Laparoscopic ovarian transposition prior to pelvic radiation in young women with anorectal malignancies: a systematic review and meta‐analysis of prevalence

Young women undergoing radiotherapy (RT) for pelvic malignancies are at risk of developing premature ovarian insufficiency. Ovarian transposition (OT) aims to preserve ovarian function in these patients. However, its role in anorectal malignancy has yet to be firmly established. The aim of this review was to determine the effectiveness of laparoscopic OT in preserving ovarian function in premenopausal women undergoing neoadjuvant pelvic RT for anorectal malignancies.

Fertility preservation in patients with anorectal malignancy is becoming an increasingly important issue, owing to the increasing incidence of these diseases amongst young patients [5][6][7]. Several reports have identified that fertility is of great importance to young cancer patients [8][9][10]. In addition to fertility concerns, survivors also experience significant side effects related to long-term oestrogen deprivation, including osteopenia and osteoporosis, cardiovascular disease and all-cause death [11][12][13]. Ovarian function is variably defined in the literature; typically, surveillance is done through a menstrual history, endocrine levels and/or pregnancy rates [4]. The exact incidence of POI after RT is unknown, given the variability in treatment regimens for different malignancies and individual patient factors such as age [3,[14][15][16][17][18]. However, previous studies have calculated that the sterilizing dose (i.e., the dose causing ovarian failure in 97.5% of treated patients) is 14-18 Gy in women of reproductive age [19].
Because the RT dose for rectal and anal malignancies is 45 Gy or greater, this patient population is at high risk of ovarian failure [1,2].
Numerous strategies aimed at preserving ovarian function in these patients have been developed and implemented. One such strategy is ovarian transposition (OT), which involves relocation of the ovaries out of the planned radiation field. Laparoscopic OT has been well studied in gynaecological malignancies and Hodgkin's lymphoma [20][21][22][23][24][25][26]. However, its role in anorectal malignancies has yet to be firmly established. This systematic review and meta-analysis aims to synthesize current evidence on the effectiveness of laparoscopic OT in preserving ovarian function in premenopausal women undergoing pelvic RT for anorectal malignancy.

Search strategy
A comprehensive search strategy covering the period from database inception through May 2022 was conducted. Searched databases included MEDLINE, Embase and the Cochrane Central Register of Controlled Trials (CENTRAL). Search terms included 'rectal neoplasms', 'fertility preservation', 'ovarian transposition', 'ovarian pexy' and more (Appendix S1). The references of included studies were also searched to ensure all relevant articles were included. This systematic review is reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [27]. A review protocol was registered a priori in the International Prospective Register of Systematic Reviews (CRD42022335403). This study did not require local ethics review board approval.

Eligibility criteria
Articles were eligible for inclusion if they were randomized controlled trials, cohort studies, case-control studies or case series examining the use of OT in young women undergoing pelvic radiation for an anorectal malignancy (i.e., rectal adenocarcinoma, anal squamous cell carcinoma, anal gland adenocarcinoma). Articles were only included if they reported postoperative ovarian function.
Conference abstracts and unpublished data were eligible for inclusion. The exclusion criteria were as follows: (1) undergoing pelvic radiation for a non-anorectal malignancy (e.g., endometrial, cervical); (2) non-human studies; (3) systematic reviews, meta-analyses, case reports, letters to the editor, editorials and any other study that did not report primary data. Studies were not excluded based on language alone.

Study selection
Two reviewers independently screened the titles and abstracts through a standardized pre-piloted form. Discrepancies that occurred at the title and abstract screening phase were resolved by inclusion in the study. All included studies were then screened based on full-text review for final inclusion in the present study. At the full-text screening stage, discrepancies were resolved by consensus between the two reviewers. If disagreement persisted, a third independent reviewer was consulted.

What does this paper add to the literature?
This is the first systematic review evaluating laparoscopic ovarian transposition for young female patients undergoing pelvic radiotherapy for anorectal malignancies. Data, although low quality, suggest that this is safe and may be efficacious at preserving fertility. Further study is warranted given the increasing prevalence of anorectal malignancies in young women.

