Introduction

Cervical cancer is the fourth most frequently diagnosed cancer in women worldwide, with 570,000 new cases in 2018 [1]. It has a high survival rate in developed countries, with the USA reporting a 5-year survival rate of 66% across stages, and 92% in localized disease [2]. Micro-invasive disease can be surgically treated with simple hysterectomy, cervical conisation, or simple trachelectomy, with the latter two preserving fertility. Early disease is commonly treated with radical hysterectomy (RH). If risk factors on the pathology specimen are present, adjuvant treatment with radiotherapy (RT) +/− chemotherapy (CT) is offered. For locally advanced disease, chemoradiotherapy (CRT) followed by brachytherapy (BT) is standard treatment. For women diagnosed with metastatic disease, CT +/− RT is offered to palliate symptoms [3,4,5,6]. Treatment for cervical cancer is often tailored to the individual, taking into account factors such as tumor stage, performance status, co-morbidity, personal preferences, frailty, and age [7].

Evidence across pooled treatments for cervical cancer indicates that women may experience a range of disease and treatment-related symptoms and side effects including incontinence, rectal bleeding, diarrhea, and decreased libido [4], which can negatively impact women’s overall health-related quality of life (HRQL). HRQL is widely accepted as “a multidimensional construct encompassing perceptions of both positive and negative aspects of dimensions, such as physical, emotional, social, and cognitive functions, as well as the negative aspects of somatic discomfort and other symptoms produced by a disease or its treatment” [8, 9]. Key aspects of this definition indicate that HRQL is a subjective phenomenon, multi-dimensional, and best assessed from patient-reports. Therefore, HRQL is commonly assessed using patient-reported outcomes (PROs), that is, “any report of the status of a patient’s health condition that comes directly from the patients, without interpretation of the patient’s response by a clinician or anyone else” [9, 10]. PROs can be divided into proximal effects, i.e., direct effects of the disease and side effects of treatment; distal effects, i.e., consequent impacts on core functioning domains (e.g., physical, social, emotional); and in turn, global HRQL. Given the high survival rate, better understanding of women’s HRQL during and after treatment is of major clinical importance, since it could facilitate shared decision-making and assist in delivering timely, tailored supportive care interventions to address HRQL issues. The aim of this systematic review was to synthesize all available evidence about the effects of each contemporary treatment modality for any stage cervical cancer on all dimensions of women’s HRQL, including symptoms, functioning, and global HRQL, before treatment and during short- and long-term follow-up.

Methods

This review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [11]. The following electronic databases were searched using the OVID web gateway: MEDLINE, Embase, PsycINFO, and CINAHL from January 2000 to September 2019, as earlier publications would not reflect current treatments. The search strategy is outlined in supplementary 1. Non-English publications and conference papers were excluded. A manual search of the references to the identified literature from the four databases, including relevant systematic reviews, was conducted. Authors of included studies who had published > 2 papers in the field were searched to identify further research not located through other sources.

Study selection and eligibility criteria

Titles and abstracts were reviewed against three preliminary screening criteria:

  1. 1.

    Study sample was women diagnosed with and treated for cervical cancer; and

  2. 2.

    Study included PROs as a primary or secondary endpoint; and

  3. 3.

    Quantitative study designs that included PROs assessed at baseline before treatment and at least one follow-up assessment during or post-treatment. Relevant review papers were also obtained.

If all three criteria were met or relevance was ambiguous, full texts were obtained and reviewed; the following inclusion criteria were applied:

  1. 1.

    Study sample was clearly defined as women diagnosed with and treated for cervical cancer or mixed samples if results for women with cervical cancer were reported separately; and

  2. 2.

    The sample of patients was ≥ 30; and

  3. 3.

    PROs were collected using a standardized and validated instrument; and

  4. 4.

    65% of study patients reported baseline PROs; and

  5. 5.

    If different treatment modalities were used, results had to be reported per treatment modality

Two researchers independently assessed titles, abstracts, and full texts against the eligibility criteria. Disagreements were resolved in team discussions.

Quality assessment

Study quality and quality of PRO reporting were assessed by two reviewers independently using the Standard Quality Assessment Criteria for Evaluating Primary Research Papers—QualSyst and the CONSORT-PRO [12, 13]. Quality assessment was cross-checked for consistency. Each quality criterion was assessed as being met and scored as fully, partially, or not met. If unsure, the item was resolved with a third reviewer. Total quality scores were calculated as a percentage of the total possible score.

