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Prognostic value of testosterone castration levels following androgen deprivation and high-dose radiotherapy in localized prostate cancer: Results from a phase III trial
Corresponding author at: Radiation Oncology Department, Hospital Universitario de la Princesa, Health Research Institute IIS-IP, Diego de León 62, 28006 Madrid, Spain.
The optimal prognostic value of testosterone following ADT is controversial.
•
It remains unknown the impact of testosterone recovery after ADT and radiotherapy.
•
We studied testosterone kinetics in prostate cancer patients treated in a clinical trial.
•
Testosterone < 20 ng/dL was not associated with better outcomes than 20–49 ng/dL.
•
Time to testosterone recovery after ADT and HRT did not impact clinical failure.
Abstract
Background/objective
The optimal prognostic value of testosterone following androgen deprivation therapy (ADT) is controversial. We studied the effect of serum testosterone levels on clinical outcome in localized prostate cancer (PCa) treated with ADT and high-dose radiotherapy (HRT).
Patients and methods
The DART01/05 trial randomized 355 men with intermediate and high-risk PCa to 4 months of ADT plus HRT (STADT, N = 178) or the same treatment followed by 24 months of ADT (LTADT, N = 177). This study included patients treated with LTADT who had at least 3 determinations of testosterone during ADT (N = 154). Patients were stratified into 3 subgroups by testosterone level: minimum <20 ng/dL; median 20–49 ng/dL; and maximum ≥50 ng/dL. Kaplan–Meyer and Cox regression analysis were used for overall survival (OS) and Fine & Gray regression model for metastasis free survival (MFS), biochemical disease-free survival (bDFS) and time to TT recovery.
Results
There were no statistically significant differences in 10-year bDFS, MFS, or OS between the <20 ng/mL and 20–49 ng/dL subgroups. Multivariate analysis showed that a median testosterone ≥50 ng/dL was significantly associated with a decrease in bDFS (HR: 6.58, 95%CI 1.28–33.76, p = 0.03). Time to testosterone recovery after ADT did not correlate with bDFS, MFS, or OS and was not significantly associated with any of the testosterone subgroups.
Conclusions
Our results do not support the concept that additional serum testosterone suppression below 20 ng/dL is associated with better outcomes than 20–49 ng/dL. Time to testosterone recovery after ADT and HRT did not impact clinical failure.
Androgen deprivation therapy (ADT) is currently the standard systemic approach for management of localized high-risk prostate cancer (PCa) in combination with high-dose radiotherapy (HRT) [
External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-year results of an EORTC randomised study.
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.
The long and short of it: new lessons on the optimal duration of androgen deprivation therapy for high-risk prostate cancer and where we need to go from here.
Morote J, Planas J, Salvador C, Raventos CX, Catalan R, Reventos J. Individual variations of serum testosterone in patients with prostate cancer receiving androgen deprivation therapy. BJU Int 2009; 103: 332-5.
Pickles T, Hamm J, Morris WJ, et al. Incomplete testosterone suppression with luteinizing hormone-releasing hormone agonists: Does it happen and does it matter? BJU Int 2012; 110: e500-7.
] have considered the 50 ng/dL cut point a potential artefact of the lower limit of quantitation of older testosterone assays, thus raising the question of whether achieving <50 ng/dL might be clinically relevant with new testosterone assays. Recent data suggest that additional suppression of serum testosterone to <20 ng/dL might improve clinical outcomes [
Nadir testosterone within first year of androgen-deprivation therapy (ADT) predicts for time to castration-resistant progression: a secondary analysis of the PR-7 trial of intermittent versus continuous ADT.
Testosterone reduction of ≥ 480 ng/dL predicts favorable prognosis of japanese men with advanced prostate cancer treated with androgen-deprivation therapy.
]. Similarly, it remains unknown whether maintenance of castrate testosterone levels after discontinuation of ADT could also impact biochemical control rates [
Kinetics of serum androgen normalization and factors associated with testosterone reserve after limited androgen deprivation therapy for nonmetastatic prostate cancer.
A randomized prospective trial evaluating testosterone, haemoglobin kinetics and quality of life, during and after 12 months of androgen deprivation after prostatectomy: results from the Postoperative Adjuvant Androgen Deprivation trial.
