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Androgen Deprivation Therapy Combined with Radiation in High-Risk Prostate Cancer . . . How Long Do We Go?
Study Overview
Objective. To compare the outcomes of 18 months versus 36 months of androgen deprivation therapy (ADT) combined with radiation in high-risk prostate cancer (HRPC).
Design. Phase 3 multicenter, randomized superiority trial.
Participants. This study enrolled patients aged ≤ 80 years with HRPC. All patients had no evidence of regional or distant metastasis. High-risk disease was defined as any of the following: clinical stage T3 or T4, prostate-specific antigen (PSA) level > 20 ng/mL, or Gleason score > 7.
Methods. Prior to randomization, all patients received 4 months of ADT with goserelin 10.8 mg and anti-androgen therapy with bicalutamide 50 mg daily for 30 days. Patients were then randomly assigned to 18 (short arm) or 36 (long arm) months of ADT in combination with radiation therapy (RT). The randomization was stratified by stage (T1-2 vs T3-4), Gleason score (< 7 vs > 7) and PSA level (< 20 ng/mL vs > 20 ng/mL). The standard radiation dose was 70 Gy to the prostate and 44 Gy to the pelvis. Computed tomography or magnetic resonance imaging exam of the abdomen and pelvis and a bone scan were performed to rule out regional or distant metastases. PSA level was monitored every 3 months for 18 months, every 6 months up to the third year, and yearly thereafter.
Main outcome measures. The 2 primary outcomes were overall survival (OS) and quality of life (QoL) at 5 years. The secondary end points were biochemical failure (BF)defined as PSA nadir plus 2, disease-free survival (DFS), and site(s) of tumor relapse.
Main results. The 5-year OS was 91% and 86% for the 36- and 18-month groups, respectively (P = 0.07). The 10-year OS was 62% for both groups (P = 0.7), and the global hazard ratio (HR) was 1.02 (P = 0.8). The disease-specific survival (DSS) was similar in both groups at 5 years (98% vs 97%) and at 10 years (91% vs 92%) in the long versus short arm, respectively. The rate of prostate cancer–specific death was 21% versus 23% in the long versus short arm, respectively. In a multivariate analysis for OS, only age and Gleason score > 7 were statistically significant survival predictors. BF rate at 10 years was 25% for 36 months as compared with 31% for 18 months (HR, 0.71, P = 0.02). The 10-year DFS rates were 45% and 39% for 36 and 18 months, respectively (HR, 0.68, P = 0.08). Forty patients in the long arm versus 43 in the short arm developed distant metastasis. Both groups developed similar sites of metastasis, which was predominantly osseous. Some aspects of the EORTC30 and PR25 scales were significant, mostly pertaining to sexual activity, fatigue, and hormone-related symptoms in favor of the 18-month group. The median time to testosterone recovery after completion of ADT was 2.1 years for the short arm versus 4 years in the long arm (P = 0.02). The compliance rate with ADT was 88% in the short arm versus 53% in the long arm. The main reason for nonadherence was side effects in 54% of the patients in the long arm and 31% in the short arm.
Conclusion. The results of the current study suggest that 18 months of ADT in combination with RT yields similar 10-year OS and improved QoL compared with 36 months in patients with HRPC.
Commentary
The role of ADT for HRPC in combination with RT has been well established by evidence from several trials; however, the comparator arms and patient characteristics between these studies have been quite heterogeneous. For instance, the Radiation Therapy Oncology Group (RTOG) 85-31 trial compared indefinite ADT with RT versus RT alone and showed significantly better 10-year OS in the ADT plus RT arm.1 Similarly, the European Organisation for Research and Treatment of Cancer (EROTC) 22961 trial showed an OS benefit for 36 months versus 6 months of ADT in combination with radiation.2 Additionally, the RTOG 92-02 trial, which compared 4 months versus 24 months of ADT with radiation, also found a significantly improved 10-year OS with a longer course of ADT.3 Taken together these data suggest that 4 to 6 months of ADT is inferior to 24 to 36 months of ADT in HRPC.