Data extraction and analysis

Data from the included studies were extracted into a predefined data extraction table. Data extraction was undertaken by two reviewers independently and was cross-checked for consistency. Discrepancies were checked by a third reviewer. We defined two time periods:

  1. 1.

    Immediately after treatment (0–3 months post-treatment)

  2. 2.

    Post-treatment long-term effects (> 3 months–5 years)

Included studies were classified according to pre-specified treatment groups (supplementary 2). These treatment groups were based on international guidelines and discussions with the research team. Results for studies with treatment subgroup analysis were included in two treatment categories.

Results

The search identified 4983 papers of which 29 papers met eligibility criteria, reporting on 23 individual studies (Fig. 1). All study designs, methods, and PROs results are summarized in Table 1. Thirteen papers (48%) reported on a patient cohort comparing different treatments [14,15,16,17,18,19,20,21,22,23,24,25,26]. Ten papers (31%) reported on a patient cohort undergoing a single treatment [27,28,29,30,31,32,33,34,35,36]; five of these reported on the EMBRACE study cohort [29, 30, 33, 35, 36]. Only six papers (21%) were randomized controlled trials, all of which evaluated systemic therapy for advanced disease [37,38,39,40,41,42]. All included studies were conducted before the update of the Féderation Internationale de Gynécologie et d’Obstétrique (FIGO) staging system in 2018 [5, 6].

Fig. 1
figure 1

Flowchart of included studies

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Table 1 Summary of characteristics of included studies
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Study quality

Individual study quality scores ranged from 50 to 91% (Fig. 2a). Only two studies met all quality criteria at least partially [37, 40]. The proportions of the included papers meeting each quality criterion are listed in Fig. 2b. Overall, 93% (27/29 papers) reported relevant PRO domains, and 52% (15/29 papers) reported all PRO domains measured. Only 24% (7/29 papers) adjusted for multiple testing, and 21% (6/29) reported approaches for handling missing data.

Fig. 2
figure 2

a Quality assessment score (%) for 29 included studies, ranked by score. b Proportion of the 29 included papers meeting each quality criterion. Abbreviation: PRO, patient reported outcomes; tx, treatment

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Results across studies by treatment category

A number of PROs were assessed using multi-scale PRO measures (Table 1). All summarized changes in PRO scores from baseline to follow-up are statistically significant. Clinically relevant differences are indicated if reported in the studies.

Radical surgery with or without adjuvant therapy

Early disease, i.e., FIGO stage IB1, IB2, or IIA1, is commonly treated with RH +/− adjuvant therapy. Ten studies reported PROs before and following these treatment modalities (Table 1). PROs that changed over time are summarized in Fig. 3

Fig. 3
figure 3

Statistically significant change in PROs from baseline to follow-up assessment time-points after treatment with radical surgery with or without adjuvant therapy across 10 studies. Proximal effects, direct effects of the disease and side effects of treatment; Distal effects, consequent impacts on core functioning domains (e.g. physical, social, emotional), and in turn, global or overall HRQL. *Overall HRQL (i.e. different from global HRQL), since it is measured using the FACT-G total score Abbreviation: m, months

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In a prospective cohort of 187 patients treated with RH +/− bilateral salpingo-oophorectomy (BSO) +/− lymph node (LN) resection, the FACT-Cx was used to measure HRQL. Functional and physical well-being decreased at 3 months and social/family well-being at 9 months after diagnosis compared with baseline. Functional and physical well-being improved at 9 months compared with baseline [17]. In another prospective cohort of 71 patients treated with a radical trachelectomy or RH, no difference was found in overall HRQL (measured with FACT-G) between groups from baseline to 24 months after surgery. In general, well-being scores improved from baseline to 24 months after surgery, except for social/family well-being. No differences in sexual dysfunction, measured with the Female Sexual Functioning Index (FSFI), were found between groups at 24 months [15]. In another prospective cohort of 39 patients treated with a radical trachelectomy, PROs were assessed with the FACT-Cx, SF-12, MDASI, and FSFI. Physical and functional well-being; social, emotional, and sexual function; and role physical scores decreased at 1 month post-surgery compared with baseline but improved by 6 months [28].