The DART 01/05 trial is a randomized phase III study comparing 4 versus 28 months of ADT combined with HRT. The 5-year results showed that 2 years of adjuvant ADT was significantly superior to 4 months of treatment [
High-dose radiotherapy with short-term or long-term androgen deprivation in localized prostate cancer (DART 01/05 GICOR): a randomized, controlled, phase 3 trial.
]. In this post hoc analysis, we studied the effect of serum testosterone levels and testosterone recovery on clinical outcome in a subgroup of localized prostate cancer patients treated in the long-term arm of the DART 01/05 trial.
Material and methods
The DART 01/05 multicenter, phase III randomized trial was designed to determine the optimal duration of ADT in patients receiving HRT. Full methods and preliminary results are detailed in the primary report [
High-dose radiotherapy with short-term or long-term androgen deprivation in localized prostate cancer (DART 01/05 GICOR): a randomized, controlled, phase 3 trial.
]. Between November 2005 and December 2010, 355 eligible patients were randomly assigned to the short-term ADT arm (STADT, 178 patients) or the long-term ADT arm (LTADT, 177 patients). Patients assigned to the STADT arm received 4 months of neoadjuvant and concomitant ADT with subcutaneous goserelin, namely, 2 months before radiotherapy and 2 months combined with HRT (minimum dose of 76 Gy, range 76–82 Gy). Antiandrogen therapy (flutamide 750 mg per day or bicalutamide 50 mg per day) was added during the first 2 months of treatment. The patients assigned to long-term suppression (LTADT arm) continued with the same luteinizing hormone-releasing analogue every 3 months for another 24 months. This trial is registered at ClinicalTrials.gov (NCT 02175212) and in the EU Clinical Trials Register (EudraCT 2005-000417-36).
Follow-up visits were at intervals of 3 months after radiotherapy during the first year, every 6 months for 5 years, and yearly thereafter. PSA concentrations, serum testosterone concentration, and a complete blood count were obtained at every visit. We included in the study only those patients treated with LTADT who had at least 3 determinations of serum testosterone during the 2 years of ADT (N = 154). Serum testosterone was not centrally measured. Each centre measured the serum testosterone in a certified laboratory for clinical research purpose using an automated chemiluminescent immunoassay method.
In order to establish the potential clinical impact of a low nadir (<20 ng/dl) of testosterone compared to the classical castration definition (<50 ng/dl), we defined 3 testosterone subgroups (<20, 20–49, and ≥50 ng/dl) for each patient. Then, we stratified the patients by the minimum, median, and maximum testosterone levels reached into the 3 testosterone subgroups as follows: (1) minimum (minTT), <20 ng/dL (<0.7 nmol/L); (2) medium (medTT), 20–49 ng/dL (0.7 to < 1.7 nmol/L); and maximum (maxTT), ≥50 ng/dL (≥1.7 nmol/L). For patients with documented baseline testosterone, we also evaluated the impact of testosterone recovery, defined according to measured testosterone levels with a lower laboratory limit above the threshold of 150 ng/dL.
Endpoints, definitions, and statistical analysis
Overall survival (OS) was analyzed by Kaplan–Meier analysis and Cox proportional hazards regression models. Biochemical disease-free survival (bDFS), metastasis-free survival (MFS), cause-specific survival (CSS) and time to testosterone recovery were compared between the subgroups using Gray’s test in the univariate analyses and multivariate Fine & Gray regression in the adjusted analyses to account for the competing risk of non-PCa mortality. Death from any cause was considered a competitive risk for MFS, bDFS, and time to testosterone recovery. Death from prostate cancer or a complication of cancer treatment was considered for CSS analysis. All endpoints were calculated from the date of randomization. Time to testosterone recovery was calculated as the interval between the last trimestral ADT injection and testosterone values within the normal range (>150 ng/dL). The t and chi-square tests were used to assess associations with other clinical variables. Two-sided p values <0.05 were considered statistically significant. The covariates used in the analysis were patient age, T stage, Gleason group, pre-treatment prostate-specific antigen (PSA), risk group, and testosterone recovery. All analyses were performed using IBM SPSS Statistics v22. The Fine & Gray analyses were performed using SAS version 9.4.
Results
Of the 355 patients randomized, 154 LTADT were eligible for the analysis. The characteristics of the patients are shown in Table 1. The median age was 71.3 years (IQR 67.6–74.9), and the median follow-up was 109.6 months (IQR: 100.6–115.3). The median and range of testosterone determinations performed per patient during ADT was 5 (range 3–7) for intermediate and 5 (IQR 3–6) for high risk patients.
