Article Text
Abstract
Objective The role of splenectomy on cytoreductive surgery in patients with ovarian cancer remains controversial. We conducted this meta-analysis to evaluate the safety and impact of survival outcome of splenectomy in patients with ovarian cancer.
Methods In this meta-analysis we analyzed studies published in PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), International Clinical Trials Registry Platform (ICTRP), and Clinical Trials. gov that appeared in our search from inception to November 10, 2023.
Result This meta-analysis included 10 studies, totaling 6297 patients, comprising one prospective and nine retrospective analyses. The results indicated no significant disparity in overall survival and mortality (OR 1.14, 95% CI 0.69 to 1.87, p=0.62) between the splenectomy cohort and the no splenectomy (required) cohort. Furthermore, relative to the no splenectomy (required) cohort, the splenectomy group showed a heightened incidence of overall post-operative complications (odds ratio (OR) 1.66, 95% CI 1.65 to 2.61, p=0.03), an extended duration of hospitalization (mean difference (MD) 2.88 days, 95% CI 2.09 to 3.67), an increased interval from surgery to the initiation of adjuvant chemotherapy (MD 4.44 days, 95% CI 2.41 to 6.07, p<0.0001), and a greater probability of undergoing reoperation (OR 4.7, 95% CI 1.91 to 11.55, p=0.0007). However, concerning the occurrence of specific post-operative complications such as anastomotic leakage (OR 0.97, 95% CI 0.33 to 2.84, p=0.95), pancreatic fistula (OR 3.25, 95% CI 0.63 to 16.7, p=0.16), abdominal abscess (OR 1.75, 95% CI 0.25 to 12.33, p=0.57), sepsis (OR 1.46, 95% CI 0.77 to 2.77, p=0.25), and thrombotic events (OR 1.82, 95% CI 0.93 to 3.57, p=0.08), no significant differences were observed between the two cohorts.
Conclusion Splenectomy does not impact the overall survival and mortality of patients with ovarian cancer. Thus, it can be considered an acceptably safe procedure to obtain optimal cytoreduction. However, caution should be taken when selecting patients for splenectomy because it is associated with an increased incidence of overall post-operative complications, prolonged hospital stays, delayed initiation of adjuvant chemotherapy, and an increased probability of requiring subsequent surgical interventions.
- Ovarian Cancer
- Postoperative complications
- Splenectomy
Data availability statement
Data are available in a public, open access repository. Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, an indication of whether changes were made, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Minimizing residual lesions after surgery is the basic goal of advanced ovarian cancer treatment. If the tumor is found in the spleen or perisplenic tissue or intra-operative splenic injury occurs, splenectomy might be necessary. However, a comprehensive evaluation of the safety and survival outcomes of splenectomy in patients with advanced ovarian cancer is still lacking.
WHAT THIS STUDY ADDS
Splenectomy does not impact overall survival or mortality. However, caution should be taken when selecting patients for splenectomy because it is associated with an increased incidence of overall post-operative complications, prolonged hospital stays, delayed initiation of adjuvant chemotherapy, and an increased probability of requiring subsequent surgical interventions.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
This review shows that splenectomy does not impact overall survival or mortality. In order to achieve better tumor cell reduction, splenectomy is advisable. However, considering peri-operative indicators, splenectomy should be individualized.
Introduction
The cornerstone of treatment for advanced ovarian cancer is primary cytoreductive surgery paired with platinum-based chemotherapy. Notably, the extent of residual disease post-surgery is a pivotal independent prognostic factor,1 with evidence indicating that a 10% reduction in residual lesions correlates with a 5.5% increase in median patient survival.2 This benefit extends even to recurrent cases, where complete cytoreductive surgery is advantageous.3
In cases of advanced ovarian cancer with substantial upper abdominal metastases, if the tumor is found in the spleen or perisplenic tissue or intra-operative splenic injury occurs, splenectomy might be necessary. The impact of splenectomy on the survival outcomes and safety of patients with ovarian cancer, however, is a matter of ongoing debate. Some studies show that splenectomy may decrease post-operative tumor load, potentially improving prognosis.4 5 In contrast, others argue that the immunological role of the spleen might confer anti-tumor benefits, and its removal could exacerbate disease progression, adversely affecting survival without significantly impacting peri-operative complications—a hypothesis corroborated in gastric cancer mouse models post-splenectomy.6 7
Current literature primarily emphasizes that the success of cytoreductive surgery is linked with improved prognostic outcomes in patients with ovarian cancer. However, explicit guidelines delineating the role of splenectomy within the ambit of cytoreductive procedures for ovarian cancer remain notably absent. Moreover, the benefits of performing splenectomy as part of cytoreductive surgery for ovarian cancer lack evidence from evidence-based medicine. This meta-analysis was conducted to scrutinize the safety and survival outcome of splenectomy in the context of cytoreductive surgery for patients with ovarian cancer.
