Short-course Androgen Deprivation Therapy Research Articles

Impact of androgen deprivation therapy in patients with unfavorable intermediate-risk prostate cancer receiving brachytherapy-based dose-escalated radiation therapy.

While the benefit of short-term androgen deprivation therapy (ADT) has been established for patients with intermediate-risk (IR) prostate cancer (PCa) receiving dose-escalated external beam radiation therapy (EBRT), the role of ADT for patients treated with brachytherapy (BT) with or without supplemental EBRT (sEBRT) is less clear. We conducted a single-institution retrospective analysis of men with National Comprehensive Cancer Network (NCCN) unfavorable IR (UIR) PCa. All patients received BT with or without sEBRT, and were stratified by the receipt of 4-6 months of ADT. Kaplan-Meier method was used to measure biochemical progression- free survival (bPFS) between men who did vs. did not receive ADT. Multivariable Cox proportional hazards with backward selection was utilized to determine association of concomitant ADT with bPFS accounting for confounding variables. We identified 201 eligible patients treated between 2002 and 2019, 78 (38.8%) of whom received ADT. Median follow-up was 15 years. On univariable analysis, there was no significant association of ADT use with bPFS (HR = 0.95, 95% CI: 0.34-2.63, p = 0.92). Only PSA ≥ 10 was significant for association with worse bPFS (HR = 3.51, 95% CI: 1.29-9.52, p = 0.014). On multivariable analysis, there was no association of ADT use with bPFS (HR = 0.97, 95% CI: 0.34-2.78, p = 0.96). Short-course ADT was not associated with improved bPFS in our study among men with UIR PCa treated with BT with or without sEBRT. These findings suggest that dose intensification achieved with BT may alone be sufficient in treating selected patients with UIR disease, but prospective studies are warranted.

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60-69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0-10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612-0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6-75·7) in the short-course ADT group and 78·1% (74·2-81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61-69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1-10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688-1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4-82·5) in the no ADT group and 80·4% (76·6-83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population. Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.

Bothersome Hot Flashes Following Neoadjuvant Androgen Deprivation Therapy and Stereotactic Body Radiotherapy for Localized Prostate Cancer.

Androgen deprivation therapy (ADT) improves local cancer control in unfavorable localized prostate cancer treated with radiotherapy. ADT is known to cause hormonally related symptoms that resolve with testosterone recovery. Hot flashes are particularly burdensome. This study sought to evaluate the timeline of hot flashes following short-course ADT and stereotactic body radiotherapy (SBRT) as well as its relationship with testosterone recovery. Institutional IRB approval was obtained for this retrospective review of prospectively collected data (IRB#: 2009-510). ADT was initiated three months prior to the start of SBRT. Hot flashes were self-reported via question 13a of the Expanded Prostate Index Composite (EPIC)-26 prior to ADT initiation, the first day of robotic SBRT, and at each follow-up (one, three, six, nine, 12, 18, 24, and 36 months). The responses were grouped into three relevant categories (no problem, very small-small problem, and moderate-big problem). Scores were transformed to a 0-100 scale with higher scores reflecting less bother. Testosterone levels were measured at each follow-up. From 2007 to 2010, 122 localized prostate cancer patients (nine low-, 64 intermediate-, and 49 high-risk according to the D'Amico classification) at a median age of 72 years (range 54.5-88.3) were treated with short course ADT (three to six months) and SBRT (35-36.25 Gy) at Georgetown University Hospital. Thirty-two percent were Black and 27% were obese. Seventy-seven percent of patients received three months of ADT. At baseline, 2% of men experienced hot flashes that were a "moderate to big problem" and that proportion peaked at the start of SBRT (45%) before returning to baseline (2%) nine months post-SBRT with a cumulative incidence of 52.4%. The median baseline EPIC-26 hot flash score of 94 declined to 50 at the start of SBRT but this returned to baseline (92) by six months post SBRT. These changes were both statistically and clinically significant (MID = 9.5083, p<0.01). Testosterone recovery (> 230 ng/dL) occurred in approximately 70% of patients by 12 months post SBRT. Resolution of hot flashes correlated with testosterone recovery. Bothersome hot flashes occur in greater than 50% of men treated with neoadjuvant ADT. Resolution of hot flashes occurs in the majority of patients within one year after treatment. Reassurance of the temporary nature of hot flashes may assist in reducing patient anxiety. Measuring testosterone levels at follow-up visits may allow for anticipatory counseling that may limit the associated bother.