Table 1Patients’ characteristics.
TOTAL N = 154
Median (IQR) follow-up, months
109.6 (100.6–115.3)
Median (IQR) age, years
71.3 (67.6–74.9)
Clinical T stage
T1
43 (28.0%)
T2
82 (53.2%)
T3
29 (18.8%)
Gleason group (ISUP 2014/WHO 2016)
1
16 (10.3%)
2
62 (40.3%)
3
33 (21.5%)
4
30 (19.5%)
5
13 (8.4%)
Pre-treatment PSA, ng/mL
Median (IQR)
10.8 (6.7–17.0)
<10
70 (45.5%)
0–20
53 (34.4%)
>20
31 (20.1%)
NCCN Risk Groups
Intermediate
73 (47.4%)
High
81 (52.6%)
Median (IQR) PSA nadir, ng/mL
0.01 (0.0–0.03)
Median (IQR) testosterone nadir, ng/dL
19 (10.0–27.0)
Testosterone recovery (>150 ng/dL)
Yes
114 (74.0%)
No
40 (26.0%)
Median (IQR) time to testosterone recovery, months)
16.3 (1.7–70.9)
IQR: Interquartile range; ISUP: International Society of Urological Pathology; WHO: World Health Organization; NCCN: National Comprehensive Cancer Network.
The median testosterone nadir was 19 ng/dL (IQR: 10–27 ng/dL), with a median time to nadir of 10.2 months (IQR: 7.3–15.9 months). A total of 82 (53.2%) patients had a minTT < 20 ng/dL, 69 (44.8%) patients had a minTT between 20 and 49 ng/dL, and only 3 (1.9%) patients had a minTT ≥ 50 ng/dL. The corresponding values for medTT and maxTT are shown in Table 2.
Table 2Distribution of nadir, median, and maximum testosterone level of every patient within 3 testosterone subgroups: minimum < 20 ng/dL (<0.7 nmol/L); medium 20–49 ng/dL (0.7 to <1.7 nmol/L); and maximum ≥ 50 ng/dL (≥1.7 nmol/L).
Overall, 21 (13.6%) patients developed biochemical failure during follow-up, and 9 (5.8%) patients developed distant metastasis. Twenty-nine (18.8%) patients died, although only 4 died from PCa. At 10 years, bDFS, MFS, CSS, and OS were 69.6% (95% CI: 61.6%–77.5%), 66.3% (95% CI: 47.8%–84.9%), 95.8% (95% CI: 91.7%–99.9%), and 77.8% (95% CI: 70.6%–85.1%), respectively.
There were no statistically significant differences in 10-year bDFS, MFS, CSS, or OS between the testosterone values of <20 ng/dL and 20–49 ng/dL for the 3 testosterone subgroups (min, med, and max TT levels) (Table 3). In the univariate analysis, the presence of a medTT value ≥50 ng/dL, the Gleason group 4–5, a pre-treatment PSA > 20 ng/mL, and the high-risk subgroup were variables significantly associated with a decrease in bDFS. The results of the multivariable Fine & Gray regression analysis showed that a medTT value ≥ 50 ng/dL remained significantly associated with a decrease in bDFS (HR: 6.42; 95% CI: 1.19–34.51; p = 0.04) (Table 4, Fig. 1). A minTT value ≥ 50 ng/dL was also found to be associated with a lower MFS (HR: 13.08; 95% CI: 2.00–106.14; p = 0.02); however, since there were only 3 patients in the minTT subgroup ≥ 50 ng/dL, this finding should be considered non-valuable.
Table 3Results of the univariate analysis for biochemical disease-free survival, metastasis-free survival (Fine & Gray) and overall survival (Cox regression).
