reasons for exclusion are reported in Fig. 1. All included studies were assessed regarding any potential A total of 395 patients were included in this review. Six conflicts of interest. of the 15 selected studies presented data regarding fertility outcomes in surgical FST, while the remaining nine studies Data Extraction and Analysis presented data on FST with the use of NACT. No studies reported data from a direct comparison between these two MCS and MR extracted data for all relevant series and FSTs. The overall pregnancy, birth, and preterm rates for the case reports. Data on the surgical approach to tumors (sur- surgical FST procedures were 22.2, 11.1, and 10%, respec- gical-FST or NACT-FST) and fertility outcomes, such as tively. Furthermore, in the NACT group, the pregnancy rate Fertility‑Sparing Treatment for Early‑Stage Cervical …       Records identified through Records identified through Pub Med searching Scopus searching (n = 374 ) (n = 1240 ) Records excluded by Records title Records title Records excluded by selection from title screened screened selection from title (n =36) (n =14) (n=338) (n=1226) Articles abstracts Articles abstracts screened screened (n = 25) (n = 10) Articles after duplicates removed (n =31) Full-text articles assessed for eligibility Insufficient data (n=8) (n =23) Studies included in qualitative synthesis (n = 15 ) FIG. 1 PRISMA flow diagram. PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses amounted to 44%, and data showed birth and preterm rates The live birth rate was 12.5%; data regarding the preterm of 45.5 and 43.9%, respectively. Pregnancy and birth rates rate are not available. were significantly higher in the NACT group (pregnancy rate Deng et al. enrolled 45 patients with stage IB1 cervical 22.2% vs. 44.4%, p = 0.0016; birth rate 11.1% vs. 45.5%, cancer who had tumors larger than 2 cm treated with ART p < 0.001). On the contrary, preterm births were more fre- guided by the sentinel lymph node biopsy (SNLB) proce- quent in NACT patients (10% vs. 43.9%, p = 0.047). The dure. After a follow-up period of 45 months, 19 patients fertility outcomes of two groups are summarized in Table 2. tried to conceive (42.2%) and five succeeded, for a total of five pregnancies after surgery (pregnancy rate 26.32%). Of Surgical Fertility‑Sparing Treatment (FST) Outcomes these five pregnancies, one was a term delivery (birth rate 5%, preterm rate 0%), one was a mid-trimester miscarriage, Cao et al. performed a retrospective comparison between and three were first-trimester miscarriages. vaginal and abdominal trachelectomy in ECC. A total of Guo et al. investigated the oncological safety of ART 48 patients with ECC > 2 cm were recruited—24 in the compared with radical hysterectomy. Seventy-five patients VRT group and 24 in the abdominal RT (ART) group. In a with ECC > 2 cm were recruited and agreed to ART. The mean follow-up period of 20 months, independently from follow-up time was 70 months. During this period, 29 the technique used, only 24 patients attempted to conceive, women tried to conceive (38.6 %), resulting in five preg - three of whom had a pregnancy (pregnancy rate 12.5 %). nancies (pregnancy rate 17.2%). Among these pregnancies, Eligibility Identification Included Screening C. Ronsini et al. TABLE 1 Study characteristics Study, year Country Study design Study year FIGO stage No. of partici- pants Cao et al. China Prospective, case-control, multicentric 2003–2012 IB1 48 De Vincenzo et al. Italy Retrospective, observational, monocentric 2014–2018 IB2 9 Deng et al. China Retrospective, observational, monocentric – IB1 > 2 cm^ 45 Guo et al. China Retrospective, observational, monocentric 2003–2016 IB1 > 2 cm^ 75 Lanowska et al. Germany Retrospective, observational, monocentric 2006–2013 IB1 > 2 cm^ 20 IB2 Li et al. China Retrospective, observational, 2004–2013 IB1 > 2 cm^ 55 monocentric Lintner et al. Hungary Retrospective, observational, 1999–2006 IB1 > 2 cm^ 31 UK multicentric IB2 USA Lu et al. China Retrospective, observational, monocentric 2005–2012 IB1 > 2 cm^ 7 Marchiole et al. France Retrospective, observational, monocentric 2007–2017 IB1 > 2 cm^ 19 IB2 IIA1 > 2 cm^ Rendón et al. Colombia Retrospective, observational, monocentric 2009–2019 IB1 >2 cm^ 23 IB2^ IIA1 > 2 cm^ Robova et al. Czech Republic Retrospective, observational, 2005–2013 IB1 > 2 cm^ 20 monocentric IB2^ Salihi et al. Belgium Retrospective, observational, 2004–2013 IB1 > 2 cm^ 5 monocentric IB2^ Tesfai et al. Netherlands Retrospective, observational, monocentric 2006–2018 IB–IIA^ 15 Wethington et al. USA Retrospective, observational, monocentric 2001–2011 IB1 9 Zusterzeel et al. Netherlands Retrospective, observational, monocentric 2009–2018 IB2 14 FIGO International Federation of Gynecology and Obstetrics TABLE 2 Surgical FST