Bothersome Hot Flashes Following Neoadjuvant Androgen Deprivation Therapy and Stereotactic Body Radiotherapy for Localized Prostate Cancer

Androgen deprivation therapy (ADT) may improve cancer control in unfavorable localized prostate cancer treated with stereotactic body radiotherapy (SBRT). ADT is known to cause hormonally related symptoms that resolve with testosterone recovery. Hot flashes are particularly burdensome. This study sought to evaluate the timeline of hot flashes following short-course ADT and SBRT as well as its relationship with testosterone recovery. Institutional IRB approval was obtained for this retrospective review of prospectively collected data (IRB#: 2009-510). ADT was initiated three months prior to the start of SBRT. Hot flashes were self-reported via question 13a a healthcare software prior to ADT initiation, the first day of robotic SBRT, and at each follow-up (1, 3, 6, 9, 12, 18, 24 and 36 months). The responses were grouped into three relevant categories (no problem, very small-small problem and moderate-big problem). Scores were transformed to a 0-100 scale with higher scores reflecting less bother. Testosterone levels were measured at each follow-up. From 2007 to 2010, 122 localized prostate cancer patients (9 low-, 64 intermediate-, and 49 high-risk according to the D'Amico classification) at a median age of 72 years (range 54.5-88.3) were treated with short course ADT (3-6 months) and SBRT (35-36.25 Gy) at Georgetown University Hospital. Thirty-two percent were black and 27% were obese. 77% of patient received three months of ADT. At baseline, 2% of men experienced hot flashes that were a "moderate to big problem" and that proportion peaked at the start of SBRT (45%) before returning to baseline 9 months post-SBRT with a cumulative incidence of 52.4%. The median baseline healthcare software hot flash score of 94 declined to 50 at the start of SBRT but this returned to baseline by six months post SBRT. These changes were both statistically and clinically significant (MID = 9.5083). Testosterone recovery (> 230 ng/dL) occurred in approximately 70% of patients by 12 months post SBRT. Resolution of hot flashes correlated with testosterone recovery. Bothersome hot flashes occur in greater than 50% of men treated with neoadjuvant ADT. Resolution of hot flashes occurs in the majority of patients within one year after treatment. Reassurance of the temporary nature of hot flashes may assist in reducing patient anxiety. Measuring testosterone levels at follow-up visits may allow for anticipatory counseling that may limit the associated bother.

Testosterone as a Biomarker for Quality of Life (QOL) Following Androgen Deprivation Therapy (ADT) and Stereotactic Body Radiotherapy (SBRT).

Androgen deprivation therapy (ADT) causes fatigue and sexual dysfunction. The time to testosterone recovery depends on patient and treatment-specific characteristics. The kinetics of testosterone recovery in men treated with neoadjuvant ADT and stereotactic body radiotherapy (SBRT) is not well established. This study seeks to characterize testosterone recovery and evaluate its relationship with the improvement in patient-reported hormonal and sexual function. Institutional review board (IRB) approval was obtained for retrospective review of prospectively collected data. All patients with localized prostate cancer treated with short-course ADT (3-6 months of Leuprolide) and robotic SBRT (35-36.25 Gy in five fractions) at a single institution were included in this analysis.Testosterone levels were measured at the start of radiation, every 3 months for the first year, and every 6 months thereafter. Total testosterone recovery was defined as a serum level of >230 ng/dL. Sexual and hormonal function was recorded using the Expanded Prostate Index Composite (EPIC)-26 prior to ADT initiation, the first day of SBRT, and at each follow-up. The EPIC-26 subdomain scores were transformed to a 0-100 scale with higher scores reflecting less bother. Between January 2009 and May 2018, 122 men with a median age of 72 years (range: 55-89 years) received ADT followed by SBRT. Thirty-two percent(N=39) were black and 27% [N=39 were obese (BMI > 30)]. The median pre-SBRT testosterone level was 15 ng/dL (range: 3-89 ng/dL). Around 77% (N=94) of patients received 3 months of ADT. The median pre-ADT EPIC-26 Hormone and Sexual Domain Scores were 94 and 41, respectively. At 12 months, 71% (N=87) of patients recovered to a eugonadal state with a mean recovery time of 4 months post-SBRT. Hormonal and sexual subdomain scores declined significantly following ADT but recovered to within the minimally important difference (MID) for sexual and hormonal domain scores by 12 months post-SBRT. Testosterone recovery following short-course ADTwith leuprolide and SBRT occurs rapidly in the majority of patients within one year after treatment. Quality of life domain improvements followed the testosterone recovery trend closely. Testosterone testing at follow-up appointments would allow for anticipatory counseling that may limit the bother associated with temporary quality of life decrements.

Neoadjuvant versus Concurrent Androgen Deprivation Therapy in Localized Prostate Cancer Treated with Radiotherapy: A Systematic Review of the Literature.