Several differences, however, exist in patient characteristics between the present trial and the earlier trials, justifiably reflecting the change of practice in the PSA era. For instance, the present study has a higher percentage of patients with Gleason scores 8-10 (60%) compared to the EROTC and RTOG studies (15%-35%) and a lower percentage of patients with T3 and T4 tumors. Patients with high Gleason scores are believed to have a higher risk of micro-metastasis at the time of diagnosis and higher chances of castration resistance. Therefore, inclusion of a (presumably) larger high-risk patient subgroup in the present study lends further credence to results indicating similar OS with a shorter course of ADT. A post hoc analysis including only patients with Gleason score 8-10 performed for OS, DSS, BF, and DFS showed no significant difference in any of these variables between the arms. Analysis of the interaction between ADT duration in the Gleason 8-10 subgroup versus Gleason 7 for OS, DFS, DSS and BF found no significant differences. This again suggests that 18 months of ADT may be sufficient for this high-risk group; however, it is difficult to draw definitive conclusions from this unplanned subgroup analysis.
Based on the results of the current study, it seems that 18 months of ADT is adequate for many, but not necessarily all, patients. For instance, there was a significantly higher incidence of BF in the 18-month arm. Applying this data to younger patients may require a more nuanced approach, as it is possible that with longer follow-up this higher rate of BF may translate into a difference in OS. Therefore, life expectancy and comorbid conditions always need to be incorporated into clinical decision making with regards to ADT duration. In a study by Rose et al, the risk of prostate cancer–specific mortality significantly decreased by using ADT plus RT for men with HRPC with a low, but not a high, competing mortality score.4 The clinical significance of this finding is that adding ADT to RT might significantly reduce the risk of death from prostate cancer only in the setting of low competing risks.
Another concept to ponder is the optimum duration of ADT in the era of RT dose escalation. Currently, there are emerging techniques for delivering higher radiation doses and combining brachytherapy with external beam radiotherapy for HRPC, and the role of whole pelvic radiation is being investigated. New data suggests that higher radiation doses can lead to improvement in outcomes for HRPC. The DART01/05 study compared 4 versus 24 months of ADT with 76 to 82 Gy of RT and reported improved 5-year OS, DFS, and metastasis-free survival with longer ADT duration.5 Moreover, Kishan et al reported improved prostate cancer–specific mortality when brachytherapy boost was added to radiation compared to radiation alone in patients with Gleason scores 9 and 10.6 Therefore, the optimal duration of ADT in the setting of dose-escalated radiotherapy is not yet known. Also, it is important to note that unlike the prior RTOG and EORTC studies, this study did not include patients with evidence of regional nodal disease, and thus the present data should not be applied to this patient population.
Applications to Clinical Practice
This study’s results suggesting that 18 months of ADT in combination with RT yields similar 10-year OS and improved QoL compared with 36 months of ADT in patients with HRPC should be interpreted with caution when treating very young patients, since the higher rate of BF in the short arm may impact the OS with longer follow-up. Additionally, patients’ QoL and tolerance to ADT-related adverse effects should be taken into consideration given that compliance with 36 months of ADT was only 53% in this study.
—Jailan Elayoubi, MD, Michigan State University, East Lansing, MI
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;61:1285-1290.
2. Bolla M, de Reijke TM, Van Tienhoven G, et al. Duration of androgen suppression in the treatment of prostate cancer. N Engl J Med. 2009;360:2516-2527.
3. Horwitz EM, Bae K, Hanks GE, Porter A, et al. Ten-year follow-up of radiation therapy oncology group protocol 92-02: a phase III trial of the duration of elective androgen deprivation in locally advanced prostate cancer. J Clin Oncol. 2008;26:2497–2504.
4. Rose BS, Chen MH, Wu J, et al. Androgen deprivation therapy use in the setting of high-dose radiation therapy and the risk of prostate cancer-specific mortality stratified by the extent of competing mortality. Int J Radiat Oncol Biol Phys. 2016;96:778-784.
5. Zapatero A, Guerrero A, Maldonado X, et al. High-dose radiotherapy with short-term or long-term androgen deprivation in localised prostate cancer (DART01/05 GICOR): a randomised, controlled, phase 3 trial. Lancet Oncol. 2015;16:320-327.
6. Kishan, AU, Cook, RR, Ciezki, JP, et al. Radical prostatectomy, external beam radiotherapy, or external beam radiotherapy with brachytherapy boost and disease progression and mortality in patients with gleason score 9-10 prostate cancer. JAMA. 2018;319:896-905.
