High-risk Localized Prostate Cancer Patients Research Articles

ASO Author Reflections: It Does Not Matter Whether Radical Prostatectomy is Performed in High-Risk Localized Disease or at the Oligometastatic Stage.

Radical prostatectomy (RP) alone has traditionally been considered insufficient for patients with high-risk localized prostate cancer (HRPC) owing to the frequent need for adjuvant salvage radiotherapy or androgen deprivation therapy (ADT) following surgery. Previously, systemic therapy, such as ADT, was the standard treatment for metastatic prostate cancer (PC) patients; RP was not considered viable for these patients. However, since 2015, there has been a recognition that metastatic PC patients can be categorized based on the extent of their metastases, leading to the consideration of RP for some metastatic cases. In recent years, the concept of cytoreductive RP has gained traction; studies suggest that it may improve survival rates in metastatic PC patients through mechanisms, such as tumor debulking and enhancement of the immune response. A meta-analysis of retrospective studies has shown that cytoreductive RP is associated with higher cancer-specific survival rates at 1-year, 3-year, and 5-year intervals compared with systemic therapy alone. In our study, which followed HRPC and oligometastatic PC patients for an average of 46 months, we observed biochemical recurrence in 17.8% of HRPC and 13% of oligometastatic patients, with overall survival rates of 96.4% and 87%, respectively. Although prospective or randomized studies are still lacking, current retrospective studies, including our own, suggest promising outcomes for RP in HRPC and oligometastatic patients. With the increasing prevalence of robotic surgery, improved pelvic anatomy observation, and growing surgical confidence, the realization of prospective randomized study results may not be far off.

Differences in real-world outcomes by risk classification for localized prostate cancer patients after radiation therapy.

Limited real-world evidence exists on the long-term clinical outcomes of patients with localized prostate cancer (LPC) who received external beam radiation therapy (EBRT) as the initial treatment. This study evaluated clinical outcomes of US patients with high-risk LPC (HR-LPC) and low/intermediate-risk LPC (LIR-LPC) who received EBRT. This retrospective study using Surveillance, Epidemiology, and End Results-Medicare linked data from 2012 to 2019 included patients ≥ 65 years old who received EBRT as initial therapy. Baseline patient characteristics were summarized, metastasis-free survival (MFS), overall survival, and time to initiation of advanced prostate cancer treatment were compared using Kaplan-Meier (KM) and adjusted Cox proportional hazard (PH) models. 5-year survival probabilities stratified by race/ethnicity (non-Hispanic [NH] White, NH Black, NH Asian, and Hispanic) were assessed. Of 11,313 eligible patients, 41% (n = 4600) had HR-LPC and 59% (n = 6713) had LIR-LPC. Patient characteristics for both groups were comparable, with mean age at EBRT initiation > 70 years, 86% white, and mean follow-up time >40 months. More patients in the HR-LPC than LIR-LPC groups (78% vs 34%) had concurrent androgen deprivation therapy use and for a longer duration (median 10.4 months vs. 7.4 months). A higher proportion of HR-LPC patients developed metastasis, died, or received advanced prostate cancer treatment. Adjusted Cox PH survival analyses showed significantly (p < 0.0001) higher risk of mortality (hazard ratios[HR], 1.57 [1.38, 2.34]), metastasis or death (HR, 1.97 [1.78, 2.17]), and advanced prostate cancer therapy use (HR, 2.57 [2.11, 3.14]) for HR-LPC than LIR-LPC patients. Within 5 years after the initial EBRT treatment, 18%-26% of patients with HR-LPC are expected to have died or developed metastasis. The 5-year MFS rate in the HR-LPC group was lower than the LIR-LPC group across all racial/ethnic subgroups. NH Black patients with HR-LPC had the highest all-cause mortality rate and lowest rate of receiving advanced prostate cancer treatment, compared to other racial/ethnic subgroups. This real-world study of clinical outcomes in patients with LPC treated with EBRT suggests substantial disease burden in patients with HR-LPC and highlights the need for additional treatment strategies to improve clinical outcomes in patients with HR-LPC.

Computed Tomography-Based Radiomics for Long-Term Prognostication of High-Risk Localized Prostate Cancer Patients Received Whole Pelvic Radiotherapy.

Given the high death rate caused by high-risk prostate cancer (PCa) (>40%) and the reliability issues associated with traditional prognostic markers, the purpose of this study is to investigate planning computed tomography (pCT)-based radiomics for the long-term prognostication of high-risk localized PCa patients who received whole pelvic radiotherapy (WPRT). This is a retrospective study with methods based on best practice procedures for radiomics research. Sixty-four patients were selected and randomly assigned to training (n = 45) and testing (n = 19) cohorts for radiomics model development with five major steps: pCT image acquisition using a Philips Big Bore CT simulator; multiple manual segmentations of clinical target volume for the prostate (CTVprostate) on the pCT images; feature extraction from the CTVprostate using PyRadiomics; feature selection for overfitting avoidance; and model development with three-fold cross-validation. The radiomics model and signature performances were evaluated based on the area under the receiver operating characteristic curve (AUC) as well as accuracy, sensitivity and specificity. This study's results show that our pCT-based radiomics model was able to predict the six-year progression-free survival of the high-risk localized PCa patients who received the WPRT with highly consistent performances (mean AUC: 0.76 (training) and 0.71 (testing)). These are comparable to findings of other similar studies including those using magnetic resonance imaging (MRI)-based radiomics. The accuracy, sensitivity and specificity of our radiomics signature that consisted of two texture features were 0.778, 0.833 and 0.556 (training) and 0.842, 0.867 and 0.750 (testing), respectively. Since CT is more readily available than MRI and is the standard-of-care modality for PCa WPRT planning, pCT-based radiomics could be used as a routine non-invasive approach to the prognostic prediction of WPRT treatment outcomes in high-risk localized PCa.

