Download Genitourinary.Warde.CRA4505

Intergroup Randomized Phase III Study of
Androgen Deprivation Therapy +
Radiation Therapy in Locally Advanced
Prostate Cancer
NCIC CTG PR.3/ MRC PR07/ SWOG JPR3
P. R. Warde, M. D. Mason, M. R. Sydes, M. K. Gospodarowicz,
G. P. Swanson, P. Kirkbride, E. Kostashuk, J. Hetherington,
K. Ding, W. R. Parulekar
On behalf of all trial collaborators
Prostate Cancer
Represents a substantial health burden in industrialized nations
 Most common malignancy in men and second to lung cancer as a cause
of cancer mortality
 Risk stratification into low, intermediate, high risk disease based on
PSA, Biopsy Gleason Score, T Category
 High risk disease (> cT2c and/or PSA > 20 ng/ml and/or Gleason > 8)
• CaPSURE Database
– 44% in 1990-1994
– 29% in 2001-2004
– 24% in 2004-2007
Jemal et al CA Cancer J Clin. 2009;59(4):225-49
D’Amico et al JAMA 1998; 280:969-974
Cooperberg et al World J Urol 2008;26:211-218
Background
 Results with RT alone disappointing
• Initial data from EORTC and RTOG studies suggested major benefit
from addition of adjuvant ADT
• Question remained whether improved results due to early use of
ADT and benefit of RT still felt to be inconclusive
• > 60% of Urologists, Radiation Oncologists in Canada, UK felt utility
of RT in locally advanced prostate cancer not established
 MRC PR02 randomised trial 1992
• 277 patients T2-T4 N0 M0
– RT alone vs Orchiectomy alone vs RT + Orchiectomy
• Closed early to accrual
• No evidence of survival benefit to addition of RT
Fellows et al Br J Urol. 1992 Sep;70(3):304-9
NCIC CTG PR.3/MRC PR07/SWOG JPR3
Objectives
 In patients with Locally advanced/High risk prostate
cancer, to evaluate the impact of the addition of
External Beam RT to ADT on
• Primary outcome measure was overall survival
• Secondary outcome measures of
–
Disease specific survival
–
Time to disease progression
–
Symptomatic local control
–
Quality of Life
NCIC CTG PR.3/MRC PR07/SWOG JPR3:
Study Scheme
T3/T4 N0/NX
or
T2 and PSA > 40 μg/L
or
T2 and PSA > 20 μg/L and GS: 8-10
Continuous Androgen
Deprivation Therapy
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Continuous Androgen
Deprivation Therapy
+
Radiotherapy
Initial PSA Level: < 20 vs 20-50 vs > 50 μg/L
Hormonal Therapy: orchiectomy vs LHRH analogue+ anti androgen
Method of lymph node staging: clinical vs radiological vs surgical
Gleason Score: < 8 vs 8-10
Prior hormonal therapy: yes vs no
Centre
Treatment
 Androgen Deprivation Therapy
• Bilateral Orchiectomy
or
• LHRH agonist
– Antiandrogen for 2 weeks, optional to continue
 Radiotherapy
• 45 Gy/25 F/5 weeks to pelvis
• 20-24 Gy/10-12 F/2-2.5 weeks to prostate
• If treating physician felt patient inappropriate for whole pelvis
then RT given to prostate only
Statistical Parameters/Study Conduct
1995: Study Activation
Sample size=650 based on based on 35% 10 year survival in
ADT alone arm, α=.05 (one sided), 80% chance of detecting 10%
improvement (target HR 0.76)
2002: Amendment (low event rate) Sample size=1200
Target HR 0.76 (survival), α=.025 (one sided), β=.2
2005: (June):
Study closed to accrual
 Accrued: 1205
2009: (August): 2nd interim analysis to DSMC, Median follow-up 6.0 years
 Disclose results to investigators
2012: Final Analysis
NCIC CTG TRIAL PR.3Accrual
PR.3 Cumulative
Cumulative Accrual
1400
1200
# Patients
1000
800
600
400
200
0
01MAR95
01MAR00
01MAR05
Time
Actual
Expected
01MAR10
Flowchart
Randomized (n=1205)
Androgen Deprivation
n=602
Androgen Deprivation + RT
n=603
Ineligible: n= 3
No data > 2 years: n=42
Ineligible: n= 5
No data > 2 years: n=61
Efficacy Analysis: n= 602
Safety Analysis: n=596
Efficacy Analysis: n= 603
Safety Analysis: n=595
Baseline Characteristics
Characteristic
ADT Alone
ADT+RT
69.7 years
69.7 years
< T2c
11%
10%
T3/T4
89%
88%
<7
81%
81%
8-10
18%
18%
<20
37%
36%
20-50
38%
38%
>50
25%
26%
Median Age
T Category
Gleason Score
PSA ng/ml
Overall Survival
Percentage
100
80
7 yr OS 74%
60
7 yr OS 66%
40
HR=0.77 (95% C.I. 0.61-0.98) P=0.0331
20
320 Deaths, 175 ADT alone, 145 RT+ADT
ADT
0
ADT+RT
0
3
ADT
602
ADT+RT
603
# at Risk
6
9
509
213
51
512
232
60
Time (Years)
Causes of Death
ADT Alone (175)
ADT+RT (145)
Total (320)
Disease
89
51
140
Cardiac/Stroke
24
24
48
Other Cancer
26
31
57
Other
24
31
55
Unknown
12
8
20
Disease Specific Survival
100
7 yr DSS 90%
80
Percentage
7 yr DSS 79%
60
40
HR=0.57 (95% C.I. 0.37-0.78) p=0.001
20
140 Deaths from Prostate Cancer
89 ADT alone, 51 RT+ADT
ADT
0
# at Risk
ADT
ADT+RT
0
ADT+RT
3
602
509
603
512
Time (Years)
6
9
213
51
232
60
Late Toxicity
Grade < 2
Grade > 3
ADT Alone
8%
0.7%
ADT +RT
14%
1.3%
ADT Alone
5%
0.5%
ADT +RT
12%
0.3%
ADT Alone
42%
2.3%
ADT +RT
44%
2.3%
Gastrointestinal
Diarrhea
Rectal Bleeding
Genitourinary
Relevance 2010
 Treatment Trends 1990-2007
• CaPSURE Database
– ADT as Primary Therapy for high risk disease
• 1990-1994
36.7%
• 2004-2007
45.5%
 Significant variation in current treatment practices highlights the
importance of randomized phase III data to define treatment
standards
• SPCG-7/SFUO-3 study
– RT + HT vs HT alone in 977 patients, T1b-T3, N0
– Improved Cancer-Specific (RR 0.44) and Overall Survival (RR 0.68)
• Current study
– Improved Cancer-Specific (HR 0.57) and Overall Survival (RR 0.77)
Widmark et al Lancet. 2009 Jan 24;373(9660):301-8.
