Neoadjuvant chemotherapy before surgery versus surgery followed by chemotherapy for initial treatment in advanced epithelial ovarian cancer.

Rationale: Epithelial ovarian cancer (EOC) presents at an advanced stage in the majority of women. These women require a combination of surgery and chemotherapy for optimal treatment. Conventional treatment has been to perform surgery first and then give chemotherapy. However, there may be advantages to using chemotherapy before surgery.

Objectives: To assess the advantages and disadvantages of treating women with advanced EOC with chemotherapy before cytoreductive surgery (neoadjuvant chemotherapy (NACT)) compared with conventional treatment where chemotherapy follows cytoreductive surgery (primary cytoreductive surgery (PCRS)).

Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform on 21 March 2024. We also checked the reference lists of relevant papers for further studies. We contacted the principal investigators of relevant trials for further information.

Eligibility criteria: Randomised controlled trials (RCTs) of women with advanced epithelial ovarian cancer (International Federation of Gynecology and Obstetrics (FIGO) stage III/IV) who were randomly allocated to treatment groups that compared platinum-based chemotherapy before cytoreductive surgery with platinum-based chemotherapy following cytoreductive surgery.

Outcomes: We extracted data on overall (OS) and progression-free survival (PFS), adverse events, surgically related mortality and morbidity, and quality of life outcomes.

Risk of bias: We used the Cochrane RoB 1 tool to assess risk of bias in RCTs.

Synthesis methods: We conducted meta-analyses using random-effects models (due to heterogeneity between studies) to calculate hazard ratios (HR), risk ratios (RR), mean differences (MD), and 95% confidence intervals (CI) for all outcomes. We assessed the certainty of evidence according to the GRADE approach.

Included studies: We identified a further 1022 titles and abstracts through our searches in this update (958 unique records after further de-duplication), adding to the 2227 titles and abstracts identified in previous versions of this review. A total of five RCTs of varying quality and size met the inclusion criteria. We identified no new completed studies in this update, but we did include additional data from existing studies. The studies assessed a total of 1774 women with stage III/IV ovarian cancer randomised to NACT followed by interval cytoreductive surgery (ICRS) or PCRS followed by chemotherapy. We included data from four studies in the meta-analyses (1692 participants).

Synthesis of results: Survival We found little or no difference between groups in OS (HR 0.96, 95% CI 0.86 to 1.08; P = 0.49; I² = 0%; 4 studies; 1692 women; high-certainty evidence) and likely little or no difference between groups in PFS (HR 0.98, 95% CI 0.88 to 1.08; P = 0.62; I² = 0%; 4 studies; 1692 women; moderate-certainty evidence). Adverse events Adverse events, surgical morbidity, and quality of life outcomes were variably and incompletely reported across studies. NACT reduces postoperative mortality (0.4% in the NACT group versus 3.3% in the PCRS group) (RR 0.18, 95% CI 0.06 to 0.52; P = 0.002; I² = 0%; 4 studies; 1542 women; high-certainty evidence). There are probably clinically meaningful differences in favour of NACT compared to PCRS in overall surgically related adverse effects (grade 3+ (G3+)) (6% in the NACT group versus 29% in the PCRS group) (RR 0.22, 95% CI 0.13 to 0.38; P < 0.001; I² = 0%; 2 studies; 435 women; moderate-certainty evidence). Organ resection NACT probably results in a large reduction in the need for stoma formation (5.8% in the NACT group versus 20.4% in the PCRS group) (RR 0.29, 95% CI 0.12 to 0.74; P = 0.009; I² = 70%; 2 studies; 632 women; moderate-certainty evidence) and probably reduces the risk of needing bowel resection at the time of surgery (13.0% in the NACT group versus 26.6% in the PCRS group) (RR 0.47, 95% CI 0.27 to 0.81; P = 0.007; I² = 84%; 4 studies; 1578 women; moderate-certainty evidence). Quality of life Global quality of life on the EORTC QLQ-C30 produced imprecise results in three studies, with high levels of heterogeneity (quality of life at six months: MD 6.62, 95% CI -2.89 to 16.13; P = 0.17; I² = 92%; 3 studies; 559 women; low-certainty evidence). Overall, functional and symptom scores may be slightly improved for NACT at 6 months, but similar by 12 months, although the differences might not be clinically meaningful.

Authors' conclusions: The available high- to moderate-certainty evidence shows there is likely little or no difference in primary survival outcomes between PCRS and NACT for those with advanced EOC who are suitable for either treatment option. NACT reduces the risk of postoperative mortality and likely reduces the risk of serious adverse events, especially those around the time of surgery, and the need for stoma formation. These data should inform women and clinicians (involving specialist gynaecological multidisciplinary teams) and allow treatment to be tailored to the individual patient, taking into account surgical resectability, age, histology, stage, and performance status. Data from an unpublished study and ongoing studies are awaited.

Funding: This Cochrane review update had no dedicated funding.

Registration: Protocol (2005): DOI: 10.1002/14651858.CD005343 Original review (2007): DOI: 10.1002/14651858.CD005343.pub2 Review update (2012): DOI: 10.1002/14651858.CD005343.pub3 Review update (2019): DOI: 10.1002/14651858.CD005343.pub4 Review update (2021): DOI: 10.1002/14651858.CD005343.pub5 Review updated (2021a): DOI: 10.1002/14651858.CD005343.pub6.