Biochemical Disease-free Survival Research Articles

A Systematic Review and Meta-Analysis of the Cancer.

Prostate cancer is the second- leading cause of cancer death among men. We aimed to evaluate high-intensity focused ultrasound (HIFU), open radical prostatectomy (ORP), robot-assisted radical prostatectomy (RARP), and external beam radiation therapy (RT) in the treatment of localized low- and intermediate-risk prostate cancer. We searched bibliographic databases for case-control, cohort, and randomized controlled studies. We used MeSH subject headings and free text terms for prostate cancer, HIFU, ORP, RARP, RT, failure-free survival (FFS), biochemical disease-free survival (BDFS), urinary incontinence (UI), and erectile dysfunction (ED). Fourteen studies were included in the review, for a total of 34 927 participants. Among the 8 studies of HIFU as the primary treatment of localized low- and intermediate- risk prostate cancer, 4 studies reported 5-year FFS rates ranging from 67.8% to 97.8%, 3 studies reported 5-year BDFS ranging from 58% to 85.4%, 5 studies reported 1-year UI rates ranging from 0% to 6%, and 4 studies reported 1-year ED rates ranging from 11.4% to 38.7%. Furthermore, our search revealed a 5-year FFS benefit favoring ORP compared to RT, a 1-year UI rate favoring ORP compared to RARP, and a 1-year ED rate favoring ORP compared to RARP. Our systematic review and meta-analysis revealed lack of studies with active comparators comparing HIFU to standard of care (ORP, RARP, or RT) in primary treatment of localized low- and intermediate-risk prostate cancer. Open radical prostatectomy has favorable efficacy outcomes compared to RT, while RARP has beneficial functional outcomes compared to ORP, respectively.

Ultra-High Prostate-Specific Antigen Level: A Potential Very-High-Risk Factor for Localized High-Risk Prostate Cancer

To examine the impact of ultra-high iPSA levels of >50 ng/mL (uhPSA) after modern radiotherapy, we compared outcomes of 214 patients with uhPSA levels to 1161 other high-risk patients. Radiotherapy included brachytherapy ± external beam radiotherapy (EBRT) and EBRT alone (intensity-modulated radiotherapy or stereotactic body radiotherapy). The biochemical disease-free survival rate (bDFS), the distant metastasis-free survival rate (DMFS), local control, and pelvic lymph node control were analyzed. Patients with uhPSA levels had an inferior bDFS (84.8% at 5 years) and DMFS (93.9% at 5 years) compared to other high-risk patients (92.7% and 97.2%, both p < 0.001). The uhPSA group showed more distant metastases than the non-uhPSA group; however, the frequencies of local failure and pelvic lymph node recurrence were similar. The uhPSA group demonstrated hazard ratios (HRs) of 2.74 for bDFS and 2.71 for DMFS, similar to those of T3b–4 (HR 2.805 and 2.678 for bDFS and DMFS) and GS 9–10 (HR 2.280 and 2.743 for bDFS and DMFS). An uhPSA level could be a candidate for a single VHR factor to identify high-risk patients who require intensified treatment.

Stereotactic body radiotherapy with CyberKnife® System for low- and intermediate-risk prostate cancer: clinical outcomes and toxicities of CyPro Trial.

Stereotactic body radiotherapy (SBRT) of 35-36.25 Gy in five fractions with the CyberKnife System yields excellent control with low toxicity in low-intermediate-risk prostate cancer patients. We found no differences in biochemical control and overall survival in relation to dose. There were no significant differences in toxicity or quality of life between the two groups. Stereotactic body radiotherapy (SBRT) is an emerging therapeutic approach for low- and intermediate-risk prostate cancer. We present retrospective data on biochemical control, toxicity, and quality of life of CyPro Trial. A total of 122 patients with low- and intermediate-risk prostate cancer were treated with the CyberKnife System at a dose of 35 Gy or 36.25 Gy in five fractions. Biochemical failure (BF)/biochemical disease-free survival (bDFS) was defined using the Phoenix method (nadir + 2 ng/ml). Acute/late rectal and urinary toxicities were assessed by the Radiation Therapy Oncology Group (RTOG) toxicity scale. Quality of life (QoL) was assessed by the European Organisation for Research and Treatment of Cancer (EORTC) QLQ C30 and PR25. International Erectile Function Index-5 (IIEF5) and International Prostate Symptom Score (IPSS) questionnaires were administered at baseline, every 3 months after treatment during the first years, and then at 24 months and 36 months. The 1-, 2-, and 5-year DFS rates were 92.9%, 92.9%, and 92.3%, respectively, while the 1-, 2-, and 5-year bDFS rates were 100%, 100%, and 95.7%, respectively. With regard to risk groups or doses, no statistically significant differences were found in terms of DFS or bDFS. Grade 2 urinary toxicity was acute in 10% and delayed in 2% of patients. No Grade 3 acute and late urinary toxicity was observed. Grade 2 rectal toxicity was acute in 8% and late in 1% of patients. No Grade 3-4 acute and late rectal toxicity was observed. Grade 2 acute toxicity appeared higher in the high-dose group (20% in the 36.25-Gy group versus 3% in the 35-Gy group) but was not statistically significant. Our study confirms that SBRT of 35-36.25 Gy in five fractions with the CyberKnife System produces excellent control with low toxicity in patients with low-intermediate-risk prostate cancer. We found no dose-related differences in biochemical control and overall survival. Further confirmation of these results is awaited through the prospective phase of this study, which is still ongoing.