In a study of 215 patients treated with laparoscopic RH, sexual function was worse at 12 months post-treatment compared with baseline (measured with FSFI, clinical relevance not reported), more so for those treated without vaginal extension than those treated with vaginal extension [22]. In a prospective cohort of 40 patients, better lubrication and sexual satisfaction were reported at 8 months post-treatment after nerve-sparing laparoscopic RH compared with conventional laparoscopic RH; however, all patients reported more sexual symptoms at 8 months post-treatment compared with baseline [14]. In another cohort, including 1863 patients receiving laparoscopic RH or open RH, sexual dysfunction and pelvic floor dysfunction at 12 months post-treatment did not differ significantly from baseline (54.7% reported sexual dysfunction at 12 months after laparoscopic RH vs 57.1% after open RH) [26]. Subgroup analysis revealed that women who received nerve-sparing laparoscopic RH reported less sexual dysfunction and urinary incontinence than those who received open RH at 12 months post-treatment (47.1% vs 56.1% for sexual dysfunction, 28.4% vs 34.7% for urinary incontinence, respectively) [26].

In a cohort of 229 patients treated with nerve-sparing RH + LN resection or RH + LN resection, diarrhea, narrower short vagina, dry vagina with little or no lubrication during intercourse, and pain during intercourse were worse at 12 and 24 months post-treatment compared with baseline (assessed with Dutch Gynecologic Leiden Questionnaire); however, sexual activity increased from baseline (58%) to 24 months (75%). Those who also had RT reported more diarrhea, lymphedema, narrower vagina, and less sexual activity compared with non-irradiated patients at 12 months [25].

In a study of 100 patients treated with any surgery, patients reported less insomnia and appetite loss at 3 and 6 months post-treatment compared with baseline measured with the EORTC QLQ-C30 and QLQ-CX24. Diarrhea improved at 3 months post-treatment but worsened at 6 months after treatment compared with baseline (clinical relevance not reported). Cognitive, emotional, and social function improved at 3 months post-treatment compared with baseline and remained stable at 6 months post-treatment. Role function and global HRQL improved at 6 months post-treatment compared with baseline (clinical relevance not reported) [27]. One study compared 105 patients with early disease treated with RH + LN resection to 122 patients with locally advanced disease receiving chemoradiation (CRT) + RH [19, 24]. For patients with early disease, anxiety (measured with Hospital Anxiety and Depression Scale (HADS)) decreased at 3 months post-treatment compared with baseline. Mean depression scores (HADS) remained below clinical thresholds from baseline to 12 months post-treatment [19]. Lymphedema was worse at 24 months post-treatment compared with baseline (clinically relevant). Menopausal symptoms worsened at 3 months post-treatment compared with baseline and persisted at 2 years (clinically relevant). Despite this, women still reported improved sexual activity and HRQL at 24 months post-treatment compared with baseline (clinically relevant) [24].

One prospective cohort study comparing 30 patients with early disease receiving surgery + CRT and 30 patients with locally advanced disease receiving CRT to healthy controls found decreased anxiety scores in patients with early disease at 3 and 6 months compared with baseline. Yet, their anxiety scores were still higher than those of healthy controls at 6 months post-treatment [16].

Neoadjuvant therapy followed by surgery

Internationally, this treatment regime is not commonly used. Three papers assessed PROs with the EORTC QLQ-C30 and QLQ-CX24 in patients with locally advanced disease (Fig. 4). One study compared 105 early disease patients treated with RH + LN resection with 122 locally advanced disease patients receiving CRT + RH [19, 24]. .A difference larger than 5% was considered clinically relevant. After treatment with CRT + RH, all patients reported worsened lymphedema and menopausal symptoms, but improved sexual activity and global HRQL at 24 months post-treatment compared with baseline [24] and a decrease in peripheral neuropathy at 12 months post-treatment compared with baseline (clinically relevant) [19]. Anxiety reduced by 24 months post-treatment compared with baseline (clinically relevant). However, a proportion of these patients (15.6%) still reported clinically elevated anxiety at 24 months post-treatment (HADS score > 11 points). Over time, no differences in depression scores were found at 24 months post-treatment compared with baseline; in fact, depression mean scores were consistently low throughout the duration of the study. Body image was worse at 24 months post-treatment compared with baseline [24].