Study Overview
Objective. To compare the outcomes of 18 months versus 36 months of androgen deprivation therapy (ADT) combined with radiation in high-risk prostate cancer (HRPC).
Design. Phase 3 multicenter, randomized superiority trial.
Participants. This study enrolled patients aged ≤ 80 years with HRPC. All patients had no evidence of regional or distant metastasis. High-risk disease was defined as any of the following: clinical stage T3 or T4, prostate-specific antigen (PSA) level > 20 ng/mL, or Gleason score > 7.
Methods. Prior to randomization, all patients received 4 months of ADT with goserelin 10.8 mg and anti-androgen therapy with bicalutamide 50 mg daily for 30 days. Patients were then randomly assigned to 18 (short arm) or 36 (long arm) months of ADT in combination with radiation therapy (RT). The randomization was stratified by stage (T1-2 vs T3-4), Gleason score (< 7 vs > 7) and PSA level (< 20 ng/mL vs > 20 ng/mL). The standard radiation dose was 70 Gy to the prostate and 44 Gy to the pelvis. Computed tomography or magnetic resonance imaging exam of the abdomen and pelvis and a bone scan were performed to rule out regional or distant metastases. PSA level was monitored every 3 months for 18 months, every 6 months up to the third year, and yearly thereafter.
Main outcome measures. The 2 primary outcomes were overall survival (OS) and quality of life (QoL) at 5 years. The secondary end points were biochemical failure (BF)defined as PSA nadir plus 2, disease-free survival (DFS), and site(s) of tumor relapse.
Main results. The 5-year OS was 91% and 86% for the 36- and 18-month groups, respectively (P = 0.07). The 10-year OS was 62% for both groups (P = 0.7), and the global hazard ratio (HR) was 1.02 (P = 0.8). The disease-specific survival (DSS) was similar in both groups at 5 years (98% vs 97%) and at 10 years (91% vs 92%) in the long versus short arm, respectively. The rate of prostate cancer–specific death was 21% versus 23% in the long versus short arm, respectively. In a multivariate analysis for OS, only age and Gleason score > 7 were statistically significant survival predictors. BF rate at 10 years was 25% for 36 months as compared with 31% for 18 months (HR, 0.71, P = 0.02). The 10-year DFS rates were 45% and 39% for 36 and 18 months, respectively (HR, 0.68, P = 0.08). Forty patients in the long arm versus 43 in the short arm developed distant metastasis. Both groups developed similar sites of metastasis, which was predominantly osseous. Some aspects of the EORTC30 and PR25 scales were significant, mostly pertaining to sexual activity, fatigue, and hormone-related symptoms in favor of the 18-month group. The median time to testosterone recovery after completion of ADT was 2.1 years for the short arm versus 4 years in the long arm (P = 0.02). The compliance rate with ADT was 88% in the short arm versus 53% in the long arm. The main reason for nonadherence was side effects in 54% of the patients in the long arm and 31% in the short arm.
Conclusion. The results of the current study suggest that 18 months of ADT in combination with RT yields similar 10-year OS and improved QoL compared with 36 months in patients with HRPC.
Commentary
The role of ADT for HRPC in combination with RT has been well established by evidence from several trials; however, the comparator arms and patient characteristics between these studies have been quite heterogeneous. For instance, the Radiation Therapy Oncology Group (RTOG) 85-31 trial compared indefinite ADT with RT versus RT alone and showed significantly better 10-year OS in the ADT plus RT arm.1 Similarly, the European Organisation for Research and Treatment of Cancer (EROTC) 22961 trial showed an OS benefit for 36 months versus 6 months of ADT in combination with radiation.2 Additionally, the RTOG 92-02 trial, which compared 4 months versus 24 months of ADT with radiation, also found a significantly improved 10-year OS with a longer course of ADT.3 Taken together these data suggest that 4 to 6 months of ADT is inferior to 24 to 36 months of ADT in HRPC.
