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Abstract

Objective

To assess the response rate and survival effect of adjuvant radiotherapy (RT) or chemoradiotherapy (CRT) during ovarian clear cell carcinoma (OCCC).

Methods

We searched Web of Science, PubMed, Cochrane library electronic databases, Clinical Trials, WanFang Data and Chinese National Knowledge Infrastructure (CNKI) up to October 2022. We also searched registers of clinical trials, abstracts of scientific meetings and reference lists of included studies.

Results

We identified a total of 4259 patients from 14 studies met the inclusion criteria. The pooled response rate of residual tumors for RT/CRT was 80.0%, the pooled 5-year progression-free survival (PFS) ratio during RT/CRT group was 61.0%, and the pooled 5-year overall survival (OS) ratio during RT/CRT group was 68.0%; heterogeneity tests demonstrated significant difference between studies (I² >50%). Cumulative results suggested adjuvant RT/CRT improved 5-year PFS ratio of OCCC patients (OR: 0.51 (95% CI: 0.42–.88), I² = 22%, P = .009), had no impact on 5-year OS ratio (OR: 0.52 (95% CI: 0.19–1.44), I² = 87%, P = .21); meta-regression of studies before and after 2000 found consistent results. Sub-analysis observed that adjuvant RT/CRT had no impact on 5-year OS ratio of early-stage (stage I + II) OCCC patients (OR: 0.67 (95% CI: 0.25–1.83), I² = 85%, P = .44), but might improve 5-year OS ratio of advanced and recurrent OCCC patients (OR: 0.13(95% CI: 0.04–.44), P = .001).

Conclusion

This analysis suggested that adjuvant RT/CRT might improve oncologic outcomes of OCCC, especially for advanced and recurrent cases. Due to the inherent selective biases of retrospective studies enrolled in the meta-analysis, more convincing evidences based on prospective randomized controlled trials (RCTs) are urgently needed.

Keywords

ovarian clear cell carcinoma radiotherapy chemoradiotherapy survival outcome response rate meta-analysis

Introduction

Epithelial Ovarian Cancer (EOC) was the most deadly disease among gynecological malignancies, according to the World Health Organization (WHO); in 2021, there were 295,400 new cases and 184,800 deaths of ovarian cancer worldwide.¹ The majority of patients were diagnosed at advanced stages (stage III or IV) because of inability to screen. Preclinical studies suggested new surveillance methods such as liquid biopsy, high-throughput sequencing, proteomics analysis, and so on might improve the early detection rate of EOC, but they were still immature, not widely adopted in clinical practice yet. Although peptidomics might identify novel targets and pivotal pathways related to the occurrence and development of cancers, they had been regarded as ideal new biomarkers; due to the significant genomic heterogeneity of EOC, lower sensitivity and specificity were the major limiting factors for its application.² Survival rate for advanced disease was poor, regardless of geography, financial resources, or modality of treatment.³ Optimal cytoreduction to minimal residual tumor burden combined with platinum-based chemotherapy was the standard protocol for EOC. During recent years, targeted therapy had progressed markedly; combined bevacizumab might extend progression-free survival (PFS) of EOC by 2.4–3.8 months. Poly (adenosine diphosphate ribose) polymerase (PARP) inhibitors might significantly extend PFS and overall survival (OS) of EOC harbored the breast cancer gene (BRCA) mutations and homologous recombination deficiency (HRD). While immunotherapy targeting to programmed cell death protein-1(PD-1)/programmed death ligand 1(PD-L1) showed some benefits in highly selective advanced EOC with sensitive targets, however, tumors had numerous mechanisms of suppressing the antitumor immune response including inducement of inhibitory cytokines, recruitment of immunosuppressive cells, and upregulation of inhibitory receptors; the effect of immunotherapy needed further investigation. EOC should not be considered as a single disease, but a group of heterogonous diseases; according to precursor lesions and genetic background, it could be divided into the less common, slow-growing type I cancers and the more common, aggressive type II cancers. It contained multiple histological types; the majority was classified as high grade serous (accounting for 30–70%); while less common types included endometrioid (10–20%), mucinous (5–20%), clear cell (3–10%), and undifferentiated (1%) types.^4-6 Different histological types might have different pathogenesis, biological behavior, natural history, treatment strategies, and prognosis. Different molecular background might determine different biological behavior, therapeutic sensitivity, and prognosis; BRCA1/2 germline mutations were the strongest known genetic risk factors for EOC and were found in 6–15% of women with EOC.⁷ The BRCA1/2 status could be used as a prognostic indicator for expected survival, as BRCA1/2 carriers responded better to platinum-based chemotherapies, which might benefit from PARP inhibitors. According to literature, the rates of 5-year OS were estimated to be 20–35% for serous, 40–63% for endometrioid, 40–69% for mucinous, 35–50% for clear cell, and 11–29% for undifferentiated, respectively.^8-11

