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Initial Quality of Life and Toxicity Analysis of a Randomized Phase 3 Study of Moderately Hypofractionated Radiation Therapy With or Without Androgen Suppression for Intermediate-Risk Adenocarcinoma of the Prostate: PCG GU003
Our objective was to report the quality of life (QoL) analysis and toxicity in patients with intermediate-risk prostate cancer treated with or without androgen deprivation therapy (ADT) in Proton Collaborative Group (PCG) GU003.
Methods and Materials
Between 2012 and 2019, patients with intermediate-risk prostate cancer were enrolled. Patients were randomized to receive moderately hypofractionated proton beam therapy (PBT) to 70 Gy relative biologic effectiveness in 28 fractions to the prostate with or without 6 months of ADT. Expanded Prostate Cancer Index Composite, Short-Form 12, and the American Urological Association Symptom Index instruments were given at baseline and 3, 6, 12, 18, and 24 months after PBT. Toxicities were assessed according to Common Terminology Criteria for Adverse Events (version 4).
Results
One hundred ten patients were randomized to PBT either with 6 months of ADT (n = 55) or without ADT (n = 55). The median follow-up was 32.4 months (range, 5.5-84.6). On average, 101 out of 110 (92%) patients filled out baseline QoL and patient-reported outcome surveys. The compliance was 84%, 82%, 64%, and 42% at 3, 6, 12, and 24 months, respectively. Baseline median American Urological Association Symptom Index was comparable between arms (6 [11%] ADT vs 5 [9%] no ADT, P = .359). Acute and late grade 2+ genitourinary and gastrointestinal toxicity were similar between arms. The ADT arm experienced a QoL decline of mean scores in the sexual (–16.1, P < .001) and hormonal (–6.3, P < .001) domains, with the largest time-specific hormonal differences at 3 (–13.8, P < .001) and 6 (–11.2, P < .001) months. The hormonal QoL domain returned to baseline 6 months after therapy. There was a trend to baseline in sexual function 6 months after completion of ADT.
Conclusions
After 6 months of ADT, sexual and hormonal domains returned to baseline 6 months after completion of treatment for men with intermediate-risk prostate cancer.
formulated a system relying on clinical stage, prostatic-specific antigen, and Gleason score for the classification of prostate cancer. Intermediate-risk patients were classified as patients having clinical stage T2b, Gleason group 2 or 3, or prostate-specific antigen (PSA) levels >10 and ≤20 ng/mL.
FIR patients have only 1 intermediate risk factor (T2b-T2c, Gleason grade group 2, or PSA 10-20 ng/mL), a Gleason grade group of 1 or 2, and <50% biopsy cores positive.
Multiple studies have demonstrated improved outcomes in patients with intermediate-risk prostate cancer when external beam radiation therapy (RT) is combined with 6 months of androgen suppression.
External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-year results of an EORTC randomised study.
Although 6 months has been confirmed beneficial in patients with intermediate-risk prostate cancer, the role of androgen deprivation therapy (ADT) in these patients remains controversial. Because intermediate-risk prostate cancer is heterogeneous in terms of prognosis and disease progression, treatment recommendations become less uniform.
A new risk classification system for therapeutic decision making with intermediate-risk prostate cancer patients undergoing dose-escalated external-beam radiation therapy.
The breakdown of intermediate into favorable versus unfavorable may potentially affect the overall utility of ADT.
Health-related quality of life (HRQoL) is a considerable component of medical decision-making in addition to a patient's pathology and prognosis. ADT has been demonstrated previously to affect QoL in multiple studies.
This prospective clinical trial randomized patients with intermediate prostate cancer to moderately hypofractionated proton beam therapy with or without short-term ADT. In addition to evaluating oncologic outcomes, the study aimed to evaluate the effect of androgen suppression on QoL measures. Herein, we report a phase 3 trial interim analysis of toxicity and QoL of patients receiving proton beam therapy and short-term ADT for intermediate-risk prostate cancer.