Dosimetric Parameters Predictive of Treatment-Related Toxicity in High Dose-Rate Brachytherapy as Monotherapy for Prostate Cancer.

High dose-rate (HDR) brachytherapy as monotherapy is an effective treatment for patients with low- and intermediate-risk prostate cancer and is increasingly being offered as a 2-fraction protocol. There is a lack of consensus on the optimal dosimetric planning parameters to use, or whether there is any benefit summating dosimetric parameters from more than one implant. Our goal is to determine planning parameters associated with disease control, toxicity and health-related quality of life (HRQOL). Data were collected on 83 patients with low- and intermediate-risk prostate cancer who received 2 fractions of 13.5 Gy HDR brachytherapy without androgen-deprivation therapy as part of a randomized phase II clinical trial. An in-house deformable, registration algorithm was used to co-register and dose-summate the plans from both implants for each patient. Acute and late GU and GI toxicities were measured using CTCAE 4.0 and HRQOL was measured in urinary, bowel, sexual and hormonal domains using the EPIC scores. Treatment efficacy was assessed through PSA measurement and imaging with or without biopsy where indicated. Covariates included baseline clinical factors, disease characteristics and treatment dosimetric parameters. Cox proportional hazards was performed to evaluate covariates impact on treatment toxicity and efficacy, and logistic regression analysis evaluated covariates impact on HRQOL. Among the 83 patients, median prostate volume was 46.7cm3. Median summated planning target volume receiving 100% prescription dose (PTV V100%) was 97.4%, median PTV V150% 42.4% and median PTV V200% 15.5%. Median highest dose to the 1cm3 rectum (D1cc) was 66.9% of the prescription dose and median rectum V80% was 0.008cm3. Median urethral D1cc was 99.0% of the prescription dose, median urethral Dmax 121.7% and median urethral D10% 116.2%. Grade ≥2 GI toxicity was uncommon (3.7% acute and 8.5% late), but grade ≥2 GU toxicity was reported in 73.2% (acute) and 46.3% (late) patients. Rectum D1cc and V80% were found to be significantly associated with grade 2 or higher acute GI toxicity, while use of a-blocker at baseline was associated with grade ≥2 acute GU toxicity. Similarly, use of a-blocker was associated with late grade ≥2 GU toxicity, but with no dosimetric associations. No other variables were associated with treatment-related toxicities. Only rectum D1cc was significantly associated with changes in bowel EPIC scores. Estimated 5-year biochemical disease-free survival was 93.9% and 5-year cumulative incidence of local failure was 3.8%. HDR monotherapy with 27 Gy delivered in 2 fractions in treatment of prostate cancer is well tolerated with high rates of disease control and minimal toxicity. Dose summation between 2 fractions of HDR brachytherapy is feasible, with rectal dose predicting acute GI toxicity. The lack of association between dose metrics and urinary toxicity raises the potential for further dose escalation.

F18-DCFPyL PSMA-PET/CT vs. mpMRI for Localizing the Gross Target Volume for Radiotherapy in Prostate Cancer

Local recurrences in prostate cancer (Pca) after radiotherapy generally occur in the site of dominant tumor burden, and recent evidence based on multi parametric (mpMRI) supports tumor-targeted escalation of dose to improve biochemical disease-free survival outcomes. With the recent emergence of prostate cancer targeted radiotracers, we hypothesize that PSMA-PET and mpMRI may not equally depict the pathological gross target volume (pGTV) at risk of recurrence after radiotherapy. Subjects who underwent both mpMRI and 18F DCFPyl PSMA-PET/CT prior to radiotherapy were identified from a prospective REB-approved registry. Patients who were naive to radiotherapy and patients with local recurrences were evaluated. Each patient underwent standard of care systematic biopsies prior to imaging and treatment. Sextants from prostate biopsy were analyzed on an independent basis. Per previous published work, pGTV at risk of recurrence was defined as the pathological dominant lesions with peak PCL (percentage core length) involvement and any sextants with ≽ 40% PCL involvement. Each imaging method was analyzed independently to determine spatial correspondence of the visible tumor to pGTV at risk of recurrence. Lesions scored 4-5 (PIRADSv2.1) were identified on mpMRI. For PSMA-PET, regions with uptake higher than the adjacent background with scaling SUVmin-max 0-10 were identified. Forty-seven patients with histopathological proven intermediate to high-risk Pca represented the study cohort. Of the 320 sextants, 135 were involved with PCa. Thirty-six percent (17∕47) of patients had a history of prior radiotherapy. PSMA-PET identified the pGTV in 89% (42∕47) of patients, while mpMRI yielded a higher detection rate at 98% (46∕47) (89% vs 98% p = 0.038). The only pGTV not detected on mpMRI was also missed by PSMA-PET, and had received EBRT in 2011. Of the four other pGTVs at risk of recurrence missed by PSMA-PET, three had no history of prior radiotherapy and one was treated with brachytherapy in 2005. Overall, we found no differences in imaging detection rates between previously treated and untreated patients. More detailed volumetric analyses are ongoing and will be presented. mpMRI may provide superior detection of the pGTV at risk of recurrence in comparison to PSMA-PET. Until further research is completed, clinicians should exercise caution in omitting mpMRI and utilizing PSMA-PET as the sole imaging method for GTV targeting.

