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Radiotherapy plus adjuvant goserelin improves survival in men with poor prognosis prostate cancer
CANCER TREATMENT REVIEWS (2005) 31, 582–586
www.elsevierhealth.com/journals/ctrv
EVIDENCE-BASED ONCOLOGY
Radiotherapy plus adjuvant goserelin improves survival in men with poor prognosis prostate cancer Abstracted from: Pilepich MV, Winter K, Lawton CA, et al. Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma: long-term results of Phase III RTOG 85-31. Int J Radiat Oncol Biol Phys 2005; 61:1285–90.
Background
Participants
Although androgen suppression is an accepted treatment for prostate cancer, it has been mostly used in a palliative capacity. There is limited evidence about the effects of combining adjuvant androgen suppression with radiotherapy or surgery on survival in people with poor prognosis prostate cancer.
945 men with well (n = 255, 27.0%), moderately (n = 462, 48.9%) or poorly (n = 228, 24.1%) differentiated prostate cancer, a Gleason score of 2–6 (n = 254, 26.9%), 7 (n = 332, 35.1%) or 8–10 (n = 276, 29.2%) and a Karnofsky performance status >60%. Men were included if they had a palpable primary tumour that extended beyond the prostate (stage T3) or had regional lymphatic involvement, or if they had a primary tumour confined to the prostate (stage T1 or T2) with radiographic or histological evidence of lymph node involvement. Men who had undergone prostatectomy with histological confirmation of tumour penetration through the prostatic capsule to the resection margin and possible spread to the seminal vesicle were also inclu-ded. Exclusions. Men with a tumour of 25 cm or larger with no lymphatic spread outside the pelvis.
Objective To evaluate the effectiveness of adjuvant goserelin treatment plus radiotherapy in men with poor prognosis prostate cancer.
Setting Several hospitals in the USA; enrolment from February 1987 to April 1992.
Method Long-term follow up of a randomised controlled trial.
Intervention Participants were randomised to receive either radiotherapy plus adjuvant goserelin (3.6 mg subcutaneously) or radiotherapy alone (minimal target dose of 60–70 Gy, 1.8–2.0 Gy/day, 4–5 times weekly) followed by goserelin at relapse. Participants in the adjuvant goserelin arm received goserelin from the last week of radiotherapy until disease progression.
0305-7372/$ - see front matter c 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.ctrv.2005.08.002
Evidence-based Oncology
583
Main outcomes
Method notes
Absolute survival; disease-free survival; diseasespecific mortality; local failure rate (reappearance of palpable tumour, tumour progression, persistence of palpable tumour, or a biopsy proven tumour more than 2 years after study entry); incidence of distant metastases.
Main results Benefits. Radiotherapy plus adjuvant goserelin significantly increased absolute and disease-free survival and reduced disease-specific mortality, local failure rate and distant metastases at 10 years compared with radiotherapy alone followed by goserelin at relapse (see Evidence Profile: Benefits). Adverse events. The study did not report on adverse events. Treatment-related mortality. The study did not report on treatment-related deaths.
Evidence Profile: Benefits Outcomes
10 year absolute survival 10 year disease-free survival 10 year disease-specific mortality 10 year local failure rate 10 year incidence of distant metastases
Radiotherapy plus adjuvant goserelin; n = 477
Radiotherapy P plus goserelin at relapse; n = 468
49%
39%
0.002
37%
23%
<0.0001
16%
22%
0.005
23%
38%
<0.0001
24%
39%
Random error Power calculation
Not reported.
Bias
Measures to prevent bias
Comparator bias Was true uncertainty about relative effects of competing treatments acknowledged?