Fig. 4
figure 4

Clinically relevant change in PROs from baseline to follow-up assessment time-points after treatment with neoadjuvant therapy followed by surgery across three studies. Proximal effects, direct effects of the disease and side effects of treatment; Distal effects, consequent impacts on core functioning domains (e.g. physical, social, emotional), and in turn, global or overall HRQL. Abbreviation: m, months

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Another prospective study with patients receiving CRT or RT followed by RH reported clinically relevant differences where at least a 10-point change in means scores was observed. Physical and role function improved at 6 months compared with baseline after CRT + RH and RT + RH, while social function improved after RT + RH. At 6 months, fatigue improved in both groups while insomnia improved only after RT + RH (all clinically relevant). Additionally, menopausal symptoms worsened in both groups at 6 months compared with baseline. Worsening of lymphedema after 6 months compared with baseline was only reported after CRT + RH. No differences were found in global HRQL or sexual function over time; however, sexual worry was clinically worse after RT + RH at 6 months compared with baseline [23].

Chemoradiation or radiotherapy

Chemoradiation is the preferred treatment for locally advanced disease, i.e., FIGO stage IB-IVa and IVb with para-aortic metastatic nodes below L1–L2 only. Eleven papers reported PROs measured at baseline and at post-treatment follow-up time-points. All studies used the EORTC QLQ-C30 and QLQ-CX24. Outcomes that changed from baseline to follow-up are summarized in Fig. 5.

Fig. 5
figure 5

Statistically significant change in PROs from baseline to follow-up assessment time-points after treatment with chemoradiation or radiotherapy across studies. Abbreviation: m, months; y, years; tx, treatment; PTSD, post-traumatic stress syndrome symptoms * Conflicting PRO results reported by studies (e.g. one found an improvement while another found a decrease in the same PRO) # most symptoms improved again within 3 months after treatment

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Two studies reported EORTC QLQ-C30 scores during treatment, and in both, clinical relevance was interpreted using the EORTC criteria for clinically small, medium, and large mean changes over time [21, 32, 43]. .One study of 138 patients treated with RT alone versus CRT versus RT with concurrent hyperthermia or neoadjuvant CT followed by RT with concurrent hyperthermia, compared with age-matched population norms, found that most symptoms worsened (clinically moderate-to-large increase), with a maximum at the end of treatment, or 1 week after treatment. This returned towards baseline at 3 months after treatment. Bowel cramps and diarrhea increased in the first 3 weeks with a plateau at the 5th week of treatment. In the 5th week of treatment, global HRQL, role, and social and physical functioning decreased compared with baseline (small-to-moderate clinically relevant effects) but returned to baseline levels by 3 months post-treatment. Cognitive functioning decreased in the 5th week but improved by 3 months post-treatment, then decreased again at 12 months post-treatment (both decreases were small clinically relevant effects) [21]. Other changed symptoms (listed in Fig. 5) had a clinically moderate-to-large increase with a maximum at the end of treatment, or 1 week after treatment, returning to baseline levels by 3 months. In a study with 50 patients treated by CRT followed by BT, diarrhea, urinary frequency, nausea, and physical and role function worsened during treatment compared with baseline but returned to baseline levels by 3 months post-treatment (all clinically relevant). Cognitive, social, and emotional function remained stable, while lymphedema, hot flushes, and sexual worries increased during and at 3 months post-treatment compared with baseline (all clinically relevant). Global HRQL improved at 3 months post-treatment compared with baseline (not clinical relevant) but was lower than population norms [32].

Five papers reported on the EMBRACE cohort (Table 1), which assessed HRQL with the EORTC QLQ-C30 and QLQ-CX24 in 1416 patients treated with CRT followed by image-guided BT (30–50 Gy) [29, 30, 33, 35, 36]. Diarrhea and inability to control bowels were worse at 3 months (37% of patients and 26% of patients, respectively) compared with baseline (26% and 11% respectively); controlling bowels was still a problem for 44% of patients at 5 years post-treatment. Constipation and abdominal cramps improved at 3 months (17.4% and 36% respectively) compared with baseline (32% and 39% respectively), with abdominal cramps improving further at 5 years post-treatment (28%) [30]. Lower limb edema was reported by 16% of women at baseline compared with 34% at 5 years post-treatment [35]. At 5 years, patients reported gradual increase in urine leakage and difficulty emptying their bladder (proportion of patients reporting “very much” or “quite a bit” 11.5% and 8.9% respectively) compared with baseline (4.6% and 3.6% respectively) [29]. Hot flushes increased from baseline (12%) to 3 months (28%) and remained above baseline levels at 3 (20%) and 5 years (19%) [36]. Moreover, in 744 patients, less pain and fatigue were reported at 4 years post-treatment compared with baseline, and while statistically higher than the general population, this difference was not clinically relevant. Over time, dyspnea, peripheral neuropathy, and lymphedema gradually worsened and remained higher than baseline levels 4 years post-treatment [33].