Methods and Materials
PCG GU003 is a multicenter, open-label, phase 3 clinical trial (NCT01492972) that received ethics approval from the Mayo Clinic institutional review board. All participants signed informed consent before participation. Patients were randomized into 2 arms: arm 1 consisted of proton therapy alone with 2.5-Gy relative biologic effectiveness (RBE) per fraction daily for 5 days a week for 28 treatments over 5.5 to 6.5 weeks (total dose: 70 Gy RBE); arm 2 consisted of the proton beam therapy regimen as described previously and androgen suppression for 6 months. Eligibility criteria included patients with prostate adenocarcinoma with at least 1 intermediate-risk factor, including T2b or T2c, Gleason 6 to 7, or a PSA 10 to 20 ng/mL. Tumor staging was assessed by digital rectal examination and magnetic resonance imaging (MRI). A multiparametric MRI with T2-weighted, diffusion-weighted, and dynamic-contrast enhanced images was used. Patients with extracapsular extension or seminal vesicle invasion identified on MRI were classified as MRI and therefore were not eligible for this study. A bone scan was performed in patients classified as unfavorable intermediate disease. Patients must not have had high-risk features such as T3, Gleason score >7, or PSA >20. Patients must not have had pelvic lymph nodes >1.5 cm in greatest dimension unless the lymph node was biopsied and returned as negative. Patients must not have had previous invasive cancer within 5 years, although basal or squamous cell skin cancers were permitted. Additional requirements included Eastern Cooperative Oncology Group performance status 0 to 1 and International Prostate Symptom Score ≤16.
Ineligibility criteria included prior prostate cancer surgery such as prostatectomy, hyperthermia, cryosurgery, prior pelvic radiation or systemic chemotherapy for prostate cancer, or prior androgen suppression therapy. Patients may not have had active rectal diverticulitis, Crohn disease affecting the rectum, or ulcerative colitis, or any major medical, addictive, or psychiatric illness that could affect the delivery or completion of therapy. Patients were ineligible if on anticoagulation such as warfarin sodium (coumadin), heparin, low-molecular-weight heparin, or clopidogrel bisulfate (Plavix).
Treatment
All patients received proton beam therapy for intact intermediate-risk prostate cancer, receiving a total of 70 Gy over 28 daily fractions (2.5 Gy per fraction) 5 days a week. Patients in arm 1 received no androgen suppression therapy. Patients in arm 2 received 6 months of ADT. Treatments were delivered using conformal proton beam therapy. For radiation planning, patients were simulated supine with a full bladder. A diagnostic 3T MRI was performed with the patient in the treatment position. The clinical target volume was defined as the prostate plus proximal seminal vesicles. The planning target volume (PTV) included the clinical target volume plus 2-mm posterior expansion and 3-mm expansion in all other directions. Treatments were delivered using opposed lateral oblique fields recommended for the proton component. The evaluation was performed based on the optimization target volume. The prescription dose is the minimum dose to 95% of the PTV and a minimum dose of 66.5 Gy (RBE) to 99.5% of the PTV. The maximum dose should not exceed the prescription dose by more than 7% (inhomogeneity less than or equal to 7% in a volume of 1 cm3 of the PTV). The dose to the rectum or bladder, even within the PTV, cannot exceed 103% of the prescribed dose (ie, 72.10 Gy [RBE]). Normal tissue constraints included rectum V44 < 35% (minor deviation V44 < 40%, major deviation V44 > 40%) and V60 < 15% (minor deviation V60 < 20% and major deviation V60 ≥ 20%), bladder V71 < 8 cc (minor deviation V71 < 12 cc and major deviation V71 ≥ 12 cc), and femoral heads V40 < 1 cc (minor deviation V40 < 2 cc and major deviation V40 ≥ 2 cc). If the small bowel was found within the radiation fields, doses received would be recorded. Small bowel recommended constraint was V40 < 125 cc and V60 < 10 cc. Daily image guidance was performed with kV to identify fiducial markers or cone beam computed tomography or computed tomography on rails if fiducial markers were absent.
Outcomes
The primary endpoint was to determine whether androgen suppression and high-dose proton RT would result in higher freedom from failure (FFF) than high-dose proton RT without androgen suppression. FFF is defined as the first occurrence of clinical feature (local recurrence, regional recurrence, or distant metastasis), biochemical failure by the Phoenix definition (PSA ≥2 ng/mL over the current nadir PSA) discounting bounces per investigator's discretion, or the start of salvage therapy including androgen suppression.
Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: Recommendations of the RTOG-ASTRO Phoenix consensus conference.
