Treatment Of High-risk Prostate Cancer Research Articles

Population-based study of disease trajectory after radical treatment for high-risk prostate cancer.

To investigate long-term disease trajectories among men with high-risk localized or locally advanced prostate cancer (HRLPC) treated with radical radiotherapy (RT) or radical prostatectomy (RP). Men diagnosed with HRLPC in 2006-2020, who received primary RT or RP, were identified from the Prostate Cancer data Base Sweden (PCBaSe) 5.0. Follow-up ended on 30 June 2021. Treatment trajectories and risk of death from prostate cancer (PCa) or other causes were assessed by competing risk analyses using cumulative incidence for each event. In total, 8317 men received RT and 4923 men underwent RP. The median (interquartile range) follow-up was 6.2 (3.6-9.5) years. After RT, the 10-year risk of PCa-related death was 0.13 (95% confidence interval [CI] 0.12-0.14) and the risk of death from all causes was 0.32 (95% CI 0.31-0.34). After RP, the 10-year risk of PCa-related death was 0.09 (95% CI 0.08-0.10) and the risk of death from all causes was 0.19 (95% CI 0.18-0.21). The 10-year risks of androgen deprivation therapy (ADT) as secondary treatment were 0.42 (95% CI 0.41-0.44) and 0.21 (95% CI 0.20-0.23) after RT and RP, respectively. Among men who received ADT as secondary treatment, the risk of PCa-related death at 10 years after initiation of ADT was 0.33 (95% CI 030-0.36) after RT and 0.27 (95% CI 0.24-0.30) after RP. Approximately one in 10 men with HRLPC who received primary RT or RP had died from PCa 10 years after diagnosis. Approximately one in three men who received secondary ADT, an indication of PCa progression, died from PCa 10 years after the start of ADT. Early identification and aggressive treatment of men with high risk of progression after radical treatment are warranted.

Treatment intensification strategies for men undergoing definitive radiotherapy for high-risk prostate cancer.

Treatment intensification of external beam radiotherapy (EBRT) plays a crucial role in the treatment of high-risk prostate cancer. We performed a critical narrative review of the relevant literature and present new developments in evidence-based treatment intensification strategies. For men with high-risk prostate cancer, there is strong evidence to support prolonging androgen deprivation therapy (ADT) to 18-36months and escalating the dose to the prostate using a brachytherapy boost. A potentially less toxic alternative to a brachytherapy boost is delivering a focal boost to dominant intraprostatic lesions using EBRT. In patients who meet STAMPEDE high-risk criteria, there is evidence to support adding a second-generation anti-androgen agent, such as abiraterone acetate, to long-term ADT. Elective pelvic lymph node irradiation may be beneficial in select patients, though more prospective data is needed to elucidate the group of patients who may benefit the most. Tumor genomic classifier (GC) testing and advanced molecular imaging will likely play a role in improving patient selection for treatment intensification as well as contribute to the evolution of treatment intensification strategies for future patients. Treatment intensification using a combination of EBRT, advanced hormonal therapies, and brachytherapy may improve patient outcomes and survival in men with high-risk prostate cancer. Shared decision-making between patients and multidisciplinary teams of radiation oncologists, urologists, and medical oncologists is essential for personalizing care in this setting and deciding which strategies make sense for individual patients.

High-risk prostate cancer treated with a stereotactic body radiation therapy boost following pelvic nodal irradiation.

Modern literature has demonstrated improvements in long-term biochemical outcomes with the use of prophylactic pelvic nodal irradiation followed by a brachytherapy boost in the management of high-risk prostate cancer. However, this comes at the cost of increased treatment-related toxicity. In this study, we explore the outcomes of the largest cohort to date, which uses a stereotactic body radiation therapy (SBRT) boost following pelvic nodal radiation for exclusively high-risk prostate cancer. A large institutional database was interrogated to identify all patients with high-risk clinical node-negative prostate cancer treated with conventionally fractionated radiotherapy to the pelvis followed by a robotic SBRT boost to the prostate and seminal vesicles. The boost was uniformly delivered over three fractions. Toxicity was measured using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Oncologic outcomes were assessed using the Kaplan-Meier method. Cox proportional hazard models were created to evaluate associations between pretreatment characteristics and clinical outcomes. A total of 440 patients with a median age of 71 years were treated, the majority of whom were diagnosed with a grade group 4 or 5 disease. Pelvic nodal irradiation was delivered at a total dose of 4,500 cGy in 25 fractions, followed by a three-fraction SBRT boost. With an early median follow-up of 2.5 years, the crude incidence of grade 2+ genitourinary (GU) and gastrointestinal (GI) toxicity was 13% and 11%, respectively. Multivariate analysis revealed grade 2+ GU toxicity was associated with older age and a higher American Joint Committee on Cancer (AJCC) stage. Multivariate analysis revealed overall survival was associated with patient age and posttreatment prostate-specific antigen (PSA) nadir. Utilization of an SBRT boost following pelvic nodal irradiation in the treatment of high-risk prostate cancer is oncologically effective with early follow-up and yields minimal high-grade toxicity. We demonstrate a 5-year freedom from biochemical recurrence (FFBCR) of over 83% with correspondingly limited grade 3+ GU and GI toxicity measured at 3.6% and 1.6%, respectively. Long-term follow-up is required to evaluate oncologic outcomes and late toxicity.