OCCC was less prevalent type, typically occurred at younger age, diagnosed at earlier stage; survival outcomes were generally favorable in the early stage, while advanced OCCC portended poor prognosis, which was often attributed to its inherent resistance to platinum-based chemotherapy.^12-14 Staging surgery or cytoreduction was recommended for OCCC, complete surgery with no macroscopic residual disease was the basis for survival benefit, was the most important prognostic factor for OCCC, even mini residual disease might significantly damage prognosis. The effect of re-cytoreduction for recurrent OCCC was not definite yet. Most RCTs for EOC included a small number of patients with OCCC due to its rarity. Therefore, clinical treatment strategies for OCCC were basically similar with other EOC, unfortunately, the treatment response rate of relapsed or refractory OCCC was lower than 10% even in platinum-sensitive OCCC patients.¹⁵ The molecular background of OCCC was unique, since it was usually negative for p53 mutations and positive for ARID1A and/or PIK3CA mutations, and might serve as potential precision oncological approaches. Immune checkpoint inhibitors and targeting the PI3K pathway as well as epigenetic treatment approaches might play an important role in the treatment of these tumor entities.¹⁶ However, evidences for specific or accurate treatment for OCCC were rare until now, novel treatment strategies were urgently needed to overcome the current treatment dilemma. Although, preclinical studies, early experimental treatments and retrospective studies found that EOC was radiosensitive, the clinical effect of RT in the modern era was dubious.^17-20

During pre-chemotherapy era, adjuvant radiotherapy for the management of EOC of all subtypes achieved reasonable results, whole abdominal radiotherapy (WAR) was adopted to eliminate diffuse intraperitoneal implanted metastatic disease. However, radiation began to fall out of favor due to the additional toxicity, the complexities compared to chemotherapy and the advent of more effective cytotoxic agents.²¹ Because of poor response to chemotherapy and updated understanding of the molecular differences with differential response to radiation therapy, adjuvant RT/CRT had generated renewed interest in the potential application in OCCC.

N. Takai.et al²² reported a case of complete response to radiation therapy with chemotherapy-resistant OCCC in 2002, and Julia Fehniger et al²³ reported a case of successful treatment of platinum refractory OCCC with secondary cytoreductive surgery and stereotactic radiation therapy in 2019. Retrospective studies^24,25 had shown durable local control rates with salvage limited- field RT after first-line chemotherapy. Nagai.et al²⁶ demonstrated a survival advantage for adjuvant radiation in 16 OCCC patients treated with WAR in comparison to postsurgical adjuvant chemotherapy, with a significantly improved 5-year OS in the RT group (81.8% vs 33.3% during chemotherapy group). A population based study by Soumyajit Roy.et al²⁷ also demonstrated superior disease-free survival with addition of whole abdominal RT (WART) to 3 cycles of chemotherapy in patients with stage IC and II OCCC patients. Conversely, the study based on the Surveillance, Epidemiology, and End Results (SEER) program²⁸ for OCCC, endometriod and mucinous of EOC of stages (I–III) found OS was lower in receiving adjuvant RT at 5 years (73% vs 76%) and 10 years (59% vs 64%, P = .039). A more recent Canadian retrospective review of 163 patients with early-stage OCCC found adjuvant pelvic and/or WAR did not improve progression-free survival or overall survival.²⁹