There is an ongoing debate on the optimal sequencing of androgen deprivation therapy (ADT) and radiotherapy (RT) in patients with localized prostate cancer (PCa). Recent data favors concurrent ADT and RT over the neoadjuvant approach. We conducted a systematic review in PubMed, EMBASE, and Cochrane Databases assessing the combination and optimal sequencing of ADT and RT for Intermediate-Risk (IR) and High-Risk (HR) PCa. Twenty randomized control trials, one abstract, one individual patient data meta-analysis, and two retrospective studies were selected. HR PCa patients had improved survival outcomes with RT and ADT, particularly when a long-course Neoadjuvant-Concurrent-Adjuvant ADT was used. This benefit was seen in IR PCa when adding short-course ADT, although less consistently. The best available evidence indicates that concurrent over neoadjuvant sequencing is associated with better metastases-free survival at 15 years. Although most patients had IR PCa, HR participants may have been undertreated with short-course ADT and the absence of pelvic RT. Conversely, retrospective data suggests a survival benefit when using the neoadjuvant approach in HR PCa patients. The available literature supports concurrent ADT and RT initiation for IR PCa. Neoadjuvant-concurrent-adjuvant sequencing should remain the standard approach for HR PCa and is an option for IR PCa.

PSOR7 Presentation Time: 12:00 PM: Toxicity and Efficacity of Whole Gland Salvage HDR Brachytherapy After Primary Radiation for Prostate Cancer

<h3>Purpose</h3> Androgen Deprivation Therapy (ADT) is the most common treatment for relapsing prostate cancer after primary radiation therapy. However, an effective local treatment could be used to obtain local control of the disease while limiting the systemic side effects of ADT. We designed a single institution prospective pilot study to assess the efficacy and safety of whole gland prostate HDR brachytherapy. <h3>Materials and Methods</h3> Fifty (50) patients with local relapse after primary radiation therapy were included in this study. A biopsy-proven local relapse, a negative bone scan, and a negative CT scan of the abdomen and pelvis were mandatory. A dose of 32Gy in 4 fractions was delivered to the whole prostate by HDR brachytherapy using CT-based treatment planning. The use of ADT was allowed if deemed clinically indicated by the treating physician. The primary objective was to evaluate early and late gastrointestinal (GI) and genitourinary (GU) toxicities, assessed with CTCAE v5 scale and IPS score. Biochemical disease-free survival (bDFS) was evaluated as a secondary outcome. <h3>Results</h3> Median follow-up was 61,1 months (0.8-106.8 months). Sixteen (16) patients received short-course ADT prior to brachytherapy. GI toxicities were low, with no grade 3 toxicities reported. 4.1% and 14,6% of patients had early and late grade 2 toxicities. Only one patient had a grade 3 GU early toxicity. However, 16,7% of patients experienced late grade 3 toxicities (12.0% at the last follow-up). Interestingly, none of the patient using neoadjuvant ADT developed late grade 3 toxicities although this association was not statistically significant (Chi-Square p-value 0.171). Mean IPSS value presented a predictable rise to 15.9 at 1 month follow-up. A subsequent decline was observed to mean IPSS under 10 after 24 months. A bDFS of 73,5% was observed after 48 months. <h3>Conclusion</h3> Whole gland salvage HDR brachytherapy is an effective treatment with an excellent biochemical disease-free survival. However, it is associated with a significant risk of late GU toxicities. In this perspective, our treatment protocol has been modified to allow for focal therapy using MR guidance. That will allow us to evaluate if a similar local control can be maintained while reducing the incidence of severe toxicities.

A Pilot Study of Salvage HDR Brachytherapy in Recurrent Prostate Cancer: 5 Year Toxicity and Outcomes

<h3>Purpose/Objective(s)</h3> Until recently, Androgen Deprivation Therapy (ADT) was the main treatment option for recurrent prostate cancer after primary radiation treatment. However, ADT is not curative and is associated with several side effects. Local ablative therapy can be curative and reduce long-term side effects associated with ADT. We designed a single institution prospective pilot study to evaluate the toxicities and outcomes of HDR brachytherapy as a salvage local therapy. <h3>Materials/Methods</h3> Sixty (60) patients with a biopsy-proven local relapse after a previous treatment with radiation were included in this study. A negative bone scan and CT scan of the abdomen and pelvis at the time of relapse was mandatory. Primary objective was to assess both early and late genitourinary (GU) and gastrointestinal (GI) toxicities. Biochemical disease-free survival (bDFS) was also assessed as a secondary objective. Toxicities were reported using CTCAE v5 scale and the IPSS. Short-course ADT could be used if deemed clinically indicated by the physician. HDR brachytherapy regimen was 32Gy delivered in 4 fractions to the whole prostate and, for the last 10 patients recruited, 27Gy in 2 fractions administered focally, due to concerns with toxicities. CT-based treatment planning using an inverse planning algorithm (IPSA) was performed for patients with whole prostate treatment (n = 50). Real-time ultrasound-based treatment planning was used for patients undergoing focal salvage radiation (n = 10). <h3>Results</h3> Median follow-up was 58.4 months (0.8-106.8 months). GI toxicities were acceptable with 3.6% and 14.5% of patients experiencing early and late grade 2 toxicities. No G3 GI toxicities were reported. Early G2 GU toxicities were overestimated at 100% (all patients used an alpha-blocker in the postoperative setting) and one patient had G3 early toxicity. Late GU toxicities were significant, with 14.5% of patients experiencing late G3 toxicity (10.0% at the last follow-up). Of interest, the use of ADT before HDR brachytherapy (n = 17) was associated with lower GU toxicities (no G3) although the association was not statistically significant (Chi-Square p-value 0.201). Good biochemical control was achieved with a bDFS of 73.9% at 48 months. <h3>Conclusion</h3> Salvage HDR brachytherapy after primary radiation to the prostate offers good biochemical control but at the cost of significant G3 GU morbidities. Patients can benefit from local therapy after primary radiation but whole-gland radiation should be used with caution because of concern with toxicities. Focal therapy to partial gland might be a good alternative to achieve local control and avoid severe toxicities.