Advancing knowledge-based intensity modulated proton planning for adaptive treatment of high-risk prostate cancer

To assess the performance of a knowledge-based planning (KBP) model for generating intensity-modulated proton therapy (IMPT) treatment plans as part of an adaptive radiotherapy (ART) strategy for patients with high-risk prostate cancer. A knowledge-based planning (KBP) model for proton adaptive treatment plan generation was developed based on thirty patient treatment plans utilizing RapidPlanTM PT (Varian Medical Systems, Palo Alto, CA). The model was subsequently validated using an additional eleven patient cases. All patients in the study were administered a prescribed dose of 70.2 Gy to the prostate and seminal vesicle (CTV70.2), along with 46.8 Gy to the pelvic lymph nodes (CTV46.8) through simultaneous integrated boost (SIB) technique. To assess the quality of the validation knowledge-based proton plans (KBPPs), target coverage and organ-at-risk (OAR) dose-volume constraints were compared against those of clinically used expert plans using paired t-tests. The KBP model training statistics (R2) (mean ± SD, 0.763 ± 0.167, range, 0.406 to 0.907) and χ² values (1.162 ± 0.0867, 1.039-1.253) indicate acceptable model training quality. Moreover, the average total treatment planning optimization and calculation time for adaptive plan generation is approximately 10 minutes. The CTV70.2 D98% for the KBPPs (mean ± SD, 69.1 ± 0.08 Gy) and expert plans (69.9 ± 0.04 Gy) shows a significant difference (p < 0.05) but are both within 1.1 Gy of the prescribed dose which is clinically acceptable. While the maximum dose for some organs-at-risk (OARs) such as the bladder and rectum is generally higher in the KBPPs, the doses still fall within clinical constraints. Among all the OARs, most of them received comparable results to the expert plan, except the cauda equina Dmax, which shows statistical significance and was lower in the KBPPs than in expert plans (48.5 ± 0.06 Gy vs 49.3 ± 0.05 Gy). The generated KBPPs were clinically comparable to manually crafted plans by expert treatment planners. The adaptive plan generation process was completed within an acceptable timeframe, offering a quick same-day adaptive treatment option. Our study supports the integration of KBP as a crucial component of an ART strategy, including maintaining plan consistency, improving quality, and enhancing efficiency. This advancement in speed and adaptability promises more precise treatment in proton ART.

Sequencing the Treatment of High-Risk Prostate Cancer: A Way Towards Multimodal Tailored Approaches: A changing Landscape

Sequencing the Treatment of High-Risk Prostate Cancer: A Way Towards Multimodal Tailored Approaches: A changing Landscape

Feasibility of simultaneous integrated boost for high-dose treatment of high-risk prostate cancer

Background. Radiation therapy for high-risk prostate cancer presents a challenge for cancer radiotherapists. The improvement of treatment outcomes is associated with radiation dose escalation and prophylactic irradiation of lymph nodes, therefore, the development of the new treatment schemes is needed. Simultaneous integrated boost technique based on the volumetric modulated arc therapy is the most efficient treatment option. Material and Methods. The anatomical data of 10 patients with high-risk prostate cancer was used for dosimetry-based treatment planning. Both simultaneous integrated boost and sequential boost technique were considered. The treatment planning goal was to deliver the equivalent dose of 96 Gy at 2 Gy per fraction (EQD2=96 Gy) (α/β=1.5 Gy) to the prostate, EQD2=62.5 Gy to the seminal vesicles and EQD2=50 Gy to lymph nodes avoiding damaging the organs at risk, mainly the bladder and rectum. The irradiation was based on volumetric modulated arc therapy with two partially coplanar arcs and two rotations at each arc. The obtained dose distributions were compared with respect to dose-volume histograms and equivalent uniform doses (EUD). Results. In the case of sequential boost, the minimal dose delivered to the prostate was equal to 95.9 ± 2.1 Gy, EUD=104.9 ± 1.7 Gy. The dose delivered to 2 cm3 (D2cc) bladder was 97.4 ± 2.0 Gy. Normal tissue complication probability (NTCP) was 1.64 %. The dose delivered to 2 cm3 (D2cc) rectum was 103.4 ± 9.2 Gy and NTCP was 27.4 %. In the case of simultaneous integrated boost, the minimal dose delivered to the prostate was equal to 90.4 ± 2.3 Gy, EUD=103.9 ± 1.3 Gy. The bladder dose was as high as D2cc=96.1 ± 5.2 Gy, NTCP=0.176 ± 0.132 %, the rectum dose - D2cc=81.1 ± 6.0 Gy, NTCP=2.34 ± 1.92 %. Conclusion. Volumetric modulated arc therapy along with simultaneous integrated boost have shown the feasibility of simultaneous irradiation of the prostate, seminal vesicles and lymph nodes up to the prescribed dose values without significant over irradiation of the organs at risk (OARs). Dose values in the tumor as high as EUD=103.9 ± 1.3 Gy along with prophylactic irradiation of lymph nodes may result in higher tumor control probability value and should be considered for clinical trials.