and NACT fertility outcomes the delivery of a healthy neonate (pregnancy rate 42.8% and birth rate 42.8%)—one at 28 weeks’ gestation (preterm rate Outcomes Surgical FST NACT p. 33.3%) and two at term. Pregnancy rate 22.2 (20) 44.4 (40) 0.0016 Wethington et al. reported a case series of nine patients Birth rate 11.1 (10) 45.5 (41) 0.00001 treated with both abdominal and laparoscopic trachelec- Preterm rate 10 (1) 43.9 (18) 0.047 tomy (LRT) and robotic trachelectomy (RRT). In a median follow-up period of 40 months, two women tried to conceive FST fertility-sparing treatment, NACT neoadjuvant chemotherapy (22.2%), one of whom had a pregnancy (pregnancy rate 50%), but none of them delivered (birth rate and pregnancy there were two live births (birth rate 6.9%); the preterm rate rate 0%). Overall, surgical FST techniques showed a preg- nancy rate of between 12.5 and 50%, a birth rate between 0 was not estimated. Li et al. conducted a retrospective review of the onco- and 42.8%, and a preterm rate of between 0 and 33.3%. The follow-up period ranged from 20 to 90 months on average. logical, surgical, and obstetric outcomes of patients undergo- ing ART for ECC ≥ 2 cm. A total of 55 patients preserved The overall results, derived from recalculation of all the mentioned studies, reported a pregnancy rate of 22.2%, birth their fertility potential. In a mean follow-up period of 30.2 months, nine patients tried to conceive (16.3%); three were rate of 11.1%, and preterm birth of 10%. These results are summarized in Table 3. successful (33%) but there was only one live birth (birth rate 11%). Neoadjuvant Chemotherapy FST Outcomes Lintner et al. reported 30 patients with ECC > 2 cm treated with ART plus PLND. These authors reported a In their retrospective observational study, De Vincenzo median follow-up time of 90 months, during which eight women tried to conceive (23.3%). Three pregnancies led to et  al. published data on nine patients treated with three Fertility‑Sparing Treatment for Early‑Stage Cervical …       TABLE 3 Surgical FST Attempted to Pregnancy Birth rate [% (n)] Preterm rate [% (n)] Mean FUP outcomes conceive/ rate [% (n)] (months) all patients [n/N (%)] Cao et al. 24/48 (50) 12.5 (3) 12.5 (3) NR 20 Deng et al. 19/45 (42.2) 26.32 (5) 5 (1) 0 45 11 a Guo et al. 29/75 (38.6) 17.2 (5) 6.9 (2) NR 70 Li et al. 9/55 (16.3) 33 (3) 11 (1) 0 30.2 14 b Lintner et al. 7/30 (23.3) 42.8 (3) 42.8 (3) 33.3 (1) 90 Wethington et al. 2/9 (22.2) 50 (1) 0 0 44 Total 90/262 (34.3) 22.2 (20) 11.1 (10) 10 (1) FST fertility-sparing treatment, FUP follow-up, NR not reported Five women had eight pregnancies Three women had four pregnancies cycles of cisplatin and paclitaxel q21 and then treated After a median follow-up period of 47 months, seven women with cold-knife conization. Among the nine patients, only delivered 11 babies and three women delivered twice (preg- three patients tried to conceive and two became pregnant, nancy rate 43.5%). There were four term deliveries, seven both spontaneously (pregnancy rate and birth rate 66.6%). preterm births (preterm rate 63.3%), and an ongoing preg- One patient underwent a cesarean section at 34 weeks 3 nancy at 18 weeks. days because of preterm premature rupture of membranes In 2014, Robova et al. reported on data regarding fertil- (PROMs). The other woman was subjected to a cesarean sec- ity outcomes from 20 patients treated with different types tion at 37 weeks and 2 days because of PROMs and maternal of NACT followed by vaginal simple trachelectomy plus request (preterm rate 50%). Both babies were in good condi- laparoscopic lymphadenectomy. Fertility-sparing procedure tion. The third patient reported several unsuccessful attempts was performed in all patients, with a pregnancy rate of 50%; to become pregnant, likely due a reported cervical stenosis. eight women delivered 10 babies, and four premature deliv- Lanowska et  al. reported on the experience of 20 eries (preterm rate 40%). patients treated with NACT followed by VRT. Seven of 20 A subanalysis of the paper by Salihi et al. showed data patients tried to become pregnant and seven pregnancies from five patients with ECC ≥ 2 cm. In this group, only one occurred in five women, with a pregnancy rate of 71.4% pregnancy occurred, with a birth rate of 20%. and a birth rate of 57.4%. One ectopic pregnancy and one Tesfai et al. presented a series of 19 women treated with miscarriage occurred. All four babies were born by cesar- ART after neoadjuvant chemotherapy. Three of 15 patients ean delivery and two premature deliveries occurred due to with a successful ART became pregnant and had eight premature rupture of the membranes and vaginal bleeding, spontaneous pregnancies (pregnancy rate 20%) during the respectively (preterm rate 50%). median follow-up period of 73 