So, the prognosis for advanced and recurrent OCCC was poor, there was no standard adjuvant therapy for these patients yet. There was no convincing evidence for RT/CRT in management of OCCC from phase III RCTs; the results came from observational clinical studies were inconsistent, the significance of RT for OCCC was undefined. We designed present systematic review and meta-analysis to compare survival outcome between adjuvant RT/CRT and non-RT during OCCC patients, in order to assess the efficacy of radiotherapy in those patients.

Materials and Methods

Literature Search

This systematic review and meta-analysis was registered in the International Prospective Register of Systematic Reviews (PROSPERO; ID: CRD42022364536).³⁰ The detailed protocol according to the Preferred Reporting Items for Systematic Reviews and Meta examinations (PRISMA) statement³¹ was defined prior to the search. Present study was not on human tissue/samples, the data were derived from published literature, so Ethics/Review board approval was needless. Systematical literature retrieval was performed using Web of Science, PubMed, Cochrane library electronic databases, ClinicalTrials, WanFang Data and Chinese National Knowledge Infrastructure (CNKI), the retrieval time limit was from each database’s earliest inception to October 2022. We sought to identify all studies comparing the prognostic outcome of postoperative adjuvant therapy for OCCC patients without restriction of language and geography. We aimed to evaluate the effect of adjuvant RT/CRT in OCCC patients, comparing PFS and/or OS of patients received RT/CRT to those received chemotherapy or observation only. We queried the literature according to the following terms: ovar* and (Adenocarcinom*, Clear Cell or Clear Cell Adenocarcinom* or Clear Cell carcinom* or Clear Cell cancer or Clear Cell neoplasm* or CCC or mesonephric) and (Radiotherap* or Radiation Therap* or Therap*, Radiation or Radiation Treatmen* or Treatment, Radiation or Radiotherap*, Targeted or Targeted Radiotherap* or Targeted Radiation Therap*). Related articles of enrolled literature and Google search were used to avoid omitting newly published and internet resources.

All original clinical studies comparing outcomes of adjuvant RT/CRT vs non-RT during patients with OCCC without language and time restriction, including RCTs, quasi-RCTs, non-randomized trials, cohort study, case control study and retrospective observational study were included. Only comparative studies contained oncological outcome between RT/CRT and non-RT were enrolled in the present review. For each study, we extracted the concerned information including number of patients, FIGO stages of tumor, baseline characteristics, data related to operation and adjuvant therapy, response rate, 5-year PFS, and 5-year OS if feasible.

Two independent reviewers (HY and YZ) evaluated all studies to enroll and exclude the clinical studies. The process of selection of studies was conducted on 2 steps. First, we screened titles and abstracts based on the following exclusion criteria: duplicate publications, letters, editorials and reviews not reporting original data. Small cases series (<10 cases) were excluded since they might impair the interpretation of cumulative results. Similarly, single-arm studies, articles reporting unclear oncological outcomes and articles enrolling cases complicated with other malignancies or unclear pathological diagnosis, in vivo and/or in vitro studies not verified by clinical studies were excluded; the remaining studies were further assessed in full-text version. Second, screening was performed using the following inclusion criteria: a) original studies included adjuvant RT/CRT in OCCC; b) original studies reported the response rate or 5-year PFS or 5-year OS or HR for survival; c) full text available. Any differences were resolved by mutual discussion.

Statistical Analysis

Higgins I² was used to assess the heterogeneity during enrolled studies.³² I² was evaluated according to the formula as follows: I²=(Q−df)/Q×100%, where Q was the Cochran heterogeneity statistic and df was degrees of freedom. I²>50% stood for substantial heterogeneity; 50–75%, meant moderate heterogeneity; and 75–100%, meant high heterogeneity. If the heterogeneity was high in all patients’ population, subgroup analysis based on stages was performed.