Long-Term Oncological Outcomes for Histologically Confirmed High-Risk Prostate Cancer.

The optimal treatment modality for locally advanced prostate cancer has not been established. Radiotherapy, hormonal therapy, and combination treatments are the main strategies, although the feasibility of radical prostatectomy as a first-line therapy needs to be considered. This retrospective analysis of pathological results of extracted specimens evaluated long-term oncological outcomes for high-risk prostate cancer treated surgically. The association of number of risk factors with long-term outcome was specifically analyzed. We identified patients with high-risk prostate cancer who underwent laparoscopic radical prostatectomy, without neoadjuvant therapy, at Nippon Medical School from 2000 to 2012. Risk factors were a prostate-specific antigen (PSA) concentration ≥20 ng/mL, pathological ≥T3, and pathological Gleason Score ≥8. Biological failure was defined as a PSA concentration ≥0.2 ng/mL. 222 men were identified. One patient had a positive lymph node status, and there was a significant difference in surgical margin positivity (52 men, 68.4% vs 56 men 38.4%) between patients with and without biochemical failure. Among patients meeting the high-risk criteria with a follow-up of up to 133 months, the biochemical recurrence (BCR) -free survival rates at 5 and 10 years were 62.8% and 58.4%, respectively, and mean time to BCR was 14.0 months. BCR-free survival rates at 5 and 10 years were 73.6% and 71.4%, respectively, for 1 risk factor, 48.7% and 34.6% for 2 factors, and 34.5% and 34.5% for 3 factors. Patients with a single risk factor had a significantly better outcome than those with multiple risk factors. The overall survival rates at 5 and 10 years were 94.6% and 93.7%, and the cancer-specific survival rate was 100% at both 5 and 10 years. Reasonable long-term oncological outcomes can be achieved by surgical treatment for high-risk prostate cancer. Patients with 1 risk factor had a significantly better BCR-free rate than those with multiple risk factors.

PD20-07 ASSOCIATIONS BETWEEN PATIENT SOCIODEMOGRAPHIC FACTORS AND RISK-APPROPRIATE PROSTATE CANCER MANAGEMENT

You have accessJournal of UrologyCME1 Apr 2023PD20-07 ASSOCIATIONS BETWEEN PATIENT SOCIODEMOGRAPHIC FACTORS AND RISK-APPROPRIATE PROSTATE CANCER MANAGEMENT Madison Novosel, Shayan Smani, Victoria Marks, Farah Jeong, Preston Sprenkle, and Michael Leapman Madison NovoselMadison Novosel More articles by this author , Shayan SmaniShayan Smani More articles by this author , Victoria MarksVictoria Marks More articles by this author , Farah JeongFarah Jeong More articles by this author , Preston SprenklePreston Sprenkle More articles by this author , and Michael LeapmanMichael Leapman More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003286.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Although definitive treatment is associated with improved survival for aggressive prostate cancer, a significant number of patients do not receive treatment. To identify gaps in practice, we sought to evaluate sociodemographic factors associated with non-treatment by clinical risk strata in the contemporary era. METHODS: We performed a retrospective study of patients with prostate cancer using the National Cancer Database. A total of 954,591 patients diagnosed with localized prostate (cT1-4N0M0) cancer from 2010 to 2020 were included in the analysis. We used descriptive statistics and multivariable logistic regression to evaluate factors associated with non-treatment, stratifying analyses by D’Amico clinical risk criteria. RESULTS: The mean patient age at diagnosis was 65 years. Overall, 26.0% were diagnosed with low, 43.4% with intermediate, and 30.6% with high-risk prostate cancer. There were 131,122 (13.7%) who did not undergo initial treatment, including 82,318 (62.8%) with low, 35,499 (27.1%) with intermediate, and 13,305 (10.2%) with high-risk disease. The proportion of patients not receiving treatment increased over time in all risk groups between 2010 and 2010, including among low (11.7% versus 59.5%), intermediate (4.5% versus 12.5%) and high risk (3.6% versus 5.1%) disease. Compared with White patients, Black patients had lower odds of definitive treatment. This effect was more pronounced for patients with high (OR 0.61, 95% CI 0.58-0.64) rather than intermediate (OR 0.76, 95% CI 0.73-0.78) risk prostate cancer. Asian patients had lower odds of treatment compared with White patients across all disease risk strata (OR 0.84, 95% CI 0.80-0.88) but not high-risk disease (OR 0.90, 95% CI 0.80-1.00). There were lower odds of treatment among American Native/Alaskan Native versus White patients but not for high-risk disease (OR 0.79, 95% CI 0.57-1.10) Uninsured (OR 0.45, 95% CI 0.42-0.47, p<0.001), and Medicaid-insured (OR 0.68, 95% CI 0.66-0.71, p<0.001) patients were less likely to be treated overall. Patients residing in higher income areas had lower odds of over-treatment for low-risk prostate cancer (OR 0.84, 95% CI 0.81-0.87) and higher odds of treatment for high-risk prostate cancer (OR 1.34, 95% CI 1.25-1.44). CONCLUSIONS: Among patients diagnosed with prostate cancer in the contemporary era race and insurance are significantly associated with non-treatment for aggressive prostate cancer. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e586 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Madison Novosel More articles by this author Shayan Smani More articles by this author Victoria Marks More articles by this author Farah Jeong More articles by this author Preston Sprenkle More articles by this author Michael Leapman More articles by this author Expand All Advertisement PDF downloadLoading ...