Secondary endpoints included grade 2 and 3 genitourinary (GU) and gastrointestinal (GI) toxicities, QoL, erectile dysfunction at 3 years, disease outcomes, and salvage androgen deprivation at 5 years. Toxicities were assessed according to Common Terminology Criteria for Adverse Events (version 4). Prostate cancer-specific HRQoL was measured by the Expanded Prostate Index Composite (EPIC) Short-Form 12 and American Urological Association Symptom Index (AUASI).
Statistical analysis
The phase 3 study was designed to test whether the 5-year FFF after radiation treatment was superior for radiation and androgen suppression. The sample size was determined to be able to detect a difference of 15% between the 2 arms. The expected 5-year FFF for the radiation alone arm at 5 years was 80% and 95% for the androgen suppression arm. Thus, 162 patients were required for accrual within 4 years for a 0.80 power and a 95% confidence. The total sample size needed was 179 patients considering that 10% of cases were ineligible.
Assessment of toxicities was performed using Common Terminology Criteria for Adverse Events version 4 criteria. Descriptive measures (mean, standard deviation, median, range) were compiled for patient and treatment variables of interest. Norms for arms of the study were established with 95% confidence limits of the mean on each variable of interest. Descriptive measurements of frequency were compiled. Comparison of frequencies and severity between group arms was performed via χ2 tests or Fisher exact tests depending on statistical assumptions for analysis. A summation of relative scores for QoL and sexual function items from the EPIC instrument was used to measure patients' QoL and sexual function. The total scores were compared between group arms using t tests or Mann-Whitney U tests, depending on the data distribution.
Results
Outcomes
One hundred ten patients were randomized to PBT either with 6 months of ADT (n = 55) or without ADT (n = 55). The median follow-up was 32.4 months (range, 5.5-84.6). Patient and tumor characteristics are described in Table 1. Characteristics were similar in both arms. The median age was 68 years (range, 45-81). Seven (6.4%) patients reported prior testosterone use. All patients had an Eastern Cooperative Oncology Group performance status of 0 to 1. Tumor distribution was as follows: 65 (59.1%) T1c, 35 (31.8%) T2a, 7 (6.4%) T2b, and 3 (2.7%) T2c. Gleason score was 3 + 4 in 69 patients (62.7%) and 4 + 3 in 38 (34.5%) patients. Three patients had a Gleason score of 3 + 3 (2.7%). The median number of positive cores was 4.5 (range, 1-12). Eighty-seven (79.1%) patients had PSA levels less than 10 ng/mL, and 23 (20.9%) had PSA between 10 and 20 ng/mL. The median pretreatment PSA was 6.92 (range, 0.970-17.46) in the ADT group and 6.26 (range, 1.46-17.3) in the no-ADT group. Thirty-four (30.9%) patients were classified as FIR and 76 (69.1%) as UIR. Thirty-nine UIR (70.9%) patients were randomized to the ADT group. SpaceOAR Hydrogel were used in 42 patients (38.5%), with even distribution between groups (38.9% ADT vs 38.2% no ADT). The median International Prostate Symptom Score before treatment was 5 (range, 0-22).
On average, 101 out of 110 (92%) patients filled out baseline QoL and patient-reported outcome (PRO) surveys. The compliance was 84%, 82%, 64%, and 42% at 3, 6, 12, and 24 months, respectively. Baseline median American Urological Association Symptom Index was similar between ADT (6 [11%]) and no ADT (5 [9%]) (P = .359) (Fig. 1). There were no differences in total urinary incontinence or urinary irritation scores (Fig. 2). Table 2 reports the rates of acute and late GU and GI toxicity. There was no statistically significant difference between acute (7.3% vs 1.8%, P = .363) and late (30.9% vs 16.4%, P = .115) grade 2+ GU toxicity. Grade 2+ GI toxicity was similar at acute (1.8% vs 0%, P = 1) and late (10.9% vs 10.9%, P = 1) time points (Fig. 3A). There was no difference in baseline adjusted grade 2+ GI (1.15% vs 0%) in patients with or without Space organs at risk. Grade 3+ toxicities occurred only in the ADT arm, with 1 patient (1.8%) with an acute grade 3 GI toxicity and 1 (1.8%) patient with a late grade 3 GU toxicity. Patients receiving ADT had worse overall QoL in the sexual domains, with mean scores of 50, 25, 24, and 38 at baseline, 3 months, 6 months, and 1 year, respectively. In comparison, the mean sexual domain score in the no-ADT arm was 60, 52, 48, and 52 at baseline, 3 months, 6 months, and 1 year, respectively. The largest time-specific differences occurred at 3 and 6 months (P < .001). The mean hormonal scores at baseline, 3 months, 6 months, and 1 year were 90, 77, 80, and 87 for the ADT arm and 93, 92, 92, and 92 for the no-ADT arm. The largest time-specific hormonal differences were at 3 (–13.8, P < .001) and 6 (–11.2, P < .001) months. There was no statistically significant difference in the sexual and hormonal domains at 1 year or 6 months after completion of ADT. There were no clinically significant differences in American Urological Association Symptom Index, urinary incontinence, urinary irritative, or bowel domains.