Random-effects model was used to pool log transformed event rates and estimated 95% CI for response rate, 5-year PFS and OS outcomes when heterogeneity test demonstrated significant between studies (I² >50.0%), fixed-effects model was used when heterogeneity test demonstrated non-significant between studies (I² <50.0%). 5-year PFS ratio was calculated on the number of patients without disease progression was divided by the total number of patients at fifth year of follow-up. 5-year OS ratio was calculated on the number of alive patients was divided by the total number of patients at fifth year of follow-up.

Funnel plot was generated to identify publication bias, which was a scatter plot of the HRs of individual studies on the x axis against the standard error (SE) of the log HR of each study on the y axis. Symmetrical inverter funnel stood for absence of publication bias.

Sensitivity analysis was conducted for all outcome measures to determine whether the conclusions were robust to arbitrary decisions, we performed sensitivity analysis by excluding single studies one by one to value whether the cumulative results change significantly.

The meta-analysis was performed using the Cochrane Review software (Review Manager version 5.3) and Stata/SE 14.0 (StataCorp LP, College Station, Texas, USA). P-value <.05 was considered statistically significant.

Results

Evidence Acquisition

After systematic searching the literature, we identified 1282 citations, 3 single-arm studies and eleven comparative studies were selected after exclusion of duplicate publications, letters, editorials, reviews not reporting original data and outcomes neither included response rate nor 5-year PFS/OS. The process of evidence acquisition is detailed in Figure 1 the main characteristics of included studies are summarized in Table 1. Overall, 4259 OCCC patients were enrolled, including 3197 early-stage (stage I + II) patients, 1062 advanced stage (stage III + IV) and recurrent patients; 378 (8.9%) and 3881 (91.1%) had adjuvant RT/CRT and non-RT, respectively.

Figure 1.

Flow diagram for evidence acquisition in the systematic review and meta-analysis.

Table 1.

Main Characteristics of the Included Studies.

Study	Study design	Period	Number of patients (n)	Early stage (n)	Advanced/recurrent (n)	RT/CRT (n)	RR (%)	5-Year PFS (%)	5-Year OS (%)	Non-RT (n)	5-Year PFS (%)	5-Year OS (%)
Manmood Yoonessi. et al, 1984³³	Comparative/retrospective	1965–1982	22	14	8	9	—	—	44.4	13	—	23.1
Mark A.Crozier. et al, 1989³²	Comparative/retrospective	1959–1985	59	38	21	15	—	33.3	60.0	44	31.8	36.4
Aaron P.Brown.et al, 2013³⁰	Single arm/retrospective	1999–2009	8	—	8	8	100.0	75.0	87.5	—	—	—
Ginger Jiang, BS.et al, 2017¹⁴	Single arm/retrospective	2013–2014	7	—	7	7	57.1	—	—	—	—	—
Sagar C,Patel.et al, 2016²⁵	Comparative/retrospective	2004–2011	3467	2685	782	68	—	—	41.2	2413		71.0
J. Al-Barrak.et al, 2011³¹	Comparative/retrospective	2000–2008	105	—	105	17	70.6	—	—	—	—	—
Liat Hogen.et al, 2016²⁶	Comparative/retrospective	1995–2014	163	163	—	44	—	70.5	81.8	119	69.7	82.4
Yutaka Nagai. et al, 2007²³	Comparative/retrospective	1996–2004	28	19	9	16	—	81.3	81.3	12	25.0	33.3
Bryan D. Macrie. et al, 2014³⁴	Comparative/retrospective	1989–2012	56	—	—	6	—	83.3	—	50	78.0	—
Gina L. Westhoff. et al, 2016³⁵	Comparative/retrospective	1994–2012	53	—	53	24	—	—	62.5	29	—	17.2
William D. et al, 1982³⁶	Comparative/retrospective	1968–1976	12	—	—	10	—	60.0	—	2	50.0	—
Mark J. Stevens et al, 2021³⁷	Single arm/prospective	2013–2018	5	4	1	5	—	100.0	100.0	—	—	—
Paul J. Hoskins et al, 2012³⁸	Comparative/retrospective	1984–2008	121	121	—	59	—	42.4	—	62	24.2	—
Soumyajit Roy. et al, 2021²⁴	Comparative/retrospective	1984–2015	153	153	—	90	—	57.2	65.8	63	45.9	54.1