Methods
Protocol Registration
This meta-analysis was conducted following the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA), and it was registered with the International Prospective Register of Systematic Reviews (CRD42023494364).
Inclusion and Exclusion Criteria
Inclusion criteria were as follows: (1) studies encompassing splenectomy and no splenectomy (required) groups in patients with ovarian cancer, comparing the safety and survival outcomes; (2) reports of at least one of the following outcomes: post-operative complications, overall survival, mortality, length of hospital stay, reoperation, and duration from surgery to commencement of adjuvant chemotherapy; (3) articles in English published in international peer-reviewed journals.
The following exclusion criteria were applied: (1) reviews, editorials, letters, case reports, or studies without control group data; (2) research on other malignant tumors or metastatic ovarian cancer; (3) case reports or literature with redundant data (preference given to the most recent or comprehensive data); and (4) studies with fewer than 20 cases.
Search Strategy and Study Selection
We analyzed studies published in PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), International Clinical Trials Registry Platform (ICTRP), and Clinical Trials. gov that appeared in our search from inception to November 10, 2023. Additionally, we reviewed the reference lists of published reviews and retrieved articles for any additional relevant trials to identify relevant literature reporting the effect of splenectomy in patients with ovarian cancer on safety and survival outcome. The following search terms were used: (Ovarian Neoplasms (MeSH) OR “Ovary neoplasm” OR “Ovary carcinoma” OR “Ovary cancer”) AND (“splenectomy” OR “no splenectomy (required)”)
Two researchers (YLC and MMC) independently assessed the eligibility of the studies based on titles and abstracts. All potential articles were then independently reviewed in full by the same two researchers for further evaluation. Any disagreements between the authors were resolved through discussion with a third independent researcher (LH).
Data Extraction
Two independent reviewers (ZJQ and MMC) extracted the data in duplicate and recorded them in a standardized database using a pre-defined extraction form that included methods, study quality, participants, and outcomes. The reviewers extracted the data while blinded to the names of the authors and institutions, sources of funding, and acknowledgments of the included trials. Double data entry was conducted by another researcher (YSW). The collected data included the period of study, geographic location, study design, patient cohort size, surgical methods, and median follow-up duration. Primary outcomes assessed were overall survival, mortality, and a spectrum of post-operative complications, encompassing anastomotic leakage, pancreatic fistula, abdominal abscess, sepsis, and thrombotic events. Secondary outcomes comprised hospital stay duration, interval from surgery to adjuvant chemotherapy initiation, and frequency of reoperation.
Quality Assessment
The Newcastle–Ottawa Quality Assessment Scale8 was used for quality assessment of observational studies. Eight elements in the scale are used to assess patient selection, comparability and outcome of interest. High-quality elements are awarded by adding one or two stars, and the stars are then added up to compare the study quality. A threshold of six stars or above has been considered indicative of high quality. The quality of the included studies was assessed independently by two reviewers (YSW and MMC) and any differences that arose were resolved by discussion; if no consensus was reached, a third review author (AZ) was involved.
Statistical Analysis
Odds ratios (OR) and corresponding 95% confidence intervals (CI) were used to analyze the binary variables. The continuity variables were analyzed using the mean difference (MD) and the corresponding 95% CI. Statistical heterogeneity was evaluated using I2 values. High heterogeneity occurs when I2 is >50%.9 Potential sources of heterogeneity were identified by sensitivity analysis and sub-group analysis. Due to the small number of included studies, we did not use funnel plots to explore the possibility of small study effects (p<0.05 was considered statistically significant).