Androgen Deprivation and Radiotherapy with or Without Docetaxel for Localized High-risk Prostate Cancer: Long-term Follow-up from the Randomized NRG Oncology RTOG 0521 Trial

BackgroundIntensification of therapy may improve outcomes for patients with high-risk localized prostate cancer. ObjectiveTo provide long-term follow-up data from phase III RTOG 0521, which compared a combination of androgen deprivation therapy (ADT) + external beam radiation therapy (EBRT) + docetaxel with ADT + EBRT. Design, setting, and participantsHigh-risk localized prostate cancer patients (>50% of patients had Gleason 9–10 disease) were prospectively randomized to 2 yr of ADT + EBRT or ADT + EBRT + six cycles of docetaxel. A total of 612 patients were accrued, and 563 were eligible and included in the modified intent-to-treat analysis. Outcome measurements and statistical analysisThe primary endpoint was overall survival (OS). Analyses with Cox proportional hazards were performed as prespecified in the protocol; however, there was evidence of nonproportional hazards. Thus, a post hoc analysis was performed using the restricted mean survival time (RMST). The secondary endpoints included biochemical failure, distant metastasis (DM) as detected by conventional imaging, and disease-free survival (DFS). Results and limitationsAfter 10.4 yr of median follow-up among survivors, the hazard ratio (HR) for OS was 0.89 (90% confidence interval [CI] 0.70–1.14; one-sided log-rank p = 0.22). Survival at 10 yr was 64% for ADT + EBRT and 69% for ADT + EBRT + docetaxel. The RMST at 12 yr was 0.45 yr and not statistically significant (one-sided p = 0.053). No differences were detected in the incidence of DFS (HR = 0.92, 95% CI 0.73–1.14), DM (HR = 0.84, 95% CI 0.73–1.14), or prostate-specific antigen recurrence risk (HR = 0.97, 95% CI 0.74–1.29). Two patients had grade 5 toxicity in the chemotherapy arm and zero patients in the control arm. ConclusionsAfter a median follow-up of 10.4 yr among surviving patients, no significant differences are observed in clinical outcomes between the experimental and control arms. These data suggest that docetaxel should not be used for high-risk localized prostate cancer. Additional research may be warranted using novel predictive biomarkers. Patient summaryNo significant differences in survival were noted after long-term follow-up for high-risk localized prostate cancer patients in a large prospective trial where patients were treated with androgen deprivation therapy + radiation to the prostate ± docetaxel.

Prostate Specific Antigen response to neoadjuvant Lutetium-177-PSMA treatment in high-risk localized prostate cancer patients

Prostate Specific Antigen response to neoadjuvant Lutetium-177-PSMA treatment in high-risk localized prostate cancer patients

Adjusting the duration of androgen deprivation therapy (ADT) based on nadir PSA for high risk localized prostate cancer patients treated with definitive external beam radiation therapy and ADT

BackgroundA nadir Prostate-Specific Antigen (nPSA) of 0.06 ng/mL has been shown to be a strong independent predictor of biochemical recurrence-free survival (bRFS) in patients with intermediate or high-risk (HR) prostate cancer treated with definitive external beam radiation therapy (RT) and androgen deprivation therapy (ADT). We aimed to examine the association between the duration of ADT and bRFS in HR localized prostate cancer, based on nPSA.MethodsBetween 1998 and 2015, 204 patients with HR localized prostate cancer were identified. Of them, 157 patients (77.0%) reached the desired nPSA of < 0.06 ng/mL (favorable group), while 47 (23.0%) did not (unfavorable group). Duration of ADT varied among patients depending on physician preference, patient tolerance, and/or compliance. Survival outcomes were calculated using Kaplan–Meier methods and predictors of outcomes using multi-variable cox regression model.ResultsIn the favorable group, ADT for at least 12 months lead to superior bRFS compared to ≤ 9 months of ADT (P = 0.036). However, no significant difference was seen when examining the value of receiving ADT beyond 12, 18, or 24 months, respectively. On univariate analysis for bRFS, the use of ADT for at least 12 months was significant (P = 0.012) as well as time to nadir PSA (tnPSA), (≤ 6 vs > 6 months); (P = 0.043). The presenting T stage was borderline significant (HR 3.074; 95% CI 0.972–9.719; P = 0.056), while PSA at presentation, Gleason Score and age were not. On multivariate analysis, the use of ADT for 12 months (P = 0.012) and tnPSA (P = 0.037) remained significant. In the unfavorable group, receiving ADT beyond 9 and 12 months was associated with improved bRFS (P = 0.044 and 0.019, respectively). However, beyond 18 months, there was no significant difference.ConclusionIn HR localized prostate cancer patients treated with definitive RT and ADT, the total duration of ADT may be adjusted according to treatment response using nPSA. In patients reaching a nPSA below 0.06 ng/mL, a total of 12 months of ADT may be sufficient, while in those not reaching a nPSA below 0.06 ng/mL, a total duration of 18 months is required.