Sequencing of Androgen Deprivation Therapy of Short Duration with Radiotherapy for Non-Metastatic Prostate Cancer (SANDSTORM): A Pooled Analysis of 12 Randomized Trials

<h3>Purpose/Objective(s)</h3> Prior evidence from randomized controlled trials (RCTs) suggests that sequencing of androgen deprivation therapy (ADT) and radiotherapy (RT) impacts clinical outcomes, with a potential interplay with pelvic nodal RT (PNRT). Herein, we aim to further investigate this finding across 12 RCTs, and assess the interplay of ADT sequencing with PNRT in localized prostate cancer (LPCa). <h3>Materials/Methods</h3> The Meta-Analysis of Randomized Trials in Cancer of the Prostate (MARCAP) consortium was accessed to obtain individual patient data (IPD) from 12 RCTs that included patients with LPCa who received neoadjuvant/concurrent (neo/conc) or concurrent/adjuvant (conc/adj) short-course ADT (4-6 months) with either prostate-only RT (PORT) or PNRT. Inverse probability of treatment weighting (IPTW) analyses were performed to balance treatment groups, with weights derived from propensity scores as a function of age, initial PSA, Gleason Score, T stage and mid-trial enrollment year. The primary endpoint was metastasis-free survival (MFS), as assessed by IPTW-adjusted Cox regression. IPTW-adjusted Fine and Gray competing risk models were developed to evaluate biochemical recurrence (BCR), distant metastasis (DM) and prostate cancer-specific mortality (PCSM). The regression models include ADT sequencing, PNRT and their interaction to account for effect modification. <h3>Results</h3> Overall, 7409 patients were included (6325 neo/conc, 1084 conc/adj) with a median follow-up of 10.2 years (10.3 neo/conc, 9.9 conc/adj). Conc/adj ADT was associated with improved MFS (10-year estimates: 66.3% vs. 60.6%, HR 0.70 [95% CI 0.59-0.83], p<0.0001), BCR (26.2% vs. 35.2%, sHR 0.43 [95% CI 0.34-0.56], p<0.0001), DM (11.5% vs. 9.0%, sHR 0.55 [95% CI 0.36-0.85], p=0.0073), and PCSM (4.6% vs. 6.2%, sHR 0.33 [95% CI 0.19-0.57], p<0.0001). A significant interaction between ADT sequencing and PNRT for all the above endpoints was observed (P-interaction <0.0001 for all). In patients receiving PORT, conc/adj ADT was associated with significantly improved BCR, DM, MFS and PCSM. In contrast, patients receiving PNRT neoadj/conc ADT was associated with significantly improved DM, MFS and PCSM. Comparing the 4 groups based on ADT sequencing and use of PNRT, after IPTW, conc/adj ADT with PORT (reference) had superior MFS compared to neo/conc + PORT (HR 1.59 [95% CI 1.33-1.91], p<0.0001), neo/conc + PNRT (HR 1.96 [95% CI 1.60-2.39], p<0.0001), or conc/adj +PNRT (HR 1.94 [95% CI 1.51-2.50], p<0.0001). <h3>Conclusion</h3> The sequencing of ADT with RT was significantly associated with clinical outcomes, with evidence of a significant interaction based on use of PNRT. PORT with conc/adj vs. neo/conc ADT had improved MFS, while PNRT with neo/conc vs. conc/adj ADT had improved MFS. Overall PORT with conc/adj ADT had superior outcomes. Given the non-randomized nature of the current pooled analysis, we await the results of NRG/RTOG 0924 to understand the role of PNRT in LPCa with neo/conc ADT sequencing.

Stereotactic body radiation therapy (SBRT) versus conventionally fractionated external beam radiation therapy in unfavorable intermediate-risk prostate cancer: An inverse propensity matched analysis.