months. All women delivered Marchiole et  al. presented a series of seven patients at full term via cesarean section (birth rate 40%). One patient treated with three or four cycles of cisplatin + paclitaxel + terminated two pregnancies due to non-medical reasons. ifosfamide with a VRT of completion. The pregnancy rate Finally, Zusterzeel et al. evaluated fertility outcomes was 50%. Three women had eight pregnancies; four first in a series of 14 women treated with NACT followed by trimester miscarriages and one therapeutic abortion at 18 VRT and PLND. In a median follow-up period of 50 months, weeks occurred, with a birth rate of 17.6%. All three babies seven women tried to conceive (50%), resulting in four were born prematurely by cesarean delivery (preterm rate patients having six pregnancies, including two first-trimester 100%). miscarriages and three live births born at term. The birth rate Lu et al. successfully treated six women who under- was 42.8% and the preterm rate was 0%. went NACT followed by total LRT. In a median follow-up The overall results, derived from recalculation of all the of 66 months, four women attempted to conceive and two mentioned studies, reported a pregnancy rate of 44%, birth succeeded (pregnancy rate 50%). One patient had a miscar- rate of 45.5%, and preterm birth rate of 43.9%. In a median riage in the first trimester and the other patient underwent a follow-up period of between 23 and 73 months, the applica- cesarean section due to PROMs. The authors reported a birth tion of NACT schemes in 90 patients resulted in 40 pregnan- rate of 25% and a preterm rate of 100%. cies, 41 live births, and 18 preterm deliveries. These results Rendón et al. reported on 23 patients treated with dif- are summarized in Table  4. Substratification by surgical ferent chemotherapy regimens combined with conization. approach after NACT showed a pregnancy rate of 41.9%, C. Ronsini et al. TABLE 4 NACT fertility outcomes Attempted to conceive/all Pregnancy rate Birth rate [% (n)] Preterm rate [% (n)] Mean patients [n/N (%)] [% (n)] FUP (months) De Vincenzo et al. 3/9 (33.3) 66.6 (2) 66.6 (2) 50 (1) 37 12 a Lanowska et al. 7/20 (35) 71.4 (5) 57.1 (4) 50(2) 23 16 b Marchiole et al. 6/17 (28.3) 50 (3) 17.6 (3) 100(3) NR Lu et al. 4/7 (54.1) 50 (2) 25 (1) 100 (1) 66 17 c Rendón et al. NR/23 43.5 (10) 47.8 (11) 63.6 (7) 47 18 d Robova et al., 2014 NR/20 50 (10) 50 (10) 40 (4) 42 Salihi et al. NR/5 20 (1) 20 (1) 0 58 20 e Tesfai et al. NR/15 20 (3) 40 (6) 0 73 22 f Zusterzeel et al. 7/14 (50) 57.1 (4) 42.8 (3) 0 50 Total 90/130 (69.2) 44.4 (40) 45.5 (41) 43.9 (18) FST fertility-sparing treatment, NACT neoadjuvant chemotherapy, FUP follow-up, NR not reported Five women had seven pregnancies Three women had eight pregnancies Seven women delivered 11 babies, three women delivered twice Eight women delivered 10 babies Three women had eight pregnancies Four women had six pregnancies Four studies did not specifically report the number of attempted conceptions; in these cases, the authors considered the total number of patients who underwent successful FST TABLE 5 NACT fertility outcomes by surgical approach preserving fertility remains a crucial challenge to gyneco- logical oncologists. Tumor size is an important prognostic Outcomes Cone VRT LRT ART factor to outline the ideal candidate for FSTs and leads to Pregnancy rate 41.9 (13/31) 55.0 (22/40) 50.0 (2/4) 20.0 (3/15) a clinical approach. In fact, National Comprehensive Can- Birth rate 45.1 (14/31) 50.0 (20/40) 50.0 (2/4) 40.0 (6/15) cer Network (NCCN) guidelines recommend fertility- Preterm rate 61.5 (8/13) 36.0 (9/25) 25.0 (1/4) 0 (0/6) sparing surgery as an option for reproductive-aged women with stage IB1 disease, and emphasize that this approach is Data are expressed as % (n/N) most validated in lesions < 2 cm in size. To date, this group NACT neoadjuvant chemotherapy, VRT vaginal radical trachelectomy, of patients can benefit from several surgical techniques to LRT laparoscopic trachelectomy, ART abdominal radical trachelec- maintain their reproductive potential. These methods include tomy 15 women delivered 21 babies a simple conization to RT with and without lymphadenec- 25,26 tomy, according to general indications for ECC. RT has evolved significantly over the years and several different approaches are available: vaginally, abdominally, or lapa- a birth rate of 45.1%, and a preterm rate of 61.5% for coni- zation; 55.0, 50.0, and 36.0% for VRT, respectively; 50.0, roscopically/robotically. When several procedures seem to offer the same oncologic outcomes, it is crucial to find 50.0, and 25.0% for minimally invasive RT, respectively; and 20.0, 40.0, and 0% for ART, respectively. These results are an acceptable compromise between the best choice of cure and fertility results. VRT or conization/simple