Abbreviations: RT = Radiotherapy, CRT = Chemoradiotherapy; RR = Response rate, PFS = Progression-free survival; OS = Overall survival.

Evidence Synthesis

Overall, the study population included 4259 OCCC patients; 378 (8.9%) had adjuvant RT/CRT (experimental group) and 3881 (91.1%) had adjuvant CT or observation only(control group). During 14 enrolled studies, 3 studies (Aaron P. Brown.et al 2013,³⁴ Ginger Jiang, BS.et al 2017,¹⁷ J. Al-Barrak.et al 2011³⁶) reported response rate of residual tumors for RT/CRT; the polled response rate was 67.0% (95% CI: 0.48–.86) (Figure 2A). Nine studies (Mark A. Crozier.et al 1989,³⁷ Aaron P. Brown.et al 2013,³⁴ Liat Hogen.et al 2016,²⁹ Yutaka Nagai.et al 2007,²⁶ Bryan D. Macrie.et al 2014,³⁸ Powlis WD.et al 1982,³³ Mark J. Stevens.et al 2021,³⁵ Soumyajit Roy.et al 2021,²⁷ Paul J. Hoskins.et al 2012³⁹) reported 5-year PFS during RT/CRT group; the polled 5-year PFS was .61 (95% CI: 0.50–.73) (Figure 2B). Nine studies (Manmood Yoonessi.et al 1984,⁴⁰ Mark A. Crozier.et al 1989,³⁷ Aaron P. Brown.et al 2013,³⁴ Sagar C,Patel.et al 2016,²⁸ Liat Hogen.et al 2016,²⁹ Yutaka Nagai.et al 2007,²⁶ Gina L. Westhoff.et al 2016,⁴¹ Mark J. Stevens.et al 2021,³⁵ Soumyajit Roy.et al 2021²⁷) reported 5-year OS during RT/CRT group; the polled 5-year OS was .68 (95% CI: 0.55–.81) (Figure 2C).

Figure 2.

The polled data by Stata/SE 14.0. A. The polled response rate for RT/CRT. B. The polled 5-year PFS during RT/CRT group. C. The polled 5-year OS during RT/CRT group.

By polling results together, we observed that adjuvant RT/CRT might improve 5-year PFS ratio of OCCC patients (OR: 0.51 (95% CI: 0.42–.88), I² = 22%, Z = 2.62, P = .009) (Figure 3A)), had not impact on 5-year OS ratio (OR: 0.52 (95% CI: 0.19–1.44), I² = 87%, Z = 1.26, P = .21) (Figure 3B). Sensitivity analysis was performed by excluding single study one by one, cumulative results did not change significantly, indicated the pooled results were stable and reliable. In order to reduce possible biases, we restricted our analysis between similar stages, sub-analysis observed that adjuvant RT/CRT had not impact on 5-year OS ratio of early-stage (stage I + II) OCCC patients (OR: 0.67 (95% CI: 0.25–1.83), I² = 85%, Z = .77, P = .44) (Figure 3C), sensitivity analysis found the study by Sagar C, Patel.et al²⁸ was the main cause for heterogeneity. In order to explore the potential causes, we analyzed the original study carefully and found the study enrolled clear cell, mucinous, and endometriod ovary cancer together; the enrolled period lasted 8 years (2004–2011); the individual difference during study population might be the cause of heterogeneity. However, after excluding the study, the I² reduced to 53%, cumulative results did not change significantly (OR: 0.13(95% CI: 0.04–.44), Z = 3.21, P = .001), suggested the results were valid. Although 5 studies contained advanced and recurrent OCCC, the 5-year OS data could only be extracted from 2 studies (Manmood Yoonessi.et al, 1984,⁴⁰ Gina L. Westhoff.et al, 2016),⁴¹ polled data indicated that adjuvant RT/CRT might improve 5-year OS (RR: 3.65 (95% CI: 1.54–8.53), test for overall effect, Z = 2.95; P = .003) (Figure 3D).