Figure 1American Urological Association (AUA) mean (A) and Expanded Prostate Index Composite (EPIC) overall scores (B) for toxicity at time points in patients with intermediate-risk prostate cancer receiving androgen deprivation therapy (ADT) versus no ADT.
Figure 2Total urinary incontinence (A) and urinary irritation (B) toxicity at time points in patients with intermediate-risk prostate cancer receiving androgen deprivation therapy (ADT) versus no ADT.
Figure 3Total bowel (A), sexual (B), and hormonal (C) mean toxicity at time points in patients with intermediate-risk prostate cancer receiving androgen deprivation therapy (ADT) versus no ADT.
To our knowledge, there is scarce clinical trial data regarding the hormonal and sexual QoL of men receiving proton beam therapy and short-term ADT for intermediate-risk prostate cancer. Our study demonstrated a trend toward baseline of sexual and hormonal function in men receiving 6 months of ADT. However, sexual function remained lower than baseline at 1 year despite not being a statistically significant difference. On the other hand, we demonstrate return of hormonal domain to baseline at the 1-year time point. Our findings are consistent with the PROs reported from the phase 3 trial, Radiation Therapy Oncology Group (RTOG) 0815, which evaluated the role of short-term ADT with dose-escalated RT for intermediate-risk prostate cancer.
Dose escalated radiotherapy (RT) alone or in combination with short-term total androgen suppression (TAS) for intermediate risk prostate cancer: Patient reported outcomes (PROs) from the NRG oncology/RTOG 0815 randomized trial.
Dose escalated radiotherapy (RT) alone or in combination with short-term total androgen suppression (TAS) for intermediate risk prostate cancer: Patient reported outcomes (PROs) from the NRG oncology/RTOG 0815 randomized trial.
Dose escalated radiotherapy (RT) alone or in combination with short-term total androgen suppression (TAS) for intermediate risk prostate cancer: Patient reported outcomes (PROs) from the NRG oncology/RTOG 0815 randomized trial.
reported no clinically significant decreases in sexual, hormonal, and urinary domains and a modest, clinically significant decrease in GI domains. Hoppe et al
Five-year biochemical results, toxicity, and patient-reported quality of life after delivery of dose-escalated image guided proton therapy for prostate cancer.
reported late effects of proton beam therapy for localized prostate cancer, with sexual scores declining 5 years from baseline in patients not receiving ADT. Our clinical trial guides physicians in counseling their patients regarding the duration of the decline of sexual and hormonal function with the use of short-term ADT for intermediate-risk prostate cancer.
Recent results with high-dose radiation for patients with intermediate-risk prostate cancer have yielded high biochemical control rates.
Combination external beam radiation and brachytherapy boost with androgen suppression for treatment of intermediate-risk prostate cancer: An initial report of CALGB 99809.
Biochemical outcome for hormone-naïve intermediate-risk prostate cancer managed with permanent interstitial brachytherapy and supplemental external beam radiation.
Long-term results of conformal radiotherapy for prostate cancer: Impact of dose escalation on biochemical tumor control and distant metastases-free survival outcomes.
6-month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer: A randomized controlled trial.
published improved survival for a phase 3 trial using androgen suppression and low-dose radiation for a patient population comprised of both intermediate- and high-risk patients. Bolla et al
Short androgen suppression and radiation dose escalation in prostate cancer: 12-year results of EORTC trial 22991 in patients with localized intermediate-risk disease.
demonstrated in the 12-year results of European Organisation for Research and Treatment of Cancer 22991 that 6 months of concurrent and adjuvant ADT significantly improved event-free survival (P < .001) and disease-free survival (P = .008).
