Neoadjuvant Androgen Deprivation Therapy Research Articles

Neoadjuvant androgen-deprivation therapy with radical prostatectomy for prostate cancer in association with age and serum testosterone.

BackgroundWe aimed to identify the candidate prostate cancer patients suitable for neoadjuvant androgen-deprivation therapy (ADT) with radical prostatectomy (RP).Materials and methodsThis study included 711 Japanese patients with clinically localized prostate cancer who were treated with RP between 2000 and 2013. Patients were treated with or without neoadjuvant ADT before RP. The prognostic significance of neoadjuvant ADT on biochemical recurrence (BCR) was analyzed according to various clinicopathological characteristics.ResultsBCR occurred in 186 (26.2%) of 711 patients. The group treated with neoadjuvant ADT showed higher levels of prostate-specific antigen at diagnosis and advanced clinical T-stage, but suppressed pathological T-stage. Neoadjuvant ADT was not associated with the risk of BCR. In subgroup analysis, neoadjuvant ADT was significantly associated with increased BCR in patients aged >65 years [hazard ratio (95% confidence interval), 2.04 (1.13–3.43), P = 0.020]. Among the 53 patients with available serum testosterone levels, neoadjuvant ADT was associated with the risk of BCR according to serum testosterone levels.ConclusionThis study demonstrated that neoadjuvant ADT showed potential deleterious effects in older patients and patients with lower serum testosterone levels, while a possible improved prognosis in patients with high serum testosterone levels treated with neoadjuvant ADT was suggested, warranting further exploration.

Impact of Therapy on Genomics and Transcriptomics in High-Risk Prostate Cancer Treated with Neoadjuvant Docetaxel and Androgen Deprivation Therapy.

Purpose: The combination of docetaxel chemotherapy and androgen deprivation therapy (ADT) has become a standard treatment for patients with metastatic prostate cancer. The recently accrued phase III CALGB 90203 trial was designed to investigate the clinical effectiveness of this treatment approach earlier in the disease. Specimens from this trial offer a unique opportunity to interrogate the acute molecular response to docetaxel and ADT and identify potential biomarkers.Experimental Design: We evaluated baseline clinical data, needle biopsies, and radical prostatectomy (RP) specimens from 52 (of 788) patients enrolled on CALGB 90203 at one high volume center. Pathology review, tumor and germline-targeted DNA sequencing (n = 72 genes), and expression profiling using NanoString platform (n = 163 genes) were performed to explore changes in critical prostate cancer pathways linked to aggression and resistance.Results: Three of 52 patients had only microfocal residual cancer at prostatectomy. The most common alterations included TMPRSS2-ERG fusion (n = 32), TP53 mutation or deletion (n = 11), PTEN deletion (n = 6), FOXA1 (n = 6), and SPOP (n = 4) mutation, with no significant enrichment in posttreated specimens. We did not observe AR amplification or mutations. The degree of AR signaling suppression varied among treated tumors and there was upregulation of both AR and AR-V7 expression as well as a subset of neuroendocrine and plasticity genes.Conclusions: These data support the feasibility of targeted and temporal genomic and transcriptome profiling of neoadjuvant-treated prostate cancer with limited formalin-fixed paraffin embedded tissue requirement. Characterization of the heterogeneity of treatment response and molecular outliers that arise posttreatment provides new insight into potential early markers of resistance. Clin Cancer Res; 23(22); 6802-11. ©2017 AACR.

Expression of PD-L1 in Hormone-naïve and Treated Prostate Cancer Patients Receiving Neoadjuvant Abiraterone Acetate plus Prednisone and Leuprolide.

Purpose: Programmed cell death ligand-1 (PD-L1)/programmed cell death-1 (PD-1) blockade has been unsuccessful in prostate cancer, with poor immunogenicity and subsequent low PD-L1 expression in prostate cancer being proposed as an explanation. However, recent studies indicate that a subset of prostate cancer may express significant levels of PD-L1. Furthermore, the androgen antagonist enzalutamide has been shown to upregulate PD-L1 expression in prostate cancer preclinical models. In this study, we evaluated the effect of neoadjuvant androgen deprivation therapy with abiraterone acetate plus prednisone and leuprolide (Neo-AAPL) on PD-L1 expression in prostate cancer.Experimental Design: Radical prostatectomy (RP) tissues were collected from 44 patients with intermediate- to high-risk prostate cancer who underwent RP after Neo-AAPL treatment. Untreated prostate cancer tissues were collected from 130 patients, including 44 matched controls for the Neo-AAPL cases. Tumor PD-L1 expression was detected by IHC using validated anti-PD-L1 antibodies. Tumor-infiltrating CD8+ cells were analyzed in trial cases and matched controls. Expression of DNA mismatch repair genes was examined in PD-L1-positive tumors.Results: Neo-AAPL-treated tumors showed a trend toward decreased PD-L1 positivity compared with matched controls (7% vs. 21% having ≥1% positive tumor cells; P = 0.062). Treated tumors also harbored significantly fewer tumor-infiltrating CD8+ cells (P = 0.029). In 130 untreated prostate cancers, African American ethnicity, elevated serum PSA, and small prostate independently predicted tumor PD-L1 positivity. Loss of MSH2 expression was observed in 1 of 21 PD-L1-positive tumors.Conclusions: A subset of prostate cancer expresses PD-L1, which is not increased by Neo-AAPL treatment, indicating that combining Neo-AAPL treatment with PD-L1/PD-1 blockade may not be synergistic. Clin Cancer Res; 23(22); 6812-22. ©2017 AACR.