Several differences, however, exist in patient characteristics between the present trial and the earlier trials, justifiably reflecting the change of practice in the PSA era. For instance, the present study has a higher percentage of patients with Gleason scores 8-10 (60%) compared to the EROTC and RTOG studies (15%-35%) and a lower percentage of patients with T3 and T4 tumors. Patients with high Gleason scores are believed to have a higher risk of micro-metastasis at the time of diagnosis and higher chances of castration resistance. Therefore, inclusion of a (presumably) larger high-risk patient subgroup in the present study lends further credence to results indicating similar OS with a shorter course of ADT. A post hoc analysis including only patients with Gleason score 8-10 performed for OS, DSS, BF, and DFS showed no significant difference in any of these variables between the arms. Analysis of the interaction between ADT duration in the Gleason 8-10 subgroup versus Gleason 7 for OS, DFS, DSS and BF found no significant differences. This again suggests that 18 months of ADT may be sufficient for this high-risk group; however, it is difficult to draw definitive conclusions from this unplanned subgroup analysis.
Based on the results of the current study, it seems that 18 months of ADT is adequate for many, but not necessarily all, patients. For instance, there was a significantly higher incidence of BF in the 18-month arm. Applying this data to younger patients may require a more nuanced approach, as it is possible that with longer follow-up this higher rate of BF may translate into a difference in OS. Therefore, life expectancy and comorbid conditions always need to be incorporated into clinical decision making with regards to ADT duration. In a study by Rose et al, the risk of prostate cancer–specific mortality significantly decreased by using ADT plus RT for men with HRPC with a low, but not a high, competing mortality score.4 The clinical significance of this finding is that adding ADT to RT might significantly reduce the risk of death from prostate cancer only in the setting of low competing risks.
Another concept to ponder is the optimum duration of ADT in the era of RT dose escalation. Currently, there are emerging techniques for delivering higher radiation doses and combining brachytherapy with external beam radiotherapy for HRPC, and the role of whole pelvic radiation is being investigated. New data suggests that higher radiation doses can lead to improvement in outcomes for HRPC. The DART01/05 study compared 4 versus 24 months of ADT with 76 to 82 Gy of RT and reported improved 5-year OS, DFS, and metastasis-free survival with longer ADT duration.5 Moreover, Kishan et al reported improved prostate cancer–specific mortality when brachytherapy boost was added to radiation compared to radiation alone in patients with Gleason scores 9 and 10.6 Therefore, the optimal duration of ADT in the setting of dose-escalated radiotherapy is not yet known. Also, it is important to note that unlike the prior RTOG and EORTC studies, this study did not include patients with evidence of regional nodal disease, and thus the present data should not be applied to this patient population.
Applications to Clinical Practice
This study’s results suggesting that 18 months of ADT in combination with RT yields similar 10-year OS and improved QoL compared with 36 months of ADT in patients with HRPC should be interpreted with caution when treating very young patients, since the higher rate of BF in the short arm may impact the OS with longer follow-up. Additionally, patients’ QoL and tolerance to ADT-related adverse effects should be taken into consideration given that compliance with 36 months of ADT was only 53% in this study.
—Jailan Elayoubi, MD, Michigan State University, East Lansing, MI
Study Overview
Objective. To compare the outcomes of 18 months versus 36 months of androgen deprivation therapy (ADT) combined with radiation in high-risk prostate cancer (HRPC).
Design. Phase 3 multicenter, randomized superiority trial.
Participants. This study enrolled patients aged ≤ 80 years with HRPC. All patients had no evidence of regional or distant metastasis. High-risk disease was defined as any of the following: clinical stage T3 or T4, prostate-specific antigen (PSA) level > 20 ng/mL, or Gleason score > 7.
Methods. Prior to randomization, all patients received 4 months of ADT with goserelin 10.8 mg and anti-androgen therapy with bicalutamide 50 mg daily for 30 days. Patients were then randomly assigned to 18 (short arm) or 36 (long arm) months of ADT in combination with radiation therapy (RT). The randomization was stratified by stage (T1-2 vs T3-4), Gleason score (< 7 vs > 7) and PSA level (< 20 ng/mL vs > 20 ng/mL). The standard radiation dose was 70 Gy to the prostate and 44 Gy to the pelvis. Computed tomography or magnetic resonance imaging exam of the abdomen and pelvis and a bone scan were performed to rule out regional or distant metastases. PSA level was monitored every 3 months for 18 months, every 6 months up to the third year, and yearly thereafter.
