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NCIC CTG PR.3/ MRC PR07/ SWOG JPR3

Intergroup Randomized Phase III Study of Androgen Deprivation Therapy + Radiation Therapy in Locally Advanced Prostate Cancer. NCIC CTG PR.3/ MRC PR07/ SWOG JPR3

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NCIC CTG PR.3/ MRC PR07/ SWOG JPR3

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  1. 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

  2. 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

  3. 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

  4. 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

  5. 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 ContinuousAndrogen Deprivation Therapy + Radiotherapy Continuous Androgen Deprivation Therapy • 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

  6. 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

  7. 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

  8. PR.3 Cumulative Accrual

  9. 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

  10. Baseline Characteristics

  11. 100 7 yr OS 74% 80 60 7 yr OS 66% Percentage 40 HR=0.77 (95% C.I. 0.61-0.98) P=0.0331 20 320 Deaths, 175 ADT alone, 145 RT+ADT ADT ADT+RT 0 0 3 6 9 # at Risk Time (Years) ADT 602 509 213 51 603 512 232 60 ADT+RT Overall Survival

  12. Causes of Death

  13. 100 80 60 Percentage 40 20 ADT ADT+RT 0 0 3 6 9 # at Risk Time (Years) ADT 602 509 213 51 ADT+RT 603 512 232 60 Disease Specific Survival 7 yr DSS 90% 7 yr DSS 79% HR=0.57 (95% C.I. 0.37-0.78) p=0.001 140 Deaths from Prostate Cancer 89 ADT alone, 51 RT+ADT

  14. Late Toxicity

  15. 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

  16. 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

  17. Acknowledgements We would like to thank all the patients and their families who participated on this trial through the following centres: • ECOG Coordinating Center • Southwest Oncology Group, Data Operations Center • 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 • 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

  18. Acknowledgements continued • 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 • 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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