trachelectomy summarized in Table 5. have shown encouraging results regarding safety and preg- 2,25 nancy rate. Much more debatable is which strategy to DISCUSSION adopt in the case of ECC ≥ 2 cm. In these patients, VRT is contraindicated due to the high risk of recurrence and Cervical cancer still represents one of the most frequently two main strategies have been proposed: abdominal surgical diagnosed cancers worldwide and the fourth leading cause FST or NACT FST. In a previous review, our group col- of cancer death in women. In the two most recent dec- lected the literature evidence regarding managing this type ades, there has been an increase in patients in their child- of patient, focusing on oncological outcomes. The results of bearing years diagnosed with ECCs due to the widespread this work ended in extremely heterogeneous data that reflect use of cervical cancer screening programs. In this scenario, Fertility‑Sparing Treatment for Early‑Stage Cervical …       current clinical practice. Nevertheless, approaches limited to to minimize gonadotoxic damage using gonadotropin- minimally invasive or vaginal techniques seem to show the releasing hormone (GnRH) agonists that decrease the risk 5 33 highest recurrence rate (RR) and ART seems to be a safer of premature ovarian failure (POF). Unfortunately, none option, according to recent evidence from the LACC trial. of the studies in the literature provided information regard- On the other hand, some literature reported that despite this ing the use of these treatment regimens, which should be oncological safety, ART proved to result in worse pregnancy considered the optimum to ensure the best chance of pre- results. In the reported series, surgical FST showed a preg- serving patients’ fertility. While less radical surgery is a 8 34 nancy rate of between 12.5 and 50%, and only Cao et al. definite trend for ECC < 2 cm, supported by a poor risk published data on fertility outcomes in patients treated with of parametria spr ead in patients with tumors > 2 cm could ART or VRT. The authors confirmed that RR was higher in be a risky strategy. Conceptually, in selected patients treated the VRT group (p = 0.040), and in four of seven recurrences, with NACT, chemotherapy responders with no residual dis- the recurrent sites after VRT were found to be located in the eases, less radical surgery could be a reasonable approach parametrical tissue. Hence, ART could be a safe option for to improve obstetric outcomes once negative lymph node patients with ECC > 2 cm, but this result does not mean it status has been assessed. This leads to another controversial is the best choice to preserve fertility potential. Obstetric point related to NACT and fertility preservation—the time results in ART FST were not encouraging, with a pregnancy of lymphadenectomy. Some authors prefer to perform lym- 29 9,12,18,19,36 rate of 20%. Our results agree, showing pregnancy and phadenectomy before administering chemotherapy, birth rates of 22 and 11%, respectively. excluding node-positive patients from NACT because of the Several factors can affect fertility after ART. First, a high risk of recurrence. On the other hand, post-NACT stag- higher risk of adhesion or a higher frequency of septic ing could have advantages in terms of no delays in treatment morbidities linked to an abdominal approach. The lower initiation and the possibility to sterilize lymph node micro- fertility rate after a laparotomic RT could also be related to metastasis in patients who would otherwise be excluded 14–16 greater disruption of pelvic nerve innervations and abnor- from the procedure. malities of the fallopian tubes. In addition, ART is usually Similarly, in patients with ECC ≥ 2 cm, the modalities of performed with ligation of the uterine arteries that theo- lymphadenectomy are also controversial. Despite the high retically impact on fertility. Nevertheless, a subanalysis risk of lymph node metastasis, using the sentinel lymph conducted by Bentivegna et al. of 735 cases showed that node (SLN) could minimize the risks of lymphadenectomy- 37,38 the infundibulopelvic and ovarian vessels could supply the related morbidity and provide information on the pres- vascular network of the uterine corpus, allowing a pregnancy ence or absence of micrometastases by ultrastaging. The to be achieved. An innovative approach that can extend upstream intent would be to identify patients with positive the possibility of an FST in women with ECC > 2 cm was lymph nodes to exclude them from the FST pathway, regard- NACT. In this work, we reported the fertility results of 90 less of the ART or NACT approach. Therefore, we believe patients treated with NACT followed by surgical proce- systematic or SLN-limited lymphadenectomy should pre- dures (simple conization, ART, or