A flexible approach for causal inference with multiple treatments and clustered survival outcomes.

When drawing causal inferences about the effects of multiple treatments on clustered survival outcomes using observational data, we need to address implications of the multilevel data structure, multiple treatments, censoring, and unmeasured confounding for causal analyses. Few off-the-shelf causal inference tools are available to simultaneously tackle these issues. We develop a flexible random-intercept accelerated failure time model, in which we use Bayesian additive regression trees to capture arbitrarily complex relationships between censored survival times and pre-treatment covariates and use the random intercepts to capture cluster-specific main effects. We develop an efficient Markov chain Monte Carlo algorithm to draw posterior inferences about the population survival effects of multiple treatments and examine the variability in cluster-level effects. We further propose an interpretable sensitivity analysis approach to evaluate the sensitivity of drawn causal inferences about treatment effect to the potential magnitude of departure from the causal assumption of no unmeasured confounding. Expansive simulations empirically validate and demonstrate good practical operating characteristics of our proposed methods. Applying the proposed methods to a dataset on older high-risk localized prostate cancer patients drawn from the National Cancer Database, we evaluate the comparative effects of three treatment approaches on patient survival, and assess the ramifications of potential unmeasured confounding. The methods developed in this work are readily available in the package .

A Prospective Study of Stereotactic Body Radiotherapy (SBRT) with Concomitant Whole-Pelvic Radiotherapy (WPRT) for High-Risk Localized Prostate Cancer Patients Using 1.5 Tesla Magnetic Resonance Guidance: The Preliminary Clinical Outcome.

Simple SummaryMagnetic resonance (MR)-guided stereotactic body radiotherapy (MRgSBRT) with concomitant whole-pelvic nodal radiotherapy (WPRT) represents a novel radiotherapy paradigm for high-risk prostate cancer (HR-PC), potentially improving online image guidance and clinical outcomes. This is the first prospective study aims to report the preliminary clinical experiences and treatment outcome of 1.5 Tesla adaptive MRgSBRT with concomitant WPRT in HR-PC patients (72.5 ± 6.8 years). Forty-two consecutive localized HR-PC patients were treated by online adaptive MRgSBRT (8 Gy(prostate)/5 Gy(WPRT) × 5 fractions) combined with androgen deprivation therapy (ADT) and followed up (median: 251 days, range: 20–609 days). The maximum cumulative acute gastrointestinal (GI)/ genitourinary (GU) grade 1 and 2 toxicity rates were 19.0%/81.0% and 2.4%/7.1%, respectively. The subacute (>30 days) GI/GU grade 1 and 2 toxicity rates were 21.4%/64.3% and 2.4%/2.4%, respectively. No grade 3 toxicities were reported. Patient-reported quality of life (QoL) showed insignificant changes in urinary, bowel, sexual, and hormonal domain scores during the follow-up period. All patients had early post-MRgSBRT biochemical responses, while biochemical recurrence (prostate-specific antigen nadir + 2 ng/mL) occurred in one patient at month 18. The early results suggested favorable treatment-related toxicities and encouraging patient-reported QoLs, but long-term follow-up is still needed. Background: Conventionally fractionated whole-pelvic nodal radiotherapy (WPRT) improves clinical outcome compared to prostate-only RT in high-risk prostate cancer (HR-PC). MR-guided stereotactic body radiotherapy (MRgSBRT) with concomitant WPRT represents a novel radiotherapy (RT) paradigm for HR-PC, potentially improving online image guidance and clinical outcomes. This study aims to report the preliminary clinical experiences and treatment outcome of 1.5 Tesla adaptive MRgSBRT with concomitant WPRT in HR-PC patients. Materials and methods: Forty-two consecutive HR-PC patients (72.5 ± 6.8 years) were prospectively enrolled, treated by online adaptive MRgSBRT (8 Gy(prostate)/5 Gy(WPRT) × 5 fractions) combined with androgen deprivation therapy (ADT) and followed up (median: 251 days, range: 20–609 days). Clinical outcomes were measured by gastrointestinal (GI) and genitourinary (GU) toxicities according to the Common Terminology Criteria for Adverse Events (CTCAE) Scale v. 5.0, patient-reported quality of life (QoL) with EPIC (Expanded Prostate Cancer Index Composite) questionnaire, and prostate-specific antigen (PSA) responses. Results: All MRgSBRT fractions achieved planning objectives and dose specifications of the targets and organs at risk, and they were successfully delivered. The maximum cumulative acute GI/GU grade 1 and 2 toxicity rates were 19.0%/81.0% and 2.4%/7.1%, respectively. The subacute (>30 days) GI/GU grade 1 and 2 toxicity rates were 21.4%/64.3% and 2.4%/2.4%, respectively. No grade 3 toxicities were reported. QoL showed insignificant changes in urinary, bowel, sexual, and hormonal domain scores during the follow-up period. All patients had early post-MRgSBRT biochemical responses, while biochemical recurrence (PSA nadir + 2 ng/mL) occurred in one patient at month 18. Conclusions: To our knowledge, this is the first prospective study that showed the clinical outcomes of MRgSBRT with concomitant WPRT in HR-PC patients. The early results suggested favorable treatment-related toxicities and encouraging patient-reported QoLs, but long-term follow-up is needed to confirm our early results.

