BACKGROUND: Several studies have shown the efficacy of endocrine therapy in combination with radiotherapy in high-risk prostate cancer. To assess the effect of radiotherapy, we did an open phase III study comparing endocrine therapy with and without local radiotherapy, followed by castration on progression.
METHODS: This randomised trial included men from 47 centres in Norway, Sweden, and Denmark. Between February, 1996, and December, 2002, 875 patients with locally advanced prostate cancer (T3; 78%; PSA<70; N0; M0) were centrally randomly assigned by computer to endocrine treatment alone (3 months of total androgen blockade followed by continuous endocrine treatment using flutamide; 439 patients), or to the same endocrine treatment combined with radiotherapy (436 patients). The primary endpoint was prostate-cancer-specific survival, and analysis was by intention to treat. This study is registered as an international standard randomised controlled trial, number ISRCTN01534787.
FINDINGS: After a median follow-up of 7.6 years, 79 men in the endocrine alone group and 37 men in the endocrine plus radiotherapy group had died of prostate cancer. The cumulative incidence at 10 years for prostate-cancer-specific mortality was 23.9% in the endocrine alone group and 11.9% in the endocrine plus radiotherapy group (difference 12.0%, 95% CI 4.9-19.1%), for a relative risk of 0.44 (0.30-0.66). At 10 years, the cumulative incidence for overall mortality was 39.4% in the endocrine alone group and 29.6% in the endocrine plus radiotherapy group (difference 9.8%, 0.8-18.8%), for a relative risk of 0.68 (0.52-0.89). Cumulative incidence at 10 years for PSA recurrence was substantially higher in men in the endocrine-alone group (74.7%vs 25.9%, p<0.0001; HR 0.16; 0.12-0.20). After 5 years, urinary, rectal, and sexual problems were slightly more frequent in the endocrine plus radiotherapy group.
INTERPRETATION: In patients with locally advanced or high-risk local prostate cancer, the addition of local radiotherapy to endocrine treatment halved the 10-year prostate-cancer-specific mortality, and substantially decreased overall mortality with fully acceptable risk of side-effects compared with endocrine treatment alone. In the light of these data, endocrine treatment plus radiotherapy should be the new standard.
Lancet. [16 Dec 2008, 373(9660):301-308] [Epub ahead of print]
Anders Widmark, MD,1 Olbjørn Klepp, MD,2 Arne Solberg, MD,3 Jan-Erik Damber, MD,4 Anders Angelsen,MD,5 Per Fransson, PhD,1 Jo-Åsmund Lund, MD,3 Ilker Tasdemir, MD,6 Morten Hoyer, MD,7 Fredrik Wiklund, PhD,8 Sophie D Fosså, MD,9
1. Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden
2. Department of Oncology, Ålesund Hospital, Ålesund, Norway
3. Department of Medical Oncology and Radiotherapy, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
4. Department of Urology, Institute of Clinical Science, Sahlgrenska Academy, Göteborg University, Sweden
5. Institute of Cancer Research and Molecular Medicine Norwegian University of Science and Technology and Department of Surgery/Urology, University Hospital of Trondheim, Norway
6. Urological Section, Stavanger University Hospital, Stavanger, Norway
7. Department of Oncology, Aarhus University Hospital, Denmark
8. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
9. National Resource Centre for Long-term Studies after Cancer Rikshospitalet-Radiumhospitalet Cancer Clinic Montebello, Oslo, Norway