Results
Study Selection
After rigorous inclusion and exclusion by the researchers, 10 studies were eligible for final inclusion in the analysis,10–19 including one prospective study and nine retrospective studies. The specific screening process is shown in Figure 1.
Characteristics and Quality
A total of 10 studies were included in the meta-analysis (Table 1). These studies were conducted in various countries, including the USA (n=3), France (n=1), Poland (n=1), Netherlands (n=1), Italy (n=1), Turkey (n=1), the UK (n=1), and Romania (n=1). The meta-analysis included 6297 patients, 542 of whom underwent splenectomy as a treatment group (8.6%) and 5755 of whom did not undergo splenectomy as a control group (91.4%). The quality of the literature was evaluated according to the Newcastle–Ottawa Quality Assessment scale. Four of the 10 studies received six stars, one article received seven stars, and the remaining five received eight stars (Table 2).
Primary Outcome Measures
Ovarall Survival and Mortality
A total of seven studies reported overall survival after surgery, and pooled data analysis of these studies showed that the splenectomy group had worse overall survival (MD −12.16, 95% CI −21.09 to −3.23, p=0.008) compared with the splenic preservation group. High heterogeneity was observed between the studies (p<0.00001, I2=99%; see Online supplemental figure S1A). We conducted sub-group analysis and sensitivity analysis but failed to find the exact source of heterogeneity. Considering that these seven studies were all retrospective studies, the median follow-up time of each study was different, and the overall survival data reported in the literature did not specify whether the overall survival time was 3 or 5 years, so the survival data of each study were statistically described. In the seven studies reported in the literature there was no significant difference in overall survival between the splenectomy group and the no splenectomy (required) group (p>0.05 in each study), indicating when the follow-up time or measured outcome index (5- or 3-year survival time) was unified, the overall survival between the two groups might be similar. However, more studies are needed to confirm these results. Five studies reported mortality in patients with ovarian cancer, involving a total of 5189 patients. The pooled results indicated that there was no significant difference in post-operative death between the splenectomy group and the no splenectomy (required) group (OR 1.14, 95% CI 0.69 to 1.87, p=0.62), with no significant heterogeneity between the studies (p=0.94, I2=0%; see Online supplemental figure S1B).
Supplemental material
Post-operative Complications
A total of five studies reported overall post-operative complications in patients with ovarian cancer undergoing cytoreductive surgery. The integrated results showed that the incidence of overall post-operative complications in the splenectomy group was higher (OR 1.66, 95% CI 1.65 to 2.61, p=0.03), with low heterogeneity between studies (p=0.12, I2=45%; see Online supplemental figure S2A). As for specific post-operative complications, four studies reported the occurrence of anastomotic leakage (especially referring to bowel) after surgery (OR 0.97, 95% CI 0.33 to 2.84, p=0.95; see Online supplemental figure S2B), four studies reported post-operative pancreatic leakage (OR 3.25, 95% CI 0.63 to 16.7, p=0.16; see Online supplemental figure S2C), and seven studies reported post-operative thromboembolic events (OR 1.82, 95% CI 0.93 to 3.57, p=0.08; see Online supplemental figure S2D). A total of three studies reported post-operative abdominal abscess (OR 1.75, 95% CI 0.25 to 12.33; p=0.57; see Online supplemental figure S2E) and four studies reported post-operative sepsis (OR 1.46, 95% CI 0.77 to 2.77, p=0.25; see Online supplemental figure S2F). There was no significant difference in the incidence of specific complications between the splenectomy and no splenectomy (required) groups, and the heterogeneity between these studies was low. Detailed data on post-operative complications are shown in Table 3.
