Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3 trial

Padraig Warde, Malcolm Mason, Keyue Ding, Peter Kirkbride, Michael Brundage, Richard Cowan, Mary Gospodarowicz, Karen Sanders, Edmund Kostashuk, Greg Swanson, Jim Barber, Andrea Hiltz, Mahesh K B Parmar, Jinka Sathya, John Anderson, Charles Hayter, John Hetherington, Matthew R Sydes, Wendy Parulekar, NCIC CTG PR.3/MRC UK PR07 investigators, K James, M Bacon, A LeMaitre, M R Sydes, S L Naylor, N Kelk, J Latham, J Nuttall, K Sanders, M K B Parmar, M R Sydes, R C Morgan, G Jovic, P Joseph, D Wilke, M Duclos, S Faria, C Freeman, L Souhami, J P Bahary, J P Guay, L Eapen, C Hayter, T Corbett, H Lukka, M Patel, L Klotz, A Bayley, R Bristow, C Catton, J Crook, M McLean, M Milosevic, J Radwan, G Rodrigues, C Springer, B Lada, H Prichard, R Samant, H Dhaliwal, S Gulavita, R Halperin, D McGowan, M Parliament, P Kirkbride, J Anderson, M Mason, J Barber, J Heatherington, C Bevis, I Pedley, R McMenimen, T Roberts, A El Sharkawi, J Hardman, H Van der Voet, D Dearnaley, R Huddart, A Horwich, R Eeles, I Syndikus, J Littler, D Errington, A Shenoy, D Sheehan, R Srinivasan, A Lydon, S Sundar, M Sokal, C Loughrey, S Stranex, P Rogers, A Folkes, A Stockdale, C Irwin, R Owen, P Jenkins, A Ritchie, R Cowan, J Wylie, A Al-Samarraie, S Gollins, R Russell, N Srihari, A Cook, C Beacock, C Parker, T Porter, P Symmonds, M Madden, S Susnerwala, D Bloomfield, P Whelan, D Cole, E Sugden, T Sreenivasan, A Harnett, T Kumar, R Mills, T Sreenivasan, S Dixit, H Newman, C Powell, H Algurafi, S Beesley, C Elwell, S Sundaram, M Murphy, P Weston, A Al-Samarraie, J Graham, S Falk, M Russell, D Bottomley, A Kiltie, A Robinson, O Koriech, C Woodward, D Wheatley, R Ellis, I Syndikus, M Stower, G Urwin, F Bramble, J Rundle, C Carter, G Sole, C Heath, D Bloomfield, M Pantelides, H Patterson, S Dixit, D Fermont, R Shah, C Read, A El-Modir, S Beesley, D Cole, R Wilson, C Humber, A Samanci, B Waymont, D Bissett, P Chakraborti, F Mckinna, I Syndikus, J Glaholm, O Kariakine, C Jose, A Abratt, Padraig Warde, Malcolm Mason, Keyue Ding, Peter Kirkbride, Michael Brundage, Richard Cowan, Mary Gospodarowicz, Karen Sanders, Edmund Kostashuk, Greg Swanson, Jim Barber, Andrea Hiltz, Mahesh K B Parmar, Jinka Sathya, John Anderson, Charles Hayter, John Hetherington, Matthew R Sydes, Wendy Parulekar, NCIC CTG PR.3/MRC UK PR07 investigators, K James, M Bacon, A LeMaitre, M R Sydes, S L Naylor, N Kelk, J Latham, J Nuttall, K Sanders, M K B Parmar, M R Sydes, R C Morgan, G Jovic, P Joseph, D Wilke, M Duclos, S Faria, C Freeman, L Souhami, J P Bahary, J P Guay, L Eapen, C Hayter, T Corbett, H Lukka, M Patel, L Klotz, A Bayley, R Bristow, C Catton, J Crook, M McLean, M Milosevic, J Radwan, G Rodrigues, C Springer, B Lada, H Prichard, R Samant, H Dhaliwal, S Gulavita, R Halperin, D McGowan, M Parliament, P Kirkbride, J Anderson, M Mason, J Barber, J Heatherington, C Bevis, I Pedley, R McMenimen, T Roberts, A El Sharkawi, J Hardman, H Van der Voet, D Dearnaley, R Huddart, A Horwich, R Eeles, I Syndikus, J Littler, D Errington, A Shenoy, D Sheehan, R Srinivasan, A Lydon, S Sundar, M Sokal, C Loughrey, S Stranex, P Rogers, A Folkes, A Stockdale, C Irwin, R Owen, P Jenkins, A Ritchie, R Cowan, J Wylie, A Al-Samarraie, S Gollins, R Russell, N Srihari, A Cook, C Beacock, C Parker, T Porter, P Symmonds, M Madden, S Susnerwala, D Bloomfield, P Whelan, D Cole, E Sugden, T Sreenivasan, A Harnett, T Kumar, R Mills, T Sreenivasan, S Dixit, H Newman, C Powell, H Algurafi, S Beesley, C Elwell, S Sundaram, M Murphy, P Weston, A Al-Samarraie, J Graham, S Falk, M Russell, D Bottomley, A Kiltie, A Robinson, O Koriech, C Woodward, D Wheatley, R Ellis, I Syndikus, M Stower, G Urwin, F Bramble, J Rundle, C Carter, G Sole, C Heath, D Bloomfield, M Pantelides, H Patterson, S Dixit, D Fermont, R Shah, C Read, A El-Modir, S Beesley, D Cole, R Wilson, C Humber, A Samanci, B Waymont, D Bissett, P Chakraborti, F Mckinna, I Syndikus, J Glaholm, O Kariakine, C Jose, A Abratt