Risk of bias analysis
Risk of bias for each included observational study was assessed using the Methodological Index for Non-Randomized Studies (MINORS) tool [36]. Two reviewers assessed the quality of each study independently. Discrepancies for data extraction and risk of bias were discussed amongst reviewers until consensus was reached.

Statistical analysis
All statistical analyses and meta-analyses were performed on STATA version 15.1 (StataCorp) and DataParty (Hamilton, Ontario).
A DerSimonian and Laird inverse variance random-effects meta-analysis of proportions was used to generate the overall effect size of each outcome along with the respective 95% CIs to confirm the effect size estimate. Mean and standard deviation was estimated for studies that only reported median and interquartile range using the method described by Wan et al. [37]. For studies that did not report a measure of central tendency, authors were contacted for missing data. Data were presumed to be unreported if no response was received from study authors within 2 weeks from the index point of contact. Missing SD data were then calculated according to the prognostic method [38]. Assessment of heterogeneity was completed using the inconsistency (I 2 ) statistic. An I 2 greater than 50% was considered to represent considerable heterogeneity [39]. A systematic narrative review was provided for each outcome. A post hoc subgroup analysis based on study type was performed for the primary outcome.

Study characteristics
From 207 relevant citations, 10 observational studies (seven retrospective, three prospective) met the inclusion criteria [28-35, 40, 41]. A PRISMA flow diagram of the study selection process is presented in Figure 1.

Treatment characteristics
All the included studies that reported operative approach for  Table 2.
Two of the included studies did not report their definition of ovarian failure [40,41]. The timing in assessment of ovarian function varied. Most commonly, ovarian function was measured at 6 months after RT or 12 months after RT [28,29,31,32,35]. Four studies did not specify when ovarian function was measured [33,34,40,41].
In the only comparative study in this review, Hilal et al. [29] found that 76% of patients with locally advanced rectal cancer undergoing OT prior to neoadjuvant therapy had preserved ovarian function at 12 months' follow-up, compared to 0% of patients not undergoing OT (P < 0.001) [29]. The median ovarian radiation dose was 1.7 Gy in patients undergoing OT, compared to a median dose of 44.8 Gy in patients not undergoing OT (P < 0.001). On regression analysis, having undergone OT was significantly associated with higher rates of preserved ovarian function (P < 0.001). Overall, six pregnancies (3.14%) were reported: one with premature delivery in Hilal et al. [29], one successful pregnancy followed by a miscarriage 2 years later in Elizur et al. [41] and three in Gareer et al. [40].

Postoperative morbidity
Seven of the included studies reported 30-day postoperative morbidity [28, 30-35, 40, 41]. Upon pooling of these studies, there was only one patient (1.2%) who experienced a postoperative complication. In the series published by Sioulas et al. one patient experienced aspiration pneumonia postoperatively [30]. There were no reported intra-operative complications.

Risk of bias
The mean MINORS score for single-armed studies was 9.7 (range 7-12;

