Rustin 2010.

Study characteristics
Methods	A randomised controlled, multi‐centre trial in ovarian cancer of immediate treatment of relapse based on CA125 level alone versus delayed treatment based on conventional clinical indicators (MRC OV05/EORTC 55955 trials) OV05/55955 was designed to determine whether there were benefits from immediate treatment based on a confirmed elevation of CA125 levels versus delaying treatment until clinically indicated Women whose CA125 levels rose to more than two times the upper limit of normal were randomised to one of two treatment arms that received immediate or delayed treatment Randomisation to the immediate or delayed treatment groups used a 1:1 ratio and was done independently by each co‐ordinating centre From 1996 to 2005, 1442 participants registered from 59 sites in 10 countries (centres across the UK, Spain, Norway, the Netherlands, France, Russia, Belgium, Ireland, Austria, and South Africa). Randomisation closed on 31 March 2008 when the targeted number of events (deaths) was reached, with 529 participants randomised (265 to the immediate treatment group and 264 to the delayed treatment group)
Participants	Eligible participants were women with ovarian cancer who were in complete clinical remission following first‐line platinum‐based chemotherapy and establishment of a normal CA125 level Women with the following histologies were included: epithelial ovarian cancers, fallopian tube cancers or primary serous peritoneal carcinoma After randomisation, baseline characteristics were well‐balanced between the groups. Median age at registration was 61 years (range: 53 to 68); 81% were FIGO stage III/IV Second‐line chemotherapy began a median of 5 months earlier in the immediate arm. Predominant histologies were serous and endometrioid, involving 53% and 17%, respectively, among randomised participants
Interventions	Women whose serum CA125 levels exceeded twice the upper limit of normal were randomised to either: Arm I: the clinician was informed of the initial rise in CA125 level. A confirmatory test was performed immediately. Within 4 weeks of the initial CA125 elevation, women with a second confirmed elevation received treatment for recurrent disease according to standard local practice. Women with a normal CA125 on the confirmatory test received no treatment until clinically indicated Arm II: the clinician was blinded to the CA125 results. Women underwent normal monitoring. When clinically indicated, women commenced treatment according to standard local practice. Relapses, regardless of modality of detection, were treated according to local standard practice by the gynaecological oncologist
Outcomes	Primary outcome Overall survival calculated from date of randomisation to date of last follow‐up or death from any cause. At the time of analysis, survivors were censored at the date they were last known to be alive Secondary outcomes Time to second‐line chemotherapy (calculated from date of randomisation to date of initiation of second‐line chemotherapy, women who did not receive second‐line chemotherapy were censored at the date of last contact) Time to third‐line treatment or death (calculated from date of randomisation to date of starting third‐line treatment or death, whichever occurred first, survivors without treatment censored at the last contact) QoL with duration of good QoL in the global health score (defined as improved or no more than a 10% decrease from pre‐randomisation score) Time of first global health‐related deterioration (defined as more than 10% decrease from pre‐randomisation score or death)
Identification	Funding UK Medical Research Council and the European Organisation for Research and Treatment of Cancer.
Notes	Intention‐to‐treat analysis Median follow‐up from randomisation was 56.9 (IQR 37.4 to 81.8) months The primary outcome measurement was overall survival and the trial was designed to detect a 10% improvement in 2‐year overall survival in the immediate treatment arm with at least 85% power and 5% significance level Median survival from randomisation was 25.7 months (95% CI 23.0 to 27.9) for women on immediate treatment and 27.1 months (95% CI 22.8 to 30.9) for those on delayed treatment, with a median follow‐up of 56.9 months (IQR 37.4 to 81.8) from randomisation and 370 deaths (186 immediate, 184 delayed) Median time spent with good global health score was 7.2 months (95% CI 5.3 to 9.3) for women assigned to immediate and 9.2 months (95% CI 6.4 to10.5) for those assigned to delayed treatment QoL assessed at baseline, at each follow‐up visit, and, if treatment was instituted, before each chemotherapy course Participants were followed‐up every 3 months
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"The method of minimisation was used with the stratification factors: International Federation of Gynecology and Obstetrics (FIGO) stage (I versus II versus III versus IV); first‐line chemotherapy (single agent platinum versus platinum combination without taxane versus platinum taxane combination versus other); time from completion of first‐line chemotherapy to raised CA125 concentration (< 6 versus 6 to 11 versus 12 to 24 versus > 24 months); age (MRC OV05 at randomisation, EORTC 55955 at registration; < 30 versus 30 to 55 versus 56 to 65 versus > 65 years); and site".
Allocation concealment (selection bias)	Low risk	"CA125 results were masked to sites and women until randomisation to early treatment or until clinical recurrence for those in the delayed treatment group".
Blinding (performance bias and detection bias) All outcomes	Low risk	"Serum CA‐125 was measured every three months but women and investigators were blinded to the results, which were only available to the trials units". Women and investigators were not blinded when HRQOL outcome was measured from randomisation to first deterioration.
Incomplete outcome data (attrition bias) All outcomes	Low risk	100% analysed: 529/529 for primary outcome, and overall survival analysed using appropriate statistical techniques that accounted for censoring 21 (4%) women were lost to follow‐up
Selective reporting (reporting bias)	Unclear risk	Insufficient information available to permit judgement
Other bias	High risk	Point estimates and 95% CIs did not tally with corresponding P values for time to first deterioration in QoL score or death for many of the individual subscales of EORTC QLQ‐C30 questionnaire (Table 4 in trial report). For example, for the emotional subscale in the functional QoL category the upper 95% CI was 1.02 and the P value was 0.02. Similarly, significant subscale factors appeared to have a vastly decreased P value from that which might be expected given the point and CI estimates It was also unclear for what the HRs in Table 4 were adjusted

Abbreviations

CI = confidence interval
FIGO = International Federation of Gynecology and Obstetrics
HR = hazard ratio
IQR = interquartile range
QoL = quality of life