5-Years Analysis of Effectivity and Toxicity of Ultra-Hypofractionated Proton Radiotherapy in the Treatment of Low- and Intermediate-Risk Prostate Cancer-A Retrospective Analysis.

We retrospectively analyzed the 5-year biochemical disease-free survival (bDFS) and occurrence of late toxicity in prostate cancer patients treated with pencil beam scanning (PBS) proton radiotherapy. In the period from January 2013 to June 2018, 853 patients with prostate cancer were treated with an ultra-hypofractionated schedule (36.25 GyE/five fractions). The mean PSA value was 6.7 (0.7-19.7) µg/L. There were 318 (37.3%), 314 (36.8%), and 221 (25.9%) patients at low (LR), favorable intermediate (F-IR), and unfavorable intermediate risk (U-IR), respectively. Neoadjuvant hormonal therapy was administered to 197 (23.1%) patients, and 7 (0.8%) patients had adjuvant hormonal therapy. The whole group of patients reached median follow-up time at 62.7 months, and their mean age was 64.8 (40.0-85.7) years. The bDFS rates and late toxicity profile were evaluated. Median treatment time was 10 (7-38) days. Estimated 5-year bDFS rates were 96.5%, 93.7%, and 91.2% for low-, favorable intermediate-, and unfavorable intermediate-risk groups, respectively. Cumulative late toxicity (CTCAE v4.0) of G2+ was as follows: gastrointestinal (GI)-G2: 9.1%; G3: 0.5%; genitourinary (GU)-G2: 4.3%, and no G3 toxicity was observed. PSA relapse was observed in 58 (6.8%) patients: 16 local, 22 lymph node, 4 bone recurrences, and 10 combined sites of relapse were detected. Throughout the follow-up period, 40 patients (4.7%) died, though none due to prostate cancer. Ultra-hypofractionated proton beam radiotherapy is an effective treatment for low- and favorable intermediate-risk prostate cancer, with long-term bDFS rates comparable to other techniques. It is promising for unfavorable intermediate-risk prostate cancer and has acceptable long-term GI and favorable GU toxicity.

Interim Toxicity Analysis From the Randomized HERMES Trial of 2- and 5-Fraction Magnetic Resonance Imaging–Guided Adaptive Prostate Radiation Therapy

Ultrahypofractionated radiation therapy (UHRT) is an effective treatment for localized prostate cancer with an acceptable toxicity profile; boosting the visible intraprostatic tumor has been shown to improve biochemical disease-free survival with no significant effect on genitourinary (GU) and gastrointestinal (GI) toxicity. HERMES is a single-center noncomparative randomized phase 2 trial in men with intermediate or lower high risk prostate cancer. Patients were allocated (1:1) to 36.25 Gy in 5 fractions over 2 weeks or 24 Gy in 2 fractions over 8 days with an integrated boost to the magnetic resonance imaging (MRI) visible tumor of 27 Gy in 2 fractions. A minimization algorithm with a random element with risk group as a balancing factor was used for participant randomization. Treatment was delivered on the Unity MR-Linac (Elekta AB) with daily online adaption. The primary endpoint was acute GU Common Terminology Criteria for Adverse Events version 5.0 toxicity with the aim of excluding a doubling of the rate of acute grade 2+ GU toxicity seen in PACE. Analysis was by treatment received and included all participants who received at least 1 fraction of study treatment. This interim analysis was prespecified (stage 1 of a 2-stage Simon design) for when 10 participants in each treatment group had completed the acute toxicity monitoring period (12 weeks after radiation therapy). Acute grade 2 GU toxicity was reported in 1 (10%) patient in the 5-fraction group and 2 (20%) patients in the 2-fraction group. No grade 3+ GU toxicities were reported. At this interim analysis, the rate of GU toxicity in the 2-fraction and 5-fraction treatment groups was found to be below the prespecified threshold (5/10 grade 2+) and continuation of the study to complete recruitment of 23 participants per group was recommended.

A Canadian center's experience on whole-gland salvage therapy for radio-recurrent prostate cancer with various modalities.

Salvage radical prostatectomy for localized radio-recurrent prostate cancer has historically been associated with significant morbidity. Prospectively collected data long-term data on salvage whole-gland cryoablation and, to a lesser extent, high-intensity focused ultrasound (HIFU), have shown they are viable treatment alternatives. This article chronicles the experience (cryoablation, n=187; HIFU, n=81) in a high-volume Canadian center and reviews the literature on other salvage ablative therapies. Whole-gland salvage ablation has yielded oncologic results comparable to those of salvage prostatectomy, with cancer-specific survival and metastatic-free survival of approximately 80%, and biochemical disease-free survival of 35%. Freedom from androgen deprivation therapy was 49% at 12 years. Improved ablative technologies and functional diagnostic imaging modalities have rendered focal salvage ablation feasible in selected patients. Preliminary oncologic and functional results of focal salvage ablation using several new ablative technologies are also reviewed in this article.