Suboptimal use of hormonal therapy among German men with localized high-risk prostate Cancer during 2005 to 2015: analysis of registry data

BackgroundThis study assesses the use of hormonal therapy to treat high-risk localized prostate cancer (HRLPCa) cases diagnosed between 2005 and 2015.MethodsAll N0-XM0 with ≥T3a, or PCa cases with poorly differentiated feature (equivalent to Gleason score ≥ 8), diagnosed between 2005 and 2015 were extracted from German population-based cancer registries. Cases treated by surgery or chemotherapy were excluded. Description of hormonal therapy use by HRLPCa cases’ profile was presented. Relative risk (RR) was computed with a log-link function to identify factors associated with hormonal therapy use among radiotherapy-treated HRLPCa cases.ResultsA total of 5361 HRLPCa cases were analyzed. Only 27.6% (95% confidence interval [CI]: 26.4–28.8%) of the HRLPCa cases received hormonal therapy in combination with radiotherapy. The use of combined hormonal therapy and radiotherapy varied from 19.8% in Saxony to 47.8% in Schleswig-Holstein.Application of hormonal therapy was higher for the locally advanced cases compared to the poorly differentiated cases (relative risk [RR] = 1.28; 95%CI: 1.19, 1.37). Older patients showed a slightly increased use of hormonal therapy (RR for a 10-year age increase = 1.09; 95%CI: 1.02, 1.16). Compared to PCa cases from the most affluent residential areas, cases from the least affluent (RR = 0.71; 95%CI: 0.55, 0.92) and medium (RR = 0.75; 95%CI: 0.58, 0.96) areas had decreased use of hormonal therapy. The introduction of the German S3-guideline did not make a marked difference in the uptake of both hormonal therapy and radiotherapy (RR = 1.02; 95%CI: 0.95, 1.09).ConclusionThis study found a low use of hormonal therapy among HRLPCa patients treated without surgery. The introduction of the German S3-guideline for prostate cancer treatment does not seem to have impacted hormonal therapy use.

PSMA-PET- and MRI-Based Focal Dose Escalated Radiation Therapy of Primary Prostate Cancer: Planned Safety Analysis of a Nonrandomized 2-Armed Phase 2 Trial (ARO2020-01)

The bicentric HypoFocal phase 2 trial investigates the implementation of molecular imaging with positron-emission tomography targeting prostate-specific membrane antigen (PSMA-PET) into modern focal dose-escalation radiation therapy (RT) concepts in 2 nonrandomized arms. We present the planned safety analysis after 6 months of follow-up. Intermediate- and high-risk localized primary prostate cancer patients staged with multiparametric magnet resonance tomography and PSMA-PET were either treated with focal dose-escalated moderately hypofractionated RT (arm A) or single fraction high-dose-rate brachytherapy followed by external beam RT (arm B). PSMA-PET was used in addition to primary prostate cancer to define the intraprostatic gross tumor volume. Gastrointestinal and genitourinary toxicities were assessed according to Common Toxicity Criteria for Adverse Events (version 5.0) criteria. International Prostate Symptom Score was measured and quality of life assessed with European Organisation for Research and Treatment of Cancer questionnaires QLQ-PR25/-PR30. We enrolled 25 patients in each study arm. The implementation of PET-information led to large median volumes for dose escalation: 10.2 mL in arm A and 6.8 mL in Arm B. RT dose-escalation was feasible in all patients of arm A with up to 75 Gy (20 fractions) and in 23 patients with up to 19 Gy (1 fraction) in arm B. Toxicities, International Prostate Symptom Scores, and European Organisation for Research and Treatment of Cancer quality of life scores were not significantly different between baselines and 6 months follow-up in both arms. No grade 3 toxicities were observed at 6 months follow-up. This is the first prospective data supporting the feasibility of PSMA-PET-implementation into definitive focal dose-escalated RT. Patients maintained a good quality of life and a low toxicity profile after 6 months of follow-up.

Outcomes of an advanced practice nurse (APN)-led cancer genetics service.