Short androgen suppression and radiation dose escalation in prostate cancer: 12-year results of EORTC trial 22991 in patients with localized intermediate-risk disease.
Short androgen suppression and radiation dose escalation in prostate cancer: 12-year results of EORTC trial 22991 in patients with localized intermediate-risk disease.
and although there have been proven beneficial outcomes with short-term ADT in patients with intermediate-risk prostate cancer, its role has become controversial in favorable versus unfavorable prostate cancer. A secondary analysis of NRG Oncology's RTOG 9408 clinical trial addressed this issue.
Effect of androgen deprivation on long-term outcomes of intermediate-risk prostate cancer stratified as favorable or unfavorable: A secondary analysis of the RTOG 9408 randomized clinical trial.
Adding short-term androgen deprivation therapy to radiation therapy in men with localized prostate cancer: Long-term update of the NRG/RTOG 9408 randomized clinical trial.
Effect of androgen deprivation on long-term outcomes of intermediate-risk prostate cancer stratified as favorable or unfavorable: A secondary analysis of the RTOG 9408 randomized clinical trial.
Adding short-term androgen deprivation therapy to radiation therapy in men with localized prostate cancer: Long-term update of the NRG/RTOG 9408 randomized clinical trial.
ADT did not improve distant metastasis, prostate cancer specific mortality, or all cause mortality in patients with favorable intermediate-risk disease.
Effect of androgen deprivation on long-term outcomes of intermediate-risk prostate cancer stratified as favorable or unfavorable: A secondary analysis of the RTOG 9408 randomized clinical trial.
Adding short-term androgen deprivation therapy to radiation therapy in men with localized prostate cancer: Long-term update of the NRG/RTOG 9408 randomized clinical trial.
Effect of androgen deprivation on long-term outcomes of intermediate-risk prostate cancer stratified as favorable or unfavorable: A secondary analysis of the RTOG 9408 randomized clinical trial.
Adding short-term androgen deprivation therapy to radiation therapy in men with localized prostate cancer: Long-term update of the NRG/RTOG 9408 randomized clinical trial.
The 15-year restricted mean survival was longer with ADT versus without ADT for patients with unfavorable intermediate risk (10.5 vs 9.8 years; P = .0497).
Effect of androgen deprivation on long-term outcomes of intermediate-risk prostate cancer stratified as favorable or unfavorable: A secondary analysis of the RTOG 9408 randomized clinical trial.
Effect of androgen deprivation on long-term outcomes of intermediate-risk prostate cancer stratified as favorable or unfavorable: A secondary analysis of the RTOG 9408 randomized clinical trial.
Quality of life assessment is an important consideration in the treatment of prostate cancer. Although we do not demonstrate significant differences in acute and late grade 2+ GU toxicity, these were quadruple and double in the ADT arm. Several studies recommend using radiation in combination with ADT to improve prostate cancer outcomes.
Short androgen suppression and radiation dose escalation in prostate cancer: 12-year results of EORTC trial 22991 in patients with localized intermediate-risk disease.
Adding short-term androgen deprivation therapy to radiation therapy in men with localized prostate cancer: Long-term update of the NRG/RTOG 9408 randomized clinical trial.
Although ADT has been shown to confer a survival benefit, its use can cause significant disruption of QoL. Symptoms related to androgen deprivation include hot flashes, erectile dysfunction, anemia, and muscle loss.
6-month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer: A randomized controlled trial.
6-month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer: A randomized controlled trial.
Altered cognitive function in men treated for prostate cancer with luteinizing hormone-releasing hormone analogues and cyproterone acetate: A randomized controlled trial.
Our study results demonstrate that symptoms related to short-term androgen deprivation are temporary and should be expected to return to normal within 6 months after completion of ADT.
Multiple studies have examined the effect of ADT using different survey instruments.
A prospective analysis of health-related quality of life in intermediate and high-risk prostate cancer patients managed with intensity modulated radiation therapy, with vs. without hormonal therapy.
A prospective analysis of health-related quality of life in intermediate and high-risk prostate cancer patients managed with intensity modulated radiation therapy, with vs. without hormonal therapy.
compared patients with intermediate- and high-risk prostate cancer receiving RT alone versus RT plus ADT. The HRQoL scores were comparable in both groups. Patients receiving RT alone experienced declines in urinary and sexual function at all times. In patients who received hormone therapy, there was a worsening of sexual function, hormonal function, and hormonal bother.