Second generation anti-androgens and androgen deprivation therapy with radiation therapy in the definitive management of high-risk prostate cancer.

Evolving data suggest that men with high-risk localized prostate cancer may benefit from more potent androgen receptor inhibition in the context of curative intent radiotherapy. Recently updated American Society for Clinical Oncology (ASCO) evidence-based guidelines and the National Comprehensive Cancer Network (NCCN) Guidelines have updated recommendations for the consideration of adding second generation anti-androgens to androgen deprivation therapy (ADT) in men receiving radiation therapy (RT) for noncastrate locally advanced high and very high risk nonmetastatic or node positive prostate cancer. We conducted a comprehensive review of existing published and abstract presented evidence behind RT with ADT for the definitive management of high-risk prostate cancer, particularly focused on the current phase II and III trial evidence for the addition of second generation anti-androgens to ADT in definitive RT treatment of high-risk prostate cancer and specifically focused on the recent STAMPEDE trial results with abiraterone acetate. We review the biological mechanisms in which second generation anti-androgens may help mitigate ADT resistance and provide radiosensitization through inhibition of DNA repair. Finally, we discuss ongoing clinical trials of potent androgen receptor (AR) inhibitors with ADT in this non-metastatic high-risk radiotherapy setting that may inform on future treatment guidelines. Recent data suggest an overall survival benefit as well as increased probabilities of disease free and metastasis free survival in men with high and very high-risk localized, node positive, and oligometastatic hormone sensitive prostate cancer with abiraterone acetate and prednisone and support the use of potent AR inhibitors in this setting after informed decision making.

Safety and Efficacy of Carbon-Ion Radiotherapy for Elderly Patients with High-Risk Prostate Cancer.

Simple SummaryAs the population ages, the number of elderly prostate cancer patients is increasing, and the choice of treatment options for elderly patients with poor general condition is becoming more difficult. The aim of our retrospective study is to assess the clinical outcomes after carbon-ion radiotherapy for elderly patients with high-risk prostate cancer. We compared 173 patients ≥75 years as the elderly group and 754 patients <75 years as the young group. Disease-specific and biochemical relapse-free survivals did not differ significantly between the young and elderly groups, and there were also no significant differences in adverse events between the two groups. Although this study is retrospective, carbon-ion radiotherapy may be a safe and effective treatment for elderly high-risk prostate cancer patients.Carbon-ion radiotherapy (CIRT) is a high-dose intensive treatment, whose safety and efficacy have been proven for prostate cancer. This study aims to evaluate the outcomes of CIRT in elderly patients with prostate cancer. Patients aged 75 years or above at the initiation of CIRT were designated as the elderly group, and younger than 75 years as the young group. The overall survival (OS), disease-specific survival (DSS), biochemical control rate (BCR), biochemical relapse-free survival (BRFS), and adverse events were compared between the elderly and young patients with high-risk prostate cancer treated with CIRT. The elderly group comprised 173 of 927 patients treated for high-risk prostate cancer between April 2000 and May 2018. The overall median age was 69 (range: 45–92) years. The median follow-up period was 91.9 (range: 12.6–232.3) months. The 10-year OS, DSS, BCR, and BRFS rates in the young and elderly groups were 86.9%/71.5%, 96.6%/96.8%, 76.8%/88.1%, and 68.6%/64.3%, respectively. The OS (p < 0.001) was longer in the younger group and the BCR was better in the elderly group (p = 0.008). The DSS and BRFS did not differ significantly between the two groups. The rates of adverse events between the two groups did not differ significantly and no patient had an adverse event of Grade 4 or higher during the study period. CIRT may be as effective and safe in elderly patients as the treatment for high-risk prostate cancer.

Advancements in the radiooncological treatment of high-risk prostate cancer: a quarter century of achievements.