Selection bias (are likes compared with likes?) Selection method Adequate Generation of Adequate allocation sequence Allocation concealment Randomisation centrally performed, allocation concealment likely adequate Balanced groups Well balanced with respect to tumour differentiation, Gleason scores, lymph node status, acid phosphatase levels and prior prostatectomy Performance bias (assessment of the effects of possible co-interventions or contamination) Blinding Open label Detection bias (outcome assessment) Assessors blinded Blinding not necessary as death was the primary outcome Attrition bias (assessment of the effect of loss of participants in the study) Withdrawals and Yes dropouts described Analysis Intention to treat analysis
<0.0001
Authors’ conclusions Radiotherapy plus adjuvant goserelin reduced disease progression and increased survival in men with poor prognosis prostate cancer compared with radiotherapy alone, with goserelin at relapse.
Adequate. Authors report on the initial analysis of this phase III trial where radiotherapy and adjuvant goserelin improved survival in people with poor prognosis prostate cancer.
Other statistical methods used
No, 32 people (3.3%) were retrospectively found to be ineligible and excluded from analysis Kaplan Meier analysis and the log-rank test. K-sample tests for measuring cumulative incidence of time to local failure, time to distant metastases and time to disease-specific mortality
Sources of funding: National Institute of Health, Bethesda, USA.
584 For correspondence: Miljenko V Pilepich, Department of Radiation Oncology, University of California, Los Angeles, School of Medicine, P.O. Box 2515, Los Angeles, CA 90265, United States. Tel: +310 597 5147; fax: +310 457 3451; e-mail: [email protected]. Abstract provided by Bazian Ltd., London.
Commentary Treatment recommendations for men with clinically localised prostate cancer should be based on the best evidence available. This update of Radiation Therapy Oncology Group (RTOG) 8531 adds to a body of phase III trials demonstrating that the most appropriate treatment for patients with bulky and high-grade disease should include longterm adjuvant hormone therapy combined with external beam radiotherapy (EBRT). 1–4 The patients included in these trials typically had high T stages (T2c to T3), high Gleason scores (7–10), and high prostate-specific antigen levels (PSAs > 20 ng/ml), with a significant number also having lymph node involvement. The findings from the individual major phase III randomised studies are consistent with the conclusions of a meta-analysis of RTOG trials.5 Several important issues remain unresolved about the use of adjuvant hormonal therapy in high-risk patients.
Is there a sub-population of high-risk patients for whom long-term adjuvant hormone therapy may not be justified? The answer is probably yes. It appears that some patients with low volume high-grade disease may have a reasonably favourable outcome if treated with high dose local regional therapy.6,7 In addition, based on the findings from RTOG 8531 and RTOG 9202 and a meta-analysis of RTOG trials, it appears that patients with early T3 but Gleason scores of 6 or less may not benefit from long-term adjuvant hormone therapy.3,5 In the largest such trial to date (RTOG 9202) 1554 men with T stages T2c-4 were randomised to receive androgen deprivation starting 2 months before and 2 months concurrent with EBRT, and then randomly assigned to receive no additional therapy or 24 months of adjuvant hormonal therapy. At 5 years overall survival was not statistically different between the two arms (80.0% vs. 78.5%, P = 0.73). However, patients with Gleason scores of 8–10 had significantly better cancer-specific and overall survival
Evidence-based Oncology if treated with 2 years of adjuvant hormonal therapy (81 % vs. 71%, P = 0.04). Other population groups did not seem to benefit from adjuvant hormonal therapy at 2 years, but this does not preclude the possibility of longer term benefit.
Is there a subset of intermediate risk patients for whom long-term adjuvant hormonal therapy should be considered? There may also be a subset of patients who would otherwise appear to be at intermediate risk based on T stage and Gleason score who might also be considered candidates for long-term HT. Intermediate risk patients with a large number of positive biopsies, or with a short PSA doubling time at diagnosis might benefit from long-term AHT.8,9 Unfortunately hard data to support this hypothesis is not yet available.