The significance of metabolic response to neoadjuvant androgen deprivation therapy detected with [68Ga]Ga-PSMA-11-PET/CT in high-risk prostate cancer patients treated with definitive radiotherapy.

We examined the prognostic significance of early changes in primary tumor SUV measured with Gallium-68-labeled prostate-specific membrane antigen positron emission tomography ([68Ga]Ga-PSMA-11-PET/CT) and serum PSA values after neoadjuvant androgen deprivation treatment (nADT) in high-risk prostate cancer (PCa) patients treated with definitive radiotherapy (RT). The clinical data and SUV parameters of 71 PCa patients were reviewed retrospectively. The serum PSA and primary tumor SUV values were calculated before and after the start of ADT. Using univariable and multivariable analyses, the prognostic factors predicting biochemical disease free survival (bDFS) and prostate cancer specific survival (PCSS) were investigated. In addition, logistic regression analysis was used to identify predictors of biochemical failure (BF). All but one patient responded with a 98.8% reduction in serum PSA (21.8ng/mL vs. 0.3ng/mL; p < 0.001), and 64 patients (91.1%) had a median 66.6% decrease in primary tumor SUV after ADT (13.2 vs. 4.8, p < 0.001). The primary tumor SUV response rate was significantly higher in patients with Gleason score (GS) of 7 than in patients with GS > 7 (59.5% vs. 40.5%; p = 0.04), and it was significantly lower in patients with inadequate treatment response than in those with complete (CR) or partial response (PR) (1.1% vs. 66.1%; p < 0.001). There was a strong and significant correlation (Spearman = 0.41, p < 0.001) and a high concordance (91.5%) between PSA response and SUV response after ADT. With a median follow-up time of 76.1months, the 5-year bDFS and PCSS rates were 77.2% and 92.2%, respectively. Nineteen patients (26.7%) patients had recurrence at a median of 44.6months after the completion of RT. In multivariate analysis, lymph node metastasis, GS greater than 7, and SD/PD after nADT were independent predictors of worse bDFS. However, no significant factor for PCSS was identified. In the multivariable logistic regression analysis, advanced age, GS of  > 7 disease, lymph node metastasis, and SD or PD after nADT were independent predictors of BF. These results imply that the metabolic response measured with [68Ga]Ga-PSMA-11-PET/CT after nADT could be used to predict progression in high-risk PCa patients treated with definitive RT.

Using 18F-DCFPyL Prostate-Specific Membrane Antigen–Directed Positron Emission Tomography/Magnetic Resonance Imaging to Define Intraprostatic Boosts for Prostate Stereotactic Body Radiation Therapy

The recently reported FLAME trial demonstrated a biochemical disease-free survival benefit to using a focal intraprostatic boost to multiparametric magnetic resonance imaging (mpMRI)-identified lesions in men with localized prostate cancer treated with definitive radiation therapy. Prostate-specific membrane antigen (PSMA)-directed positron emission tomography (PET) may identify additional areas of disease. In this work, we investigated using both PSMA PET and mpMRI in planning focal intraprostatic boosts using stereotactic body radiation therapy (SBRT). We evaluated a cohort of patients (n=13) with localized prostate cancer who were imaged with 2-(3-(1-carboxy-5-[(6-[18F]fluoro-pyridine-2-carbonyl)-amino]-pentyl)-ureido)-pentanedioic acid (18F-DCFPyL) PET/MRI on a prospective imaging trial before undergoing definitive therapy. The number of lesions concordant (overlapping) and discordant (no overlap) on PET and MRI was assessed. Overlap between concordant lesions was evaluated using the Dice and Jaccard similarity coefficients. Prostate SBRT plans were created fusing the PET/MRI imaging to computed tomography scans acquired the same day. Plans were created using only MRI-identified lesions, only PET-identified lesions, and the combined PET/MRI lesions. Coverage of the intraprostatic lesions and doses to the rectum and urethra were assessed for each of these plans. The majority of lesions (21/39, 53.8%) were discordant between MRI and PET, with more lesions seen by PET alone (12) than MRI alone (9). Of lesions that were concordant between PET and MRI, there were still areas that did not overlap between scans (average Dice coefficient, 0.34). Prostate SBRT planning using all lesions to define a focal intraprostatic boost provided the best coverage of all lesions without compromising constraints on the rectum and urethra. Using both mpMRI and PSMA-directed PET may better identify all areas of gross disease within the prostate. Using both imaging modalities could improve the planning of focal intraprostatic boosts.

Focal Cryoablation of the Prostate: Primary Treatment in 163 Patients With Localized Prostate Cancer.