A prospective analysis of health-related quality of life in intermediate and high-risk prostate cancer patients managed with intensity modulated radiation therapy, with vs. without hormonal therapy.
Like Caumont et al, our study demonstrated the sexual and hormonal domains, with the most significant time-specific hormonal differences at 3 and 6 months. For patients with intermediate-risk prostate cancer, our study demonstrated that patients receiving proton beam RT and 6 months of ADT would have a return to baseline in sexual and hormonal domains in 6 months after the completion of treatment. Caumont et al
A prospective analysis of health-related quality of life in intermediate and high-risk prostate cancer patients managed with intensity modulated radiation therapy, with vs. without hormonal therapy.
found no statistically significant differences in urinary function, urinary bother, sexual bother, bowel function, and bowel bother as part of the EPIC questionnaire. Similarly, we report that the addition of 6 months of ADT has no effect on GU or GI toxicity. In another study, Dacal et al
reported that patients with prostate cancer receiving ADT suffered in areas such as physical function, general health, and physical health in men not receiving ADT. Important to note in this study was that men receiving ADT had higher body fat and comorbidity index, which could contribute to reduced QoL. These are important considerations to be aware of in men receiving longer courses of ADT.
This study has several limitations. There was a small cohort of patients randomized between proton beam therapy with and without ADT. Additionally, compliance to PRO and QoL surveys decreased over time. The HRQoL and treatment toxicity assessment were limited to overall, sexual, GU, and bowel. Assessments did not include mental, emotional, or social health aspects. For the primary analysis, more follow-up time is needed to determine 5-year FFF for patients with ADT versus no ADT.
Conclusion
For intermediate-risk prostate cancer, ADT is associated with declines in hormonal QoL and sexual function for 6 months. Hormonal QoL returns to baseline 6 months after completion of ADT. Sexual function trends toward baseline 6 months after completion of ADT. Further follow-up evaluation and compliance will be pertinent to determine the effect of ADT on hormonal, sexual, and GU toxicity between the groups.
References
D'Amico AV
Whittington R
Malkowicz SB
et al.
Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer.
External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-year results of an EORTC randomised study.
A new risk classification system for therapeutic decision making with intermediate-risk prostate cancer patients undergoing dose-escalated external-beam radiation therapy.
Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: Recommendations of the RTOG-ASTRO Phoenix consensus conference.
Dose escalated radiotherapy (RT) alone or in combination with short-term total androgen suppression (TAS) for intermediate risk prostate cancer: Patient reported outcomes (PROs) from the NRG oncology/RTOG 0815 randomized trial.
Five-year biochemical results, toxicity, and patient-reported quality of life after delivery of dose-escalated image guided proton therapy for prostate cancer.
Combination external beam radiation and brachytherapy boost with androgen suppression for treatment of intermediate-risk prostate cancer: An initial report of CALGB 99809.
Biochemical outcome for hormone-naïve intermediate-risk prostate cancer managed with permanent interstitial brachytherapy and supplemental external beam radiation.
Long-term results of conformal radiotherapy for prostate cancer: Impact of dose escalation on biochemical tumor control and distant metastases-free survival outcomes.
6-month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer: A randomized controlled trial.
Short androgen suppression and radiation dose escalation in prostate cancer: 12-year results of EORTC trial 22991 in patients with localized intermediate-risk disease.
Effect of androgen deprivation on long-term outcomes of intermediate-risk prostate cancer stratified as favorable or unfavorable: A secondary analysis of the RTOG 9408 randomized clinical trial.
Adding short-term androgen deprivation therapy to radiation therapy in men with localized prostate cancer: Long-term update of the NRG/RTOG 9408 randomized clinical trial.
Altered cognitive function in men treated for prostate cancer with luteinizing hormone-releasing hormone analogues and cyproterone acetate: A randomized controlled trial.
A prospective analysis of health-related quality of life in intermediate and high-risk prostate cancer patients managed with intensity modulated radiation therapy, with vs. without hormonal therapy.
Sources of support: This work received no specific funding.
Disclosures: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Data sharing statement: The data sets generated during the present study are not publicly available due to restricted access to the institutional repository but can be available from the corresponding author on reasonable request.
Two patients missing.
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