Should neoadjuvant hormonal therapy be used in addition to adjuvant hormonal therapy? Support for the combination of neoadjuvant with adjuvant hormonal therapy is based on consistent evidence that short-term NHT is beneficial in patients with intermediate risk disease.10 There have been three prospective randomised trials published to date of patients treated with neoadjuvant hormonal therapy in combination with EBRT, with or without adjuvant hormonal therapy. All three trials showed at least some improvement in progression-free survival.11–13 Based on these studies, and the fact that there appears to be a biologic interaction between hormonal therapy and radiation, I would recommend the use of combined neoadjuvant and adjuvant hormonal therapy in high-risk patients.14 Unfortunately, as no trials have directly compared the different timings of hormonal therapy (neoadjuvant, concurrent, adjuvant, and combinations of these), we really don’t know for sure which schedule is best.
Should the recommendations be modified for patients treated with high dose rate brachytherapy boost? Despite the provocative studies reported by a group of investigators claiming that hormonal therapy may not be required in patients undergoing high dose rate (HDR) temporary implants combined with EBRT, I would say probably not.6 The studies in question were retrospective, and as such, prone to selection biases. Therefore, these
Evidence-based Oncology
585
studies should not be used to disprove the findings of large prospective phase III randomised multicentre trials. The patients included in most of the retrospective studies were not as high risk as the patients treated in the phase III trials. For example, the average PSA for patients treated in phase III RTOG trials (8531 and 9202) was >20 ng/ml compared with <10 ng/ml for the majority of patients treated in the largest pooled study of patients treated with HDR.6 In addition neither the radiation fields nor the duration of hormonal therapy were comparable between the retrospective studies and the phase III randomised trials. Finally, there is also a biological argument for using long-term adjuvant hormonal therapy, increasing the radiation dose to the prostate cannot do anything about occult microscopic distant disease. This concept is analogous to the use of adjuvant hormonal therapy in women with breast cancer.15
Most importantly, what is the optimum duration of adjuvant hormone therapy use? This is perhaps the most difficult question to answer. Given the results of major randomised trials it is clear that long-term hormone therapy is indicated for patients with high-risk disease (T3 and Gleason 7; or Gleason 8–10).1–3 The question is whether we should use 2 years, 3 years or lifelong hormonal therapy? Data from the meta-analysis of RTOG trials suggest that 5 years or longer is better than <5 years, which is consistent with the adjuvant breast cancer data.5,15 Thus, lifelong hormonal therapy could be best. In practice however, unless a patient has very high-risk disease (positive lymph nodes, very high PSA, and Gleason 9 or greater) I would tend to favour 2 years of adjuvant hormonal therapy. The preponderance of data supports the use of adjuvant hormonal therapy in high-risk patients, but the optimal timing and duration remains to be elucidated. The long-term findings of RTOG 8531 have answered some questions but many more remain to be addressed.
Quality assessment (1 = fair; 4 = excellent) Relevance Validity Applicability Feasibility Impact Knowledge context
4 4 3 4 3 3
Mack Roach III MD, FACR Professor of Radiation Oncology and Urology Departments of Radiation Oncology and Urology University of California San Francisco UCSF Comprehensive Cancer Center San Francisco, California, United States