Objective Whole gland treatment of the prostate has known efficacy in treating many grades of prostate cancer. However, it is often associated with increased morbidity, including erectile dysfunction and urinary incontinence. Focal ablative therapies, including focal cryoablation (FC), are utilized to minimize the risk of tumor progression and preserve erectile and urinary function. There is little to no consensus on whether intermediate or high-risk prostate cancer should be treated with focal therapy. However, there is a growing body of literature on the effectiveness of FC as an effective means of prostate cancer control. We characterize our experience with 163 patients who underwent FC with a median follow-up of 39 months (IQR: 24-60). Methods A 163-patient retrospective cohort underwent FC of the prostate at a single clinic by a physician from November 2008 to December 2020. Each of these T1c patients in this single-tail study was monitored for biochemical recurrence (BCR) and oncologic outcomes. American Society for Radiation Oncology (ASTRO) definition of BCR is three consecutive prostate-specific antigens (PSA) increases of more than 0.5 ng/mL or, along with the utilization of the Phoenix definition, a PSA greater than nadir by 2 ng/mL was used to define BCR. This study's primary endpoint includes BCR or biochemical disease-free survival rates. Secondary endpoints include patient side effects, such as measuring for urinary incontinence and outcomes of salvage treatments. Cox proportional hazard analyses defined univariate HRs and 95% CIs for pre-operative PSA (POPSA), Decipher, and Gleason Grade Groups (GGGs) to determine the prognostic impact of pathologic factors. Statistical analysis and BCR timeline analysis also included logistic regression and the Kaplan-Meier method, with significance considered at p < 0.05. Select focal cryotherapy patients were monitored utilizing genomic sequencing tests. Results Our cohort included 27 patients (16.5%) with D'Amico low, 115 patients (70.5%) with intermediate, and 23 patients (14.1%) with high-risk prostate cancers. One month after FC, a 73% reduction in PSA resulted in a median post-operative PSA of 1.39 ng/mL (IQR: 0.46-2.80 ng/mL). At five years, our cohort yielded biochemical disease-free recurrence rates of 78%, 74%, and 55% for low, intermediate, and high-grade cancers, respectively. Genetic risk stratification results showed very similar BCR rates to patients whose tissues did not undergo genomic testing, at 27%, 26%, and 46% for low, intermediate, and high-grade cancers, respectively. Log-rank tests to map for BCR and HRs for pathologic factors did not yield any statistically significant predictive results. Urinary incontinence and erectile dysfunction were reported in 1.8% and 3.1% of patients in the focal cohort. Conclusions Our results add to the expanding body of literature around the efficacy of focal ablative therapies in contrast to whole gland treatment. The definitive extent of FC's efficacy still remains to be explored, but our conclusions demonstrate favorable PSA kinetics at five years follow-up.

Feasibility of MRI targeted single fraction HDR brachytherapy for localized prostate carcinoma: ProFocAL-study

PurposeA potential method for focal therapy in locally advanced prostate cancer is focal brachytherapy (F-BT). The purpose of this research was to evaluate midterm F-BT oncologic, functional, and toxicological results in men who had therapy for prostate cancer.Materials and methodsBetween 2016 and 2020, F-BT was used to treat 37 patients with low- to intermediate-risk prostate cancer. The recommended dosage was 20 Gy. Failure was defined as the existence of any prostate cancer that has persisted in-field after treatment. The F-BT oncologic and functional outcomes served as the main and secondary objectives, respectively.ResultsA median 20-month follow-up (range 14–48 months). 37 patients received F-BT and enrolled in the study; no patient experienced a biochemical recurrence in the first 24 months, according to Phoenix criteria. In the control biopsies, only 6 patients showed in-field failure. The median initial IPSS was 6.5, at 6 months was 6.0, and at 24 months was 5.0. When the median ICIQ-SF score was 0 at the baseline, it remained 0 at 6-, 12-, and 24 months. Overall survival and biochemical disease-free survival after 3 years were all at 100% and 86.4%, respectively. There was no notable acute gastro-intestinal (GI) or genitourinary (GU) adverse effects. No intraoperative or perioperative complications occurred.ConclusionsFor selected patients with low- or intermediate-risk localized prostate cancer, F-BT is a safe and effective therapy.

Friday, June 17, 20229:00 AM - 10:00 AM PP01  Presentation Time: 9:00 AM: Propensity-Matched Analysis of High-Dose-Rate Brachytherapy in Intermediate Risk Prostate Cancer: Monotherapy or Boost?

