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Early treatment of relapsed ovarian cancer based on CA125 level alone versus

Early treatment of relapsed ovarian cancer based on CA125 level alone versus delayed treatment based on conventional clinical indicators Results of the randomized MRC OV05 and EORTC 55955 trials Gordon Rustin (Mount Vernon Cancer Centre) and Maria van der Burg

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Early treatment of relapsed ovarian cancer based on CA125 level alone versus

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  1. Early treatment of relapsed ovarian cancer based on CA125 level alone versus delayed treatment based on conventional clinical indicators Results of the randomized MRC OV05 and EORTC 55955 trials Gordon Rustin (Mount Vernon Cancer Centre) and Maria van der Burg On behalf of all OV05 and 55955 Collaborators 31st May 2009

  2. Ovarian Cancer • 80% of patients with advanced ovarian cancer will relapse after first line chemotherapy • Most of these patients will benefit from further therapy • Serial measurement of circulating tumour markers have the potential for earlier detection of relapse • It is unclear whether patients benefit from earlier treatment of relapse

  3. Objective of Trial • To investigate the benefit of early chemotherapy for relapsed ovarian cancer, based on a raised CA125 level alone, versus delayed chemotherapy based on conventional clinical indicators

  4. Trial Design Ovarian cancer in complete remission after first-line platinum based chemotherapy and a normal CA125 REGISTER Blinded CA125 measured every 3 months CA125>2 x upper limit of normal RANDOMISED Early treatment Clinician and patient informed Delayed treatment Clinician not informed, treatment delayed until clinically indicated

  5. Inclusion criteria • Histologically confirmed epithelial ovarian, fallopian tube, or primary serous peritoneal carcinoma • In complete remission with a normal CA125 following first-line platinum based chemotherapy • Able to attend regular follow-up visits and have regular blood tests • Local laboratory able to blind CA125 results and willing to participate in an approved quality assurance scheme • Written informed consent

  6. Outcome measures and sample size • Primary outcome measure • Overall Survival • Secondary outcome measures • Time to second-line treatment • Time to third-line treatment or death • Quality of life • Sample size • To detect a 10% improvement in 2-year overall survival with early treatment (5% significance level and 85% power) We required • 345 events (deaths from all causes) • 1400 registered patients

  7. 35 EORTC MRC 30 25 20 15 10 5 0 Feb-00 Feb-01 Feb-02 Feb-03 Feb-99 Feb-97 Feb-98 Nov-99 Nov-00 Nov-01 Nov-02 Nov-03 Feb-04 Feb-05 Aug-99 Aug-00 Aug-01 Aug-02 Aug-03 May-99 May-00 May-01 May-02 May-03 Nov-96 Nov-97 Nov-98 Nov-04 Aug-96 Aug-97 Aug-98 Aug-04 Aug-05 May-96 May-97 May-98 May-04 May-05 Monthly registrations Total registered=1442 Number of registrations • OV05 (55955) opened for recruitment May 1996 (May 1999) • OV05/55955 closed to registrations 31st August 2005

  8. 600 EORTC MRC 500 400 Number of randomisations 300 200 100 0 Feb-00 Feb-01 Feb-02 Feb-03 Feb-04 Feb-05 Feb-06 Feb-08 Feb-97 Feb-98 Feb-99 Feb-07 Aug-00 Aug-01 Aug-02 Aug-03 Aug-04 Aug-05 Aug-06 Aug-97 Aug-98 Aug-99 Aug-07 Cumulative randomisations Registrations closed • OV05/55955 closed to randomisations 31st March 2008 • CA125 unblinded for all patients after 1st October 2008

  9. Trial Profile Registered patients N=1442 Non randomised patients N (%) 421 (29) CA125<2ULN and no relapse at trial closure 61 (4) Relapsed at same time as CA125>2ULN 213 (15) Relapsed without CA125>2ULN 56 (4) Died 133 (9) Patient withdrawal 29 (2) Other/unknown reasons Randomised N=529 (37%) Early treatment N=265 N=254 (96%) started second-line chemotherapy Delayed treatment N=264 N=233 (88%)started second-line chemotherapy

  10. Baseline characteristics:All registered patients (N=1442)

  11. 1.00 0.75 0.50 Proportion surviving 0.25 0.00 0 12 24 36 48 60 72 Months since first line chemotherapy completed Number at risk 1442 1343 1162 963 749 533 357 Overall survival – all registered patients Median survival 70.8 months (95%CI =64.1-78.0)