References 1. Pilepich MV, Winter K, Lawton CA, et al. Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma – long-term results of phase III RTOG 85-31. Int J Radiat Oncol Biol Phys 2005;61:1285–90. 2. Bolla M, Collette L, Blank L, et al. Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet 2002;360: 103–6. 3. Hanks GE, Pajak TF, Porter A, et al. Phase III trial of longterm adjuvant androgen deprivation after neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate: the Radiation Therapy Oncology Group Protocol 92-02. J Clin Oncol 2003;21: 3972–8. 4. Granfors T, Modig H, Damber JE, et al. Combined orchiectomy and external radiotherapy versus radiotherapy alone for nonmetastatic prostate cancer with or without pelvic lymph node involvement: a prospective randomized study. J Urol 1998;159:2030–4. 5. Roach M, Lu J, Pilepich MV, et al. Predicting long term survival, and the need for hormonal therapy: a metaanalysis of RTOG prostate cancer trials. Int J Radiat Oncol Biol Phys 2000;47:617–27. 6. Martinez AA, Demanes DJ, Galalae R, et al. Lack of benefit from a short course of androgen deprivation for unfavorable prostate cancer patients treated with an accelerated hypofractionated regime. Int J Radiat Oncol Biol Phys 2005;62: 1322–31. 7. Fiveash JB, Hanks G, Roach M, et al. 3D conformal radiation therapy (3DCRT) for high grade prostate cancer: a multiinstitutional review. Int J Radiat Oncol Biol Phys 2000;47: 335–42. 8. D’Amico AV, Renshaw AA, Cote K, et al. Impact of the percentage of positive prostate cores on prostate cancerspecific mortality for patients with low or favorable intermediate-risk disease. J Clin Oncol 2004;22:3726–32. 9. D’Amico AV, Chen MH, Roehl KA, et al. Preoperative PSA velocity and the risk of death from prostate cancer after radical prostatectomy. N Engl J Med 2004;351:125–35. 10. Roach III M. Neoadjuvant hormonal therapy in men being treated with radiotherapy for localized prostate cancer. Rev Urol 2004;6:S24–31. 11. Laverdiere J, Nabid A, De Bedoya LD, et al. The efficacy and sequencing of a short course of androgen suppression on freedom from biochemical failure when administered with radiation therapy for T2-T3 prostate cancer. J Urol 2004;171: 1137–40. 12. Pilepich MV, Krall JM, Al-Sarraf M, et al. Androgen deprivation with radiation therapy compared with radiation therapy alone for locally advanced prostatic carcinoma: a randomized comparative trial of the Radiation Therapy Oncology Group. Urology 1995;45:616–23.
586 13. D’Amico AV, Manola J, Loffredo M, et al. 6-month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer: a randomized controlled trial. JAMA 2004;292:821–7. 14. Roach 3rd M, DeSilvio M, Lawton C, et al. Phase III trial comparing whole-pelvic versus prostate-only radiotherapy
Evidence-based Oncology and neoadjuvant versus adjuvant combined androgen suppression: Radiation Therapy Oncology Group 9413. J Clin Oncol 2003;21:1904–11. 15. Group EBCTC. Tamoxifen for early breast cancer: an overview of the randomized trials. Lancet 1998;351: 1451–67.
www.elsevierhealth.com/journals/ctrv
EVIDENCE-BASED ONCOLOGY
Radiotherapy plus adjuvant goserelin improves survival in men with poor prognosis prostate cancer Abstracted from: Pilepich MV, Winter K, Lawton CA, et al. Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma: long-term results of Phase III RTOG 85-31. Int J Radiat Oncol Biol Phys 2005; 61:1285–90.
Background
Participants
Although androgen suppression is an accepted treatment for prostate cancer, it has been mostly used in a palliative capacity. There is limited evidence about the effects of combining adjuvant androgen suppression with radiotherapy or surgery on survival in people with poor prognosis prostate cancer.
945 men with well (n = 255, 27.0%), moderately (n = 462, 48.9%) or poorly (n = 228, 24.1%) differentiated prostate cancer, a Gleason score of 2–6 (n = 254, 26.9%), 7 (n = 332, 35.1%) or 8–10 (n = 276, 29.2%) and a Karnofsky performance status >60%. Men were included if they had a palpable primary tumour that extended beyond the prostate (stage T3) or had regional lymphatic involvement, or if they had a primary tumour confined to the prostate (stage T1 or T2) with radiographic or histological evidence of lymph node involvement. Men who had undergone prostatectomy with histological confirmation of tumour penetration through the prostatic capsule to the resection margin and possible spread to the seminal vesicle were also inclu-ded. Exclusions. Men with a tumour of 25 cm or larger with no lymphatic spread outside the pelvis.
Objective To evaluate the effectiveness of adjuvant goserelin treatment plus radiotherapy in men with poor prognosis prostate cancer.
Setting Several hospitals in the USA; enrolment from February 1987 to April 1992.
Method Long-term follow up of a randomised controlled trial.
