Residual Disease Threshold After Primary Surgical Treatment for Advanced Epithelial Ovarian Cancer, Part 1: A Systematic Review and Network Meta-Analysis

Abstract

Background: We present a systematic review and network meta-analysis (NMA) that is the precursor underpinning the Bayesian analyses that adjust for publication bias, presented in the same edition in AJT. The review assesses optimal cytoreduction for women undergoing primary advanced epithelial ovarian cancer (EOC) surgery.Areas of Uncertainty: To assess the impact of residual disease (RD) after primary debulking surgery in women with advanced EOC. This review explores the impact of leaving varying levels of primary debulking surgery.Data Sources: We conducted a systematic review and random-effects NMA for overall survival (OS) to incorporate direct and indirect estimates of RD thresholds, including concurrent comparative, retrospective studies of $100 adult women (18+ years) with surgically staged advanced EOC (FIGO stage III/IV) who had confirmed histological diagnoses of ovarian cancer. Pairwise meta-analyses of all directly compared RD thresholds was previously performed before conducting this NMA, and the statistical heterogeneity of studies within each comparison was evaluated using recommended methods.Therapeutic Advances: Twenty-five studies (n 5 20,927) were included. Analyses demonstrated the prognostic importance of complete cytoreduction to no macroscopic residual disease (NMRD), with a hazard ratio for OS of 2.0 (95% confidence interval, 1.8-2.2) for ,1 cm RD threshold versus NMRD. NMRD was associated with prolonged survival across all RD thresholds. Leaving NMRD was predicted to provide longest survival (probability of being best 5 99%). The results were robust to sensitivity analysis including only those studies that adjusted for extent of disease at primary surgery (hazard ratio 2.3, 95% confidence interval, 1.9-2.6). The overall certainty of evidence was moderate and statistical adjustment of effect estimates in included studies minimized bias. Conclusions:The results confirm a strong association between complete cytoreduction to NMRD and improved OS. The NMA approach forms part of the methods guidance underpinning policy making in many jurisdictions. Our analyses present an extension to the previous work in this area.

Residual Disease After Primary Surgical Treatment for Advanced Epithelial Ovarian Cancer, Part 2: Network Meta-analysis Incorporating Expert Elicitation to Adjust for Publication Bias

“…42–44 Owing to the volume of sensitivity analyses, we did not conduct any further node splitting 42–44 because this was previously performed in the base case analysis. 2…”

“…Forty-six references, reporting on 25 primary studies which included 28 analyses (n 5 20,927), met our inclusion criteria. Full details of searches along with a PRISMA flowchart, characteristics of included studies, and risk of bias assessments are provided by Bryant et al 2 The network diagram 41 and summary of designs in our network show the range of RD threshold comparisons after optimal cytoreductive surgery for advanced EOC (Figure 2). The most common RD thresholds were complete (0 cm) and near-optimal (,1 cm), while this was also the most widely reported comparison.…”

“…The results of the base case Bayesian NMA were consistent with the frequentist analysis, and there was also no evidence of inconsistency in the network. 2 There were no issues with model convergence in WinBUGS, 39 as indicated by Brooks-Gelman-Rubin, trace and autocorrelation plots, with the number of simulations used adequate (see Appendix Figures 3-8, http://links. lww.com/AJT/A124, http://links.lww.com/AJT/ A125, http://links.lww.com/AJT/A126, http://links.…”

“…A more extensive description of the aims of primary surgery in achieving "optimal cytoreduction" has been described in previous publications. 1,2 Evidence suggests that where there is "complete cytoreduction" (surgery that completely removes all visible tumour), survival is significantly improved compared with less-than-complete cytoreduction. [3][4][5] However, publication bias 6 leaves room for uncertainty as to the true value of complete cytoreduction, and opponents to the approach have raised concerns regarding the strength of the evidence base.…”

“…Ovarian cancers remain a major concern to women worldwide. 1 , 2 In advanced disease, surgery and platinum-based chemotherapy are the standard treatment options. Traditionally, this included upfront primary debulking surgery (PDS) which is performed to remove as much visible disease as possible.…”