Figure 3.

The forest plot by Review Manager version 5.3. A. Adjuvant RT/CRT improve 5-year PFS of OCCC patients. B. Adjuvant RT/CRT did not impact on 5-year OS of OCCC patients. C. Adjuvant RT/CRT did not impact on 5-year OS of early-stage (stage I + II) OCCC patients. D. Adjuvant RT/CRT might improve 5-year OS of advanced and recurrent OCCC patients.

With the rapid development of radiotherapy technology, novel radiotherapy techniques, such as three-dimensional conformal radiotherapy (3D-CRT), intensity modulation radiation therapy(IMRT), might reduce the toxicity and improve the therapeutic effect, and might change the prognosis of OCCC. We tried to sub-analyze the effect of different RT technologies on PFS/OS of OCCC, but it was not feasible due to obvious heterogeneity and variations of adopted RT technologies between studies, so we adopted meta-regression of studies before and after 2000 to explore potential discordance with the results. By polling results before 2000, we observed that adjuvant RT/CRT had no impact on 5-year PFS (OR: 0.89 (95% CI: 0.28–2.81), P = .84) (Figure 4A) and 5-year OS of OCCC (OR: 0.38(95% CI: 0.14–1.04), P = .06) (Figure 4B). By polling results after 2000, we observed that adjuvant RT/CRT might improve 5-year PFS (OR: 0.43 (95% CI: 0.19–.93), P = .03) (Figure 4C), had not impact on 5-year OS (OR: 0.58 (95% CI: 0.17–1.97), P = .38) (Figure 4D).

Figure 4.

The forest plot by Review Manager version 5.3. A. Before 2000, adjuvant RT/CRT did not impact on 5-year PFS of OCCC patients. B. Before 2000, adjuvant RT/CRT did not impact on 5-year OS of OCCC patients. C. After 2000, adjuvant RT/CRT might improve 5-year PFS of OCCC patients. D. After 2000, adjuvant RT/CRT did not impact on 5-year OS of OCCC patients.

Methodological Quality and Risk of Bias Assessment

All included fourteen studies were retrospective studies except 1 prospective single-arm study. The quality assessment based on Newcastle Ottawa Scale (NOS) was high in eleven comparative studies; however, inferior quality during there single-arm studies (Figure 5A). All included studies had high risk of allocation biases. There was a relatively low heterogeneity (I² = 35%) in term of 5-year PFS ratio outcomes among studies; However, a relatively high heterogeneity (I² = 82%) in term of 5-year OS ratio outcomes. The funnel plot for the 8 eligible studies in term of 5-year PFS ratio outcomes was symmetrical, which meant no significant publication bias existed (Figure 5B); however, the funnel plot for the 7 eligible studies in term of 5-year OS ratio outcomes was asymmetrical, which meant significant publication bias might exist (Figure 5C).

Figure 5.

Methodological quality and risk of bias assessment. A. The quality assessment based on NOS. B. The funnel plot for the 8 eligible studies in term of 5-year PFS outcomes. C. The funnel plot for the 7 eligible studies in term of 5-year OS outcomes.

Discussion

The present systematic review and meta-analysis reviewed the current evidences concerned the effect of adjuvant radiotherapy in OCCC, thus reported valuable findings. First, we reported pooled outcomes of the largest series (N = 4259 patients) of OCCC until now, observed the 5-year PFS and OS ratio were 61% and 68% in adjuvant RT/CRT group respectively, the response rate for RT/CRT was 67%. Second, we observed that the adoption of adjuvant radiotherapy might improve oncologic outcomes of OCCC. Third, focused on patients affected by advanced and recurrent OCCC, we observed that the administration of radiotherapy might improve 5-year overall survival.