Intervention Participants were randomised to receive either radiotherapy plus adjuvant goserelin (3.6 mg subcutaneously) or radiotherapy alone (minimal target dose of 60–70 Gy, 1.8–2.0 Gy/day, 4–5 times weekly) followed by goserelin at relapse. Participants in the adjuvant goserelin arm received goserelin from the last week of radiotherapy until disease progression.
0305-7372/$ - see front matter c 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.ctrv.2005.08.002
Evidence-based Oncology
583
Main outcomes
Method notes
Absolute survival; disease-free survival; diseasespecific mortality; local failure rate (reappearance of palpable tumour, tumour progression, persistence of palpable tumour, or a biopsy proven tumour more than 2 years after study entry); incidence of distant metastases.
Main results Benefits. Radiotherapy plus adjuvant goserelin significantly increased absolute and disease-free survival and reduced disease-specific mortality, local failure rate and distant metastases at 10 years compared with radiotherapy alone followed by goserelin at relapse (see Evidence Profile: Benefits). Adverse events. The study did not report on adverse events. Treatment-related mortality. The study did not report on treatment-related deaths.
Evidence Profile: Benefits Outcomes
10 year absolute survival 10 year disease-free survival 10 year disease-specific mortality 10 year local failure rate 10 year incidence of distant metastases
Radiotherapy plus adjuvant goserelin; n = 477
Radiotherapy P plus goserelin at relapse; n = 468
49%
39%
0.002
37%
23%
<0.0001
16%
22%
0.005
23%
38%
<0.0001
24%
39%
Random error Power calculation
Not reported.
Bias
Measures to prevent bias
Comparator bias Was true uncertainty about relative effects of competing treatments acknowledged?
Selection bias (are likes compared with likes?) Selection method Adequate Generation of Adequate allocation sequence Allocation concealment Randomisation centrally performed, allocation concealment likely adequate Balanced groups Well balanced with respect to tumour differentiation, Gleason scores, lymph node status, acid phosphatase levels and prior prostatectomy Performance bias (assessment of the effects of possible co-interventions or contamination) Blinding Open label Detection bias (outcome assessment) Assessors blinded Blinding not necessary as death was the primary outcome Attrition bias (assessment of the effect of loss of participants in the study) Withdrawals and Yes dropouts described Analysis Intention to treat analysis
<0.0001
Authors’ conclusions Radiotherapy plus adjuvant goserelin reduced disease progression and increased survival in men with poor prognosis prostate cancer compared with radiotherapy alone, with goserelin at relapse.
Adequate. Authors report on the initial analysis of this phase III trial where radiotherapy and adjuvant goserelin improved survival in people with poor prognosis prostate cancer.
Other statistical methods used
No, 32 people (3.3%) were retrospectively found to be ineligible and excluded from analysis Kaplan Meier analysis and the log-rank test. K-sample tests for measuring cumulative incidence of time to local failure, time to distant metastases and time to disease-specific mortality
Sources of funding: National Institute of Health, Bethesda, USA.
584 For correspondence: Miljenko V Pilepich, Department of Radiation Oncology, University of California, Los Angeles, School of Medicine, P.O. Box 2515, Los Angeles, CA 90265, United States. Tel: +310 597 5147; fax: +310 457 3451; e-mail: [email protected]. Abstract provided by Bazian Ltd., London.
Commentary Treatment recommendations for men with clinically localised prostate cancer should be based on the best evidence available. This update of Radiation Therapy Oncology Group (RTOG) 8531 adds to a body of phase III trials demonstrating that the most appropriate treatment for patients with bulky and high-grade disease should include longterm adjuvant hormone therapy combined with external beam radiotherapy (EBRT). 1–4 The patients included in these trials typically had high T stages (T2c to T3), high Gleason scores (7–10), and high prostate-specific antigen levels (PSAs > 20 ng/ml), with a significant number also having lymph node involvement. The findings from the individual major phase III randomised studies are consistent with the conclusions of a meta-analysis of RTOG trials.5 Several important issues remain unresolved about the use of adjuvant hormonal therapy in high-risk patients.