71 Background: In oncology practice, there are increasing numbers of patients for whom genetic testing is recommended by the National Cancer Care Network (NCCN), including all metastatic and high-risk localized prostate cancer patients. However, there is a critical shortage of genetics services providers. Acuity for these consults can be high, particularly in the context of a treatment related decision. We hypothesized that nurses, particularly advanced practice nurses (APNs), can provide a workforce within VA that can address genetic testing and genetic care needs of prostate cancer patients. Methods: We initiated a cancer genetics service staffed with an advanced practice nurse (APN) geneticist and evaluated the success of the program at a large urban, academic-affiliated Veteran’s Affairs Medical Center (VAMC). Results: In the one year prior to the initiation of the APN geneticist-run program (10/1/2019-9/30/2020), 61 unaffected patients with a family history of cancer and 85 patients with cancer (36 with prostate cancer) were referred to a VA centralized telegenetics service. An average of seven cancer patients (average three with prostate cancer) were referred to VA telegenetics per month. Genetic testing was completed in eleven (18%) of unaffected patients and 21 (25%) of cancer patients. Five (13%) of tested patients were found to have a pathogenic or likely pathogenic mutation or variant of uncertain significance (VUS). In the eight months after initiation of the APN geneticist-run consult service (10/1/2020 - 5/30/2021), 39 unaffected patients with a family history of cancer and 90 patients with cancer (38 with prostate cancer) were referred. An average of 11 cancer patients (average five with prostate cancer) per month were referred. This represents a 57% increase in all cancer patient and a 67% increase in prostate cancer patient referrals. For those patients referred to the APN geneticist-run consult service, genetic testing was completed in three (7%) of unaffected patients and 30 (33%) of cancer patients (including 15 prostate cancer patients). The genetic testing rate therefore improved from 1.7 oncology patients per month to 3.9 oncology patients per month, an 130% increase in genetic testing. For prostate cancer patients, the genetic testing rate improved from 0.8 to 1.9 patients tested per month, representing a 137% increase. Comparison of genetic testing outcomes at one year will be included in the final presentation. Conclusions: Inclusion of an APN geneticist-run consult service embedded in oncology clinics will likely improve access to genetics services and genetic testing rates in cancer patients.

Long-Term Outcomes of a Phase I Trial of Weekly Docetaxel, Total Androgen Blockade, and Image-Guided Intensity-Modulated Radiotherapy for Localized High-Risk Prostate Adenocarcinoma

<h3>Purpose/Objective(s)</h3> In high-risk localized prostate cancer (HRLPC), the standard of care is dose-escalated radiation therapy (DERT) with long-term androgen deprivation therapy (LTADT). Unfortunately, outcomes are less than ideal. There is significant interest in improving outcomes by intensifying treatment for these patients using docetaxel (D). This phase I study was designed to find the maximum tolerable dose (MTD) of concurrent weekly D when combined with DERT to the prostate with long-term androgen deprivation therapy (LTADT) in HRLPC patients. Initial results reported demonstrated a MTD for docetaxel of 25 mg/m² with acceptable toxicities. Here we describe the long-term outcomes in these patients. <h3>Materials/Methods</h3> We enrolled 19 patients with HRLPC (≥1 of ≥cT2c, PSA ≥20ng/ml, or Gleason ≥8) on this phase 1 study. Patients received neoadjuvant combined androgen blockade for 2 months and then during radiation of 77.4 Gy to the prostate and 45 Gy to the seminal vesicles with concurrent weekly D. No pelvic/nodal radiotherapy was given. D was administered in a standard dose-escalated scheme requiring ≥3 patients per cohort, starting at 10mg/m² and increasing to 30mg/m² in 5mg/m² increments. The GnRH agonist was continued for an additional 24 months. The primary objective of the study was to determine the MTD of D in combination with DERT and LTADT. Secondary end points included progression free survival (PFS), metastasis free survival (MFS) and overall survival (OS). Kaplan-Meier analysis was used to estimate the survival probabilities. <h3>Results</h3> MTD was found to be 25mg/m². There was no grade ≥3 toxicity at this or lower dose levels. At a median follow up of 10.5 years the median OS was not reached. 5-year and 10-year OS was found to be 89.5% and 68.4%, respectively. Median MFS was found to be 11.3 years with 5- and 10-year MFS of 84.2% and 57.9%. Median PFS was 9.0 years with 73.7% and 42.1% at 5 and 10 years, respectively. <h3>Conclusion</h3> In the setting of high-dose IMRT to the prostate with concurrent LTADT the MTD of concurrent weekly docetaxel is 25mg/m². This study showed a 5-year OS of 89.5% with a median OS not reached with > 10 years of follow-up. This mature data suggests that the addition of concurrent weekly docetaxel at 25mg/m² to high-dose IMRT to the prostate is safe and may provide cancer control rates similar to those recently reported for adjuvant full-dose D.

Timing of high-dose rate brachytherapy with external beam radiotherapy in intermediate and high-risk localized prostate cancer (THEPCA) patients and its effects on toxicity and quality of life: Results of a randomized feasibility trial.

