Outcomes in patients with early stage uterine clear cell carcinoma treated with chemotherapy and radiotherapy: A systematic review and meta-analysis

Background : Uterine clear cell carcinoma (UCCC) is a rare histological type of endometrial cancer with poor prognosis and high risk of tumor relapse. Although adjuvant chemotherapy (CT) and/or radiotherapy (RT) are often recommended for early stage UCCC patients, the effectiveness of these treatment strategies remains unclear. Methods : Systematic review and meta-analysis were applied to evaluate treatment-related outcomes of stage I-II UCCC patients. Search strategy was applied using electronic databases until June 1st, 2019. Inclusion criteria were retrospective, observational and prospective studies that reported outcome of UCCC patients receiving adjuvant therapy. Clinical endpoints like overall survival (OS) and progression-free survival (PFS) were evaluated. Data were extracted by two independent reviewers and a meta-analysis was performed. Results : 13 articles with a total of 3967 patients were analyzed. Overall, adjuvant CT after surgery could improve 5 year-OS significantly compared to patients without CT (odds ratio 0.75, 95% confidence interval [CI] 0.58-0.96; p=0.02). In comparison, RT could also improve OS in UCCC patients of early stage (odds ratio 0.58, 95% CI 0.44-0.77; p=0.0002) compared to the patients without RT, especially in US and Europe patients. Lastly, when comparing the patients undergoing both CT and RT with those receiving CT or RT alone, no further improvement in OS was observed (odds ratio 1.12, 95% CI 0.63-1.99; P=0.70). Conclusions : Either CT or RT after surgery could improve the OS of early stage of UCCC patients. However, combinatorial CT and RT treatment did not improve the OS compared with CT or RT treatment alone. when Subgroup study sample Y-axis pooled presence when plot whereas symmetrical plot the assessed Begg’s test regression test calculated by Rstudio 1.2.1335 using package “Metafor”.


Abstract
Background : Uterine clear cell carcinoma (UCCC) is a rare histological type of endometrial cancer with poor prognosis and high risk of tumor relapse. Although adjuvant chemotherapy (CT) and/or radiotherapy (RT) are often recommended for early stage UCCC patients, the effectiveness of these treatment strategies remains unclear.
Methods : Systematic review and meta-analysis were applied to evaluate treatment-related outcomes of stage I-II UCCC patients. Search strategy was applied using electronic databases until June 1st, 2019. Inclusion criteria were retrospective, observational and prospective studies that reported outcome of UCCC patients receiving adjuvant therapy. Clinical endpoints like overall survival (OS) and progression-free survival (PFS) were evaluated. Data were extracted by two independent reviewers and a meta-analysis was performed.
Results : 13 articles with a total of 3967 patients were analyzed. Overall, adjuvant CT after surgery could improve 5 year-OS significantly compared to patients without CT (odds ratio 0.75, 95% confidence interval [CI] 0.58-0.96; p=0.02). In comparison, RT could also improve OS in UCCC patients of early stage (odds ratio 0.58, 95% CI 0.44-0.77; p=0.0002) compared to the patients without RT, especially in US and Europe patients. Lastly, when comparing the patients undergoing both CT and RT with those receiving CT or RT alone, no further improvement in OS was observed (odds ratio 1.12, 95% CI 0.63-1.99; P=0.70).
Conclusions : Either CT or RT after surgery could improve the OS of early stage of UCCC patients.
However, combinatorial CT and RT treatment did not improve the OS compared with CT or RT treatment alone.

Background
Uterine clear cell carcinoma (UCCC), which accounts for 1-5% of endometrial cancers, is a highly aggressive cancer subtype that is frequently associated to poor prognosis and high tumor recurrence (1). Notably, up to 30% of UCCC patients demonstrated pelvic recurrence, whereas distant recurrence was found in up to 60% of these patients. Moreover, the 5-year overall survival (OS) for UCCC was approximately 60% compared to over 80% OS for other endometrial cancers (2). There is not enough data on the use of chemotherapy in early-stage clear cell cancers, although some clinical trials from Gynecologic Oncology Group (GOG) have investigated the effect of adjuvant therapy on UCCC (4). Furthermore, most retrospective studies often categorize both serous and clear cell subtypes as type II endometrial cancer, assuming that their clinical outcomes are same.
Consequently, none of the individual studies could provide sufficient power for precise evaluation of the effect of adjuvant therapy in UCCC patients.
To our knowledge, the prognostic index of adjuvant therapy including progress free survival (PFS), disease free survival (DFS) or overall survival (OS) has not been systematically evaluated in early stage UCCC patients combining the data from all eligible previous studies. Therefore, in this metaanalysis, we aim to summarize and compare the impact of different adjuvant therapy regimens on prognostic value of early stage UCCC, thus providing practical implications for these disease.

