Impact of residual disease as a prognostic factor for survival in women with advanced epithelial ovarian cancer after primary surgery.

BACKGROUND: Ovarian cancer is the seventh most common cancer among women and a leading cause of death from gynaecological malignancies. Epithelial ovarian cancer is the most common type, accounting for around 90% of all ovarian cancers. This specific type of ovarian cancer starts in the surface layer covering the ovary or lining of the fallopian tube. Surgery is performed either before chemotherapy (upfront or primary debulking surgery (PDS)) or in the middle of a course of treatment with chemotherapy (neoadjuvant chemotherapy (NACT) and interval debulking surgery (IDS)), with the aim of removing all visible tumour and achieving no macroscopic residual disease (NMRD). The aim of this review is to investigate the prognostic impact of size of residual disease nodules (RD) in women who received upfront or interval cytoreductive surgery for advanced (stage III and IV) epithelial ovarian cancer (EOC). OBJECTIVES: To assess the prognostic impact of residual disease after primary surgery on survival outcomes for advanced (stage III and IV) epithelial ovarian cancer. In separate analyses, primary surgery included both upfront primary debulking surgery (PDS) followed by adjuvant chemotherapy and neoadjuvant chemotherapy followed by interval debulking surgery (IDS). Each residual disease threshold is considered as a separate prognostic factor. SEARCH METHODS: We searched CENTRAL (2021, Issue 8), MEDLINE via Ovid (to 30 August 2021) and Embase via Ovid (to 30 August 2021). SELECTION CRITERIA: We included survival data from studies of at least 100 women with advanced EOC after primary surgery. Residual disease was assessed as a prognostic factor in multivariate prognostic models. We excluded studies that reported fewer than 100 women, women with concurrent malignancies or studies that only reported unadjusted results. Women were included into two distinct groups: those who received PDS followed by platinum-based chemotherapy and those who received IDS, analysed separately. We included studies that reported all RD thresholds after surgery, but the main thresholds of interest were microscopic RD (labelled NMRD), RD 0.1 cm to 1 cm (small-volume residual disease (SVRD)) and RD > 1 cm (large-volume residual disease (LVRD)). DATA COLLECTION AND ANALYSIS: Two review authors independently abstracted data and assessed risk of bias. Where possible, we synthesised the data in meta-analysis. To assess the adequacy of adjustment factors used in multivariate Cox models, we used the 'adjustment for other prognostic factors' and 'statistical analysis and reporting' domains of the quality in prognosis studies (QUIPS) tool. We also made judgements about the certainty of the evidence for each outcome in the main comparisons, using GRADE. We examined differences between FIGO stages III and IV for different thresholds of RD after primary surgery. We considered factors such as age, grade, length of follow-up, type and experience of surgeon, and type of surgery in the interpretation of any heterogeneity. We also performed sensitivity analyses that distinguished between studies that included NMRD in RD categories of < 1 cm and those that did not. This was applicable to comparisons involving RD < 1 cm with the exception of RD < 1 cm versus NMRD. We evaluated women undergoing PDS and IDS in separate analyses. MAIN RESULTS: We found 46 studies reporting multivariate prognostic analyses, including RD as a prognostic factor, which met our inclusion criteria: 22,376 women who underwent PDS and 3697 who underwent IDS, all with varying levels of RD. While we identified a range of different