BackgroundThe aim of the study was to evaluate the development of treatment of primary high-risk prostate cancer in regards to biochemical no evidence of disease (bNED), acute and late gastrointestinal (GI) and genitourinary (GU) side effects.Patients and methodsPrimary high-risk prostate cancer patients treated between 1994 and 2016 were included. Applied doses ranged from 60 to 80 Gy, with a dose of 1.8 or 2 Gy per fraction. Techniques were either 3D conformal or intensity modulated radiotherapy and volumetric intensity modulated arc therapy.Results142 patients were treated with doses up to 70 Gy (median dose 66 Gy; 66 Gy group), 282 with doses between 70 and 76 Gy (median dose 74 Gy; 74 Gy group), and 141 with doses >76 Gy (median dose 78 Gy; 78 Gy group). The median follow-up was 48 months. The bNED rates were 50% after 5 years and 44% after 9 years in the 66 Gy group; 65% and 54%, respectively, in the 74 Gy group; and 83% and 66%, respectively, in the 78 Gy group (p = 0.03 vs. 74 Gy and p < 0.0001 vs. 66 Gy). We found a higher rate of acute GI side effects in the 78 Gy group compared to the other groups, but not in maximum acute GU side effects and late maximum GI and GU effects.ConclusionsHigh-risk prostate cancer patients treated with doses of 78 Gy had significantly better bNED rates. Compared to the historical 66 Gy group, 50% more patients achieved bNED after a follow-up of 9 years.

Bone health assessment with dual energy X-ray absorptiometry in men with high-risk prostate carcinoma commencing adjuvant androgen deprivation therapy.

BackgroundAndrogen deprivation therapy (ADT) is a key component of therapy for patients with high-risk prostate carcinoma, but it may be deleterious for bone health. We sought to determine the frequency of dual energy x-ray absorptiometry (DXA) scanning in patients commencing adjuvant ADT for treatment of high-risk prostate cancer at a large integrated regional cancer centre.Material and methodsThe electronic medical records (EMR) of all patients with high-risk prostate carcinoma commenced on adjuvant ADT between January 1, 2016 and December 31, 2017 at the Mid-North Coast Cancer Institute, Coffs Harbour, Australia were reviewed. Patients commenced on neoadjuvant ADT and long-term suppressive ADT for metastatic disease were excluded. The following data were obtained: socio-demographic information, prostate cancer data, ADT details and DXA results.Results188 men (mean age ± SD, 75.4 ± 7 years) were commenced on adjuvant ADT for a total duration (mean ± SD) of 23.4 ± 7 months. Most (n = 155/188, 82%) were commenced on leuprorelin acetate. While only 26/188 (14%) had a DXA scan performed prior to ADT, another 133 (71%) had a DXA scan at a median of 20 days (interquartile range 7–98), later. Of the 159 men with DXA readings, 76 (48%) were osteopaenic and 38 (24%) were osteoporotic by DXA criteria.ConclusionA high level (85%) of DXA scanning in men commencing ADT for prostate cancer can be achieved at a regional centre. The high prevalence (72%) of low bone mass in our unselected cohort underscores the importance of routine DXA scanning to guide bone health management during ADT.

Radiobiological analysis of preliminary results of a phase II study of pelvic hypofractionated and accelerated radiotherapy for high-risk prostate cancer patients.

PurposeConventionally fractionated radiotherapy (CRT) is widely applied for the treatment of high-risk prostate cancer. Pelvic node irradiation improves control of the disease. Although the therapeutic guidelines support the use of hypofractionated and accelerated radiotherapy (HypoAR), this is addressed to prostate and seminal vesicles. At the same time, the safety and efficacy of HypoAR for pelvic node irradiation remain obscure.Material and MethodsIn a phase II study, we evaluated the feasibility of pelvic HypoAR in 22 high-risk prostate cancer patients. The RT scheme delivers 14 consecutive fractions of 3.67 Gy (total 51.38 Gy) to the prostate, 3.5 Gy (total 49 Gy) to the seminal vesicles, and 2.7 Gy (total 37.8 Gy) to the lymph nodes, using image-guided volumetric modulated arc therapy. A comparative radiobiological analysis of dose-volume histogram is performed (HypoAR vs. hypothetical equivalent CRT regimens, without and with time correction).ResultsOur clinical experience shows impressively low early and short-term late toxicities, without any grade III events, within a median follow-up of 30 months. Only one biochemical relapse was recorded 30 months after irradiation. In radiobiological analysis, considering an α/β-value of 4 Gy and a λ-value of 0.2 Gy/day for late effects, all comparisons predicted significantly lower toxicity for the HypoAR regimen (p < 0.05). For early toxicities (α/β = 10 Gy), a λ-value lower than 0.4 Gy/day favors the HypoAR regimen, which is along with the clinical results.ConclusionRadiobiological analysis favors HypoAR as a safe and effective regimen for high-risk prostate cancer patients, which is confirmed in the current phase II clinical study.