<h3>Purpose</h3> High-Dose-Rate Brachytherapy (HDR BT) either as monotherapy or boost has excellent reported prostate cancer control outcomes. Monotherapy is more commonly used for those with favorable risk features, while HDR tends to be combined with external beam radiotherapy (EBRT) for those with higher risk disease. Patients with intermediate risk prostate cancer (IR-PCa) can be managed either with monotherapy or boost. In the absence of randomized data, our objective is to compare biochemical response and oncological outcomes for patients with intermediate risk prostate cancer treated with either HDR as monotherapy or as a boost in combination with EBRT. <h3>Materials and Methods</h3> A propensity score matching analysis was performed of IR-PCa patients treated with either HDR monotherapy (27 Gy in 2 fractions), or HDR boost (15 Gy followed by EBRT; 37.5 Gy in 15 fractions delivered with Intensity modulated radiotherapy). The former patients were included in a prospective clinical trial whereas the latter were selected from a retrospective institutional database. Matching was based on age, baseline PSA, T stage, grade group, perineural invasion, and percentage of positive cores. No patient received androgen deprivation therapy. The primary outcome was biochemical disease-free survival (bDFS) defined as time from treatment to PSA nadir +2 or death. Secondary outcomes included PSA nadir and incidence of grade (G) ≥3 genitourinary (GU) and gastrointestinal (GI) toxicities measured using CTCAE v.4. A General Linear Mixed Model and Analysis of Covariance was used to investigate changes in PSA over time. <h3>Results</h3> A total of 132 patients were matched, 66 in each cohort with a median age of 66 years (range: 48-80). Median follow up was 59 months (interquartile range (IQR) 54, 62) for the HDR monotherapy cohort and 63 months (IQR 42, 81) for the boost BT group. They were well matched with a Propensity Score of 0.4615 and 0.4612, respectively. Thirty-eight percent of patients had unfavorable intermediate risk disease. Patients treated with monotherapy had slightly higher PSA in the first 4 years, Figure 1 (p=0.034), although by 5-years median PSA was 0.14 ng/ml (IQR 0.06, 0.34) with monotherapy and 0.15 ng/ml (IQR 0.07, 0.51) with boost. At 4 years, 24 (36%) monotherapy patients and 26 (44%) boost patients had PSA <0.2 ng/ml. Among all patients, 7% (10 of 132) experienced biochemical failure: six patients in the HDR monotherapy group and four in the boost group, resulting in 5-year bDFS of 93.5% and 93.3%, respectively. Favorable and Unfavorable IR-PCa had similar risk of recurrence. Late G3 GU toxicity occurred in 2 out of 66 boost patients and was not seen in the monotherapy patients. <h3>Conclusions</h3> Although limited by small sample size, we report high efficacy of HDR brachytherapy as either monotherapy or boost for all patients with intermediate risk disease. Boost patients had a lower PSA value in the first 4 years, although with a suggestion of greater G3 urinary toxicity.

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.

Correlation between Obesity and Treatment Failure Following Stereotactic Body Radiation Therapy (SBRT) for Clinically Localized Prostate Cancer

<h3>Purpose/Objective(s)</h3> Cancer control outcomes are significantly worse in obese prostate cancer patients. Over the past decade, stereotactic body radiation therapy (SBRT) has been established as a safe and effective treatment for localized prostate cancer. Accurate delivery of external beam radiation could be adversely affected by increased pelvic adipose tissue and result in worse biochemical control. Data reporting on the efficacy of SBRT stratified by BMI is limited. This single-institution study sought to evaluate oncologic outcomes following SBRT for prostate cancer in men based on BMI. <h3>Materials/Methods</h3> A retrospective chart review was performed on all patients with localized prostate cancer treated with SBRT at a single institution between 2006 to 2021. Treatment was delivered using robotic SBRT with doses of 35-36.25 Gy in 5 fractions, per institutional protocol. Biochemical recurrence was defined by the Phoenix definition (PSA rise ≥ 2 ng/mL above nadir). Multiple regression Cox proportional hazard analysis was performed. <h3>Results</h3> 1306 patients were identified, with a mean follow-up of 47 months. The patients were elderly (Median age = 70 years) and overweight (Median BMI = 27.6 kg/m²). The majority were low to intermediate risk (88%) according to the D'Amico classification. Median pre-treatment PSA was 7.4 ng/mL. 23.7% received neoadjuvant ADT. BMI (kg/m²) was calculated prior to initiation of treatment and patients were stratified as thus: BMI < 25, 25 – 29.9, 30 – 34.9, ≥ 35. There was no statistically significant difference between pre-treatment PSA or Gleason's score between BMI groups. A multiple regression Cox proportional hazard analysis was performed, with BMI < 25 set as the reference. There was no statistically significant difference in biochemical disease-free survival, distant metastasis-free survival, or disease-specific survival between BMI subgroups. <h3>Conclusion</h3> In the general population, cancer control following prostate SBRT is equivalent to other standard radiation options. In this analysis, increased BMI did not portend worse oncologic outcomes following SBRT when analyzing bDFS, DMFS, or DSS. Thus, in the opinion of the authors, obesity should not be considered a contraindication to prostate SBRT.

Prognostic Utility of Biopsy-Based PTEN and ERG Status on Biochemical Progression and Overall Survival after SBRT for Localized Prostate Cancer