Another three studies reported PROs after CRT followed by BT. In 35 patients, vaginal function improved 12 months post-treatment compared with baseline, but sexual function remained stable over time [34]. Four years post-treatment, an increase in sexual activity was reported by 219 patients despite more menopausal symptoms and pain during intercourse. At 3 months post-treatment, physical function decreased while social function increased compared with baseline. More pain, fatigue, appetite loss, nausea, and vomiting were reported by patients treated with CRT at 3 months post-treatment compared with CRT + BT [18]. In a cohort of 50 patients treated with CRT followed by high-dose rate MRI-guided BT, 41% of patients at 3 months after BT reported symptoms of post-traumatic stress syndrome [31].

Moreover, 30 patients treated with CRT reported less anxiety 6 months post-treatment compared with baseline, but still reported higher anxiety scores than healthy controls [16].

Ultraradical surgery

Ultraradical surgery is used as salvage therapy for relapsed disease. Only one study investigated pelvic exenteration compared with a Wertheim’s procedure in 129 patients with advanced disease [20]. Four months post-treatment, all patients reported more sexual uncertainty (baseline mean score 1.60, 4-month mean score 2.37, total score range 0–6), attractiveness or self-confidence (11.44 and 10.37, respectively; total score range 0–15), and HRQL compared with baseline (0.70 and 0.75, respectively; mean values > 0.5 indicate problems). More physical and sexual problems were reported after pelvic exenteration compared with patients who underwent the Wertheim’s procedure (physical mean value 1.14 and 0.66, and sexual mean value 1.61 vs 0.88, respectively; mean values > 0.5 indicate problem). Twelve months post-treatment, patients with two ostomies reported lower body image and decreased global HRQL compared with patients with one or no ostomy (mean values not provided) [20].

Systemic therapy for advanced disease

Advanced (i.e., FIGO stage IVB), recurrent, or persistent disease is commonly treated with CT. Before receiving CT, patients might have had other treatments which may also affect PROs, making it difficult to isolate the PRO impacts of CT. Six studies reported PROs measured at baseline, i.e., before beginning CT, and at follow-up times. Most regimens included cisplatin and the longest follow-up time was 9 months post-first cycle of CT. All studies used the FACT-Cx (with or without the neurotoxicity subscale) and the Brief Pain Inventory (BPI).

Two papers reported on the same randomized controlled trial including 264 patients receiving cisplatin versus cisplatin + paclitaxel [39, 41]. Pain decreased from baseline to the 4th cycle of CT, with the largest decline in the cisplatin-only arm, but all scores were below the clinical threshold of pain, while emotional well-being improved [39]. No differences in global HRQL were found over time or between treatment groups [41].

Three studies compared cisplatin + topotecan with other CT regimens. No difference in global HRQL between treatments was found [37, 38, 40]. In 434 patients treated with cisplatin and topotecan or paclitaxel or vinorelbine or gemcitabine, neurotoxic symptoms decreased from the start of the 5th CT cycle to 9 months post-CT cycle 1. Patients reported stable pain scores from baseline to 9 months post-CT cycle 1 (ranging from 2.3 to 4.0; total score range 0–10) [37]. In 293 patients treated with cisplatin +/− topotecan, neurotoxicity increased from baseline to 9 months post-baseline, with the highest increase from cycle 5 to 9 months after starting treatment. No differences in cervical cancer PROs (FACT-Cx) were observed from baseline to 9 months post-baseline between the different CT schedules [40]. In a study comparing 186 patients treated with cisplatin +/− topotecan or cisplatin + methotrexate + vinblastine + doxorubicin, no differences were found in cervical cancer PROs (FACT-Cx total score) over time or between treatment arms [38].