Cooperberg et al J Clin Oncol 2010; 28:1117-1123
Conclusions
 Combined Modality Therapy (ADT+RT) in
Management of Locally Advanced/High Risk Prostate
Cancer
• Improved Overall Survival
• Improved Disease Specific Survival
• RT Well tolerated with no significant toxicity
 Should be Considered Standard of Care for this group
of patients
• Optimal duration of androgen deprivation therapy remains
undefined
• Benefit of RT in modern era may be greater with dose
escalation
Acknowledgements
We would like to thank all the patients and their families
who participated on this trial through the following centres:
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QEII Health Sciences Center
McGill University - Dept. Oncology
CHUM - Hopital Notre-Dame
Ottawa Health Research Institute - Civic Division
Cancer Centre of Southeastern Ontario at Kingston
Ottawa Health Research Institute - General Division
Juravinski Cancer Centre at Hamilton Health Sciences
Humber River Regional Hospital
Odette Cancer Centre
Univ. Health Network-Princess Margaret Hospital
London Regional Cancer Program
Windsor Regional Cancer Centre
Regional Cancer Program of the Hopital Regional
Algoma District Cancer Program
Thunder Bay Regional Health Science Centre
CancerCare Manitoba
Saskatoon Cancer Centre
Tom Baker Cancer Centre
Cross Cancer Institute
BCCA - Vancouver Cancer Centre
BCCA - Fraser Valley Cancer Centre
BCCA - Cancer Centre for the Southern Interior
 ECOG Coordinating Center
 Southwest Oncology Group, Data Operations Center
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Sutton Coldfield, Good Hope Hospital
Eastbourne Hospital
Southport & Formby District General Hospital
Burton upon Trent, Queen's Hospital
Aberdeen Royal Infirmary
SOUTH AFRICA: Groote Schuur Hospital
Wolverhampton, New Cross Hospital
Sandwell General Hospital
Grimsby, Diana Princess of Wales Hospital
Swindon, The Great Western Hospital
Warwick Hospital
St Leonards-on-Sea, Conquest Hospital
Bolton, Royal Bolton Hospital
Taunton & Somerset Hospital
Cambridge, Addenbrooke's Hospital
Northwood, Mount Vernon Hospital
Preston, Royal Preston Hospital
Hereford County Hospital
Southampton, Royal South Hants Hospital
Acknowledgements continued
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Sussex Oncology Centre
Bournemouth & Christchurch Hospitals
Warrington Hospital
York District Hospital
Bury St Edmunds, West Suffolk Hospital
Truro, Royal Cornwall Hospital
Southend General Hospital
Bristol Oncology Centre
Leeds, Cookridge Hospital
NEW ZEALAND: Auckland Hospital
Glasgow, Beatson Oncology Centre
Northampton Oncology Centre
Croydon, Mayday Hospital
Chester, Countess of Chester
Maidstone, The Kent Cancer Centre
Wakefield, Pinderfields Hospital
Bath, Royal United Hospital
Wrexham Maelor Hospital
Norwich, Norfolk & Norwich Hospital
Scunthorpe General Hospital
United Lincolnshire Trust
Oxford, Churchill Hospital
Blackpool Victoria Hospital
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Brighton Hospitals
Leeds, St.James's University Hospital
Leicester Royal Infirmary
Yeovil District Hospital
Shrewsbury, Royal Shrewsbury Hospital
Rhyl, Glan Clwyd Hospital
Coventry, Walsgrave Hospital
Gloucestershire Hospitals
Berkshire, Royal Berkshire & Battle Hospitals
Manchester, Christie Hospital
Belfast, Belfast City & Belvoir Park Hospitals
Nottingham City Hospital
Clatterbridge Centre for Oncology
Exeter, Royal Devon & Exeter
Torbay Hospital
Royal Marsden Hospitals
Middlesbrough, The James Cook University Hospital
RUSSIA: Obninsk, MRRC RAMS
Swansea, Singleton Hospital
Newcastle General Hospital
Cottingham, Castle Hill Hospital
Cardiff, Velindre Hospital & UHW
Sheffield, Weston Park & Royal Hallamshire