Methods
To conduct systematic review and meta-analysis, electronic searches from Web of Science, PubMed and Medline were performed independently by two reviewers (X.Y. and J.C.) to identify all relevant studies that evaluated the efficacy of adjuvant therapy in early stage UCCC. The selection strategy for the database search is: ("adjuvant therapy" or "systemic therapy" or "chemotherapy" or "radiotherapy" AND "Uterine Clear Cell Carcinoma" or "UCCC" or "Endometrial Clear Cell Carcinoma").
The search was concluded on June 1st, 2019, and was limited to publications written in English.
Additional publications that were not identified during the electronic searches were selected manually. Publications in the forms of retrospective, observational and prospective randomized controlled trials were included, while publications like letters, case studies, or reviews were excluded.
In addition, studies with unclear description of data on the outcomes of interests were also excluded from the analyses. Authors of identified studies were contacted for clarification on methods and outcomes when necessary. Disagreements between the two reviewers were resolved through discussion. All extracted data from the selected studies was arranged using a standard PRISMA data extraction form.
General characteristics of the extracted data included author names, year of publication, country, number and age of patients, different type of therapies and cases of different events based on 5-year OS and PFS. To ensure the completeness and accuracy of the extracted data, two reviewers (X.Y. and J.C.) extracted the data from the identified studies independently and then cross-checked their results. When discrepancies arose, the final decision was made through discussion. If the relevant data were not clear in a particular study, the corresponding author of the publication was contacted by email for further clarification.
The risk of bias was assessed by the reviewers in accordance to the Cochrane Handbook for Systematic Reviews of Interventions. The seven domains related to risk of bias that were evaluated for each trial included: (1) details of the randomization method, (2) concealment of treatment allocation, (3) masking of the participants and personnel, (4) blinding of the outcome assessment, (5) incomplete outcome data, (6) selective reporting, and (7) other bias. For each criterion, the risk of bias was rated as low, high, or unclear. Disagreement was resolved through discussion.
Data synthesis was performed using RevMan 5.3 (Cochrane Collaboration, London, UK). Continuous data were presented as mean value and standard deviation, and the weighted mean difference and 95% confidence interval (CI) were also calculated. Dichotomous data were expressed as odds ratios (ORs) with 95% CIs. p < 0.05 was considered statistically significant. The heterogeneity in outcomes across all the trials was assessed using the χ 2 and I 2 tests. An I 2 value > 50% was considered to indicate substantial heterogeneity, which prompted the use of a random-effect model for the subsequent analysis; otherwise, a fixed-effect model was applied. Meta-regression was applied when the heterogeneity was existed. Subgroup analysis was also performed to further meta-analysis when the study number is no smaller than 10. Publication bias was assessed by a funnel plot, in which the sample size was plotted on the Y-axis and the pooled OR on the X-axis. The presence of bias was considered when an asymmetrical plot was evidenced, whereas a symmetrical plot suggested no bias in the assessed publication. Begg's test and Egger's regression test for publication bias were calculated by Rstudio 1.2.1335 using package "Metafor".

Eligible studies and their characteristics.
After initial search of the databases, we identified 59 potentially relevant reports from Pubmed and Medline (n = 27) and Web of Science (n = 32). After excluding repeated publications, a final 36 articles were examined. 14 articles were eliminated for analyses for the following reasons: (1) the reports were review or abstract (n = 5), (2) non-English articles (n = 1), (3) the reports were not related to adjuvant therapy in UCCC (n = 8). Full-text review were performed on 22 articles and 1 manually inquired articles. After carefully performing data extraction, an addition of 10 articles was removed from the analyses due to insufficient data. In the end, 13 articles were included in this meta-analysis (5-17) (Supplemental Fig. 1). 13 articles included consisted 3963 patients in total. The quality assessment and main characteristics of the included studies were summarized in Table 1 and Supplemental Fig. 2 respectively. All studies selected were assessed to be in a good quality. The follow-up time of patients was more than 60 months to achieve the 5-year overall survival.

