Discussion
The debate about the efficacy of systematic lymphadenectomy in ovarian cancer in the literature remains unsettled. In this meta-analysis, we observed marginal significance in OS among sysLA in all stage ovarian cancer. In addition, sysLA was associated with improved PFS in all stage ovarian cancer. However, sysLA was associated with significantly higher intraoperative, but not postoperative, complications rate.
Early stage (Stage I-IIA) ovarian cancer should be distinguished from advanced stage (Stage IIB-IV) as the prognosis of the two diseases is quite different. Early stage ovarian cancer has a 10-year survival of more than 80%, while advanced stage ovarian cancer has a 5-year survival rate less than 40% (35-38). In early stage ovarian cancer, sysLA allows complete staging by confirming no distant microscopic disease and provides prognostic information that can guide treatment. Also, accurate staging may prevent unnecessary adjuvant chemotherapy. While the role of sysLA in advanced stage is still controversial. It was hypothesized that radical lymphadenectomy may benefit those who may have extensive lymph node metastasis since the surgery goal is to achieve optimal debulking. Another hypothesis pushed the case for the therapeutic role of lymphadenectomy in advanced disease is the pharmacologic sanctuary hypothesis. This hypothesis assumed that nodal metastasis of ovarian cancer may be less sensitive to systemic chemotherapy due to diminished blood supply, hence sysLA may be therapeutic in advanced disease to remove the occult lymph node metastasis and improve the survival (39-41).
There are 6 meta-analyses in the literature that addressed this debate. Those conducted before the Lymphadenectomy in Ovarian Neoplasm (LION) RCT provided a survival benefit of sysLA in all stage disease. Kim et al concluded that sysLA is efficient in improving OS in all stage disease compared to unsystematic lymphadenectomy (USL). However, this study did not clearly define follow up period for survival analysis and there were no data regarding PFS or recurrence rate (42). Similarly, Gao et al concluded that sysLA was efficient in improving 5-year OS in all stage disease and advanced ovarian cancer compared to USL. This study is limited by inconsistency of definition of USL, lack of data on impact of residual tumor status, PFS or recurrence rate (43). Zhou et al reported that SysLA was efficient in improving 5-year OS in all stage, early and advanced disease compared to USL in addition to improving PFS in advanced disease. Similarly, definition of unsystematic lymphadenectomy was not consistent among the included studies, and impact of residual tumor status was not considered (44).
When the LION trial was published, the results tipped the balance in favor of abandoning sysLA in advanced ovarian cancer because of no survival benefit in addition to higher incidence of postoperative complications. The LION trial results weighted in heavily in the meta-analyses that were conducted this year. Lin et al concluded that SysLA did not improve OS or PFS in optimally cytoreduction all stage ovarian cancer patients. However, definition of unsystematic lymphadenectomy was not consistent and no subgroup analysis was conducted according to cancer stage (45). Xu et al reported that analysis of RCT demonstrated that sysLA cannot improve OS or PFS in advanced ovarian cancer which is quite the opposite of his analysis of observational studies (46). Wang et al revealed that sysLA may improve OS but not PFS in optimally debulked advanced ovarian cancer (47).
Our metanalysis included 22 studies with 6,825 patients with ovarian cancer. The meta-analysis pooled results show that sysLA did not improve OS in all stage disease. Since the studies included a range of study population questioning whether pooled data may present a mixed effect of sysLA, we performed a thorough subgroup analysis. While results were close to significance, subgroup analysis of OS by splitting studies into RCTs and retrospective demonstrated that RCTs showed no significance, but retrospective studies were close to significance. However, subgroup analysis by RCT demonstrated statistical significance of sysLA regarding PFS in both RCT and observational studies. The LION trial was a prospectively randomized, well powered, multicenter international trial with large sample size. While the LION weight in the meta-analyses that included RCTs will affect the results heavily, the controversy between observational studies and the LION questions whether this discrepancy is a result of inherited pitfalls in observational studies. However, another explanation may be related to LION study design. First, the LION assessed the participating centers and deemed them to be proficient in performing sysLA and the patients who participated in the trial were of median age 60 years and had good performance score. However, morbidity and mortality figures in the lymphadenectomy group were relatively high. Also, the LION excluded 65% of the registered population before randomization for different reasons, one must question the possible survival benefit that lymphadenectomy could have provided if patients with poor prognosis indicators were included. Nevertheless, LION still presents the best available evidence and should be considered over other observational studies.