OCCC accounted for less than 10.0% of ovarian cancers, was categorized as a rare gynecologic disease. However, OCCC had become the second most common subtype of EOC in North America,⁴² a relatively high frequency (16–25%) was observed in Taiwan and Japan.^43,44 OCCC had unique features different from common high grade serous carcinoma, might had poorer prognosis than those with other histological subtypes.⁴⁵ The relative lack of chemotherapy efficacy was well known, with response rates to platinum-based regimens of 22%–70%,^46-48 lack of any apparent additional benefit with chemotherapy compared with surgery alone in early-stage patients,⁴⁹ the response rate of relapsed or refractory OCCC was lower than 10% even in platinum-sensitive patients, this relative chemotherapy resistance prompted us to explore novel strategies to improve survival. The treatment strategy for EOC had made great progress, anti-angiogenesis, immunotherapy, PARP inhibitors or combined regimes had improved the prognosis of certain EOC,^50-52 most RCTs for EOC enrolled a small number of OCCC due to its rarity. Therefore, the treatment for OCCC had not been supported by high level evidences, several clinical studies focused on OCCC, adopted novel regimes including immunotherapy and targeted therapy, are underway, available preliminary results were not promising, the prognosis did not improve significantly,^53,54 the treatment for OCCC is still challenging.

Despite radiotherapy was part of the protocol for EOC, because of concerns about its toxicities, long-term morbidity and controversial effect, some oncologists consistently avoided the use of RT/CRT until the last resort.⁵⁵ The chemotherapeutic resistance of OCCC might be the main motive for adopting radiation in this unique clinical and molecular subtype. A few successful cases had been reported, experimental treatment on a small scale achieved gratifying results, some retrospective studies suggested that radiotherapy had a role in improving prognosis of OCCC; however, the results were inconsistent between studies. To date, the role of RT/CRT in OCCC was still controversial, highlighting the clinical need to address the question whether adjuvant radiotherapy was useful in those patients.

As aforementioned, the efficacy of adjuvant radiotherapy on OCCC was discordant and the clinical value of CRT/RT in OCCC was unclear. Excitingly, the present meta-analysis found adjuvant RT/CRT might improve 5-year PFS of OCCC; further, a meta-regression of studies before and after 2000 also reached similar result, which suggested the results were valid. Although we observed that the administration of radiotherapy might improve 5-year overall survival of advanced and recurrent OCCC, the result should have been treated with caution because the 2 enrolled studies, during study by Manmood Yoonessi.et al, none of the patients survived more than 5 years in either experimental group or control group, so the polled results entirely depended on the study by Gina L. Westhoff. et al. We must highlight the inherent limitations of this retrospective study, although the study found RT might improve both PFS and OS of recurrent OCCC, we found compared with no-RT group, the RT group had higher ratio of focal/isolated recurrence and secondary cytoreduction, these factors might directly influence the prognosis, the survival benefits might not due to adjuvant radiotherapy.

One important aspect of performing a meta-analysis was to try to provide more convincing evidence to answer the key question than those addressed by the primary studies; the key question we focused was whether the administration of radiotherapy improves prognosis of OCCC. However, the oncologic outcomes were influenced by characteristics of individuals, adjuvant therapy details, type of surgery, pathological characteristics, and so on. There was a wide variation of prognostic factors between studies. They were the most important biases of the present study. Another potential limitation of this meta-analysis was that most included studies were single-institution retrospective analysis, the selection bias and limited cases enrolled might affect the final results of this study.

Relevant toxicity, complication, and long-term morbidity were the major barriers for radiotherapy for OCCC; unfortunately, only a few studies reported the RT-related advance events; we could not adopt meta-analysis to evaluate whether RT had potential advance effect for OCCC. However, we needed to be aware of potential fatal complication, such as enterobrosis, adhesive ileus, and secondary neoplasms. Newer radiotherapy techniques were urgently needed to reduce potential toxicity.