Conventional Versus Hypofractionated Radiation for High-Risk Prostate Cancer Patients (CHIRP): 24-Month Patient-Reported Outcomes of the Randomized Phase 2 CHIRP Trial

In this study, we report the 24-month patient-reported outcomes of the randomized phase 2 CHIRP trial that compared conventional and hypofractionated radiation therapy (RT) in the treatment of high-risk prostate cancer. Men with high-risk localized prostate cancer were randomized to either conventional (78 Gy/39 fractions) or hypofractionated RT (68 Gy/25 fractions). All patients received pelvic nodal RT and adjuvant androgen deprivation therapy. Quality of life (QoL) data were collected through the expanded prostate cancer index composite and the short-form 12 (SF-12) health-related QoL questionnaire at baseline and at 3, 6, 12, 18, and 24 months posttreatment. We assessed change from baseline to account for differences in baseline comorbidities. Independent t test was used to identify differences between the 2 groups. Ninety-six participants were included in the QoL analysis, 49 in the hypofractionation arm and 47 in the standard fractionation arm. Urinary and sexual scores were similar between the 2 arms at all time points. Bowel bother scores exhibited a consistent trend favoring the standard arm from 3- to 18-months posttreatment and were statistically significant at 12 months (P = .016). SF-12 physical component scores showed a consistent trend favoring the hypofractionation arm from 6- to 18-months posttreatment and were statistically significant at 18 months (P = .017). At 24 months, there were no significant differences in QoL scores between the 2 groups. At 24 months post-RT, there were no major differences in patient-reported QoL between standard and hypofractionated RT. Early statistically significant differences in bowel bother and SF-12 physical component scores were no longer present at 24 months.

Interplay Between Duration of Androgen Deprivation Therapy and External Beam Radiotherapy With or Without a Brachytherapy Boost for Optimal Treatment of High-risk Prostate Cancer

Radiotherapy combined with androgen deprivation therapy (ADT) is a standard of care for high-risk prostate cancer. However, the interplay between radiotherapy dose and the required minimum duration of ADT is uncertain. To determine the specific ADT duration threshold that provides a distant metastasis-free survival (DMFS) benefit in patients with high-risk prostate cancer receiving external beam radiotherapy (EBRT) or EBRT with a brachytherapy boost (EBRT+BT). This was a cohort study of 3 cohorts assembled from a multicenter retrospective study (2000-2013); a post hoc analysis of the Randomized Androgen Deprivation and Radiotherapy 03/04 (RADAR; 2003-2007) randomized clinical trial (RCT); and a cross-trial comparison of the RADAR vs the Deprivación Androgénica y Radio Terapía (Androgen Deprivation and Radiation Therapy; DART) 01/05 RCT (2005-2010). In all, the study analyzed 1827 patients treated with EBRT and 1108 patients treated with EBRT+BT from the retrospective cohort; 181 treated with EBRT and 203 with EBRT+BT from RADAR; and 91 patients treated with EBRT from DART. The study was conducted from October 15, 2020, to July 1, 2021, and the data analyses, from January 5 to June 15, 2021. High-dose EBRT or EBRT+BT for an ADT duration determined by patient-physician choice (retrospective) or by randomization (RCTs). The primary outcome was DMFS; secondary outcome was overall survival (OS). Natural cubic spline analysis identified minimum thresholds (months). This cohort study of 3 studies totaling 3410 men (mean age [SD], 68 [62-74] years; race and ethnicity not collected) with high-risk prostate cancer found a significant interaction between the treatment type (EBRT vs EBRT+BT) and ADT duration (binned to <6, 6 to <18, and ≥18 months). Natural cubic spline analysis identified minimum duration thresholds of 26.3 months (95% CI, 25.4-36.0 months) for EBRT and 12 months (95% CI, 4.9-36.0 months) for EBRT+BT for optimal effect on DMFS. In RADAR, the prolongation of ADT for patients receiving only EBRT was not associated with significant improvements in DMFS (hazard ratio [HR], 1.01; 95% CI, 0.65-1.57); however, for patients receiving EBRT+BT, a longer duration was associated with improved DMFS (DMFS HR, 0.56; 95% CI, 0.36-0.87; P = .01). For patients receiving EBRT alone (DART), 28 months of ADT was associated with improved DMFS compared with 18 months (RADAR HR, 0.37; 95% CI, 0.17-0.80; P = .01). These cohort study findings suggest that the optimal minimum ADT duration for treatment with high-dose EBRT alone is more than 18 months; and for EBRT+BT, it is 18 months or possibly less. Additional studies are needed to determine more precise minimum durations.