RD thresholds, we mainly report on comparisons that are the focus of a key area of clinical uncertainty (involving NMRD, SVRD and LVRD). The comparison involving any visible disease (RD > 0 cm) and NMRD was also important. SVRD versus NMRD in a PDS setting In PDS studies, most showed an increased risk of death in all RD groups when those with macroscopic RD (MRD) were compared to NMRD. Women who had SVRD after PDS had more than twice the risk of death compared to women with NMRD (hazard ratio (HR) 2.03, 95% confidence interval (CI) 1.80 to 2.29; I2 = 50%; 17 studies; 9404 participants; moderate-certainty). The analysis of progression-free survival found that women who had SVRD after PDS had nearly twice the risk of death compared to women with NMRD (HR 1.88, 95% CI 1.63 to 2.16; I2 = 63%; 10 studies; 6596 participants; moderate-certainty). LVRD versus SVRD in a PDS setting When we compared LVRD versus SVRD following surgery, the estimates were attenuated compared to NMRD comparisons. All analyses showed an overall survival benefit in women who had RD < 1 cm after surgery (HR 1.22, 95% CI 1.13 to 1.32; I2 = 0%; 5 studies; 6000 participants; moderate-certainty). The results were robust to analyses of progression-free survival. SVRD and LVRD versus NMRD in an IDS setting The one study that defined the categories as NMRD, SVRD and LVRD showed that women who had SVRD and LVRD after IDS had more than twice the risk of death compared to women who had NMRD (HR 2.09, 95% CI 1.20 to 3.66; 310 participants; I2 = 56%, and HR 2.23, 95% CI 1.49 to 3.34; 343 participants; I2 = 35%; very low-certainty, for SVRD versus NMRD and LVRD versus NMRD, respectively). LVRD versus SVRD + NMRD in an IDS setting Meta-analysis found that women who had LVRD had a greater risk of death and disease progression compared to women who had either SVRD or NMRD (HR 1.60, 95% CI 1.21 to 2.11; 6 studies; 1572 participants; I2 = 58% for overall survival and HR 1.76, 95% CI 1.23 to 2.52; 1145 participants; I2 = 60% for progression-free survival; very low-certainty). However, this result is biased as in all but one study it was not possible to distinguish NMRD within the < 1 cm thresholds. Only one study separated NMRD from SVRD; all others included NMRD in the SVRD group, which may create bias when comparing with LVRD, making interpretation challenging. MRD versus NMRD in an IDS setting Women who had any amount of MRD after IDS had more than twice the risk of death compared to women with NMRD (HR 2.11, 95% CI 1.35 to 3.29, I2 = 81%; 906 participants; very low-certainty). AUTHORS' CONCLUSIONS: In a PDS setting, there is moderate-certainty evidence that the amount of RD after primary surgery is a prognostic factor for overall and progression-free survival in women with advanced ovarian cancer. We separated our analysis into three distinct categories for the survival outcome including NMRD, SVRD and LVRD. After IDS, there may be only two categories required, although this is based on very low-certainty evidence, as all but one study included NMRD in the SVRD category. The one study that separated NMRD from SVRD showed no improved survival outcome in the SVRD category, compared to LVRD. Further low-certainty evidence also supported restricting to two categories, where women who had any amount of MRD after IDS had a significantly greater risk of death compared to women with NMRD. Therefore, the evidence presented in this review cannot conclude that using three categories applies in an IDS setting (very low-certainty evidence), as was supported for PDS (which has convincing moderate-certainty evidence).

Ultra-radical (extensive) surgery versus standard surgery for the primary cytoreduction of advanced epithelial ovarian cancer.