236 Background: Advances in brachytherapy, external beam radiotherapy (EBRT) and image-guided radiotherapy have revolutionized radiotherapy delivery. Acute and late genitourinary (GU) and gastrointestinal (GI) toxicities remain a significant issue. Currently there is no European consensus on the timing of high-dose rate (HDR) brachytherapy in relation to EBRT. Schedules of HDR boost before or after EBRT vary significantly between institutions.The incidence of GI and GU toxicities was assessed in patients receiving HDR brachytherapy before and after EBRT. Methods: Men with Intermediate/high risk localized prostate cancer were randomized to Arm A (HDR brachytherapy before EBRT) or Arm B (HDR brachytherapy after EBRT). Both arms received a HDR boost of 15Gy and 46Gy in 23 fractions of EBRT. All patients received neoadjuvant and adjuvant hormone therapy for up to 2 years. Patients were followed quarterly up to a year. CTCAE scores for GU and GI toxicities were taken. IPSS, IEFL and FACT-P scores were collected. Fisher’s exact test was used to analyze the association between GU and GI toxicities. The T-test compared the mean differences in IPSS total scores at each follow-up. Analysis of variance evaluated the difference at follow up. Post-hoc testing and Bonferroni correction was applied. Results: 100 patients were randomized between 2015 and 2017. Data for 88 patients was available at cutoff. Mean age was 69 years (SD: 4.6). Age, Gleason score, TNM and clinical staging were similar in each arm. Mean IPSS Score was similar between both arms at baseline Arm A (6.52) &amp; Arm B (6.57). 12 months follow up showed mild worsening of symptoms in both arms, but no significant difference noticed between Arm A (8.02) &amp; Arm B (8.14) p=0.55. At 12 months, Grade 1 and 2 GU toxicities were more frequent in Arm A (22.88% &amp; 5.28%, p=0.669) compared to Arm B (19.36% and 2.64%, p=0.485). Grade 1 GI toxicity was more common in Arm B (23.76%) than Arm A (21.2%), p=0.396. Grade 2 GI toxicities were more common in Arm A 5.28% vs 3.52%, p=0.739. Baseline mean IIEF scores were 10.9 and 10.53 in Arm A and B respectively. At 12 months this was 6.6 in Arm A and 7.11 in Arm B, but not statistically significant. FACT-P scores were not different in either arm, with good QOL scores maintained throughout. Mean score at baseline (125.18) was observed to be similar at 12 months follow up at (126.10). The PTV, CTV &amp; OAR dose were compared and no significant differences were found. Conclusions: There were no significant differences in GI and GU related toxicities up to a year between patients receiving HDR brachytherapy before or after EBRT. There were no grade 3 or 4 toxicities. Treatment was well tolerated in both arms with good QOL scores. Longer follow up and a phase III multicenter RCT would be needed to validate findings. Clinical trial information: NCT02618161.

14: Seventeen Years Experience of Ebrt Plus Hdr Brachytherapy Boost in High-Risk Localized Prostate Cancer Patients: A Competing Risks Analysis

14: Seventeen Years Experience of Ebrt Plus Hdr Brachytherapy Boost in High-Risk Localized Prostate Cancer Patients: A Competing Risks Analysis

Adaptive radiotherapy and the dosimetric impact of inter- and intrafractional motion on the planning target volume for prostate cancer patients

PurposeTo investigate the dosimetric influence of daily interfractional (inter) setup errors and intrafractional (intra) target motion on the planning target volume (PTV) and the possibility of an offline adaptive radiotherapy (ART) method to correct larger patient positioning uncertainties in image-guided radiotherapy for prostate cancer (PCa).Materials and methodsA CTV (clinical target volume)-to-PTV margin ranging from 15 mm in LR (left-right) and SI (superior-inferior) and 5–10 mm in AP (anterior-posterior) direction was applied to all patients. The dosimetric influence of this margin was retrospectively calculated by analysing systematic and random components of inter and intra errors of 31 consecutive intermediate- and high-risk localized PCa patients using daily cone beam computed tomography and kV/kV (kilo-Voltage) imaging. For each patient inter variation was assessed by observing the first 4 treatment days, which led to an offline ART-based treatment plan in case of larger variations.Results:Systematic inter uncertainties were larger (1.12 in LR, 2.28 in SI and 1.48 mm in AP) than intra systematic errors (0.44 in LR, 0.69 in SI and 0.80 mm in AP). Same findings for the random error in SI direction with 3.19 (inter) and 2.30 mm (intra), whereas in LR and AP results were alike with 1.89 (inter) and 1.91 mm (intra) and 2.10 (inter) and 2.27 mm (intra), respectively. The calculated margin revealed dimensions of 4–5 mm in LR, 8–9 mm in SI and 6–7 mm in AP direction. Treatment plans which had to be adapted showed smaller variations with 1.12 (LR) and 1.72 mm (SI) for Σ and 4.17 (LR) and 3.75 mm (SI) for σ compared to initial plans with 1.77 and 2.62 mm for Σ and 4.46 and 5.39 mm for σ in LR and SI, respectively.ConclusionThe currently clinically used margin of 15 mm in LR and SI and 5–10 mm in AP direction includes inter and intra uncertainties. The results show that offline ART is feasible which becomes a necessity with further reductions in PTV margins.

Stereotactic pelvic radiotherapy with HDR boost for dose escalation in intermediate and high-risk prostate cancer (SPARE): Efficacy, survival, and late toxicity outcomes.