Main outcome measures. The 2 primary outcomes were overall survival (OS) and quality of life (QoL) at 5 years. The secondary end points were biochemical failure (BF)defined as PSA nadir plus 2, disease-free survival (DFS), and site(s) of tumor relapse.
Main results. The 5-year OS was 91% and 86% for the 36- and 18-month groups, respectively (P = 0.07). The 10-year OS was 62% for both groups (P = 0.7), and the global hazard ratio (HR) was 1.02 (P = 0.8). The disease-specific survival (DSS) was similar in both groups at 5 years (98% vs 97%) and at 10 years (91% vs 92%) in the long versus short arm, respectively. The rate of prostate cancer–specific death was 21% versus 23% in the long versus short arm, respectively. In a multivariate analysis for OS, only age and Gleason score > 7 were statistically significant survival predictors. BF rate at 10 years was 25% for 36 months as compared with 31% for 18 months (HR, 0.71, P = 0.02). The 10-year DFS rates were 45% and 39% for 36 and 18 months, respectively (HR, 0.68, P = 0.08). Forty patients in the long arm versus 43 in the short arm developed distant metastasis. Both groups developed similar sites of metastasis, which was predominantly osseous. Some aspects of the EORTC30 and PR25 scales were significant, mostly pertaining to sexual activity, fatigue, and hormone-related symptoms in favor of the 18-month group. The median time to testosterone recovery after completion of ADT was 2.1 years for the short arm versus 4 years in the long arm (P = 0.02). The compliance rate with ADT was 88% in the short arm versus 53% in the long arm. The main reason for nonadherence was side effects in 54% of the patients in the long arm and 31% in the short arm.
Conclusion. The results of the current study suggest that 18 months of ADT in combination with RT yields similar 10-year OS and improved QoL compared with 36 months in patients with HRPC.
Commentary
The role of ADT for HRPC in combination with RT has been well established by evidence from several trials; however, the comparator arms and patient characteristics between these studies have been quite heterogeneous. For instance, the Radiation Therapy Oncology Group (RTOG) 85-31 trial compared indefinite ADT with RT versus RT alone and showed significantly better 10-year OS in the ADT plus RT arm.1 Similarly, the European Organisation for Research and Treatment of Cancer (EROTC) 22961 trial showed an OS benefit for 36 months versus 6 months of ADT in combination with radiation.2 Additionally, the RTOG 92-02 trial, which compared 4 months versus 24 months of ADT with radiation, also found a significantly improved 10-year OS with a longer course of ADT.3 Taken together these data suggest that 4 to 6 months of ADT is inferior to 24 to 36 months of ADT in HRPC.
Several differences, however, exist in patient characteristics between the present trial and the earlier trials, justifiably reflecting the change of practice in the PSA era. For instance, the present study has a higher percentage of patients with Gleason scores 8-10 (60%) compared to the EROTC and RTOG studies (15%-35%) and a lower percentage of patients with T3 and T4 tumors. Patients with high Gleason scores are believed to have a higher risk of micro-metastasis at the time of diagnosis and higher chances of castration resistance. Therefore, inclusion of a (presumably) larger high-risk patient subgroup in the present study lends further credence to results indicating similar OS with a shorter course of ADT. A post hoc analysis including only patients with Gleason score 8-10 performed for OS, DSS, BF, and DFS showed no significant difference in any of these variables between the arms. Analysis of the interaction between ADT duration in the Gleason 8-10 subgroup versus Gleason 7 for OS, DFS, DSS and BF found no significant differences. This again suggests that 18 months of ADT may be sufficient for this high-risk group; however, it is difficult to draw definitive conclusions from this unplanned subgroup analysis.
Based on the results of the current study, it seems that 18 months of ADT is adequate for many, but not necessarily all, patients. For instance, there was a significantly higher incidence of BF in the 18-month arm. Applying this data to younger patients may require a more nuanced approach, as it is possible that with longer follow-up this higher rate of BF may translate into a difference in OS. Therefore, life expectancy and comorbid conditions always need to be incorporated into clinical decision making with regards to ADT duration. In a study by Rose et al, the risk of prostate cancer–specific mortality significantly decreased by using ADT plus RT for men with HRPC with a low, but not a high, competing mortality score.4 The clinical significance of this finding is that adding ADT to RT might significantly reduce the risk of death from prostate cancer only in the setting of low competing risks.