Effect on prostate volume following neoadjuvant treatment with an androgen receptor inhibitor monotherapy versus castration plus an androgen receptor inhibitor in prostate cancer patients intended for curative radiation therapy: A randomised study.

To avoid pubic arch interference, prostate cancer patients are treated with neoadjuvant androgen deprivation therapy (ADT) to achieve prostate volume (PV) reduction prior to radiation treatment. The aim of the present randomised study was to compare the effects on PV of two regimens of ADT, an androgen receptor inhibitor monotherapy vs. castration plus an androgen receptor inhibitor. Consecutive patients with non-metastatic prostate cancer were included in a randomised neoadjuvant study, comparing an androgen receptor inhibitor monotherapy vs. castration plus an androgen receptor inhibitor. PV was assessed prior to the start of endocrine neoadjuvant treatment and prior to the start of radiation therapy (RT). PV assessment was performed by transrectal ultrasound. A total of 110 patients were included. Final sample constituted 88 (80%) patients due to lack of PV information. Castration plus an androgen receptor inhibitor was more effective in PV reduction compared with an androgen receptor inhibitor alone (P<0.001). Planning target volume decreased in the combination arm. There was no significant difference in clinical or demographic or length of neoadjuvant hormonal treatment between the groups. Overall, a significantly larger PV reduction was achieved by castration plus androgen receptor inhibitor, as compared with androgen receptor inhibitor monotherapy. The PV reduction, however, appeared not to translate into better health associated quality of life during the subsequently given curative intended combined EBRT and HDR-brachytherapy. Potential differences between these two treatments regarding anti-tumor effects on micro metastatic disease and radiation potentiating effect remains to be addressed in future prospective trials.

Changes in magnetic resonance imaging radiomic features in response to androgen deprivation therapy in patients with high-risk PCa

Background: Biochemical response to neoadjuvant androgen deprivation therapy (nADT) predicts recurrence-free and overall survival for prostate cancer (PCa). PSA decline during nADT may represent intrinsic androgen sensitivity with poor response indicating higher risk of progression. With nADT, PSA often becomes undetectable making true quantification of the changes difficult. We performed radiomic feature extraction on magnetic resonance imaging (MRI) before and after nADT to identify potential surrogate biomarkers associated with the tumoral response to nADT.

The Response of Male Erectile Tissues to Androgen Deprivation Therapy and Radiation

