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 trials
Gordon Rustin (Mount Vernon Cancer Centre)
and Maria van der Burg
On behalf of all OV05 and 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. Monthly registrations5 10 15 20 25 30 35
May-96
Aug-96
Nov-96
Feb-97
May-97
Aug-97
Nov-97
Feb-98
May-98
Aug-98
Nov-98
Feb-99
May-99
Aug-99
Nov-99
Feb-00
May-00
Aug-00
Nov-00
Feb-01
May-01
Aug-01
Nov-01
Feb-02
May-02
Aug-02
Nov-02
Feb-03
May-03
Aug-03
Nov-03
Feb-04
May-04
Aug-04
Nov-04
Feb-05
May-05
Aug-05
EORTC
MRC
Total registered=1442
Number of registrations
OV05 (55955) opened for recruitment May 1996 (May 1999)
OV05/55955 closed to registrations 31st August 2005

8. Cumulative randomisations
100
200
300
400
500
600
Feb-97
Aug-97
Feb-98
Aug-98
Feb-99
Aug-99
Feb-00
Aug-00
Feb-01
Aug-01
Feb-02
Aug-02
Feb-03
Aug-03
Feb-04
Aug-04
Feb-05
Aug-05
Feb-06
Aug-06
Feb-07
Aug-07
Feb-08
Number of randomisations
EORTC
MRC
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
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)
Age
Median (range)
60 (23-93)
FIGO stage I II
III IV
18%
15%
58% 9%
WHO Performance
Status 1
2 & 3
72%
27% 1%
Histology
Serous
Endometroid
Mucinous
Clear cell
Undifferentiated
Adenocarcinoma not otherwise specified
Other
53%
17% 7% 6%
10%

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

12. Randomised patients only

13. Baseline characteristics: All randomised patients (N=529)
Early
Delayed
Age
Median (range)
60 (35-86)
61 (37-93)
FIGO
stage I II
III IV 9%
11%
68%
12% 8%
10%
69%
13%
WHO PS 1
2 & 3
29% 2%
75%
25%
<1%
Histology
Serous
Endometroid
Mucinous
Clear cell
Undifferentiated
Adenocarcinoma not otherwise specified
Other
66% 3% 4% 6% 1%
59%
15%

14. Second-line chemotherapy
Regimen administered
Early
N (%)
Delayed
Single agent platinum
Combination platinum (no taxane)
Platinum + taxane based
Taxane without platinum
Other
Unknown treatment
No treatment given
Not yet given (no clinical relapse)
78 (29)
40 (15)
91 (34)
15 (6)
28 (11)
2 (1)
11 (4)
67 (25) 33 (13) 101 (38)
9 (3)
8 (3)
24 (9)
7 (3)
Total
265
264

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

16. Outcomes (data frozen 16th February 2009)
Alive
Dead
Cause of death:
Disease related
Chemotherapy related
Disease & Chemotherapy related
Other
Missing
150 (28%)
379 (72%)
364 1 2 11
Median follow-up (months)
56.9

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

18. Third-line treatment or death
Early
N=265
Delayed
N=264
Alive, no third-line treatment
Alive, after third-line treatment
Died, after third-line treatment
Died, no third-line treatment 9%
16%
52% 23%
12%
14% 41% 33%
68% on early arm and 56% on delayed arm
received third-line treatment p =

19. Time from randomisation to third-line treatment or death
0.00
0.25
0.50
0.75
1.00
Proportion alive not receiving
third-line chemotherapy
264
232
173
117 76 48 35
Delayed
265
224
138 70 38 22 17
Early
Number at risk 6 12 18 24 30 36
Months since randomisation
Median (months)
Early
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. Proportion alive without Months since randomisation
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 6 12 18 24
Months since randomisation
Number at risk
Early
190 68 44 23 12
Delayed
194 93 55 38 25

22. Overall time spent with ‘good’ GHS5 10 15 20 25 30
Number of patients 3 6 9 12 18 21 24
Number of months spent with good GHS score 5 10 15 20 25 30
Number of patients 3 6 9 12 18 21 24
Number of months spent with good GHS score
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 , 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 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 ( 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