  12. Randomised patients only N=529

  13. Baseline characteristics:All randomised patients (N=529)

  14. Second-line chemotherapy

  15. 1.00 0.75 Proportion alive not started second-line chemotherapy 0.50 0.25 0.00 0 3 6 9 12 15 18 21 24 Months since randomisation Number at risk Early 265 23 16 14 11 11 10 10 9 264 177 116 91 69 56 49 42 33 Delayed Time from randomisation to second-line chemotherapy Median (months) Early 0.8 Delayed 5.6 HR=0.29 (95% CI 0.24, 0.35) p<0.00001

  16. Outcomes(data frozen 16th February 2009)

  17. 1.00 0.75 Proportion surviving 0.50 0.25 0.00 0 6 12 18 24 30 36 42 48 54 60 Months since randomisation Number at risk Early 265 247 211 165 131 94 72 51 38 31 22 Delayed 264 236 203 167 129 103 69 53 38 31 19 Overall Survival HR=1.00 (95%CI 0.82-1.22) p=0.98 Abs diff at 2 years= 0.1% (95% CI diff= -6.8, 6.3%) Early Delayed

  18. Third-line treatment or death 68% on early arm and 56% on delayed arm received third-line treatment p = 0.0021

  19. 1.00 0.75 Proportion alive not receiving third-line chemotherapy 0.50 0.25 0.00 0 6 12 18 24 30 36 Months since randomisation Number at risk Early 265 224 138 70 38 22 17 264 232 173 117 76 48 35 Delayed Time from randomisation to third-line treatment or death Median (months) Early 12.5 Delayed 17.1 HR=0.69 (95% CI 0.58, 0.83) p=0.0001

  20. Quality of life • EORTC QLQ-C30 questionnaire collected every 3 months from registration and prior to each cycle of chemotherapy until the end of third-line treatment • Primary outcome measures: • Time until first Global Health related deterioration or death • Overall time with ‘good’ Global Health Score (GHS) during first two years after randomisation • ‘Good’ GHS score: improved or <10% decrease from pre-randomisation score • Global Health deterioration: >10% decrease from pre-randomisation score

  21. Time from randomisation to first deterioration in Global Health Score (or death) 1.00 Median (months) Early 3.1 Delayed 5.8 HR=0.71 (95% CI 0.57, 0.87) p=0.001 0.75 Proportion alive without deterioration in GHS 0.50 0.25 0.00 0 6 12 18 24 Months since randomisation Number at risk 190 68 44 23 12 Early Delayed 194 93 55 38 25

  22. 30 30 25 25 20 20 Number of patients 15 Number of patients 15 10 10 5 5 0 0 3 6 9 12 15 18 21 24 0 0 3 6 9 12 15 18 21 24 Number of months spent with good GHS score Number of months spent with good GHS score Overall time spent with ‘good’ GHS Median (months) Early 7.1 Delayed 9.2 p=0.15 (Mann-Whitney test)

  23. Conclusions • In early treatment arm based on rise in CA125 • Second-line chemotherapy started a median of 4.8 months earlier • Third-line chemotherapy started a median of 4.6 months earlier • This early treatment did not improve overall survival • HR=1.00, 95% CI 0.82-1.22, p=0.98 • Absolute difference at 2 years 0.1% (95%CI -6.8, 6.3%) • Early chemotherapy does not improve Qol

  24. How should this trial influence practice? • Women can be reassured that • There is no benefit from early detection of relapse by routine CA125 measurements • Even if CA125 rises, chemotherapy can be delayed until signs or symptoms of tumor recurrence • Women can be offered choices in follow-up • No routine CA125 measurements but rapid access to CA125 testing if symptoms or signs of relapse • Regular CA125 measurements

  25. Acknowledgements • A huge thank you to all women and all OV05 and 55955 collaborators who participated in these trials for over a decade • OV05 was funded by the MRC • 55955 was funded by the EORTC

  26. OV05 and 55955 trial teams • OV05/55955 Trial Management Group • Gordon Rustin (OV05 Chief Investigator) • Maria E.L. van der Burg (55955 Study Co-ordinator) • David Guthrie • Alan Lamont • Gordon Jayson • Max Parmar • Ann Marie Swart • Corneel Coens • MRC CTU Trial Team • Wendi Qian • Clare Murray • Katharine Goodall • Emma Hainsworth • Andrea Cradduck • Ken Law • Claire Amos • Nick Chadwick • Matt Sydes • Sarah Kirk • Sue Collins • Julia Bland • EORTC Headquarters Team • Maarten De Rouck • Livia Giurgea

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