Supplemental material
Secondary Outcome Measures
A pooled analysis of data from eight studies reporting post-operative hospital stay including 5850 patients showed that the splenectomy group had a longer hospital stay than the no splenectomy (required) group (MD 3.22, 95% CI 1.63 to 4.81, p<0.0001). However, high heterogeneity was observed between these studies (p=0.004, I2=66%; see Online supplemental figure S3A). We performed sensitivity analyses to assess potential heterogeneity. Sensitivity analysis found that one study may be the source of heterogeneity.11 Excluding this factor greatly reduced the heterogeneity (p=0.78, I2=0%), and the pooled data analysis of the remaining seven studies still suggested that the splenectomy group required a longer hospital stay after surgery (MD 2.88, 95% CI 2.09 to 3.67, p<0.00001; see Online supplemental figure S3B)
Supplemental material
Five studies reported the time from surgery to adjuvant chemotherapy includig 5234 patients and a pooled data analysis of these studies showed that the splenectomy group took a longer time to adjuvant chemotherapy than the no splenectomy (required) group (MD 3.33, 95% CI 0.99 to 5.67, p=0.005), but there was high heterogeneity among studies (p=0.02, I2=64%; see Online supplemental figure S3C). Sensitivity analysis found that one study may be the source of heterogeneity.10 Exclusion of this factor significantly reduced heterogeneity (p=0.69, I2=0%), and pooled data analysis of the results of the remaining four studies still suggested that the splenectomy group needed longer to start adjuvant chemotherapy after surgery (MD 4.44, 95% CI 2.41 to 6.07, p<0.0001; see Online supplemental figure S3D). Three studies reported reoperation, including a total of 1072 patients. According to the aggregated data analysis, compared with the splenectomy group, more patients in the splenectomy group required reoperation after surgery (OR 4.7, 95% CI 1.91 to 11.55, p=0.0007) and no significant heterogeneity was observed between the studies (p=0.44, I2=0%; see Online supplemental figure S3E).
Discussion
Summary of Main Results
The findings indicate no difference in overall survival and mortality between the groups undergoing splenectomy and those with no splenectomy (required). Nevertheless, the splenectomy cohort had a higher incidence of overall post-operative complications, prolonged hospitalization, increased duration from surgery to initiation of adjuvant chemotherapy, and an increased risk of subsequent reoperations.
Results in the Context of Published Literature
Our meta-analysis showed no marked differences in overall survival and mortality between groups undergoing splenectomy and those opting for no splenectomy (required). Parallel findings were reported by Eisenhauer et al, who observed no significant differences in survival rates and overall survival among patients subjected to extensive upper abdominal surgeries, including splenectomy and diaphragm stripping, compared with those undergoing less extensive procedures with analogous residual lesion sizes.20 A contributing factor to this outcome may be the heightened incidence of post-operative complications in patients who underwent splenectomy, underscoring the need to consider the implications of such extensive surgeries on survival.
Lepinay et al found a notably reduced survival duration in patients who received intestinal resection compared with those who did not.21 Furthermore, Szubert et al investigated ultra-radical surgical groups including total colectomy and found a significantly shortened survival span even in instances of negligible residual disease.22 Additionally, the histopathology of tumor tissue profoundly influences patient outcomes.
The Cancer Genome Atlas (TCGA) research network categorizes high-grade serous ovarian cancer into four transcriptional sub-types: immune-reactive, differentiated, proliferative, and mesenchymal.23 The findings by Ohsuga et al suggest that patients with the mesenchymal sub-type, often diagnosed at an advanced stage, typically present with extensive upper abdominal metastasis, miliary dissemination, a high likelihood of ascites, and are prone to diffuse peritoneal disease and pancake-like omental metastases.24 Such disease profiles, frequently entailing extensive upper abdominal metastasis involving the diaphragm and spleen, are associated with lower rates of complete resection. The presence of upper abdominal metastasis is generally indicative of aggressive tumor biology, portending a grim prognosis.25 The findings of Horowitz et al corroborate that, even with thorough optimal cytoreduction, an initial high disease burden may result in a poorer prognosis.26 Consequently, the varying prognoses in late-stage ovarian cancer involving splenectomy are attributable to distinct tumor tissue biologies. Future surgical strategies for patients with ovarian cancer could be tailored more precisely based on the specific tumor biology.