VRT). The pregnancy cede FST and be part of the standard diagnostic pathway of and birth rates were higher compared with those observed patients with ECC ≥ 2 cm. after an upfront RT, i.e. 44 and 45% versus 22% and 11 Another consideration to be made relates to the pregnancy (p < 0.001). Furthermore, it should be pointed out that in rate. No studies, regardless of approach, have reported on the NACT group, some authors reported high pregnancy whether or not patients were directed to specialized in vitro and birth rates in patients with the use of conization or VRT fertilization (IVF) centers. Cancer patients, all the more so 9,17 after NACT. if they have undergone NACT cycles, need to be assisted in This is easily understood if we focus on the surgical their procreation journey. On the other hand, patients should implications on fertility. The use of NACT is conceived to be framed from a fertility point of view before being referred minimize surgical aggressiveness. Combining NACT with to FST. None of the reported studies performed an anti-mul- ART means adding the surgical impact of pelvic anatomy to lerian hormone (AMH) assay prior to FST. Currently, the chemotherapeutic damage to the ovaries. However, patients main guidelines give 40 years of age as the limit to FST, treated with simple conization or VRT did not present opti- which may not reflect the patient’s reproductive capacity at mal fertility outcomes. This finding can be partly explained all. This biased view of the problem is perhaps related to by considering that the leading cause of obstetrical failure is the specifics of individual teams, which, dealing primarily related to cervical stenosis, lack of cervical mucus, and the with oncologic pathology, may need to be more trained in length of the cervix or isthmus. On the other hand, the gon- obstetrics and medically assisted procreation issues. There- adotoxicity exerted by chemotherapy should be mentioned. fore, FST treatments should be multidisciplinary. Drugs such as platinum and paclitaxel are considered at Finally, it is worth considering that in this review, the intermediate risk of gonadotoxicity. There are strategies overall birth rate of 14.4 % is related to a preterm rate of C. Ronsini et al. 37%. In particular, premature delivery is often caused by obstetric care, and mode of delivery. All three confounders 9,12,15 PROM, likely caused by clinical or subclinical chorio- have implications in fertility outcomes. amnionitis. Hence, although the fertility outcome is prom- ising, premature birth or first-trimester fetal loss remains CONCLUSION a main problem. The main explanation is likely related to a shortened cervix length and potential exposure of the Fertility-sparing treatment in patients with ECC ≥ 2 cm amniotic membrane to the bacteria of the vagina, which remains a challenge, especially considering the significant can lead to an increase in infections. The literature reported heterogeneity in clinical management. This becomes even several strategies to decrease this risk, such as prophylactic more challenging when the point of evaluation in best treat- 10,14 41 cerclage and the Saling procedure, a total occlusion of ments should include oncological and obstetrical outcomes the uteri cervix using vaginal mucosa. Vice versa, consider- together. Nevertheless, NACT followed by minimally inva- ing cerclage might result in bladder irritation, pelvic infec- sive surgery seems to be a reasonable compromise, from an 42,43 tion, and stenosis, some groups abandoned performing obstetrical point of view. Still, standardization of treatments a prophylactic cerclage and preferred to monitor the length remains a distant goal due to the many factors involved in 44,45 of the cervix during pregnancy using T VU and placed evaluating these patients. Moreover, guidelines on the man- a cerclage when necessary. However, a routine cerclage agement of pregnancy after FST are lacking and future stud- during ART may justify the lower percentage of preterm ies are needed to investigate the best strategy to reduce the births in the surgical group of patients, even if the low num- high risk of preterm delivery and PROMs. ber of births makes it obligatory to look at these data with skepticism. SUPPLEMENTARY INFORMATION The online version con- tains supplementary material available at https:// doi. or g/ 10. 