A1258690667otspz

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


CA125gt2 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 registrations
Total registered1442
Number of registrations

• OV05 (55955) opened for recruitment May 1996
  (May 1999)
• OV05/55955 closed to registrations 31st August
  2005

8
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 N1442
Non randomised patients N () 421 (29)
CA125lt2ULN and no relapse at
trial closure 61 (4) Relapsed at same time
as CA125gt2ULN 213
(15) Relapsed without CA125gt2ULN 56 (4)
Died 133 (9) Patient withdrawal 29 (2)
Other/unknown reasons
Randomised N529 (37)
Delayed treatment N264 N233 (88) started
second-line chemotherapy
Early treatment N265 N254 (96) started
second-line chemotherapy
10
Baseline characteristicsAll registered patients
(N1442)
Age Median (range) 60 (23-93)
FIGO stage I II IIIIV 18 15 58 9
WHO Performance Status 0 1 2 3 72 27 1
Histology Serous Endometroid Mucinous Clear cell Undifferentiated Adenocarcinoma not otherwise specified Other 53 17 7 6 6 10 1
11
Overall survival all registered patients
Median survival 70.8 months (95CI 64.1-78.0)
12

• Randomised patients only
• N529

13
Baseline characteristicsAll randomised patients
(N529)
Early Delayed
Age Median (range) 60 (35-86) 61 (37-93)
FIGO stage I II IIIIV 9 11 68 12 8 10 69 13
WHO PS 0 1 2 3 69 29 2 75 25 lt1
Histology Serous Endometroid Mucinous Clear cell Undifferentiated Adenocarcinoma not otherwise specified Other 66 12 3 4 8 6 1 59 12 3 4 6 15 1
14
Second-line chemotherapy
Regimen administered Early N () Delayed N ()
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) 0 67 (25)33 (13)101 (38) 9 (3) 15 (6) 8 (3) 24 (9) 7 (3)
Total 265 264
15
Time from randomisation to second-line
chemotherapy
Median (months) Early
0.8 Delayed 5.6 HR0.29 (95 CI
0.24, 0.35) plt0.00001
16
Outcomes(data frozen 16th February 2009)
N529
Alive Dead Cause of death Disease related Chemotherapy related Disease Chemotherapy related Other Missing 150 (28) 379 (72) 364 1 2 11 1
Median follow-up (months) 56.9
17
Overall Survival
HR1.00 (95CI 0.82-1.22) p0.98
Abs diff at 2 years 0.1 (95 CI diff -6.8,
6.3)
Early Delayed
18
Third-line treatment or death
Early N265 Delayed N264
Alive, no third-line treatment Alive, after third-line treatment Died, after third-line treatment Died, no third-line treatment 9 16 5223 12 144133
68 on early arm and 56 on delayed arm received
third-line treatment p 0.0021
19
Time from randomisation to third-line treatment
or death
Median (months) Early
12.5 Delayed 17.1 HR0.69 (95 CI
0.58, 0.83) p0.0001
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 lt10 decrease from
  pre-randomisation score
• Global Health deterioration gt10 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 HR0.71 (95 CI 0.57, 0.87)
p0.001
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
Overall time spent with good GHS
Median (months) Early 7.1 Delayed 9.2 p0.15
(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
• HR1.00, 95 CI 0.82-1.22, p0.98
• Absolute difference at 2 years 0.1 (95CI -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

• EORTC Headquarters Team
• Maarten De Rouck
• Livia Giurgea