e17054 Background: Conventionally fractionated radiotherapy (CFRT) or moderately hypofractionated radiotherapy (MFRT) ± short-course androgen deprivation therapy (ADT) is commonly employed for unfavorable intermediate-risk (UIR) prostate cancer. Stereotactic body radiation therapy (SBRT) has not been widely adopted, but may have radiobiologic advantages over more conventionally fractionated treatments. We hypothesized that radiotherapy dose-escalation with SBRT (35-40Gy in ≤5 fractions) is associated with improved overall survival (OS) relative to biologically equivalent doses of CFRT (72-86.4Gy in 1.8-2.0Gy/fraction) or MFRT (≥60Gy in 2.4-3.2Gy/fraction) ± ADT. Methods: The National Cancer Database (NCDB) was used to identify 28,028 men with UIR prostate cancer who received CFRT with (n = 12,872) or without ADT (n = 12,984), MFRT with (n = 251) or without ADT (n = 281), and SBRT with (n = 212) or without ADT (n = 1,428). SBRT+ADT patients were excluded due to low patient numbers. Inverse probability of treatment weighting was used to balance measured confounders. Unweighted- and weighted- multivariable analysis (MVA) using Cox regression was used to compare OS hazard ratios. Results: Relative to CFRT without ADT, CFRT+ADT (Hazard Ratio (HR): 0.92, [95% Confidence Interval: 0.87-0.97], P = .002) and SBRT without ADT (HR: 0.74 [0.61-0.89], P = .002) were both associated with improved OS on MVA. Relative to CFRT+ADT, SBRT without ADT correlated with improved OS on MVA (HR: 0.81 [0.67-0.99], P = .04). Weight-adjusted MVA demonstrated that SBRT (HR: 0.80 [0.65-0.98], P = .036) and ADT (HR: 0.91 [0.86-0.97], P = .002) correlated with improved OS. SBRT was not associated with improved OS relative to MFRT. Conclusions: Using inverse propensity treatment weighting, we adjusted for age, comorbidity score, and tumor factors, and observed a significant overall survival benefit in favor of administering dose-escalated SBRT over CFRT+ADT. To our knowledge, this is the first study to show that SBRT is associated with improved OS relative to CFRT for men with UIR prostate cancer. Together, this suggests that SBRT offers a cheaper and shorter course of therapy that mitigates COVID-19 exposure, which also is associated with improved OS relative to CFRT for UIR prostate cancer and may obviate the need for ADT in this population. While we await results from several ongoing clinical trials, we believe this study lends support to the use of SBRT in men with UIR prostate cancer.

Salvage radiotherapy in patients affected by oligorecurrent pelvic nodal prostate cancer

Metastasis-directed therapy (MDT) is an investigational treatment option in patients with oligorecurrent prostate cancer (PCa). The aim of this retrospective study is to report oncologic outcome and toxicity of elective nodal radiotherapy (ENRT) in PCa patients affected by pelvic nodal oligorecurrence. 41 consecutive patients were treated with salvage radiotherapy. At biochemical recurrence after primary treatment, oligorecurrent disease was detected by positron emission tomography (PET) in 94% of the patients. Image-guided intensity modulated radiation therapy (IMRT) was delivered using tomotherapy. 83% of the patients received androgen deprivation therapy (ADT) in combination with ENRT. Survival analysis was performed with Kaplan-Meier method, log-rank test was used to analyze associations between survival end-points and clinical parameters. Multivariate analysis was performed using Cox proportional hazards regression models. Toxicity was registered according to Common Terminology Criteria for Adverse Events (CTCAE) v4.0. The median at follow-up was 33.6months. At 3years, overall survival (OS), cancer-specific survival (CSS), and biochemical progression-free survival (b-PFS) were 89%, 92%, and 53%, respectively. At univariate analysis, all survival end-points were correlated with the number of positive pelvic lymph nodes at oligorecurrence (≤ 3 vs > 3). Biochemical-PFS was correlated with PSA (p = 0.034) and PSA doubling time (p = 0.004) at oligorecurrence. At multivariate analysis, no independent variable was statistically significant. No patient experienced grade ≥ 2 late toxicity after radiotherapy. The number of metastatic lymph nodes and PSA doubling time seems to be important prognostic factors in the pelvic oligorecurrent setting. Salvage radiotherapy combined with short-course ADT might be a valid treatment strategy.

Outcomes for Young Men With Localized Intermediate-Risk Prostate Cancer: An Analysis of the NCDB.

Primary management of localized, intermediate-risk prostate cancer consists of radical prostatectomy (RP), radiotherapy (RT) with short-course androgen deprivation therapy (ADT), or RT alone. The purpose of this study was to determine if these treatment strategies have equivalent overall survival (OS) in patients< 55 years old with intermediate-risk prostate cancer. We identified 35,134 patients in the National Cancer Data Base with localized intermediate-risk prostate cancer treated with RP, RT+ ADT, or RT from 2004 to 2013. Ten-year OS rates were estimated by the Kaplan-Meier method. Adjusted hazard ratios (HR) with 95% confidence intervals (CI) were computed by multivariate Cox regression. A total of 29,920 patients (85.2%) underwent RP, 1393 (4.0%) RT+ ADT, and 3821 (10.9%) RT. Median patient age was 51 years old, and median follow-up was 59.9 months. Ten-year OS was estimated to be 94.2% for RP, 80.7% for RT+ ADT, and 85.2% for RT (P< .0001). On multivariate analysis, treatment with RT+ ADT or RT was associated with significantly worse OS compared to treatment with RP (RT+ ADT HR= 2.06, 95% CI 1.67-2.54, P< .0001; RT HR= 2.0, 95% CI 1.71-2.33, P< .0001). Patients who metall 3 of the intermediate-risk criteria showed worse OS compared to patients who met only one criterion (HR= 1.80; 95% CI, 1.32-2.44; P= .0002). RP is significantly more likely than RT+ ADT or RT to be used as a primary treatment for young men with localized intermediate prostate cancer. RP was also associated with improved OS compared to RT+ ADT and RT.