HoSAGE: sarcopenia in older patient with intermediate / high-risk prostate cancer, prevalence and incidence after androgen deprivation therapy: study protocol for a cohort trial

BackgroundSarcopenia is defined by a loss of muscle strength associated to a decrease in skeletal muscle mass. Ageing greatly contributes to sarcopenia as may many other factors such as cancer or androgen deprivation therapies (ADT). This cohort study aims to evaluate (1) the prevalence of muscle disorders and sarcopenia in older patients before initiation of intermediate to high risk prostate cancer treatment with ADT and radiotherapy, and (2) the occurrence and/or aggravation of muscle disorders and sarcopenia at the end of cancer treatment.MethodsThis cohort study is monocentric and prospective. The primary objectives are to determine the risk factor of sarcopenia prevalence and to study the relationship between ADT and sarcopenia incidence, in patients 70 years and older with histologically proven localized or locally advanced prostate cancer, addressed to a geriatrician (G8 score ≤14) for comprehensive geriatric assessment (CGA) in Marseille University Hospital. Secondary objectives encompass, measurement of sarcopenia clinical criteria along prostate oncological treatment; evaluation of the quality of life of patients with sarcopenia; evaluation of the impact of socio-behavioral and anthropological factors on sarcopenia evolution and incidence; finally the evaluation of the impact of ADT exposure on sarcopenia. Sarcopenia prevalence was estimated to be between 20 and 30%, therefore the study will enroll 200 patients.DiscussionThe current guidelines for older patients with prostate cancer recommend a pelvic radiotherapy treatment associated to variable duration (6 to 36 months) of ADT. However ADT impacts muscle mass and could exacerbate the risks of sarcopenia. Our study intends to assess the specific effect of ADT on sarcopenia incidence and/or worsening as well as to estimate sarcopenia prevalence in this population. The results of this cohort trial will lead to a better understanding of sarcopenia prevalence and incidence necessary to further elaborate a prevention plan.Trial registrationThe protocol was registered to the French drug and device regulation agency under the number 2019-A02319-48, before beginning the study (11/12/2019). The ClinicalTrials.gov identifier is NCT04484246, registration on the ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/NCT04484246).

Evaluation of two independent dose prediction methods to personalize the automated radiotherapy planning process for prostate cancer.

Background and purposeCurrently, automatic approaches for radiotherapy planning are widely used, however creation of high quality treatment plans is still challenging. In this study, two independent dose prediction methods were used to personalize the initial settings for the automated planning template for optimizing prostate cancer treatment plans. This study evaluated the dose metrics of these plans comparing both methods with the current clinical automated prostate cancer treatment plans.Material and methodsDatasets of 20 high-risk prostate cancer treatment plans were taken from our clinical database. The prescription dose for these plans was 70 Gy given in fractions of 2.5 Gy. Plans were replanned using the current clinical automated treatment and compared with two personalized automated planning methods. The feasibility dose volume histogram (FDVH) and modified filter back projection (mFBP) methods were used to calculate independent dose predictions. Parameters for the initial objective values of the planning template were extracted from these predictions and used to personalize the optimization of the automated planning process.ResultsThe current automated replanned clinical plans and the automated plans optimized with the personalized template methods fulfilled the clinical dose criteria. For both methods a reduction in the average mean dose of the rectal wall was found, from 22.5 to 20.1 Gy for the FDVH and from 22.5 to 19.6 Gy for the mFBP method.ConclusionsWith both dose-prediction methods the initial settings of the template could be personalized. Hereby, the average dose to the rectal wall was reduced compared to the standard template method.

Online adaptive radiotherapy potentially reduces toxicity for high-risk prostate cancer treatment

Background and purposeWith daily, MR-guided online adapted radiotherapy (MRgART) it may be possible to reduce the PTV in pelvic RT. This study investigated the potential reduction in normal tissue complication probability (NTCP) of MRgART compared to standard radiotherapy for high-risk prostate cancer. Materials and methodsTwenty patients treated with 78 Gy to the prostate and 56 Gy to elective pelvic lymph nodes were included. VMAT plans were generated with standard clinical PTV margins. Additionally to the planning MR, patients had three MRI scans during treatment to simulate an MRgART. A reference plan with PTV margins determined for MRgART was created per patient and adapted to each of the following MRs. Adapted plans were warped to the planning MR for dose accumulation. The standard plan was rigidly registered to each adaptation MR before it was warped to the planning MR for dose accumulation. Dosimetric impact was compared by DVH analysis and potential clinical effects were assessed by NTCP modeling. ResultsMRgART yielded statistically significant lower doses for the bladder wall, rectum and peritoneal cavity, compared to the standard RT, which translated into reduced median risks of urine incontinence (ΔNTCP 2.8%), urine voiding pain (ΔNTCP 2.8%) and acute gastrointestinal toxicity (ΔNTCP 17.4%). Mean population accumulated doses were as good or better for all investigated OAR when planned for MRgART as standard RT. ConclusionOnline adapted radiotherapy may reduce the dose to organs at risk in high-risk prostate cancer patients, due to reduced PTV margins. This potentially translates to significant reductions in the risks of acute and late adverse effects.