Post-operative complications serve as critical metrics for assessing the safety of surgical procedures. Splenectomy has been identified as an independent risk factor contributing to peri-operative morbidity and mortality, with complication rates ranging from 29% to 46%.27 28 Typical complications following splenectomy include anastomotic and pancreatic leakage, thrombosis, abdominal abscess, and sepsis. Our meta-analysis indicates a higher overall incidence of complications in patients undergoing splenectomy compared with those retaining the spleen, although no substantial difference was observed in specific post-operative complications between the two cohorts. Bristow et al reported a more complex surgical profile in patients with ovarian cancer undergoing splenectomy compared with the control group.29 This complexity, possibly associated with efforts to achieve complete R0 resection, may necessitate additional extensive surgical procedures such as intestinal and diaphragm resections, thereby prolonging surgery duration, escalating intra-operative bleeding, and consequently increasing the risk of post-operative complications. McCann et al suggest that the heightened overall complication rates in the splenectomy cohort may also be attributable to a greater proportion of patients with advanced stage (International Federation of Gynecology and Obstetrics IV) disease and increased comorbidities.15 Therefore, these complications are not solely a consequence of splenectomy, but also stem from the impacts of other extensive surgical interventions and pre-existing comorbidities.
Concerning the secondary outcomes, the splenectomy group showed a heightened incidence of post-operative complications, potentially leading to extended hospitalizations and an increased need for surgical reintervention. On the other hand, patient age, post-operative anemia, infection, thromboembolic events, and gastrointestinal complications also prolong hospital stay. In terms of the interval between surgery and the initiation of adjuvant chemotherapy, the research by Joneborg et al indicated that, despite an upsurge in post-operative complications and prolonged hospital stays, upper abdominal surgery did not significantly delay the onset of adjuvant chemotherapy.30 Contrarily, our meta-analysis shows that patients who underwent splenectomy experienced longer hospital stays and also faced delays in commencing adjuvant chemotherapy compared with those in the no splenectomy (required) group, thereby extending the Return to Intended Oncologic Treatment (RIOT)—a novel oncological quality indicator measuring the duration until full recovery and resumption of cancer therapy.31 Few articles analyzed the impact of splenectomy on RIOT. McCann et al found in their case–control study a significant delay in recovery of 4.5 days in the splenectomy group.15 This postponement is likely attributable to the amplified incidence of post-operative complications and the protracted recovery phase necessitated by the more extensive surgical approach. As for the reason for the reoperation, Eisenkop et al reported that reoperation was associated with post-operative bleeding.17 However, lymphocysts with infection, thromboembolism, and gastrointestinal complications should also be taken into account.
Strengths and Weaknesses
To the best of our knowledge, this study is the first meta-analysis to examine the impact of splenectomy on safety and survival outcomes in patients with advanced ovarian cancer. In addition, the article involves a number of peri-operative indicators including post-operative complications, length of hospital stay, and time from operation to initiation of adjuvant chemotherapy, providing specific information for individualized clinical tumor treatment.
However, our meta-analysis is subject to certain limitations. First, there was notable heterogeneity in the overall survival analysis across the studies, with specific follow-up durations and 3- or 5-year survival times not uniformly reported, but rather statistically inferred. Second, the majority of the included studies were retrospective in nature and the current pool of related research is somewhat limited. Factors such as regional variations, patient demographics, surgical expertise, types of surgical procedures, and the duration of follow-up introduce potential confounders, rendering the substantial heterogeneity among the studies an issue that cannot be overlooked. Therefore, further prospective studies are essential to corroborate these findings.
Implications for Practice and Future Research
High-quality studies on the survival of patients with ovarian cancer after splenectomy are limited and the conclusions between studies have not been unified. After our search, no meta-analysis of this study could be found to make a comprehensive evaluation and reach a conclusion, therefore this research investigates the safety and survival outcomes of splenectomy in patients with ovarian cancer.
Conclusion
Splenectomy does not impact the overall survival and mortality of patients with ovarian cancer. Thus, it can be considered an acceptably safe procedure to obtain optimal cytoreduction. However, caution should be taken when selecting patients for splenectomy because it is associated with an increased incidence of overall post-operative complications, prolonged hospital stays, delayed initiation of adjuvant chemotherapy, and an increased probability of requiring subsequent surgical interventions.
Data availability statement
Data are available in a public, open access repository. Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information.
Ethics statements
Patient consent for publication
Ethics approval
Not applicable.
References
Footnotes
Contributors YW: Conceptualization, data curation. YC: Writing - original draft preparation. ZQ: Methodology, software, validation, visualization, investigation. MC: Methodology, formal analysis. AZ: Supervision. LH: Writing - review editing, guarantor.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.