Abstract

Background: Whether the addition of radiation therapy (RT) improves overall survival in men with locally advanced prostate cancer managed with androgen deprivation therapy (ADT) is unclear. Our aim was to compare outcomes in such patients with locally advanced prostate cancer.

Methods: Patients with: locally advanced (T3 or T4) prostate cancer (n=1057); or organ-confined disease (T2) with either a prostate-specific antigen (PSA) concentration more than 40 ng/mL (n=119) or PSA concentration more than 20 ng/mL and a Gleason score of 8 or higher (n=25), were randomly assigned (done centrally with stratification and dynamic minimisation, not masked) to receive lifelong ADT and RT (65-69 Gy to the prostate and seminal vesicles, 45 Gy to the pelvic nodes). The primary endpoint was overall survival. The results presented here are of an interim analysis planned for when two-thirds of the events for the final analysis were recorded. All efficacy analyses were done by intention to treat and were based on data from all patients. This trial is registered at controlledtrials.com as ISRCTN24991896 and Clinicaltrials.gov as NCT00002633.

Results: Between 1995 and 2005, 1205 patients were randomly assigned (602 in the ADT only group and 603 in the ADT and RT group); median follow-up was 6·0 years (IQR 4·4-8·0). At the time of analysis, a total of 320 patients had died, 175 in the ADT only group and 145 in the ADT and RT group. The addition of RT to ADT improved overall survival at 7 years (74%, 95% CI 70-78 vs 66%, 60-70; hazard ratio [HR] 0·77, 95% CI 0·61-0·98, p=0·033). Both toxicity and health-related quality-of-life results showed a small effect of RT on late gastrointestinal toxicity (rectal bleeding grade >3, three patients (0·5%) in the ADT only group, two (0·3%) in the ADT and RT group; diarrhoea grade >3, four patients (0·7%) vs eight (1·3%); urinary toxicity grade >3, 14 patients (2·3%) in both groups).

Interpretation: The benefits of combined modality treatment--ADT and RT--should be discussed with all patients with locally advanced prostate cancer.

Funding: Canadian Cancer Society Research Institute, US National Cancer Institute, and UK Medical Research Council.

Copyright © 2011 Elsevier Ltd. All rights reserved.

Figures

Figure 1
Figure 1
Trial profile ADT=androgen deprivation therapy. RT=radiation therapy.
Figure 2
Figure 2
Overall and disease-specific survival at 7 years (A) Kaplan-Meier curve for overall survival by treatment group. (B) Kaplan-Meier curve for disease-specific survival by treatment group, and (C) cumulative incidence of disease-specific survival. ADT=androgen deprivation therapy. RT=radiation therapy.
Figure 3
Figure 3
Mean quality-of-life scores over time for symptom measures. A high mean score represents a high symptom burden. ADT=androgen deprivation therapy. EORTC=European Organisation for Research and Treatment of Cancer. FACT-P=Functional Assessment of Cancer Therapy–Prostate.

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