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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Total registered=1442

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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%

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0.75

1.00

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urv

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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

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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

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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

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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)

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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

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Number of months spent with good GHS score0

510

1520

2530

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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