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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 Collaborators31st May 2009
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
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
Trial Design
Ovarian cancer in complete remission after first-line platinum based chemotherapy
and a normal CA125
CA125>2 x upper limit of normalRANDOMISED
Early treatmentClinician and patient informed
Delayed treatmentClinician not informed, treatment
delayed until clinically indicated
REGISTERBlinded CA125 measured
every 3 months
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
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
Monthly registrations
• OV05 (55955) opened for recruitment May 1996 (May 1999)• OV05/55955 closed to registrations 31st August 2005
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EORTC
MRC
Num
ber
of
reg
istr
ati
on
s
Total registered=1442
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-97
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ber
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isati
ons
EORTC MRC
Cumulative randomisations
• OV05/55955 closed to randomisations 31st March 2008• CA125 unblinded for all patients after 1st October 2008
Registrations closed
Trial Profile
Registered patientsN=1442
RandomisedN=529 (37%)
Delayed treatmentN=264N=233 (88%) started second-line chemotherapy
Early treatmentN=265N=254 (96%) started second-line chemotherapy
Non randomised patientsN (%)421 (29) CA125<2ULN and no relapse at trial closure61 (4) Relapsed at same time as CA125>2ULN213 (15) Relapsed without CA125>2ULN56 (4) Died133 (9) Patient withdrawal29 (2) Other/unknown reasons
Baseline characteristics:All registered patients (N=1442)
Age Median (range) 60 (23-93)
FIGO stage IIIIIIIV
18%15%58%9%
WHO PerformanceStatus
012 & 3
72%27%1%
Histology Serous EndometroidMucinousClear cellUndifferentiatedAdenocarcinoma not otherwise specifiedOther
53%17%7%6%6%
10%1%
0.00
0.25
0.50
0.75
1.00
Pro
po
rtio
n s
urv
ivin
g
1442 1343 1162 963 749 533 357
Number at risk
0 12 24 36 48 60 72
Months since first line chemotherapy completed
Overall survival – all registered patients
Median survival 70.8 months (95%CI =64.1-78.0)
Randomised patients onlyN=529
Baseline characteristics:All randomised patients (N=529)
Early Delayed
Age Median (range) 60 (35-86) 61 (37-93)
FIGOstage
IIIIIIIV
9%11%68%12%
8%10%69%13%
WHO PS 012 & 3
69%29%2%
75%25%<1%
Histology Serous EndometroidMucinousClear cellUndifferentiatedAdenocarcinoma not otherwise specifiedOther
66%12%3%4%8%6%1%
59%12%3%4%6%
15%1%
Second-line chemotherapy
Regimen administered Early N (%)
Delayed N (%)
Single agent platinum Combination platinum (no taxane)Platinum + taxane basedTaxane without platinumOtherUnknown treatmentNo treatment givenNot 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
0.00
0.25
0.50
0.75
1.00
Pro
po
rtio
n a
live
no
t st
arte
d
sec
on
d-l
ine
chem
oth
era
py
264 177 116 91 69 56 49 42 33Delayed265 23 16 14 11 11 10 10 9Early
Number at risk
0 3 6 9 12 15 18 21 24
Months since randomisation
Time from randomisation to second-line chemotherapy
Median (months)Early 0.8Delayed 5.6 HR=0.29 (95% CI 0.24, 0.35) p<0.00001
Outcomes(data frozen 16th February 2009)
N=529
AliveDeadCause of death: Disease related Chemotherapy related Disease & Chemotherapy related Other Missing
150 (28%)379 (72%)
36412111
Median follow-up (months) 56.9
0.00
0.25
0.50
0.75
1.00
Pro
po
rtio
n s
urv
ivin
g
264 236 203 167 129 103 69 53 38 31 19Delayed265 247 211 165 131 94 72 51 38 31 22Early
Number at risk
0 6 12 18 24 30 36 42 48 54 60Months since randomisation
Overall Survival
HR=1.00 (95%CI 0.82-1.22) p=0.98
EarlyDelayed
Abs diff at 2 years= 0.1% (95% CI diff= -6.8, 6.3%)
Third-line treatment or death
EarlyN=265
DelayedN=264
Alive, no third-line treatmentAlive, after third-line treatmentDied, after third-line treatmentDied, 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 = 0.0021
0.00
0.25
0.50
0.75
1.00
Pro
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live
no
t re
cei
vin
g
thir
d-l
ine
che
mo
ther
apy
264 232 173 117 76 48 35Delayed265 224 138 70 38 22 17Early
Number at risk
0 6 12 18 24 30 36
Months since randomisation
Time from randomisation to third-line treatment or death
Median (months)Early 12.5Delayed 17.1 HR=0.69 (95% CI 0.58, 0.83) p=0.0001
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:1. Time until first Global Health related deterioration or
death2. 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
Time from randomisation to first deterioration in Global Health Score (or death)
0.00
0.25
0.50
0.75
1.00
Pro
po
rtio
n a
live
wit
ho
ut
det
erio
rati
on
in
GH
S
194 93 55 38 25Delayed190 68 44 23 12Early
Number at risk
0 6 12 18 24
Months since randomisation
Median (months)Early 3.1Delayed 5.8 HR=0.71 (95% CI 0.57, 0.87) p=0.001
Overall time spent with ‘good’ GHS
Median (months)Early 7.1 Delayed 9.2
p=0.15 (Mann-Whitney test)
05
1015
2025
30
Nu
mb
er o
f p
atie
nts
0 3 6 9 12 15 18 21 24
Number of months spent with good GHS score0
510
1520
2530
Nu
mb
er o
f p
atie
nts
0 3 6 9 12 15 18 21 24
Number of months spent with good GHS score
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
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
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
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