Our novel MOGGE Meta-analysis Matrix (MMM) revealed interesting findings. Subgroup analysis by stage revealed statistically significant superiority of sysLA in OS in advanced disease (stage IIB-IV) whether they received adjuvant or neoadjuvant chemotherapy (C0). The clear advantage of sysLA on OS in advanced ovarian cancer was consolidated by a further subgroup analysis in the adjuvant chemotherapy group (C3). So, while the LION trial was among the included studies in this subgroup analysis, the scales here were tipped in favor of sysLA in this particular population. Survival benefit of sysLA was more prominent in studies covering particularly stage III-IV compared to stage IIB-IV (D3). This may be attributed to the weight of LION trial, which is included in the first, but not the second subgroup analysis. Although this may be apparently reflective of superiority of LION trial study design, impact of disease stage was investigated. Approximately 78% of study population in LION trial were staged as IIIB to IV (10). Similarly, Du Bios el al. is another study included in the first but not the second analysis (included population was stage IIB to IV). Of their cohort, only 79.6% were staged as IIIB to IV. In comparison, all patients reported by Chang et al. were staged as IIIC (23), all patients reported by Eoh et. al. were stage IIIC-IV (16), and 94% of patients reported by Paik et. al. were stage IIIB-IV (18). In addition, LION trial did not present subgroup results based on disease stage. Therefore, study design may not be the only contributing factor, and OS benefit of sysLA may be associated with more advanced stages, including stage IIIB or IIIC, compared to earlier stages, including stage IIB. Unfortunately, specific studies on stage IIIB or IIIC are too few to draw a direct conclusion. Therefore, it seems that although LION study provides the most robust level of evidence, our current results may warrant further assessment/subgroup analysis that narrows the spectrum toward more advanced stages specifically stage IIIB, IIIC.
Unlike women who received adjuvant chemotherapy, there was clearly no survival benefit of sysLA among women who received neoadjuvant chemotherapy regardless of disease stage. Therefore, neoadjuvant chemotherapy seems to omit need for sysLA if ever needed. This outcome may reflect either that: (1) neoadjuvant chemotherapy provides therapeutic benefit that deems sysLA unnecessary, or (2) selected patients for neoadjuvant chemotherapy who responded to treatment may still yield a poor prognosis that limits survival benefit of sysLA. However, recent evidence reflects that prognosis among women with advanced ovarian cancer receiving neoadjuvant chemotherapy is non inferior to adjuvant chemotherapy after surgery (6, 48). Given surgical complications of sysLA, these findings raise a question whether neoadjuvant chemotherapy may be considered in women with stage III-IV to avert sysLA if the latter is anticipated to improve survival.
Our metanalysis is the first to date to evaluate intraoperative complications of sysLA in ovarian cancer. It is of crucial importance in determining the benefit risk of performing a complex procedure as lymphadenectomy. Our metanalysis overcame the common limitation that most of the previously published metanalyses faced which is non-consistent definition of unsystematic lymphadenectomy among the included studies by dividing the control groups into selective lymphadenectomy and no lymphadenectomy groups. This meta-analysis provides a novel and comprehensive subgroup analysis to reveal specific conclusions.
However, this meta-analysis is limited by heterogeneity of the included studies. Since most of the studies were retrospective, they might contain selection and confounding biases. No subgroup analysis was conducted with regard to histological type because of no individual patient data or aggregate level data available. Histological subtype may present different biological tumor behaviors and hence different therapy lines.
In conclusion, sysLA was associated with improved PFS, but not improved OS, in all stages of ovarian cancer. Current evidence, based on a well-designed RCT, did not endorse a prognostic role of sysLA in women with advanced ovarian cancer. Nevertheless, future studies on a narrow spectrum of patients with stage IIIB and IIIC may be warranted particularly those who received adjuvant chemotherapy. On the contrary, women who received neoadjuvant chemotherapy did not seem to benefit from sysLA regardless of study design or disease stage.
Acknowledgement: none
Disclosure of Interests: The authors have no conflicts of interest. No financial disclosure to declare