1245/ Undeniable is that when a pregnancy occurs in women s10434- 023- 13542-z. who underwent an FST, this pregnancy is at high risk. A standardized follow-up modality should be applied to AUTHOR CONTRIBUTIONS CR: Conceptualization and meth- improve obstetrical outcomes in pregnant women after FST. odology. MCS: Data curation and writing – original draft. RM: Data In addition, it is interesting to note that considering only curation. FP: Data curation. LC: Review and editing. PdF: Review and editing. NC: Validation. series with available data, only 35% of women who com- pleted FST tried to conceive during follow-up. In their work, FUNDING Open access funding provided by Università degli Studi Carter et al. showed that many women who have undergone della Campania Luigi Vanvitelli within the CRUI-CARE Agreement. an RT experience distress that persists for up 6 months No specific funding was disclosed. in terms of sexual disorders. In fact, pregnancy concerns DISCLOSURE Carlo Ronsini, Maria Cristina Solazzo, Rossella appear to increase after FST, leading to lower fertility out- Molitierno, Pasquale de Franciscis, Francesca Pasanisi, Luigi Cobel- comes. However, studies investigating factors that affect a lis, and Nicola Colacurci have made no disclosures. women’s choice to conceive are lacking, underestimating a crucial aspect of the physical and emotional impact on OPEN ACCESS This article is licensed under a Creative Commons patients undergoing FST. Future studies in this area are Attribution 4.0 International License, which permits use, sharing, adap- needed to offer these women more complete and personal- tation, distribution and reproduction in any medium or format, as long ized counseling before treatments. as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes Fertility outcomes should only be considered in light were made. The images or other third party material in this article are of the comparable oncological safety of the different tech- included in the article’s Creative Commons licence, unless indicated niques. This could be the truth for ART and NACT, as previ- otherwise in a credit line to the material. If material is not included in ously published by our group. the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will The strengths of this study lie in its systematic nature and need to obtain permission directly from the copyright holder. To view a rigor of the research, collecting the largest number of FSTs copy of this licence, visit http://cr eativ ecommons. or g/licen ses/ b y/4.0/ . in patients with ECC >2 and adding the most possible infor- mation on obstetrical outcomes. However, the main weak- ness of the study is that most of the analyzed series focused REFERENCES on oncological outcomes, and only some of them detailed the total number of patients wishing to become pregnant, as 1. Quinn MA, Benedet JL, Odicino F, et al. carcinoma of the cervix well as every detail about each pregnancy. It almost seems uteri. Int J Gynaecol Obstet. 2006;95(Suppl 1):S43–103. that fertility outcomes have always been regarded as sec- 2. Plante M, Gregoire J, Renaud MC, Roy M. The vaginal radical trachelectomy: an update of a series of 125 cases and 106 preg- ondary to oncological outcomes. This is understandable nancies. Gynecol Oncol. 2011;121(2):290–7. https://d oi.o rg/1 0. in the hierarchy of these concepts, but makes it difficult to 1016/j. ygyno. 2010. 12. 345. obtain standardized information on the mode of conception, Fertility‑Sparing Treatment for Early‑Stage Cervical …       3. van Kol KGG, Vergeldt TFM, Bekkers RLM. Abdominal radical 17. Rendón GJ, Lopez Blanco A, Aragona A, et al. Oncological and trachelectomy versus chemotherapy followed by vaginal radical obstetrical outcomes after neo-adjuvant chemotherapy followed trachelectomy in stage 1B2 (FIGO 2018) cervical cancer. A sys- by fertility-sparing surgery in patients with cervical cancer ≥2 tematic review on fertility and recurrence rates. Gynecol Oncol. cm. Int J Gynecol Cancer. 2021;31(3):462–7. https://doi. or g/10. 2019;155(3):515–21. https:// doi. org/ 10. 1016/j. ygyno. 2019. 09. 1136/ ijgc- 2020- 002076. 025. 18. Robova H, Halaska MJ, Pluta M, et al. Oncological and preg- 4. Nezhat C, Roman RA, Rambhatla A, Nezhat F. Reproduc- nancy outcomes after high-dose density neoadjuvant chemo- tive and oncologic outcomes after fertility-sparing surgery for therapy and fertility-sparing surgery in cervical cancer. Gynecol early stage cervical cancer: a systematic review. Fertil Steril. Oncol. 2014;135(2):213–6. https:// doi. or g/ 10. 1016/j. y gyno. 2020;113(4):685–703. https:// doi. org/ 10. 1016/j. fertn stert. 2020. 2014. 08. 021. 02. 003. 19. Salihi R, Leunen K, van Limbergen E, Moerman P, Neven P, 5. Ronsini C, Solazzo MC, Bizzarri N, et al. Fertility-sparing treat- Vergote I. Neoadjuvant chemotherapy followed by large cone ment for early-stage cervical cancer ≥ 2 cm: a problem with resection as fertility-sparing therapy in stage IB cervical cancer. a thousand nuances—a systematic review of oncological out- Gynecol Oncol. 2015;139(3):447–51. https:// doi. org/ 10. 1016/j. comes. Ann Surg Oncol. 2022;29(13):8346–58. https:// doi. org/ ygyno. 2015. 05. 043. 10. 