Disease Control With Delayed Salvage Radiotherapy for Macroscopic Local Recurrence Following Radical Prostatectomy.

Purpose: To retrospectively assess clinical outcomes and toxicity profile of prostate cancer patients treated with delayed dose-escalated image-guided salvage radiotherapy (SRT) for macroscopic local recurrence after radical prostatectomy (RP).Material and Methods: We report on a cohort of 69 consecutive patients with local recurrence after RP and no evidence of regional or distant metastasis who were referred for salvage radiotherapy between 2007 and 2016. SRT consisted of 64–66 Gy (2 Gy/fraction) to the prostatic bed followed by dose escalation to 72–74 Gy (2Gy/fraction) to the macroscopic disease. All patients received concurrent short-term androgen deprivation therapy (ADT). Biochemical recurrence-free survival (bRFS) and clinical progression-free-survival (cPFS) were depicted using Kaplan-Meier method. Multivariable Cox proportional hazards regression assessed predictors of survival outcomes. Baseline, acute, and late urinary and gastrointestinal (GI) toxicity rates were reported using CTCAE v4.03.Results: Median time from RP to SRT was 66 months (IQR: 32–124). Median pre-SRT prostate-specific antigen (PSA) was 2.7 ng/ml (IQR: 0.9–6.5). Median follow-up after SRT was 38 months (IQR: 24–66). The 3- and 5-year bRFS were 58 and 44%, respectively. The 3- and 5-year cPFS were 91 and 76%, respectively. Median time from SRT to clinical disease progression was 102 months (IQR 77.5–165). At baseline, 3 patients (4%) had grade 3 urinary symptoms. Six patients (9%) developed acute and six patients (9%) developed late grade 3 urinary toxicity. Five patients (7%) had acute grade 2 GI toxicity. No acute grade 3 GI toxicity was reported. Late grade 3 GI toxicity was reported in one patient (1.5%).Conclusions: Delayed dose-escalated SRT combined with short-course ADT for macroscopic LR after RP was associated with 44% bRFS and 76% cPFS at 5 years. Albeit improved patient stratification is warranted, these data suggest that delayed SRT provides inferior tumor control compared to early intervention.

Cardiovascular Mortality Following Long-course Androgen Deprivation in Unfavorable Prostate Cancer Patients Treated with Brachytherapy and/or External Beam Radiation Therapy

To investigate whether long-course androgen deprivation therapy (ADT) is associated with an increased risk of cardiovascular mortality (CVM) in Japanese patients treated with brachytherapy and/or external beam radiotherapy (EBRT) for unfavorable localized prostate cancer. This is a retrospective analysis of prospectively collected data from men treated at Tokyo Medical Center between 2003 and 2012. Data on 1,628 patients treated for intermediate (n=1,234) or high-risk (n=394) prostate cancer with brachytherapy (n=486), EBRT (n=196), and a combination of brachytherapy and EBRT (n=946) were included. In total, 1,005 patients (61.7%) received neoadjuvant, concurrent with or in the absence of adjuvant ADT. Patients were divided into two groups according to the total duration of ADT: a short-course group (n = 803) received ≤ 12 months (median duration 6 months), and a long-course group (n = 202) received > 12 months (median duration 24 months). The primary endpoint of this study was a CVM, which was defined as a death from myocardial infarction, sudden cardiac arrest, coronary artery disease, cardiac ischemia, malignant arrhythmia, or cerebrovascular stroke. Statistical analysis was conducted using Kaplan-Meier estimator. Cox regression analyses were performed to assess whether long-course ADT was associated with CVM after controlling for age, presence of baseline cardiovascular disease or diabetes, radiation modality, and risk groups. After a median follow-up of 7.6 years (range=0.5-14 years), overall survival was 85.1% at 10 years. In total, 194 men died; 53 cardiovascular deaths, 41 prostate cancer deaths, 67 other malignancy deaths, 16 infectious disease deaths, 15 other benign disease deaths, and two unknown causes were observed. In terms of baseline patient characteristics, long-course ADT was significantly associated with younger patients, EBRT treatment, high risk group, and total androgen blockade. The 10-year CVM rate was 4.2% in the no-ADT group, 3.9% in the short-course ADT group, and 12.2% in the long-course ADT group (p<.001). In Cox regression analysis, long-course ADT (adjusted hazard ratio [AHR]=2.94; 95% confidence interval [CI]=1.31 to 6.59; p=.009), age (AHR=1.15; 95% CI=1.10 to 1.21; p<.001), baseline cardiovascular disease (AHR=2.62; 95% CI=1.49 to 4.62; p=.001), and baseline diabetes (AHR=2.71; 95% CI=1.36 to 5.41; p=.005) were associated with statistically significantly increased CVM. Long-course ADT is associated with an increased risk of CVM in Japanese patients undergoing brachytherapy and/or EBRT for unfavorable prostate cancer. Although Japan’s CVM is much lower than that of the USA, CVM appears to increase noticeably after long-course ADT in the otherwise this long-lived Japanese population.