Covariate
Metastasis-free survival
Biochemical disease–free survival
Overall Survival
HR (95% CI) p value
HR (95% CI) p value
HR (95% CI) p value
Minimum testosterone
p = 0.06
p = 0.29
p = 0.47
<20 ng/dL (Ref. v)
20–49 ng/dL
2.08 (0.50–8.66)
1.53 (0.64–3.66)
1.26 (0.60–2.65)
≥50 ng/dL*
13.08 (2.00–106.14)
5.41 (0.52–56.54)
3.35 (0.43–25,96)
Median testosterone
p > 0.99
p = 0.03
p = 0.56
<20 ng/dL (Ref. v)
20–49 ng/dL
NOT ESTIMABLE
1.96 (0.46–8.47)
1.05 (0.39–2,80)
≥50 ng/dL
6.58 (1.28–33.76)
1.86 (0.50–6 0.96)
Maximum testosterone
p > 0.99
p > 0.99
p = 0.22
<20 ng/dL (Ref. v)
20–49 ng/dL
NOT ESTIMABLE
NOT ESTIMABLE
NOT ESTIMABLE
≥50 ng/dL
Time to testosterone recovery
p = 0.16 0.95 (0.86–1.02)
p = 0.14 0.97 (0.94–1.01)
p = 0.10 0.96 (0.91–1.01)
Clinical T stage
p = 0.31
p = 0.18
p = 0.37
T1-2 (Ref.v)
T3
2.11 (0.49–9.01)
1.93 (0.74–5.01)
0.62 (0.21–1.77)
Gleason Group
p = 0.71
p = 0.03
p = 0.20
Groups 1–3 (Ref. v)
Groups 4–5
1.29 (0.33–5.01)
2.57 (1.10–5.99)
0.54 (0.20–1.40)
Pre-treatment PSA
p = 0.19
p = 0.03
p = 0.04
<10 ng/mL (Ref. v)
10–20 ng/mL
0.35 (0.04–3.03)
0.94 (0.30–2.93)
3.25 (1.32–7.99)
>20 ng/mL
2.34 (0.60–9.16)
3.09 (1.17–8.16)
2.14 (0.75–6.09)
Risk group
p = 0.15
p = 0.01
p = 0.47
Intermediate (Ref.v)
High
3.15 (0.66–15.03)
4.21 (1.45–12.29)
0.77 (0.37–1.59)
Patient age
p = 0.73 0.97 (0.83–1.14)
p = 0.22 0.95 (0.87–1.03)
p = 0.09 1.07 (0.99–1.16)
Ref. v: Reference value; *: Only 3 cases; **: Only 1 event.
HR: hazard ratio; CI: confidence interval; ISUP: International Society of Urological Pathology; PSA: prostate-specific antigen.
A total of 114 patients (74%) recovered testosterone values within the normal range (>150 ng/dL) on completion of ADT, with a median time to testosterone recovery of 16.3 months (IQR: 1.7–70.9). Time to testosterone recovery was not significantly associated with any of the testosterone subgroups (minTT p = 0.34; medTT p = 0.14; max TT p = 0.11) or with any of the other clinical variables (patient age, p = 0.27; pre-treatment PSA, p = 0.45; T stage, p = 0.12; and Gleason group, p = 0.07), with the exception of the risk subgroup. The median time to testosterone recovery was 14.5 and 17.8 months for intermediate and high-risk prostate cancer, respectively (p = 0.02).
Time to testosterone recovery after ADT did not associate with bDFS, MFS, or OS. However, our data revealed a significant association with CSS (HR: 0.91; 95% CI: 0.85–0.98; p = 0.02). Again, since only 4 patients died from PCa, these data should be interpreted with caution.
Discussion
Our results do not support the notion that better outcomes are associated with testosterone below 20 ng/dL. Similarly, we did not observe an independent association between the kinetics of testosterone recovery and the risk of clinical failure.
As most studies investigating the prognostic value of testosterone levels following ADT have been performed in advanced or metastatic PCa, available information in localized PCa patients is scant and controversial. Nabid et al. [
Significance of testosterone suppression in localized prostate cancer treated with androgen deprivation therapy and radiotherapy: data from 2 phase 3 trials.
] reported in abstract form their results from a subgroup of 796 patients in 2 randomized trials of ADT combined with radiotherapy in localized PCa. With a median follow-up of 9.15 years, the authors found no significant differences in outcome between testosterone levels <20 and <50 ng/dL. Conversely, recent data from a retrospective study of 764 patients with localized PCa from the Veterans Affairs database who had received ADT (median duration 12 months) and radiotherapy showed that additional serum testosterone suppression <20 ng/dL was associated with lower rates of biochemical recurrence and metastasis [
In the scenario of patients with more advanced PCa, the available evidence comes mainly from the subanalysis of clinical trials of intermittent ADT, where data are also contradictory. The results published by Tombal et al. [
Clinical outcomes and testosterone levels following continuous androgen deprivation in patients with relapsing or locally advanced prostate cancer: a post hoc analysis of the ICELAND study.