1245/ s10434- 022- 12436-w. 20. Tesfai FM, Kroep JR, Gaarenstroom K, et al. Fertility-sparing 6. Page MJ, Moher D, Bossuyt PM, et al. PRISMA 2020 explana- surgery of cervical cancer > 2 cm (International Federation of tion and elaboration: updated guidance and exemplars for report- Gynecology and Obstetrics 2009 stage IB1-IIA) after neoadju- ing systematic reviews. BMJ. 2021;372:n160. https://doi. or g/10. vant chemotherapy. Int J Gynecol Cancer. 2020;30(1):115–21. 1136/ bmj. n160.https:// doi. org/ 10. 1136/ ijgc- 2019- 000647. 7. Kansagara D, O’Neil M, Zakher B, Motu’apuaka M, Paynter 21. Wethington SL, Sonoda Y, Park KJ, et al. Expanding the indica- R, et al. Quality Assessment Criteria for Observational Stud- tions for radical trachelectomy a report on 29 patients with stage ies, Based on the Newcastle-Ottawa Scale. 2017. Available at: IB1 tumors measuring 2 to 4 centimeters. Int J Gynecol Cancer. https://www .ncbi. nlm. nih. go v/book s/NBK47 6448/ t able/appc. t4 . 2013;23(6):1092–8. https:// doi. or g/ 10. 1097/ IGC. 0b013 e3182 Accessed 27 Mar 2022. 96034e. 8. Cao DY, Yang JX, Wu XH, et al. Comparisons of vaginal and 22. Zusterzeel PLM, Aarts JWM, Pol FJM, Ottevanger PB, van abdominal radical trachelectomy for early-stage cervical can- Ham MAPC. Neoadjuvant chemotherapy followed by vagi- cer: preliminary results of a multi-center research in China. Br nal radical trachelectomy as fertility-preserving treatment for J Cancer. 2013;109(11):2778–82. https:// doi. org/ 10. 1038/ bjc. patients with FIGO 2018 stage 1B2 cervical cancer. Oncolo‑ 2013. 656. gist. 2020;25(7):e1051–9. https://doi. or g/10. 1634/ t heoncolog is t. 9. de Vincenzo R, Ricci C, Fanfani F, et al. Neoadjuvant chemo-2020- 0063. therapy followed by conization in stage IB2–IIA1 cervical cancer 23. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: larger than 2 cm: a pilot study. Fertil Steril. 2021;115(1):148–56. GLOBOCAN estimates of incidence and mortality worldwide for https:// doi. org/ 10. 1016/j. fertn stert. 2020. 07. 006. 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209– 10. Deng X, Zhang Y, Li D, et al. Abdominal radical trachelectomy 49. https:// doi. org/ 10. 3322/ caac. 21660. guided by sentinel lymph node biopsy for stage IB1 cervical 24. Koh WJ, Abu-Rustum NR, Bean S, et al. Cervical cancer, version cancer with tumors > 2 Cm. Oncotarget. 2017;8(2):3422–9. 3.2019, NCCN clinical practice guidelines in oncology. J Natl 11. Guo J, Zhang Y, Chen X, Sun L, Chen K, Sheng X. Surgical and Compr Cancer Netw. 2019;17(1):64–84. https://doi. or g/10. 6004/ oncologic outcomes of radical abdominal trachelectomy versus jnccn. 2019. 0001. hysterectomy for stage IA2-IB1 cervical cancer. J Minim Inva‑ 25. Plante M. Evolution in fertility-preserving options for early- sive Gynecol. 2019;26(3):484–91. https://d oi.o rg/1 0.1 016/j.j mig. stage cervical cancer: radical trachelectomy, simple trache- 2018. 06. 006. lectomy, neoadjuvant chemotherapy. Int J Gynecol Cancer. 12. Lanowska M, Mangler M, Speiser D, et al. Radical vaginal tra- 2013;23(6):982–9. https:// doi. or g/ 10. 1097/ IGC. 0b013 e3182 chelectomy after laparoscopic staging and neoadjuvant chemo- 95906b. therapy in women with early-stage cervical cancer over 2 cm: 26. Bentivegna E, Gouy S, Maulard A, Chargari C, Leary A, Morice oncologic, fertility, and neonatal outcome in a series of 20 P. Oncological outcomes after fertility-sparing surgery for cervi- patients. Int J Gynecol Cancer. 2014;24(3):586–93. https:// doi. cal cancer: a systematic review. Lancet Oncol. 2016;17(6):e240– org/ 10. 1097/ IGC. 00000 00000 000080. 53. https:// doi. org/ 10. 1016/ S1470- 2045(16) 30032-8. 13. Li J, Wu X, Li X, Ju X. Abdominal radical trachelectomy: is it 27. Covens A, Rosen B, Murphy J, et al. How important is removal safe for IB1 cervical cancer with tumors ≥ 2 cm. Gynecol Oncol. of the parametrium at surgery for carcinoma of the cervix? 2013;131(1):87–92. https:// doi. or g/ 10. 1016/j. y gyno. 2013. 07. Gynecol Oncol. 2002;84(1):145–9. https://doi. or g/10. 1006/ gyno. 079.2001. 6493. 14. Lintner B, Saso S, Tarnai L, et al. Use of abdominal radical tra- 28. Di Donato V, Caruso G, Sassu CM, et al. Fertility-sparing sur- chelectomy to treat cervical cancer greater than 2 cm in diameter. gery for women with stage I cervical cancer of 4 cm or larger: a Int J Gynecol Cancer. 2013;23(6):1065–70. https:// doi. org/ 10. systematic review. J Gynecol Oncol. 2021;32(6):e83. https://doi. 1097/ IGC. 0b013 e3182 95fb41.org/ 10. 3802/ jgo. 2021. 32. e83. 15. Lu Q, Zhang Y, Wang S, et al. Neoadjuvant intra-arterial chem- 29. Canis MJ, Triopon G, Daraï E, et al. Adhesion prevention after otherapy followed by total laparoscopic radical trachelectomy myomectomy by laparotomy: a prospective multicenter compara- in stage IB1 cervical cancer. Fertil Steril. 