Vergote 2010.

Study characteristics
Methods	EORTC‐GCG 55971 Multicentre non‐inferiority RCT; 59 institutions in Belgium, Canada, the UK, Sweden, the Netherlands, Italy, Norway, Spain, Austria, Portugal, Ireland and Argentina Recruitment period: 1998 to 2006 Median follow‐up: 56.4 months
Participants	718 women enrolled, 48 excluded post‐randomisation owing to authorisation irregularities at the Argentinian centre leaving 670 women Inclusion criteria: evidence of stage IIIc/IV EOC, primary peritoneal cancer or fallopian tube cancer by intraperitoneal biopsy or FNA plus presence of extra‐pelvic tumour of at least 2 cm (excluding ovaries) on laparoscopy or CT scan; WHO performance status of 0 to 2; no other serious disabling diseases contraindicating PDS or NACT; no prior primary malignancies; no brain metastases; adequate haematological, renal and hepatic function; absence of other factors that could affect compliance; CA‐125:CEA ratio higher than 25. Treatment had to start within 3 weeks of initial biopsy/FNA
Interventions	Experimental: NACT (334 women) ‐ 3 cycles of platinum‐based NACT, followed by IDS within 6 weeks of third cycle, then at least 3 more cycles of NACT Control: PDS (336 women) plus at least 6 cycles of platinum‐based chemotherapy ± IDS All surgery was performed by gynaecological oncologists
Outcomes	OS, PFS, QoL (QLQ‐C30 and QLQ‐Ov28), surgical morbidity and mortality, toxicity, optimal debulking Chemotherapy details: Platinum‐taxane: NACT = 283(87.9%) ; PDS = 243 (78.4%) Platinum only: NACT = 20 (6.2%); PDS = 25 (8.1%) Other: NACT = 19 (5.9%); PDS 21 (6.8%) No chemotherapy: NACT = 0 (0%); PDS = 21 (6.8%) Median time to re‐start chemotherapy after surgery in days (range): NACT = 18 days (5 to 55) versus PDS 19 days (0 to 84) 336 were assigned to PDS 315 received assigned intervention 21 did not receive assigned intervention 8 (38%) were withdrawn by physician 3 (14%) declined to participate 3 (14%) had different histologic diagnosis 1 (5%) died 2 (10%) had unresectable tumour 3 (14%) had logistic or administrative problem 1 (5%) had unknown reason 315 (94%) underwent primary debulking 297 (88%) started chemotherapy 57 (17%) underwent interval debulking 11 (3%) underwent second‐look procedure 334 were assigned to NACT 326 received assigned intervention 8 did not receive assigned intervention 3 (38%) were withdrawn by physician 2 (25%) declined to participate 1 (13%) had different histologic diagnosis 1 (13%) died 1 (13%) had logistic or administrative problem 2 (1%) underwent primary debulking 326 (98%) started NACT 295 (88%) underwent interval debulking 6 (2%) underwent second‐look procedure
Notes	Baseline characteristics were similar: stage IIIc (75.7% versus 76.5%) or stage IV (22.9% versus 24.3%); mean age 63 years (NACT) versus 62 years (PDS); at least 6 cycles received by 276/322 (85.8%) of NACT group and 253/310 (81.6%) of PDS group The number of women with metastases > 5 cm at the time of surgery in the NACT group was half that of the PDS group (37.2% versus 74.5%) suggesting NACT‐related tumour shrinkage. Optimal debulking (80.6% versus 41.6%) and complete debulking were achieved more often in NACT group, but this did not translate into improved survival, even though complete debulking was a prognostic indicator for OS Median OS was 30 versus 29 months (NACT versus PDS) and median PFS was 12 months for both groups Intervention effects on OS differed significantly between participating countries A per‐protocol analysis of those who underwent surgery (322/334 in NACT arm and 310/336 in PDS arm) was performed. However, 295 women in the NACT underwent IDS and 315 women underwent PDS. Data from the published supplementary data and differ from those in Figure 2 of the published paper. These data are from the supplementary data although we note the percentages are calculated from the 295 and 315 denominators of women who actually had NACT/IDS and PDS respectively, rather than the per‐protocol analysis as the table