<h3>Purpose/Objective(s)</h3> PTEN deletions and ERG rearrangements are two of the most common genetic abnormalities associated with prostate cancer. Prior studies revealed that changes in wild-type PTEN and ERG portend worse clinical outcomes. While early studies were performed on whole-gland samples after radical prostatectomy, subsequent biopsy-based analyses have led to their inclusion in several genomic assays and prostate cancer outcome scores. However, evaluations of therapeutic response to radiotherapy are quite heterogenous. Our objective is to evaluate the impact of biopsy-determined <i>PTEN</i> losses and <i>TMPRSS2-ERG</i> fusion on biochemical disease-free survival (bDFS) in patients who receive SBRT for localized prostate cancer. <h3>Materials/Methods</h3> Patients included in this analysis underwent SBRT for localized prostate cancer and are followed on an institutional prospective quality of life and survival study. For each patient, the single biopsy core with the highest volume of cancer was evaluated for PTEN and ERG abnormalities. Differences in baseline patient and disease characteristics between groups were analyzed using ANOVA for age and χ<b>²</b> for categorical groupings. bDFS and OS were calculated using the Kaplan Meier (KM) method with Log-Rank test comparison between groups. Predictors of bDFS and OS were evaluated using Cox proportional hazard method. For all analyses, <i>p</i> <0.05 was considered statistically significant. <h3>Results</h3> Ninety-three patients were included in the analysis with a median follow up of 72 months (IQR 52 - 85 months). The 5-year bDFS for all patients was 85.2% with a median bDFS of 98 months. The 5-year OS for all patients was 91.8% with a median OS of 123 months. Differences between ERG and PTEN status groups by age, race, T-stage, NCCN risk group, PSA group, PSA density group, and Charlson Comorbidity Index were not statistically significant. Differences in grade group were statistically significant (<i>p</i> = 0.0329). The estimated 5-year bDFS was 100%, 76.6%, 72.9%, and 63.8% for the ERG+/PTEN, ERG-/PTEN+, ERG+/PTEN-, and ERG-/PTEN- groups respectively (<i>p</i> =0.0107). Multivariate analysis (MVA) confirmed an increased likelihood of 5-year biochemical progression with higher NCCN risk group (<i>p</i> <0.0001) and increasing ERG/PTEN mutational burden (<i>p</i><0.0001). <h3>Conclusion</h3> <i>ERG Fusion with PTEN</i> loss is associated with an increased risk of biochemical progression. However, <i>ERG</i> status alone is not predictive of bPFS. Biopsy-based PTEN and ERG assays demonstrate utility in predicting 5-year oncologic outcomes in patients who receive prostate SBRT.

The Influence of the Pretreatment Immune State on Response to Radiation Therapy in High-Risk Prostate Cancer: A Validation Study From NRG/RTOG 0521

The immunoinflammatory state has been shown to be associated with poor outcomes after radiation therapy (RT). We conducted an a priori designed validation study using serum specimens from Radiation Therapy Oncology Group (RTOG) 0521. It was hypothesized the pretreatment inflammatory state would correlate with clinical outcomes. Patients on RTOG 0521 had serum banked for biomarker validation. This study was designed to validate previous findings showing an association between elevations in C-reactive protein (CRP) and shorter biochemical disease free survival (bDFS). CRP levels were measured in pretreatment samples. An exploratory panel of related cytokines was also measured including: monocyte chemotactic protein-1, granulocyte-macrophage colony-stimulating factor, interferon-γ, interleukin (IL)-1b, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, IL-17A, IL-23, and tumor necrosis factor. The primary endpoint examined was bDFS. Additional exploratory endpoints included overall survival, distant metastases, and toxicity events attributed to RT. Two hundred and two patients in RTOG/NRG 0521 had serum samples available. Median age was 66 years (48-83), and 90% of patients were White. There was not an association between CRP and bDFS (adjusted hazard ratio [HR], 1.07 per 1 log increase in CRP; 95% confidence interval, 0.83-1.38; P = .60). In the exploratory, unplanned analysis, pretreatment IL-10 was significantly associated with worse bDFS (adjusted HR, 1.61 per log increase; P = .0027) and distant metastases (HR, 1.55 per log increase; P = .028). The association of IL-10 with bDFS was maintained on a multiplicity adjustment. The exploratory analyses of pretreatment levels of interferon-γ, IL-1b, IL-2, IL-13, IL-23 were negatively associated with grade 2 or higher pollakiuria (adjusted odds ratio, 0.64, 0.65, 0.71, 0.72, and 0.74, respectively, all P < .05), and IL-6 was negatively associated with grade 2 or higher erectile dysfunction (odds ratio, 0.62; P = .027). Pretreatment CRP was not associated with a poorer bDFS after RT. In a hypothesis- generating analysis, higher baseline levels of IL-10 were associated with lower rates of bDFS. These findings require additional prospective evaluation.

High-dose radiotherapy and risk-adapted androgen deprivation in localised prostate cancer (DART 01/05): 10-year results of a phase 3 randomised, controlled trial