The main strengths of present meta-analysis were the first meta-analysis assessing the significance of RT/CRT in OCCC to our knowledge, enrolled the largest number of patients until now, provided more reliable evidence compared to previous clinical observation studies, through polling outcome of 4259 patients from 14 studies, we observed that results supported that adjuvant radiotherapy might improve 5-year PFS in total patients and 5-year OS in advanced/recurrent patients. The rationale of these findings might be related to the number of patients included for the 5-year PFS (n = 592) and OS (n = 3965) survivals based on available data from enrolled studies. Due to rarity, there are currently no prospective or randomized trials comparing prognostic significance of RT/CRT to non-RT during OCCC; high quality studies was lack, the actual level of evidence is low. Additionally, 3 main points of the present meta-analysis had to be pointed out. First, the pooled result of 5-year PFS largely depended on the study by Liat Hogen. et al, 2016. However, we had to point out that in the original study, they failed to find a clinical 5-year PFS benefit of adjuvant radiotherapy. Second, in our meta-analysis, the 5-year OS benefit only existed in advanced/recurrent subgroup, entirely depending on the result published by Gina L. Westhoff. et al, 2016. However, we had to highlight the major limits of selection bias of this study and the limited cases enrolled. Third, unfortunately, it was not possible to evaluate the adverse events of radiotherapy because these data were not available in most of the included studies. We had to take in account that adverse events might impact on patients’ prognosis and clinical application.

The weaknesses of this review include the aforementioned inherent biases arising from the dose and method of RT varying between the included studies; the enrolled OCCC might receive a variety of antitumor therapies and might affect the survival outcome of patients and the results of the study. Meanwhile, complete surgery was the major prognostic factor for OCCC, cytoreduction with no macroscopic residual disease was the basis for survival benefit, the outcome of surgery during most enrolled studies were lack, so we could not rule out that the survival benefit in the RT/CRT group might due to the effect of surgery. Similarly, the prognosis for advanced and recurrent OCCC was poor; various follow-up lengths might influence the evaluation of progression and death rates. 5-year PFS and 5-year OS might not sensitively detect the different oncology outcome. Another point deserving attention is that all studies included in the present article were non-randomized, retrospective analysis; the selection bias and the limited enrolled cases were the major limits for present meta-analysis. Therefore, owing to these limitations, we stress that the pooled results of the meta-analysis should be interpreted with caution.

Conclusions

The present investigation reviewed the current evidence on the role of adjuvant radiotherapy in OCCC. Although OCCC was considered to be relatively rarer and poorer prognosis subtype compared to common subtype of EOC, only small number of patients had adjuvant RT/CRT. The administration of radiotherapy might improve oncologic outcomes of OCCC; especially for advanced and recurrent cases, it might improve 5-year PFS of total cases and 5-year OS of advanced and recurrent cases. However, this review and meta-analysis was at high risk of bias and the results should be interpreted with caution. The available evidence was very limited; more convincing evidences based on RCTs are urgently needed.

Footnotes

Author Contributions

HY and YZ were major contributor in writing the manuscript and in charge of the final approval of the version to be published. All authors read and approved the final manuscript. All authors analyzed the literature review.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Availability of Data and Materials

The data generated in the present study may be requested from the corresponding author

ORCID iD

Hua Yang

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The Significance of Radiotherapy in Ovarian Clear Cell Carcinoma: A Systematic Review and Meta-Analysis

Abstract

Objective

Methods

Results

Conclusion

Keywords

Introduction

Materials and Methods

Literature Search

Statistical Analysis

Results

Evidence Acquisition

Evidence Synthesis

Methodological Quality and Risk of Bias Assessment

Discussion

Conclusions

Footnotes

Author Contributions

Declaration of Conflicting Interests

Funding

Availability of Data and Materials

ORCID iD

References