328 Background: The ASCO/CCO guidelines recommend brachytherapy boost for all eligible intermediate- or high-risk localized prostate cancer patients. We present efficacy, survival and late toxicity outcomes in patients treated on a prospective, single institutional protocol of MRI dose painted HDR brachytherapy boost (HDR-BT) followed by pelvic stereotactic body radiotherapy (SBRT) and androgen deprivation therapy (ADT). Methods: A phase I/II study was performed where intermediate (IR) or high-risk (HR) prostate cancer patients received HDR-BT 15Gy x 1 to the prostate and up to 22.5Gy to the MRI nodule and followed by gantry-based SBRT 25Gy in 5 weekly fractions delivered to pelvis, seminal vesicles and prostate. ADT was used for 6-18 months. CTCAEv3 was used to assess toxicities and was captured q6months x 5 years. Biochemical failure (BF; nadir + 2 definition), nadir PSA, proportion of patients with PSA &lt; 0.4 ng/ml at 4 years (4yPSARR), incidence of salvage therapy, cause specific survival and overall survival were calculated. Day 0 was HDR-BT date for all time-to-event analyses. Results: Thirty-two patients (NCCN 3% favorable IR, 47% unfavorable IR and 50% HR) completed the planned treatment with a median follow-up of 50 months; 31 of these had an MRI nodule. Four patients had BF with actuarial 4-year BF rate of 11.5%; 3 of these received salvage ADT. Median nPSA was 0.02 ng/ml; 4yPSARR was 68.8%. One patient died (of prostate cancer) at 45 months. For late toxicities, grade 1, 2 and 3+ GU and GI toxicities were: 40.6%, 37.5%, 3% and 28.1%, 0%, 0%, respectively. Conclusions: This novel treatment protocol incorporating MRI-dose painted HDR brachytherapy boost and SBRT pelvic radiation for intermediate- and high-risk prostate cancer in combination with ADT is feasible, effective and well tolerated. Clinical trial information: 12345678. [Table: see text]

Stereotactic radiotherapy +/- HDR boost for unfavorable-risk prostate cancer: Comparison of efficacy, survival, and late toxicity outcomes.

372 Background: The ASCO/CCO guidelines recommend brachytherapy boost for all eligible intermediate- or high-risk localized prostate cancer patients. Stereotactic body radiotherapy (SBRT) is an emerging treatment for prostate cancer but its use in high risk disease is limited. We compare efficacy, survival and late toxicity outcomes in patients treated on 2 prospective, phase 2 protocols that both use pelvic SBRT and androgen deprivation therapy (ADT). One used MR-guided HDR brachytherapy boost (SPARE) and the other uses a SBRT boost (SATURN). Methods: SPARE was a phase I/II study where intermediate (IR) or high-risk (HR) prostate cancer patients received HDR-BT 15Gy x 1 to the prostate and up to 22.5Gy to the MRI nodule and followed by gantry-based SBRT 25Gy in 5 weekly fractions delivered to pelvis. ADT was used for 6-18 months. SATURN was a phase II study where high risk patients received 40Gy to prostate and 25Gy to pelvis along in 5 weekly fractions with 12-18 months ADT. CTCAEv3 was used to assess toxicities and was captured q6months x 5 years. Biochemical failure (BF; nadir + 2 definition), nadir PSA, proportion of patients with PSA &lt; 0.4 ng/ml at 4 years (4yPSARR), incidence of salvage therapy, cause specific survival were calculated. Day 0 was first day of RT for all time-to-event analyses. Results: Thirty-two patients (NCCN 3% favorable IR, 47% unfavorable IR (UIR), 50% HR) completed SPARE while 30 patients (7% UIR, 93% HR) completed SATURN. Median follow-up of 50 and 48 months, respectively. Actuarial 4-year BF was 11.5% and 0%. Median nPSA was 0.02 ng/ml for both studies. 4yPSARR was 69% and 93%. 4-year cause-specific survival was 96% and 100%. Toxicities are listed in Table. Conclusions: In the context of SBRT pelvis and ADT, SBRT boost provides similar efficacy for unfavorable risk prostate cancer with acceptable but worse toxicities compared to HDR boost. A randomized study is recommended to answer this question. Clinical trial information: 01953055. [Table: see text]

Phase 2 Randomized Study of Radiation Therapy and 3-Year Androgen Deprivation With or Without Concurrent Weekly Docetaxel in High-Risk Localized Prostate Cancer Patients