Comparison of OS between CT and non-CT groups
In order to compare OS between patients receiving chemotherapy (CT group) and patients receiving

Meta-regression and subgroup analyses
The heterogeneity issue between all included studies was addressed. We performed meta-regression analyses to explain expected heterogeneity in the comparison of OS between patients receiving RT and non-RT, (I 2 = 55%), by testing the effects of factors like sample size (case number > 80 versus < 80), nationality (Asia versus Europe and US) and publication year (before versus after 2010).
Interestingly, the results indicated that difference in nationality contributed significantly to the overall heterogeneity (Z = 0.03, p = 0.0172) ( Table 2). Therefore, subgroup analyses were performed. Data revealed that analyses on left 9 publications from Europe and US with a total number of 1785 patient indicated no heterogeneity (I 2 = 0%). The pooled data revealed OR of RT versus non-RT was 0.58 (95% CI: 0.44-0.77) and 5-year OS in RT group was significantly higher compared to the non-RT group using a fixed-effect model (p = 0.0002). Analysis on patients from Asia was not performed due to limited number of publication (n = 1) ( Table 3).

Publication bias
In CT and non-CT groups, funnel plots formed a very distinctive symmetrical funnel shape with log ORs of the OS. These results implied that no publication bias was detected in the present study (Begg's test, p = 0.07, Egger's test, p = 0.62) (Supplemental Fig. 8). In RT and non-RT groups, no evidence of publication bias was detected as well (Begg's test, p = 0.48, Egger's test, p = 0.32) (Supplemental Fig. 9).

Discussion
UCCC, a relatively rare cancer of the endometrium, exhibits poor patients' prognosis even at early stage of the disease such as stage I-II. CT or RT has been applied as the adjuvant treatment after surgery to improve prognosis. However, it remains controversial of the effectiveness of CT or RT as the adjuvant therapy for early stage UCCC due to small number of cases reported in a limited few studies. Our study is the first meta-analysis, which aims to evaluate the effectiveness of adjuvant CT or RT on survival outcomes in stage I-II UCCC.
Our meta-analysis results have supported the notion that CT is beneficial for early stage, i.e. stage I-II UCCC. In particular, we found that patients receiving CT showed a significant higher 5 year-OS rate compared to those receiving non-CT (p = 0.007). This result was evidenced based on the pooled extracted data from 494 CT and 1860 non-CT patients without internal difference from a total of 7 trials (p = 0.48, I 2 = 0%). Interestingly, in the study of Hsu et al., 2 cases of death were reported from a total of 30 cases receiving adjuvant CT, while 9 death cases found from the 62 cases without receiving CT. According to the authors of this study, patients that did not receive adjuvant treatment tended to have lower risk of recurrence as evidenced by smaller tumor sizes and less myometrial invasion (6). In a study that consisted the largest study cohort, Hong et al. analyzed the data from the National Cancer Data Base (NCDB) and found that women undergoing hysterectomy, lymph node dissection (LND) and CT had the highest 5-year OS, followed by those with hysterectomy and LND without CT (13). Taken together, these results supported the use of CT in the treatment of early stage UCCC.
In individual study, such as the CT regimens and types of RT, was different, which might influence the final reporting of our meta-analysis.
In conclusion, as the first meta-analysis with nearly 4000 patients, our results support the administration of RT and CT for stage I-II UCCC patients. However, it remains to be elucidated how the treatments should be integrated into the adjuvant setting. Therefore, more prospective and randomized clinical trials with larger sampling size should be performed in the future.

Abbreviations
and X.Y. Authors read and approved the manuscript Figure 2 Pooled studies of overall survival between patients received Radiotherapy (RT) and not-Radiotherapy (Not-RT).

Figure 3
Pooled studies of overall survival between patients received combinatorial radiotherapy and chemotherapy (RT+CT) and radiotherapy or radiotherapy (RT or CT) alone.

Supplementary Files
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