BACKGROUND: Ovarian cancer is the seventh most common cancer among women and the leading cause of death in women with gynaecological malignancies. Opinions differ regarding the role of ultra-radical (extensive) cytoreductive surgery in ovarian cancer treatment. OBJECTIVES: To evaluate the effectiveness and morbidity associated with ultra-radical/extensive surgery in the management of advanced-stage epithelial ovarian cancer. SEARCH METHODS: We searched CENTRAL (2021, Issue 11), MEDLINE Ovid and Embase Ovid up to November 2021. We also searched registers of clinical trials, abstracts of scientific meetings, reference lists of included studies and contacted experts in the field. SELECTION CRITERIA: Randomised controlled trials (RCTs) or non-randomised studies (NRS), analysed using multivariate methods, that compared ultra-radical/extensive and standard surgery in women with advanced primary epithelial ovarian cancer. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed whether potentially relevant studies met the inclusion criteria, abstracted data and assessed the risk of bias. We identified three NRS and conducted meta-analyses where possible. MAIN RESULTS: We identified three retrospective observational studies for inclusion in the review. Two studies included women exclusively undergoing upfront primary debulking surgery (PDS) and the other study including both PDS and interval debulking surgical (IDS) procedures. All studies were at critical risk of bias due to retrospective and non-randomised study designs. Meta-analysis of two studies, assessing 397 participants, found that women who underwent radical procedures, as part of PDS, may have a lower risk of mortality compared to women who underwent standard surgery (adjusted HR 0.60, 95% CI 0.43 to 0.82; I2 = 0%; very low-certainty evidence), but the evidence is very uncertain. The results were robust to a sensitivity analysis including women with more-extensive disease (carcinomatosis) (adjusted HR 0.61, 95% CI 0.44 to 0.85; I2 = 0%; n = 283, very low-certainty evidence), but the evidence is very uncertain. One study reported a comparison of radical versus standard surgical procedures associated with both PDS and IDS procedures, but a multivariate analysis was only undertaken for disease-free survival (DFS) and therefore the certainty of the evidence was not assessable for overall survival (OS) and remains very low. The lack of reporting of OS meant the study was at high risk of bias for selective reporting of outcomes. One study, 203 participants, found that women who underwent radical procedures as part of PDS may have a lower risk of disease progression or death compared to women who underwent standard surgery (adjusted HR 0.62, 95% CI 0.42 to 0.92; very low-certainty evidence), but the evidence is very uncertain. The results were robust to a sensitivity analysis in one study including women with carcinomatosis (adjusted HR 0.52, 95% CI 0.33 to 0.82; n = 139; very low-certainty evidence), but the evidence is very uncertain. A combined analysis in one study found that women who underwent radical procedures (using both PDS and IDS) may have an increased chance of disease progression or death than those who received standard surgery (adjusted HR 1.60, 95% CI 1.11 to 2.31; I2 = 0%; n = 527; very low-certainty evidence), but the evidence is very uncertain. In absolute and unadjusted terms, the DFS was 19.3 months in the standard surgery group, 15.8 in the PDS group and 15.9 months in the IDS group. All studies were at critical risk of bias and we only identified very low-certainty evidence for all outcomes reported in the review. Perioperative mortality, adverse events and quality of life (QoL) outcomes were either not reported or inadequately reported in the included studies. Two studies reported perioperative mortality (death within 30 days of surgery), but they did not use any statistical adjustment. In total, there were only four deaths within 30 days of surgery in both studies. All were observed in the standard surgery group, but we did not report a risk ratio (RR) to avoid potentially misleading results with so few deaths and very low-certainty evidence. Similarly, one study reported postoperative morbidity, but the authors did not use any statistical adjustment. Postoperative morbidity occurred more commonly in women who received ultra-radical surgery compared to standard surgery, but the certainty of the evidence was very low. AUTHORS' CONCLUSIONS: We found only very low-certainty evidence comparing ultra-radical surgery and standard surgery in women with advanced ovarian cancer. The evidence was limited to retrospective, NRSs and so is at critical risk of bias. The results may suggest that ultra-radical surgery could result in improved OS, but results are based on very few women who were chosen to undergo each intervention, rather than a randomised study and intention-to-treat analysis, and so the evidence is very uncertain. Results for progression/DFS were inconsistent and evidence was sparse. QoL and morbidity was incompletely or not reported in the three included studies. A separate prognostic review assessing residual disease as a prognostic factor in this area has been addressed elsewhere, which demonstrates the prognostic effect of macroscopic debulking to no macroscopic residual disease. In order to aid existing guidelines, the role of ultra-radical surgery in the management of advanced-stage ovarian cancer could be addressed through the conduct of a sufficiently powered, RCT comparing ultra-radical and standard surgery, or well-designed NRSs, if this is not possible.