The optimal duration of androgen deprivation combined with high-dose radiotherapy in prostate cancer remains controversial. The DART 01/05 trial was designed to determine whether long-term androgen deprivation is superior to short-term androgen deprivation when combined with high-dose radiotherapy. The 5-year results showed that 2 years of adjuvant androgen deprivation combined with high-dose radiotherapy significantly improved biochemical control, metastasis, and overall survival, especially in patients with high-risk disease. In this report, we present the 10-year final results of the trial. This open-label, phase 3, randomised, controlled trial was done in ten hospitals in Spain. The eligibility criteria included patients aged 18 years or older with histologically confirmed T1c to T3, N0, and M0 adenocarcinoma of the prostate, according to the 2002 classification of the American Joint Committee on Cancer, with intermediate-risk and high-risk factors, prostate-specific antigen (PSA) less than 100 ng/mL, and a Karnofsky performance score of at least 70%. Patients were randomly assigned (1:1) to receive 4 months of neoadjuvant and concomitant short-term androgen deprivation (STAD) plus high-dose radiotherapy (minimum dose 76 Gy; median dose 78 Gy) or to receive the same treatment followed by 24 months of adjuvant long-term androgen deprivation (LTAD), via a randomisation scheduled generated by Statistical Analysis Software programme (version 9.1) and an interactive web response system. Patients assigned to the STAD group received 4 months of neoadjuvant and concomitant androgen deprivation (oral flutamide 750 mg per day or oral bicalutamide 50 mg per day) with subcutaneous goserelin (2 months before and 2 months combined with high-dose radiotherapy). Anti-androgen therapy was added during the first 2 months of treatment. Patients assigned to LTAD continued with goserelin every 3 months for another 24 months. The primary endpoint was biochemical disease-free survival at 5 years. For this 10-year study we analysed overall survival, metastasis-free survival, biochemical disease-free survival, and cause-specific survival. Analysis was by intention to treat. This trial is closed and is registered at ClinicalTrials.gov (NCT02175212) and in the EU Clinical Trials Register (EudraCT 2005-000417-36). Between Nov 7, 2005, and Dec 20, 2010, 355 patients were enrolled. One patient in the STAD group withdrew from the trial, hence 354 participants were randomly assigned to STAD (n=177) or LTAD (n=177). The median follow-up was 119·4 months (IQR 100·6-124·3). The 10-year biochemical disease-free survival for LTAD was 70·2% (95% CI 63·1-77·3) and for STAD was 62·3% (54·9-69·7; hazard ratio [HR] 0·84; 95% CI 0·50-1·43; p=0·52). At 10 years, overall survival was 78·4% (72·1-84·8) for LTAD and 73·3% (66·6-80·0) for STAD (HR 0·84; 95% CI 0·55-1·27; p=0·40), and metastasis-free survival was 76·0% (69·4-82·7) for LTAD and 70·9% (64·0-77·8) for STAD (HR 0·90; 95% CI, 0·37-2·19; p=0·81). For the subgroup of high-risk patients, the 10-year biochemical disease-free survival was 67·2% (57·2-77·2) for LTAD and 53·7% (43·3-64·1) for STAD (HR 0·90; 95% CI 0·49-1·64; p=0·73), the 10-year overall survival was 78·5% (69·6-87·3) for LTAD and 67·0% (57·3-76·7) for STAD (HR 0·58; 95% CI 0·33-1·01; p=0·054), and the 10-year metastasis-free survival was 76·6% (95% CI 67·6-85·6) for LTAD and 65·0% (55·1-74·8) for STAD (HR 0·89; 95% CI 0·33-2·43; p=0·82). Only 11 (3%) of 354 patients died from prostate cancer, all of them in the high-risk subgroup (five in the LTAD group and six in the STAD group). 76 (21%) patients died from other causes (mainly second malignancies in 31 [9%] and cardiovascular disease in 21 [6%]). No treatment-related deaths were observed. After an extended 10-year follow-up, we were unable to support the significant benefit of LTAD reported at 5 years. However, the magnitude of the benefit was clinically relevant in high-risk patients. Intermediate-risk patients treated with high-dose radiotherapy do not benefit from LTAD. A biological characterisation with the inclusion of genomic testing is needed in the decision-making process. Grupo de Investigación en Oncología Radioterápica and Sociedad Española de Oncología Radioterápica, the National Health Investigation Fund, and AstraZeneca.

Brachytherapy focal dose escalation using ultrasound based tissue characterization by patients with non-metastatic prostate cancer: Five-year results from single-center phase 2 trial

This prospective trial investigates side effects and efficacy of focal dose escalation with brachytherapy for patients with prostate cancer. In the Phase II, monocentric prospective trial 101 patients with low-/intermediate- and high-risk prostate cancer were enrolled between 2011 and 2013. Patients received either PDR-/HDR-brachytherapy alone with 86-90 Gy (EQD2, α/β = 3 Gy) or PDR-/HDR-brachytherapy as boost after external beam radiation therapy up to a total dose of 91-96 Gy (EQD2, α/β = 3 Gy). Taking place brachytherapy all patients received the simultaneous integrated focal boost to the intra-prostatic tumor lesions visible in computer-aided ultrasonography (HistoScanning™) - up to a total dose of 108-119 Gy (EQD2, α/β = 3 Gy). The primary endpoint was toxicity. Secondary endpoints were cumulative freedom from local recurrence, PSA-free survival, distant metastases-free survival, and overall survival. This trial is registered with ClinicalTrials.gov, number NCT01409876. Median follow-up was 65 months. Late toxicity was generally low with only four patients scoring urinary grade 3 toxicity (4/101, 4%). Occurrence of any grade of late rectal toxicities was very low. We did not register any grade ≥2 of late rectal toxicities. The cumulative 5 years local recurrence rate (LRR) for all patients was 1%. Five years- biochemical disease-free survival estimates according Kaplan-Meier were 98,1% and 81,3% for low-/intermediate-risk and high-risk patients, respectively. Five years metastases-free survival estimates according Kaplan-Meier were 98,0% and 83,3% for all patients, low-/intermediate-risk and high-risk patients, respectively. The 5 years-results from this Phase II Trial show that focal dose escalation with computer-aided ultrasonography and brachytherapy for patients with non-metastatic prostate cancer is safe and effective.