DISCUSS ION
This is the first systematic review to provide an overview of the efficacy of OT in patients undergoing pelvic RT for anorectal malignancies. In this review, the incidence of preserved ovarian function after OT was 66.9% (95% CI 55.0%-79.0%, I 2 = 43%). Only one study reported a postoperative complication, suggesting that this is a safe procedure. These findings were at risk of bias due to the observational nature of the data, lack of prospective sample size calculation and lack of outcome assessor blinding, as reflected by the low mean MINORS score.
The ovaries are extremely radiosensitive: a dose of less than 2 Gy causes depletion of 50% of immature oocytes [43]. Moreover, ovarian tissue sensitivity to radiation increases with age of the patient [14][15][16][17][18][19]. Hilal et al. and Sioulas et al. found increased incidence of POI after OT in patients over 40 years old [29,30]. Radiation dose is also an important risk factor for POI [3,41]. The final location of the transposed ovary is an important factor in the success of OT [15,46,47]. The transposed ovaries should be secured at least 4 cm above the upper limit of the irradiated field or 1.5 cm above the iliac crest [46,47]. However, the transposed ovaries may potentially migrate to a lower position, thus increasing the exposure to radiation [15,22,26]. To mitigate this risk, the ovaries should be secured at an adequate distance from the RT field, and delays between the procedure and RT should be minimized [15,26]. In the included studies, the ovaries were secured at or above the level of the anterior superior iliac spine. Also, caution must be taken to avoid excessive stretching, torsion or kinking of the infundibulopelvic ligaments which puts the ovaries at risk of vascular compromise [15,22].
Diminished blood supply to the ovaries may be a cause of POI after OT [15,48,49].
Risks specific to OT include injury to ovarian blood vessels, benign ovarian cysts, chronic pain and metastasis in the transposed ovaries [7,21,[50][51][52]. The morbidity rate in the present review was 1.2%, with one event of postoperative aspiration pneumonia [30].
Theoretically, there is concern for the delay in delivering RT and
Shylasree and Patil and Sioulas et al. both found no clinically significant delay to cancer treatment [28,30]. In addition, it is important to recognize the limitations in fertility outcomes with OT. Radiation to the uterus left in situ may adversely affect prospects for pregnancy [19,53,54]. Despite these risks, six pregnancies are reported amongst the included studies [29,40,41].
Other methods of fertility preservation include embryo cryopreservation, oocyte cryopreservation and ovarian cortex cryopreservation. Embryo cryopreservation is most successful, with cumulative pregnancy rates up to 60% [44,55]. One drawback is the need for a fertile male partner or donor sperm. Oocyte cryopreservation circumvents this prerequisite. A recent study reported a live birth rate of 15%, 60.5% and 85% for women under 36 years old who had five, 10 and 15 vitrified eggs, respectively [56]. Although these results are promising, a major pitfall for both embryo and oocyte cryopreservation is the requirement of ovarian stimulation, which can delay cancer treatment by several weeks [44,56,57]. Furthermore, these patients are still at risk for POI as the ovaries are left in the pelvis [58].
There is currently no consensus on the optimal fertility preservation strategy for rectal cancer [58]. Further research is necessary to assess long-term outcomes in fertility preservation techniques for F I G U R E 2 Forest plot corresponding with a meta-analysis of proportions of preserved ovarian function. Additionally, these surgeries may adversely affect fertility by causing adhesions and influencing tubal patency, thus representing a possible source of residual confounding in our observed results [59]. Next, four of the included studies had insufficient follow-up data, which may not be adequate to answer our clinical question [34,35,40].
Finally, nine of the 10 studies were single-armed, which precluded the ability to perform a pairwise meta-analysis and allow for objective comparison between OT and non-OT patients. Without comparative data, demonstrating superiority of this technique over the current standard of care is not possible. This review highlights the need for randomized controlled trials with objective measurements of ovarian function and adequate long-term follow-up.

CON CLUS ION
The findings of this review demonstrate that OT in premenopausal patients undergoing pelvic radiation for anorectal malignancies may contribute to preserved ovarian function in up to two-thirds of patients. OT might be an effective and safe technique at reducing ovarian exposure to RT. However, the current data are of very low quality.
Randomized controlled trials with objective measurements of ovarian function and long-term follow-up are required to fully investigate the outcomes of OT in this patient population. Future studies should also compare the effectiveness of OT and other fertility-preserving options for patients desiring future pregnancies.

ACK N O WLE D G E M ENTS
None.

CO N FLI C T O F I NTER E S T S TATEM ENT
The authors have no related conflicts of interest to declare.

DATA AVA I L A B I L I T Y S TAT E M E N T
Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

E TH I C S S TATEM ENT
This study did not require local ethics review board approval.

PATI ENT CO N S ENT S TATEM ENT
This study did not require consent from included patient data.

PER M I SS I O N TO R EPRO D U CE M ATER N A L FRO M OTH ER SO U RCE S
Not applicable.