Oligorecurrent Nodal Prostate Cancer: Long-term Results of an Elective Nodal Irradiation Approach.

The objective of this study was to report long-term results of elective nodal radiotherapy (ENRT) in prostate cancer (PCa) patients with oligorecurrent nodal disease after primary treatment. Data of 53 oligorecurrent PCa patients (N1 and/or M1a) with ≤5 nodal metastases (n=108) treated with ENRT combined with androgen deprivation therapy (ADT) between 2004 and 2016 were retrospectively reviewed. Median prostate-specific antigen (PSA) and PSA doubling time (DT) were 3.4 ng/mL and 5 months, respectively. At restaging, 45% of the patients presented single nodal metastases, mainly located in the pelvis (n=38). All patients underwent ENRT between 45 and 50.4 Gy with a boost on positive nodes (median 64.4 Gy; 54 to 69 Gy) using mainly VMAT (n=24) or IMRT (n=21) techniques. Concomitant ADT was administered to all patients for a median time of 6 months. After a median follow-up after ENRT of 44 months (range, 2 to 133), the 5-year biochemical disease-free and distant progression-free survival (DPFS) rates were 43% and 58%, respectively, with worse DPFS observed in patients with a PSA-doubling time <3 months (36.8% vs. 63.6%; P=0.029). Seventeen of 19 clinically relapsing patients presented lesions out of the ENRT field, and 10 were again oligometastatic. Only 2 patients presented with a CTCAE v3.0 grade ≥2 genitourinary toxicity. ENRT combined with short-course ADT is a safe and effective salvage modality for patients with oligorecurrent nodal PCa. Prospective randomized studies comparing focal SBRT versus ENRT are warranted to define the best treatment strategy.

Undetectable prostate-specific antigen after short-course androgen deprivation therapy for biochemically recurrent patients correlates with metastasis-free survival and prostate cancer-specific survival.

Optimal utilization of novel therapies for advanced prostate cancer is challenging without a validated surrogate efficacy endpoint. Ongoing trials are using durable undetectable prostate-specific antigen (PSA) levels as a marker of efficacy. The clinical relevance of prolonged undetectable PSA after a short course of androgen deprivation therapy (ADT) is uncertain. The University of Washington Caisis database was queried for radical prostatectomy patients who received 6-12 months of ADT after biochemical recurrence (BCR), defined as PSA ≥0.2 ng/mL and no radiographically detectable metastasis. Proportions of men with undetectable PSA 12 and 24 months after ending ADT were compared to a hypothesized 5% rate using exact binomial tests. Associations with patient and tumor characteristics were examined using logistic regression, and associations with risk of subsequent metastasis and death were evaluated by log-rank tests. After ineligibility exclusions, 23/93 (25%; 95%CI 16-35%; P < 0.001) and 14/93 (15%; 95%CI 9-24%; P < 0.001) had undetectable PSA 12 and 24 months after ending ADT, respectively. Detectable PSA at 12 months was associated with increased risk of metastasis (P = 0.006), prostate cancer-specific death (P = 0.028), and death from any cause (P = 0.065). Being 1 year older at diagnosis was associated with a 14% (95%CI 5-24%; P = 0.006) decrease in the odds of having a detectable PSA after controlling for PSA at diagnosis, PSA doubling time, grade group, and time from initial therapy to BCR. This single-institution retrospective analysis shows that it is not uncommon to have undetectable PSA 12 or 24 months after a short course of ADT. No baseline prognostic characteristic other than age was associated with a durable (12 month) undetectable PSA. Because a durable undetectable PSA was associated with lower risks of metastasis and prostate cancer-specific death, it may be a reasonable clinical trial endpoint.

Association of undetectable PSA with time to metastasis and survival after short-course androgen deprivation therapy for biochemically-recurrent prostate cancer patients.

e17073Background: Optimal utilization of novel therapies for advanced prostate cancer is challenging without a validated surrogate efficacy endpoint. Durable undetectable prostate-specific antigen ...

Proportion of biochemically-recurrent prostate cancer patients with durable undetectable PSA after short-course androgen deprivation therapy.