2014;101(3):812–7. tive randomized single-blind study with second-look laparos- TM https:// doi. org/ 10. 1016/j. fertn stert. 2013. 12. 001. copy to assess the effectiveness of PREVADH . Eur J Obstet 16. Marchiolè P, Ferraioli D, Moran E, et  al. NACT and laparo- Gynecol Reprod Biol. 2014;178:42–7. https://doi. or g/10. 1016/j. scopic-assisted radical vaginal trachelectomy in young patients ejogrb. 2014. 03. 020. with large (2–5 cm) high risk cervical cancers: safety and obstet- 30. Donnez J. CO laser laparoscopy in infertile women with endo- rical outcome. Surg Oncol. 2018;27(2):236–44. https:// doi. org/ metriosis and women with adnexal adhesions. Fertil Steril. 10. 1016/j. suronc. 2018. 04. 006. 1987;48(3):390–4. h tt p s: / / d oi . o r g / 1 0. 1 01 6/ S 00 15 - 0 28 2 (1 6 ) 59404-7. C. Ronsini et al. 31. Bentivegna E, Maulard A, Pautier P, Chargari C, Gouy S, Morice the detection of sentinel lymph node metastasis in endome- P. Fertility results and pregnancy outcomes after conservative trial cancer patients: a retrospective cohort comparison. Int J treatment of cervical cancer: a systematic review of the litera- Gynecol Cancer. 2020;30(3):372–7. https:// doi. or g/ 10. 1136/ ture. Fertil Steril. 2016;106(5):1195-1211.e5. https://do i.o rg/1 0. ijgc- 2019- 000937. 1016/j. fertn stert. 2016. 06. 032. 40. Boss EA, van Golde RJT, Beerendonk CCM, Massuger LFAG. 32. Plante M. Evolution in fertility-preserving options for early-stage Pregnancy after radical trachelectomy: a real option? Gynecol cervical cancer. Int J Gynecol Cancer. 2013;23(6):982–9. https:// Oncol. 2005;99(3):S152–6. https:// doi. or g/ 10. 1016/j. y gyno. doi. org/ 10. 1097/ IGC. 0b013 e3182 95906b.2005. 07. 071. 33. Sonmezer M, Oktay K. Fertility preservation in young women 41. Saling E. Prevention of habitual abortion and prematurity undergoing breast cancer therapy. Oncologist. 2006;11(5):422– by early total occlusion of the external os uteri. Eur J Obstet 34. https:// doi. org/ 10. 1634/ theon colog ist. 11-5- 422. Gynecol Reprod Biol. 1984;17(2–3):165–70. https:// doi. org/ 10. 34. Badawy A, Elnashar A, El-Ashry M, Shahat M. Gonadotropin-1016/ 0028- 2243(84) 90140-0. releasing hormone agonists for prevention of chemotherapy- 42. Plante M, Renaud MC, Roy M. Radical vaginal trachelectomy: induced ovarian damage: prospective randomized study. Fertil a fertility-preserving option for young women with early stage Steril. 2009;91(3):694–7. https:// doi. or g/ 10. 1016/j. fer tn s ter t. cervical cancer. Gynecol Oncol. 2005;99(3):S143–6. https://doi. 2007. 12. 044.org/ 10. 1016/j. ygyno. 2005. 07. 067. 35. Lanowska M, Morawietz L, Sikora A, et al. Prevalence of lymph 43. Pareja FR, Ramirez PT, Borrero FM, Angel CG. Abdominal radi- nodes in the parametrium of radical vaginal trachelectomy (RVT) cal trachelectomy for invasive cervical cancer: a case series and specimen. Gynecol Oncol. 2011;121(2):298–302. https://doi. or g/ literature review. Gynecol Oncol. 2008;111(3):555–60. https:// 10. 1016/j. ygyno. 2011. 01. 011.doi. org/ 10. 1016/j. ygyno. 2008. 07. 019. 36. Vercellino GF, Piek JMJ, Schneider A, et al. Laparoscopic lymph 44. Bouchard-Fortier G, Reade CJ, Covens A. Non-radical surgery node dissection should be performed before fertility preserv- for small early-stage cervical cancer. Is it time? Gynecol Oncol. ing treatment of patients with cervical cancer. Gynecol Oncol. 2014;132(3):624–7. https:// doi. or g/ 10. 1016/j. y gyno. 2014. 01. 2012;126(3):325–9. https:// doi. or g/ 10. 1016/j. y gyno. 2012. 05. 037. 033. 45. Kasuga Y, Miyakoshi K, Nishio H, et al. Mid-trimester residual 37. Restaino S, Ronsini C, Finelli A, Perrone E, Scambia G, Fanfani cervical length and the risk of preterm birth in pregnancies after F. Role of blue dye for sentinel lymph node detection in early abdominal radical trachelectomy: a retrospective analysis. BJOG. endometrial cancer. Gynecol Surg. 2017;14(1):23. https:// doi. 2017;124(11):1729–35. https:// doi. or g/ 10. 1111/ 1471- 0528. org/ 10. 1186/ s10397- 017- 1026-0. 14688. 38. Ronsini C, de Franciscis P, Carotenuto RM, Pasanisi F, Cobellis L, Colacurci N. The oncological implication of sentinel lymph Publisher’s Note Springer Nature remains neutral with regard to node in early cervical cancer: a meta-analysis of oncological jurisdictional claims in published maps and institutional affiliations. outcomes and type of recurrences. Medicina. 2022;58(11):1539. https:// doi. org/ 10. 3390/ medic ina58 111539. 39. Fanfani F, Monterossi G, di Meo ML, et  al. Standard ultra- staging compared to one-step nucleic acid amplification for

Journal

Annals of Surgical OncologySpringer Journals

Published: Sep 1, 2023

Keywords: Cervical cancer; Fertility sparing treatment; Trachelectomy; Birth rat; Pre-term rate; Pregnancy rate

There are no references for this article.