] in a subgroup of 345 patients from the ICELAND trial receiving continuous androgen deprivation did not reveal a significant difference between the 3 testosterone subgroups in time to CSS and progression of PSA. These data are in contrast to the results of the PR7 trial of intermittent versus continuous ADT reported by Klotz et al. [
Nadir testosterone within first year of androgen-deprivation therapy (ADT) predicts for time to castration-resistant progression: a secondary analysis of the PR-7 trial of intermittent versus continuous ADT.
]. Several other studies have also reported a correlation between lower testosterone levels (≤0.7 nmol/L) and a longer time to castration-resistant PCa and/or death [
Pickles T, Hamm J, Morris WJ, et al. Incomplete testosterone suppression with luteinizing hormone-releasing hormone agonists: Does it happen and does it matter? BJU Int 2012; 110: e500-7.
]. Interestingly, most of these studies were performed in patients with more advanced or metastatic PCa, a noticeably different scenario.
The discrepancies between studies and the contradictory data reported can be explained by factors such as the retrospective approach, differences in serum testosterone determinations, and differences in study design, regimen, and duration of ADT. The variety of LHRH agonists used, different cohort sizes, and the wide range of the target populations also make the results difficult to interpret. A recent systematic review and meta-analysis [
] analyzed the impact of testosterone levels in different clinical settings during the natural history of PCa. The authors reported a dynamic interplay between serum testosterone and PCa biology that changes during the natural history of the disease.
The rate and the time course of testosterone recovery after ADT and radiotherapy is not well characterized [
Kinetics of serum androgen normalization and factors associated with testosterone reserve after limited androgen deprivation therapy for nonmetastatic prostate cancer.
]. Multiple small series have shown that the use of STADT (3–6 months) results in a reversible effect on serum testosterone in most patients within 1 year of cessation of ADT. However, data regarding testosterone recovery after LTADT are more limited and conflicting [
Dumont C, Baciarello G, Bosset PO, et al. Long-term castration-related outcomes in patients with high-risk localized prostate cancer treated with androgen deprivation therapy with or without docetaxel and estramustine in the UNICANCER GETUG-12 Trial. Clin Genitourin Cancer 2020 (in press). https://doi.org/10.1016/j.clgc.2020.03.017.
Time course of serum testosterone and luteinizing hormone levels after cessation of long-term luteinizing hormone-releasing hormone agonist treatment in patients with prostate cancer.
]. In the present analysis, 74% of patients recovered testosterone values within the normal range (>150 ng/dL) after the end of adjuvant ADT, with a median time to recovery of 16.3 months (IQR: 1.7–70.9). We observed a shorter median time to testosterone recovery for intermediate versus high-risk prostate cancer (14.5 and 17.8 months respectively, p = 0.02). We cannot provide a satisfactory explanation for this finding other than sample bias related to the number of determinations.
It remains unclear whether maintaining castrate testosterone levels is associated with a risk of relapse [
]. In our study, time to testosterone recovery did not correlate with bDFS, MFS, or OS. Similarly, a recent report from a secondary analysis of a phase III trial analyzing a 6-month ADT regimen revealed no significant association between the kinetics of testosterone recovery and the risk of subsequent relapse [
]. Interestingly, other authors have observed a correlation between time to testosterone rebound and PCa mortality in patients treated with 6 months of ADT and radiotherapy irrespective of the degree of comorbidity, although cardiovascular mortality increased in patients with moderate-severe comorbidity [
]. Whether there is a difference in biological behavior depending on the duration of ADT remains to be determined. A previous report on toxicity from the DART trial showed that LTADT was significantly associated with an increase in nonfatal cardiovascular toxicity (HR: 2.090; 95% CI: 1.170–3.720, p = 0.012) [
Late radiation and cardiovascular adverse effects after androgen deprivation and high-dose radiation therapy in prostate cancer: results from the DART 01/05 randomized phase 3 trial.
]. Shore et al. have recently reported the results of HERO phase III trial that compared the efficacy and safety of relugolix (an oral GnRh antagonist) with leuprolide in patients with advanced PCa [
]. Although data on survival are awaited, the results showed that relugolix achieved a lower and quicker testosterone nadir, a shorter time of testosterone recovery and a 54% lower risk of major adverse cardiovascular events than leuprolide.