In a study of 452 patients treated with paclitaxel + cisplatin +/− bevacizumab or paclitaxel + topotecan +/− bevacizumab, self-reported neurotoxicity was higher at 9 months post-first CT cycle compared with baseline. However, less neurotoxic symptoms were reported after CT with bevacizumab (OR 0.58; 98.75% CI 0.17–0.98) compared with CT without bevacizumab. No differences in pain scores or global HRQL were found over time or between treatments [42].

Discussion

Twenty-nine papers were found reporting 23 studies that assessed PROs before and after treatment for cervical cancer. Studies were categorized per treatment to gain insights into differential treatment effects. Persistent long-term problems after treatments with curative intent for early or locally advanced disease included lymphedema, diarrhea, menopausal symptoms, tight and shorter vagina, and pain during intercourse. In general, this resulted in more sexual worries, but despite these symptoms and worries, sexual activity increased one or more years post-treatment. Across these curative treatments, global HRQL and core domains of HRQL (functioning and well-being) and psychological distress were impacted during treatment but improved by 3 to 6 months after treatment. After salvage therapy for relapsed disease (ultraradical surgery), patients were more sexually uncertain and had less self-confidence/perceived attractiveness and worse HRQL 4 months post-treatment compared with baseline. Among patients with advanced disease, PROs were measured after several CT regimes, most involving cisplatin. In general, pain improved during treatment or remained stable, likely representing the palliative effect of CT but this was not generally accompanied by improvements in global HRQL.

In order to interpret whether a statistically significant change in a PRO represents an impact on the patient, information about clinically meaningful differences is needed. Few studies included in this review provided information on whether statistically significant differences were clinically relevant, and none of the studies reported effect sizes. Another aid to interpreting the clinical impact of diagnosis and treatment on PROs is to compare patients’ PRO results with those of an age- and sex-matched population, which was done in five studies [16, 17, 21, 32, 33], .However, the difference still needs to be above the minimally important difference to be interpreted as clinically relevant.

In order to determine differential treatment effects on PROs, studies with pooled treatment groups were excluded. However, even within one treatment category, heterogeneity existed. For instance, among studies examining RH +/− adjuvant therapy, different adjuvant therapies were given, which is likely to have impacted on PROs differently. Similarly, different CT regimes were given to those with advanced disease, so results should be interpreted with caution. Moreover, although the size and location of the radiation field have an influence on PROs during and after treatment, these details are often not reported.

A limitation of this review is that it only included studies published in English, and most of the studies were conducted in Europe or the USA. Therefore, results may not be generalizable to patients in other continents due to differences in contextual health care factors. Furthermore, PROs may also be influenced by socio-economic status [44]. Further, increasing attrition rate over time and whether or not treatment is successful can lead to bias in PROs.

This is the first systematic review, utilizing robust methods, comparing PROs between treatment groups, during and after contemporary treatments for cervical cancer. Previous reviews reporting HRQL following treatment for cervical cancer share a number of limitations: they (1) focus on a limited range of treatment modalities (e.g., variations of RH, ovarian transposition) [45,46,47]; (2) investigate a specific time frame (e.g., only long-term treatment side effects) [48, 49]; (3) assess only few dimensions of HRQL [50]; and (4) include study designs that obscure differential treatment effects (i.e., results pooled across different treatment modalities) or the effect of treatment over time (e.g., limited to cross-sectional, retrospective designs) [47,48,49,50,51,52], and none of the reviews compared PROs between contemporary treatments.

The results of this review have important clinical implications. Better understanding of the impact of specific treatments for cervical cancer on HRQL of patients may facilitate patient-clinician communications about concerning issues, better prepare patients for treatment effects, facilitate shared decision-making, and assist clinicians to deliver timely, tailored supportive care interventions to address these issues.

Our review highlights the impact of treatments on core aspects of HRQL, such as social and sexual functioning, psychological well-being, and global HRQL. Treatment causes many symptoms, and while some improve within the first 3 months, other issues like lymphedema, menopausal symptoms, and sexual worries develop gradually after treatment and persist for years. Little is known about the quality of life impact of treatment for very early-stage cervical cancer on PROs, and very limited information is published about fertility sparing therapy. Future research should address these gaps.