Docetaxel improves survival in patients with metastatic prostate cancer. This randomized phase 2 trial aimed to assess the activity of weekly docetaxel with radiation therapy (RT) plus androgen deprivation in patients with high-risk localized prostate cancer. The study examined the benefit of 9 weekly docetaxel administrations to RT plus 3years of luteinizing hormone-releasing hormone analogues. A total of 132 patients were recruited for the study. Patients' characteristics included T3-T4 stage (81.1%), Gleason score ≥8 (77.3%), prostate-specific antigen level >20ng/mL (28.9%), and pN+ (18.2%). All patients included in the trial received either the standard-of-care control arm with luteinizing hormone-releasing hormone analogues plus RT (arm A) or the experimental arm (RT+9 weekly cycles of docetaxel+3years of androgen deprivation therapy, arm B). The primary objective was to achieve a high percentage of patients who were free of biochemical recurrence within 5years of randomization. Secondary endpoints included biochemical recurrence-free survival (BRFS), progression-free survival (PFS), overall survival (OS), clinical response rate, biochemical response rate, and toxicity. No difference between the arms of the study was found in biochemical recurrence (93.4% at 60months for arm A vs 85.3% for arm B; P=.3297). PFS at 60months was 93.4% and 83.7% in arms A and B, respectively (P=.2532). Five-year survival was 93.3% (95% confidence interval, 83.1-97.45) in arm A versus 93.6% (83.8-97.55) in arm B; median PFS and OS have not been reached. Prostate-specific antigen level ≤0.2ng/mL at 3months after the end of treatment was seen in 81.25% of patients in arm A compared with 90.48% of patients in arm B (P=.2028). BRFS was not significantly different between treatment arms. Diarrhea was the main nonhematologic toxicity. Long-term follow-up has not yet been enough to meet median PFS and OS. Concurrent weekly docetaxel can be administered safely with standard doses of RT without a significant increase in the toxicity profile. No statistically significant differences for 5-year BRFS, PFS, and OS have been observed when docetaxel was added to conventional treatment.

Adjuvant androgen-deprivation therapy following prostate total cryoablation in high-risk localized prostate cancer patients — Open-labeled randomized clinical trial

PurposeTo investigate the efficacy and safety profile of 12-month adjuvant androgen-deprivation therapy (ADT) following total-gland cryoablation (TGC) in patients with high-risk localized prostate cancer (HRLPC). Materials and MethodsThis open-label randomized trial included 38 HRLPC patients who received TGC between July 2011 and March 2013. Within 4 weeks after TGC, subjects were randomly assigned (1:1) to either the 12-month adjuvant ADT or non-adjuvant ADT group. The primary outcome was biochemical failure measured by the Phoenix definition. Adverse events were measured at month 1, 2, 3, 6, 9 and 12. In addition, a cohort of 145 HRLPC patients was selected retrospectively for outcome validation. ResultsThe adjuvant ADT and non-adjuvant ADT groups did't differ in peri-operative characters, such as age, preoperative PSA, tumor stages, Gleason score, prostate size and cryoprobe number. Four patients with adjuvant ADT withdrew from this trial for personal reasons (N = 2), elevated liver function (N = 1) and poorly controlled hyperglycemia (N = 1). In contrast, none in non-adjuvant ADT group experienced adverse events. Biochemical failures were identified in 5 (26%) patients in each group during a median follow-up duration of 45 months. The median times to biochemical failure were 25 and 5.5 months for adjuvant ADT and non-adjuvant ADT groups, respectively. Biochemical-failure survival curves converged 24 months after TGC. Univariable and multivariable analyses revealed adjuvant ADT was not associated with biochemical recurrences in the validation cohort. ConclusionsAdjuvant ADT does not reduce biochemical failure for HRPLC patients undergoing TGC. It should be further confirmed by a larger cohort.

Testosterone nadir and PSA recurrence-free survival in men with intermediate and high-risk localized prostate cancer undergoing definitive radiotherapy and androgen deprivation therapy.

100 Background: There is limited data on the relationship between testosterone level during androgen deprivation and clinical outcomes of localized prostate cancer treated with hormone therapy and radiation therapy (RT). Here we investigate the association between testosterone nadir during androgen deprivation therapy and prostate-specific antigen (PSA) response and survival. Methods: Using a nationwide Veterans Affairs database, we identified 899 patients with intermediate- or high-risk localized prostate adenocarcinoma diagnosed between 2000 and 2015 and treated with gonadotropin-releasing hormone agonists and RT. All patients had total testosterone measurements while receiving hormone therapy and between 6 weeks and 6 months after the start of hormone therapy. Using univariable and multivariable models we examined the effect of testosterone nadir on 3-month post-treatment PSA, PSA recurrence-free survival, and prostate cancer-specific survival. Multivariable models included age at diagnosis, Gleason score, tumor stage, anti-androgen therapy, hormone therapy duration, comorbidity, BMI, and pre-treatment PSA. Results: Of the 899 patients with testosterone data, 481 patients had a testosterone nadir of &lt; 20 ng/dL, 305 had a nadir between 20 and 49 ng/dL, and 113 had a nadir ≥50 ng/dL. Higher testosterone nadir was associated with higher 3-month post-treatment PSA on univariable (Spearman rho = 0.22, p &lt; 0.001, n = 651) and multivariable (ß = 0.03, 95% CI 0.01-0.05, p = 0.004) analysis. In multivariable Cox regression, higher testosterone nadir was associated with an increased risk of PSA recurrence (hazard ratio [HR] 1.43 per 10-fold increase in testosterone nadir, 95% CI 1.07-1.90, p = 0.01, n = 715) but not prostate cancer-specific mortality (HR 1.45, 95% CI 0.87-2.42, p = 0.16, n = 891). Conclusions: Higher nadir testosterone levels in intermediate- or high-risk localized prostate cancer patients undergoing hormone therapy is associated with higher 3-month post-treatment PSA and inferior PSA recurrence-free survival, though there was no significant effect on prostate cancer-specific mortality.