Is there a sub-population of high-risk patients for whom long-term adjuvant hormone therapy may not be justified? The answer is probably yes. It appears that some patients with low volume high-grade disease may have a reasonably favourable outcome if treated with high dose local regional therapy.6,7 In addition, based on the findings from RTOG 8531 and RTOG 9202 and a meta-analysis of RTOG trials, it appears that patients with early T3 but Gleason scores of 6 or less may not benefit from long-term adjuvant hormone therapy.3,5 In the largest such trial to date (RTOG 9202) 1554 men with T stages T2c-4 were randomised to receive androgen deprivation starting 2 months before and 2 months concurrent with EBRT, and then randomly assigned to receive no additional therapy or 24 months of adjuvant hormonal therapy. At 5 years overall survival was not statistically different between the two arms (80.0% vs. 78.5%, P = 0.73). However, patients with Gleason scores of 8–10 had significantly better cancer-specific and overall survival
Evidence-based Oncology if treated with 2 years of adjuvant hormonal therapy (81 % vs. 71%, P = 0.04). Other population groups did not seem to benefit from adjuvant hormonal therapy at 2 years, but this does not preclude the possibility of longer term benefit.
Is there a subset of intermediate risk patients for whom long-term adjuvant hormonal therapy should be considered? There may also be a subset of patients who would otherwise appear to be at intermediate risk based on T stage and Gleason score who might also be considered candidates for long-term HT. Intermediate risk patients with a large number of positive biopsies, or with a short PSA doubling time at diagnosis might benefit from long-term AHT.8,9 Unfortunately hard data to support this hypothesis is not yet available.
Should neoadjuvant hormonal therapy be used in addition to adjuvant hormonal therapy? Support for the combination of neoadjuvant with adjuvant hormonal therapy is based on consistent evidence that short-term NHT is beneficial in patients with intermediate risk disease.10 There have been three prospective randomised trials published to date of patients treated with neoadjuvant hormonal therapy in combination with EBRT, with or without adjuvant hormonal therapy. All three trials showed at least some improvement in progression-free survival.11–13 Based on these studies, and the fact that there appears to be a biologic interaction between hormonal therapy and radiation, I would recommend the use of combined neoadjuvant and adjuvant hormonal therapy in high-risk patients.14 Unfortunately, as no trials have directly compared the different timings of hormonal therapy (neoadjuvant, concurrent, adjuvant, and combinations of these), we really don’t know for sure which schedule is best.
Should the recommendations be modified for patients treated with high dose rate brachytherapy boost? Despite the provocative studies reported by a group of investigators claiming that hormonal therapy may not be required in patients undergoing high dose rate (HDR) temporary implants combined with EBRT, I would say probably not.6 The studies in question were retrospective, and as such, prone to selection biases. Therefore, these
Evidence-based Oncology
585
studies should not be used to disprove the findings of large prospective phase III randomised multicentre trials. The patients included in most of the retrospective studies were not as high risk as the patients treated in the phase III trials. For example, the average PSA for patients treated in phase III RTOG trials (8531 and 9202) was >20 ng/ml compared with <10 ng/ml for the majority of patients treated in the largest pooled study of patients treated with HDR.6 In addition neither the radiation fields nor the duration of hormonal therapy were comparable between the retrospective studies and the phase III randomised trials. Finally, there is also a biological argument for using long-term adjuvant hormonal therapy, increasing the radiation dose to the prostate cannot do anything about occult microscopic distant disease. This concept is analogous to the use of adjuvant hormonal therapy in women with breast cancer.15
Most importantly, what is the optimum duration of adjuvant hormone therapy use? This is perhaps the most difficult question to answer. Given the results of major randomised trials it is clear that long-term hormone therapy is indicated for patients with high-risk disease (T3 and Gleason 7; or Gleason 8–10).1–3 The question is whether we should use 2 years, 3 years or lifelong hormonal therapy? Data from the meta-analysis of RTOG trials suggest that 5 years or longer is better than <5 years, which is consistent with the adjuvant breast cancer data.5,15 Thus, lifelong hormonal therapy could be best. In practice however, unless a patient has very high-risk disease (positive lymph nodes, very high PSA, and Gleason 9 or greater) I would tend to favour 2 years of adjuvant hormonal therapy. The preponderance of data supports the use of adjuvant hormonal therapy in high-risk patients, but the optimal timing and duration remains to be elucidated. The long-term findings of RTOG 8531 have answered some questions but many more remain to be addressed.