Another concept to ponder is the optimum duration of ADT in the era of RT dose escalation. Currently, there are emerging techniques for delivering higher radiation doses and combining brachytherapy with external beam radiotherapy for HRPC, and the role of whole pelvic radiation is being investigated. New data suggests that higher radiation doses can lead to improvement in outcomes for HRPC. The DART01/05 study compared 4 versus 24 months of ADT with 76 to 82 Gy of RT and reported improved 5-year OS, DFS, and metastasis-free survival with longer ADT duration.5 Moreover, Kishan et al reported improved prostate cancer–specific mortality when brachytherapy boost was added to radiation compared to radiation alone in patients with Gleason scores 9 and 10.6 Therefore, the optimal duration of ADT in the setting of dose-escalated radiotherapy is not yet known. Also, it is important to note that unlike the prior RTOG and EORTC studies, this study did not include patients with evidence of regional nodal disease, and thus the present data should not be applied to this patient population.
Applications to Clinical Practice
This study’s results suggesting that 18 months of ADT in combination with RT yields similar 10-year OS and improved QoL compared with 36 months of ADT in patients with HRPC should be interpreted with caution when treating very young patients, since the higher rate of BF in the short arm may impact the OS with longer follow-up. Additionally, patients’ QoL and tolerance to ADT-related adverse effects should be taken into consideration given that compliance with 36 months of ADT was only 53% in this study.
—Jailan Elayoubi, MD, Michigan State University, East Lansing, MI
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;61:1285-1290.
2. Bolla M, de Reijke TM, Van Tienhoven G, et al. Duration of androgen suppression in the treatment of prostate cancer. N Engl J Med. 2009;360:2516-2527.
3. Horwitz EM, Bae K, Hanks GE, Porter A, et al. Ten-year follow-up of radiation therapy oncology group protocol 92-02: a phase III trial of the duration of elective androgen deprivation in locally advanced prostate cancer. J Clin Oncol. 2008;26:2497–2504.
4. Rose BS, Chen MH, Wu J, et al. Androgen deprivation therapy use in the setting of high-dose radiation therapy and the risk of prostate cancer-specific mortality stratified by the extent of competing mortality. Int J Radiat Oncol Biol Phys. 2016;96:778-784.
5. Zapatero A, Guerrero A, Maldonado X, et al. High-dose radiotherapy with short-term or long-term androgen deprivation in localised prostate cancer (DART01/05 GICOR): a randomised, controlled, phase 3 trial. Lancet Oncol. 2015;16:320-327.
6. Kishan, AU, Cook, RR, Ciezki, JP, et al. Radical prostatectomy, external beam radiotherapy, or external beam radiotherapy with brachytherapy boost and disease progression and mortality in patients with gleason score 9-10 prostate cancer. JAMA. 2018;319:896-905.
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;61:1285-1290.
2. Bolla M, de Reijke TM, Van Tienhoven G, et al. Duration of androgen suppression in the treatment of prostate cancer. N Engl J Med. 2009;360:2516-2527.
3. Horwitz EM, Bae K, Hanks GE, Porter A, et al. Ten-year follow-up of radiation therapy oncology group protocol 92-02: a phase III trial of the duration of elective androgen deprivation in locally advanced prostate cancer. J Clin Oncol. 2008;26:2497–2504.
4. Rose BS, Chen MH, Wu J, et al. Androgen deprivation therapy use in the setting of high-dose radiation therapy and the risk of prostate cancer-specific mortality stratified by the extent of competing mortality. Int J Radiat Oncol Biol Phys. 2016;96:778-784.
5. Zapatero A, Guerrero A, Maldonado X, et al. High-dose radiotherapy with short-term or long-term androgen deprivation in localised prostate cancer (DART01/05 GICOR): a randomised, controlled, phase 3 trial. Lancet Oncol. 2015;16:320-327.
6. Kishan, AU, Cook, RR, Ciezki, JP, et al. Radical prostatectomy, external beam radiotherapy, or external beam radiotherapy with brachytherapy boost and disease progression and mortality in patients with gleason score 9-10 prostate cancer. JAMA. 2018;319:896-905.