207 Background: Optimal utilization of novel therapies for advanced prostate cancer is challenging without a validated surrogate efficacy endpoint. Ongoing trials are using durable undetectable prostate specific antigen (PSA) levels as a marker of efficacy. The proportion of patients and clinical relevance of those with a prolonged undetectable PSA after a short course of androgen deprivation therapy (ADT) is uncertain. Methods: The University of Washington Caisis database was queried for radical prostatectomy patients who received 6–12 months of ADT after biochemical recurrence (BCR), defined as PSA ≥ 0.2 ng/mL and no radiographically detectable metastasis. Proportions of patients with undetectable PSA 12 and 24 months after ending ADT were compared to a hypothesized 5% rate using exact binomial tests. Associations with patient and tumor characteristics were examined using logistic regression, and associations with risk of subsequent metastasis and death from any cause were evaluated by log-rank tests. Results: After ineligibility exclusions, data were abstracted from 93 patients. Proportions of patients with undetectable PSA 12 and 24 months after ending ADT were n=23/93 (24.7%; 95% CI 16.4–34.8%; P&lt;0.001) and n=14/93 (15.1%; 95% CI 8.5–24.0%; P&lt;0.001), respectively. Proportions of patients with undetectable PSA 12 and 24 months after testosterone recovery ≥ 50 ng/dL were n=16/65 (24.6%; 95% CI 14.8-36.9%) and n=10/65 (15.4%; 95% CI 7.6-26.5%), respectively. Being 1 year older at diagnosis was associated with an 11.5% (95% CI 3.1–21.9%; P=0.01) increase in the odds of having a detectable PSA after controlling for PSA at diagnosis, Gleason sum and time from initial therapy to BCR. Detectable PSA was associated with increased risk of metastasis (P=0.006) with marginal evidence of association with death from any cause (P=0.07). Conclusions: This single-institution retrospective analysis shows that it is not uncommon to have undetectable PSA 12 or 24 months after a short course of ADT. Additional analysis is needed to demonstrate the clinical value of this measure as a surrogate for prostate cancer outcomes and for consideration as a trial endpoint.

Stereotactic Body Radiotherapy for High-Risk Prostate Cancer: Preliminary Toxicity Results of a Phase 2 Trial

Stereotactic body radiotherapy (SBRT) for high-risk prostate cancer (CaP) remains investigational not only due to undetermined efficacy but also due to concerns for the potential toxicity when the treatment volumes extend beyond the prostate gland itself. Herein we present the preliminary toxicity results of a phase II trial evaluating a five fraction SBRT regimen for high-risk CaP that allows for the integration pelvic nodal radiation (RT) and androgen deprivation therapy (ADT). Men with high-risk CaP, as defined by Gleason score >= 8, clinical stage T3-T4, or initial PSA >= 20 ng/mL, were enrolled on a multicenter phase II trial and were treated with 40 Gy to prostate. Radiation to the pelvic nodes with 25 Gy in a simultaneous integrated boost plan (5 Gy per fraction) and/or a nine months neoadjuvant and concurrent androgen deprivation therapy (ADT) could be integrated with prostate SBRT at the discretion of the treating physician. Follow-up assessment was with CTCAE v4 and Expanded Prostate Composite Index (EPIC). SBRT was delivered with a linear accelerator using volumetric modulated arc therapy or with a CyberKnife system. A total of 73 patients have been treated on this protocol, with a median follow-up of 13.8 months. Forty-six (63%) received ADT and 23 (32%) received nodal RT. The median initial PSA was 8.8 ng/mL and 11% of patients had clinical T3-T4 disease; 48% and 33% had Gleason score 8 and 9-10 disease, respectively. No grade 3 or higher genitourinary (GU) or gastrointestinal (GI) toxicities were seen. For patients receiving nodal radiation, rates of acute grade 1 and 2 GU toxicities were 18.2% and 4.5%; for those not receiving nodal RT, they were 23.5% and 17.6%. Rates of acute grade 1 and 2 GI toxicities were 9.1% and 9.1% with and 11.8% and 3.9% without nodal RT. Late grade 1 and 2 GU toxicities rates with nodal RT were 27.3% and 4.5%; without nodal RT, the rates were 18.6% and 7.0%. Late grade 1 and 2 GI rates were 13.6% and 13.6% with nodal radiation and 11.6% and 4.7% without it. Mean changes in EPIC urinary and bowel domain scores at 4 months were +0.13 and -4.17 with nodal RT, and +0.79 and -2.97 without it. Mean changes in EPIC urinary and bowel domain scores at 12 months were -1.52 and -5.12 with nodal RT and -1.71 and -5.67 without it. Overall, the receipt of nodal RT had no significant association with either physician- or patient-reported toxicity profiles (p > 0.1, Fisher’s exact test). Similarly, the receipt of ADT had no significant association with any toxicity parameter. Two patients (2.7%) experienced biochemical failure; in both cases, the PSA never decreased after SBRT. SBRT regimens can be safely utilized to deliver the entire course in 5 treatment days in patients with high-risk localized CaP, with or without the integration of nodal RT and/or short-course ADT. Despite the short followup, the low rate of biochemical failure is encouraging.