The present study was subject to several limitations, mainly the relatively small sample size and the low number of events that restricts the power of the analysis. Another potential limitation was that testosterone values were not centrally measured. Nevertheless, we cannot obviate the strengths of this report, which lie in its prospective design, the use of a similar formulation and duration for adjuvant ADT, and the HRT schedule. The analysis also required documented baseline testosterone before initiation of ADT and during follow-up. Finally and noteworthy, the long-term follow-up of this study enabled us to evaluate the association with clinical outcome. To our knowledge, this is the first full-text prospective report to show the effect of serum testosterone levels and testosterone recovery on long-term survival in localized PCa treated with HRT combined with LTADT.
Conclusion
Our results show that additional suppression of serum testosterone to <20 ng/dL is not associated with better outcomes than 20–49 ng/dL. We were unable to prove a correlation between time to testosterone recovery after ADT and radiotherapy and biochemical failure or distant metastasis.
Research support
This work was supported by a grant from the GICOR/SEOR (Grupo de Investigación en Oncología Radioterápica/Sociedad Española de Oncología Radioterápica) (1910,2018) and AstraZeneca.
Declaration of interest statement
Other than the grants from the GICOR/SEOR (Grupo de Investigación en Oncología Radioterápica/Sociedad Española de Oncología Radioterápica) and AstraZeneca, the authors declare no potential conflicts of interest.
Study code: DART01/05.
EudraCT, 2005-000417-36; NCT, 02175212.
Acknowledgments
The authors thank Juan Luis Sanz from Apices Data Management and Biostatistics, for his participation in data management and critical review of the initial draft of the manuscript. We are also grateful to Elena Pintos, Elena Santos, and Gina Mejías for their review of the clinical data and to Thomas O’Boyle for medical writing.
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External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-year results of an EORTC randomised study.
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.
The long and short of it: new lessons on the optimal duration of androgen deprivation therapy for high-risk prostate cancer and where we need to go from here.
Morote J, Planas J, Salvador C, Raventos CX, Catalan R, Reventos J. Individual variations of serum testosterone in patients with prostate cancer receiving androgen deprivation therapy. BJU Int 2009; 103: 332-5.
Pickles T, Hamm J, Morris WJ, et al. Incomplete testosterone suppression with luteinizing hormone-releasing hormone agonists: Does it happen and does it matter? BJU Int 2012; 110: e500-7.
Nadir testosterone within first year of androgen-deprivation therapy (ADT) predicts for time to castration-resistant progression: a secondary analysis of the PR-7 trial of intermittent versus continuous ADT.
Testosterone reduction of ≥ 480 ng/dL predicts favorable prognosis of japanese men with advanced prostate cancer treated with androgen-deprivation therapy.
Kinetics of serum androgen normalization and factors associated with testosterone reserve after limited androgen deprivation therapy for nonmetastatic prostate cancer.
A randomized prospective trial evaluating testosterone, haemoglobin kinetics and quality of life, during and after 12 months of androgen deprivation after prostatectomy: results from the Postoperative Adjuvant Androgen Deprivation trial.
High-dose radiotherapy with short-term or long-term androgen deprivation in localized prostate cancer (DART 01/05 GICOR): a randomized, controlled, phase 3 trial.
Significance of testosterone suppression in localized prostate cancer treated with androgen deprivation therapy and radiotherapy: data from 2 phase 3 trials.
Clinical outcomes and testosterone levels following continuous androgen deprivation in patients with relapsing or locally advanced prostate cancer: a post hoc analysis of the ICELAND study.
Dumont C, Baciarello G, Bosset PO, et al. Long-term castration-related outcomes in patients with high-risk localized prostate cancer treated with androgen deprivation therapy with or without docetaxel and estramustine in the UNICANCER GETUG-12 Trial. Clin Genitourin Cancer 2020 (in press). https://doi.org/10.1016/j.clgc.2020.03.017.
Time course of serum testosterone and luteinizing hormone levels after cessation of long-term luteinizing hormone-releasing hormone agonist treatment in patients with prostate cancer.
Late radiation and cardiovascular adverse effects after androgen deprivation and high-dose radiation therapy in prostate cancer: results from the DART 01/05 randomized phase 3 trial.
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