suggests. After debulking surgery 7 women assigned to NACT 11 women assigned to PDS and in were found not to have EOC. QoL data reported in separate publication (Greimel and et al. 2013 see additional reference underVergote 2010)) Only 404 women included in QoL analysis. QoL was limited to data from institutions with the best compliance. Over 50% baseline compliance rate and 35% at follow up chosen as pragmatic cut off. Women in QoL study subset differed to entire population. Institutions with good QoL compliance and included in QoL sub‐study: better OS (median 32.30 versus 23.29 months; P = 0.0006); PFS (median 12.35 versus 9.92 months; P = 0.0002); 39.9% optimal debulking surgery compared to 19.9% in excluded institutions (P = 0.0011). more women with biopsy proven EOC (90.3% versus 79.3%; P = 0.0050); more women with larger tumours (P = 0.0034); laparoscopy used more frequently (40.3% versus 21.4%) and FNA cytology used less frequently (36.1% versus 56.0%) for biopsy in the selected centres (P = 0.0002); fewer women with unknown tumour grade (35.6% versus 48.5% ; P = 0.0009); No differences were found in terms of age, WHO performance status and FIGO stage between institutions. Quote: "No differences between the treatment arms in the QoL functioning or symptoms scales, except for pain and dyspnea. At baseline women treated with PDS had significantly higher pain scores (P = 0.046; PDS mean 36.7; NACT mean 29.9) and significantly lower dyspnea scores (P = 0.049; PDS mean 22.9; NACT mean 27.9) compared to women treated with NACT. However, the difference was below 10 points indicating no clinically relevant difference."
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomisation done centrally. Minimisation used to stratify for institution, biopsy method, tumour stage and largest preoperative tumour size. QoL outcomes were based on a selected number of institutions selected for their QoL data compliance
Allocation concealment (selection bias)	Unclear risk	Central allocation
Blinding of participants and personnel (performance bias) All outcomes	High risk	Unblinded, therefore high risk for some outcomes assessed by investigators involved with patient care (e.g. optimal debulking)
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not reported
Incomplete outcome data (attrition bias) All outcomes	Low risk	3/336 versus 5/334 lost to follow‐up but substantial proportion were missing for QoL outcome but overall outcomes were complete
Selective reporting (reporting bias)	Unclear risk	All pre‐specified outcomes reported. Analysis by ITT and per‐protocol However, QoL outcome was based on a selected number of institutions with better QoL compliance. While the trial authors offer justification for their approach, several differences were found when comparing the outcomes of the 404 selected women (of which only 212 of these were assessed in QoL domains) to the overall populations of 670 women. Women from the selected institutions had significantly better OS and PFS when compared to women treated in institutions which were excluded because of poor compliance rates
Other bias	Unclear risk	48 post‐randomisation exclusions from the Argentinian centre owing to quote: "authorisation irregularities" were indicated erroneously as pre‐randomisation exclusions on the study‐flow diagram. The investigators state that "The results of the study were similar whether the 48 patients....were included or excluded"

BSO: bilateral salpingo oophorectomy; CEA: carcinoembryonic antigen; CT: computer tomography; EOC: epithelial ovarian cancer; FIGO: Federation of International Gynaecologists and Obstetricians; FNA: fine needle aspiration; HR: hazard ratio; IDS: interval debulking surgery; ITT: intention to treat; IQR: interquartile range; MRI: magnetic resonance imaging; NACT: neoadjuvant chemotherapy; OS: overall survival; PDS: primary debulking surgery; PFS: progression‐free survival; QoL: quality of life; RCT: randomised controlled trial; WHO: World Health Organization.