Conventional vs. Hypofractionation Radiation for High-Risk Prostate Cancer Patients (CHIRP): 24 Months Patient-Reported Quality of Life Outcomes of the Randomized Phase II CHIRP Trial

<h3>Purpose/Objective(s)</h3> The CHIRP study is a randomized phase II clinical trial that compared clinical outcomes between standard fractionation (78Gy in 39 fractions) and hypofractionation (68Gy in 25 fractions) in the treatment of high-risk prostate cancer. We performed a quality of life (QoL) sub-study to assess patient-reported outcomes up to 24 months post therapy. <h3>Materials/Methods</h3> Men with high-risk prostate cancer (stage T3/T4 and/or PSA ≥20 ng/ml and/or Gleason score 8 to 10) without clinical or radiological evidence of nodal or distant metastases were included in the CHIRP trial. QoL data was collected through the Expanded Prostate Cancer Index Composite (EPIC) and the Short Form 12 (SF12) health-related QoL questionnaire at baseline, 3 months, 6 months, 12 months, 18 months and 24 months post treatment. We assessed change from baseline (follow-up score minus bassline score) to account for differences in baseline comorbidities. Analysis of Variance (ANOVA), using a significance level of 0.05, was used to identify differences between the two groups. <h3>Results</h3> A total of 96 participants were included in the QoL sub-study, with 49 patients in the hypofractionation arm and 47 patients in the standard fractionation arm. Baseline urinary function favored patients in the standard arm (<i>P</i> = 0.04). All other baseline QoL parameters were balanced. At 3 months (<i>P</i> = 0.155), 6 months (<i>P</i> = 0.197), 12 months (<i>P</i> = 0.016) and 18 months (<i>P</i> = 0.120) post treatment, the bowel bother scores trended to favor the standard fractionation arm, and was statistically significant at 12 months (<i>P</i> = 0.016). At 6 months (<i>P</i> = 0.187), 12 months (<i>P</i> = 0.063) and 18 months (<i>P</i> = 0.017) post treatment, the SF12 physical component score (PCS) trended to favor the hypofractionation arm, and was statistically significant at 18 months (<i>P</i> = 0.017). At 24 months, there were no differences in QoL scores between the 2 groups. <h3>Conclusion</h3> The patient-reported QoL scores were similar between the standard fractionation arm (78Gy in 39 fractions) and the hypofractionation arm (68Gy in 25 fractions) up to 24 months after radiotherapy. Early statistically significant differences in bowel bother and physical component score were no longer present at 24 months.

The Dual Effect of the HDAC Inhibitor Romidepsin on Androgen Receptor Signaling and DNA Damage Repair in Prostate Cancer.

Aberrant epigenetic modifications play an important role in prostate cancer development and progression. Histone deacetylase inhibitors (HDACi) are a novel class of small-molecular compounds that have been shown to have activity in several tumor types. Some HDACi's induce a stress response that affects DNA damage repair (radiosensitization) and androgen receptor (AR) signaling (increased sensitivity to androgen blockage). We hypothesized that the HDACi, romidepsin, would increase prostate cancer cell killing through dual effects on AR signaling and radiation DNA damage response.The prostate cancer cell lines LNCaP (androgen sensitive) and 22Rv1 (androgen insensitive) were treated with romidepsin (10 nM) plus or minus 2 Gy radiation. The added effect of enzalutamide (10 mM) was also tested. Cell viability was performed by Real-time Cell assay (RTCA), whole-transcriptome analysis by RNA sequencing, western blot analyses, immunofluorescent quantification of γ-H2AX double strand break foci, and colonogenic survival. Western blot analysis was used to measure the expression of (i) AR signaling pathway proteins that included wild-type AR and its AR-V7 splice variant and (ii) DNA repair genes that included Rad51, DNA-PK and γ-H2AX.Romidepsin reduced cell viability by RTCA of both cell lines in a dose dependent manner. The addition of enzalutamide further reduced cell viability and clonogenic survival. Gene ontology analysis from RNA-Seq data in both LNCaP and 22Rv1 cells revealed that romidepsin suppressed pathways related to prostate cancer aggressiveness including the AR, MYC, DNA damage response, and cell cycle progression pathways. By western blot analysis, romidepsin suppressed AR (LNCaP) and AR-V7 (22Rv1) expression and reduced DNA repair genes including RAD51, DNA-PK and phospho-ATM levels. After 2 Gy radiation, we found that treatment with 10nM romidepsin for 24 hours resulted in an increase in γ-H2AX foci in 35.2% in LNCaP and 27% in 22Rv1 cells respectively. By colonogenic assay, 10 nM romidepsin for 24 hours prior to 2 Gy to 8 Gy radiation resulted in a significant reduction in the surviving fractions. The addition of enzalutamide resulted in the greatest reduction in colonogenic survival.Our study demonstrated for the first time that HDACi romidepsin exerted dual effects on AR signaling and DNA damage response genes in androgen sensitive and insensitive prostate cancer cell lines, and that there is an added suppressive effect with the addition of enzalutamide to HDAC inhibition plus radiation. The use of HDACi's have promise clinically for the treatment of high-risk prostate cancer, for which androgen deprivation plus radiotherapy are the standard treatments.