Quality assessment (1 = fair; 4 = excellent) Relevance Validity Applicability Feasibility Impact Knowledge context
4 4 3 4 3 3
Mack Roach III MD, FACR Professor of Radiation Oncology and Urology Departments of Radiation Oncology and Urology University of California San Francisco UCSF Comprehensive Cancer Center San Francisco, California, United States
References 1. Pilepich MV, Winter K, Lawton CA, et al. Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma – long-term results of phase III RTOG 85-31. Int J Radiat Oncol Biol Phys 2005;61:1285–90. 2. Bolla M, Collette L, Blank L, et al. Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet 2002;360: 103–6. 3. Hanks GE, Pajak TF, Porter A, et al. Phase III trial of longterm adjuvant androgen deprivation after neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate: the Radiation Therapy Oncology Group Protocol 92-02. J Clin Oncol 2003;21: 3972–8. 4. Granfors T, Modig H, Damber JE, et al. Combined orchiectomy and external radiotherapy versus radiotherapy alone for nonmetastatic prostate cancer with or without pelvic lymph node involvement: a prospective randomized study. J Urol 1998;159:2030–4. 5. Roach M, Lu J, Pilepich MV, et al. Predicting long term survival, and the need for hormonal therapy: a metaanalysis of RTOG prostate cancer trials. Int J Radiat Oncol Biol Phys 2000;47:617–27. 6. Martinez AA, Demanes DJ, Galalae R, et al. Lack of benefit from a short course of androgen deprivation for unfavorable prostate cancer patients treated with an accelerated hypofractionated regime. Int J Radiat Oncol Biol Phys 2005;62: 1322–31. 7. Fiveash JB, Hanks G, Roach M, et al. 3D conformal radiation therapy (3DCRT) for high grade prostate cancer: a multiinstitutional review. Int J Radiat Oncol Biol Phys 2000;47: 335–42. 8. D’Amico AV, Renshaw AA, Cote K, et al. Impact of the percentage of positive prostate cores on prostate cancerspecific mortality for patients with low or favorable intermediate-risk disease. J Clin Oncol 2004;22:3726–32. 9. D’Amico AV, Chen MH, Roehl KA, et al. Preoperative PSA velocity and the risk of death from prostate cancer after radical prostatectomy. N Engl J Med 2004;351:125–35. 10. Roach III M. Neoadjuvant hormonal therapy in men being treated with radiotherapy for localized prostate cancer. Rev Urol 2004;6:S24–31. 11. Laverdiere J, Nabid A, De Bedoya LD, et al. The efficacy and sequencing of a short course of androgen suppression on freedom from biochemical failure when administered with radiation therapy for T2-T3 prostate cancer. J Urol 2004;171: 1137–40. 12. Pilepich MV, Krall JM, Al-Sarraf M, et al. Androgen deprivation with radiation therapy compared with radiation therapy alone for locally advanced prostatic carcinoma: a randomized comparative trial of the Radiation Therapy Oncology Group. Urology 1995;45:616–23.
586 13. D’Amico AV, Manola J, Loffredo M, et al. 6-month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer: a randomized controlled trial. JAMA 2004;292:821–7. 14. Roach 3rd M, DeSilvio M, Lawton C, et al. Phase III trial comparing whole-pelvic versus prostate-only radiotherapy
Evidence-based Oncology and neoadjuvant versus adjuvant combined androgen suppression: Radiation Therapy Oncology Group 9413. J Clin Oncol 2003;21:1904–11. 15. Group EBCTC. Tamoxifen for early breast cancer: an overview of the randomized trials. Lancet 1998;351: 1451–67.