Androgen deprivation therapy (ADT) plays an important role in the treatment of men undergoing radiation therapy (RT) for high-risk prostate cancer. Erectile dysfunction (ED) is a common side effect after combined RT and ADT. Both RT and ADT may have cardiovascular effects, thus we hypothesized that penile vascular tissue contracts in response to ADT and RT, and that this change correlates with worsening ED. Penile bulb (PB) volume and corpus cavernosum (CC) width were measured retrospectively on computed tomography (CT) scans obtained pre and post-neoadjuvant ADT (but prior to RT) in a cohort of prostate cancer patients treated with prostate RT+ADT. The same measurements were also obtained from a cohort of male cancer patients treated with RT alone using two CT image sets obtained with similar chronologic spacing. PB volume was measured based on RTOG contouring guidelines. CC width was measured at the position of the anterior border of the inferior pubic ramus. To confirm these findings with a separate image modality and to allow analysis of post-RT changes, we evaluated penile tissue changes with pre-treatment, post-neoadjuvant ADT, and post-RT Magnetic Resonance Imaging (MRI) in prostate cancer patients treated with RT+ADT. Sexual Health Inventory for Men (SHIM) scores were obtained pre-treatment and at least 18 months (range 18-30 months) after discontinuing ADT. Worsening ED was defined as an escalation in SHIM severity classification or initiation of medication for ED. Two-tailed paired t-tests were used to compare differences between cohorts and time points. In the prostate cancer RT+ADT cohort (n=41), both the PB (-3.28 cm3, 95%CI: -4.097 to -2.469; p<0.0001) and the CC (-0.12 cm, 95%CI: -0.1554 to -0.0909; p<0.0001) underwent significant reductions in size in response to neoadjuvant ADT. In the cohort not exposed to ADT (n=20), there was no significant change in PB (+1.38 cm3, 95%CI: -0.9424 to 3.709; p=0.2283) and CC (+0.04 cm, 95%CI: -0.0669 to 0.1510; p=0.4298). Findings from the MRI cohort (n=25) with imaging at three time points confirmed a significant PB reduction after neoadjuvant ADT (-104.4 mm2, 95% CI -137.6 to-71.22, p<0.0001), but not after subsequent treatment with RT (-18.34 mm2. 95% CI -49.81 to 13.13, p=0.2407). In the subset of RT+ADT patients with available SHIM data at late follow up (n=17), there was a nonsignificant trend toward worsening of ED with greater reductions in the percent volume of the PB (p=0.4346) and the percent width of the CC (p=0.112) with neoadjuvant ADT. This retrospective series demonstrates a significant reduction in the volume of erectile tissue with short-term neoadjuvant ADT, and no significant change with the addition of RT. Additional work is needed to determine if these changes persist at later time points or correlate to late ED in larger cohorts.

Long-Term Outcomes of Low Dose Rate Prostate Brachytherapy at a Single Institution

To report long-term oncologic outcomes for 441 men treated with Iodine-125 or Palladium-103 low dose rate prostate brachytherapy (LDR-BT) at a single institution. A total of 441 men, median age 70 years, were treated with either Iodine-125 (37%) or Palladium-103 (63%) LDR-BT for low, intermediate or high-risk prostate cancer as stratified by D'Amico criteria, between March 1997 and July 2008. Mean prostate-specific antigen (PSA) level was 7.66 ng/ml (SD 5.1). T stage was cT1c in 54% and cT2 in 45% of patients. Gleason score was 6 in 67%, 7 in 28%, or 8-10 in 5% of patients. A 3-6 month neoadjuvant androgen deprivation therapy (ADT) course was used in 32% of patients primarily for prostate gland downsizing to <65cc. External beam radiation therapy (EBRT) to 4500 cGy in 25 fractions combined with LDR-BT was used in 43.7% (n = 191) of patients. Post-implant dosimetry was done 30 days after implantation with doses converted to the biologically effective dose (BED). Statistical analyses including Kaplan-Meier curves, Wilcoxon signed-rank and Chi square tests were performed. There was no significant difference in biochemical recurrence or prostate cancer specific survival based on initial PSA, LDR-BT isotope, EBRT, or ADT use. Median follow-up and inter-quartile (Q1-Q3) follow-up was 92 (65-130) months respectively. There were 55 failures (12% of the cohort), as defined by the ASTRO guidelines for biochemical recurrence with median time to recurrence and (Q1-Q3) of 58 (25-90) months. A total of 67 deaths occurred, with only 8 deaths from prostate cancer, at a median of 116 (72-130) months. Overall survival was 83% with prostate cancer specific survival at 98.3% overall, 99.6% for low-risk, 97.6% for intermediate-risk, and 88.9% for high-risk patients, with a median follow up of 92 (70-136) months. Kaplan-Meier analysis showed the difference of prostate cancer free survival between the risk groups to be statistically significant (p < 0.01). When D90 (the radiation dose delivered to 90% of the prostate) was less than 160% of the prescription dose, PSA control was 84%, but when D90 was > or =160%, PSA control was 92%. All failures in the cohort never experienced reduction of PSA to < 2.0 ng/ml after LDR-BT, which suggests that occult metastatic disease may have been present at the time of treatment. Iodine-125 and/or Palladium-103 LDR-BT either as monotherapy or in combination with ADT and/or EBRT is a highly effective treatment option for prostate cancer and yields excellent long-term oncologic outcomes comparable to other modalities.

5-Year Outcomes of Hypofractionated Radiation Therapy With VMAT in Prostate Cancer and Analysis of Qualiy of Life

Hypofractionated radiotherapy (HR) has been suggested might be equally or more effective with a shortened overall treatment duration for prostate cancer (PC). However, the quality of life (QoL) and late toxicity is an important issue in PC treatment decisions. Our aim was to report our clinical outcomes of patients receiving HR and investigate the toxicity and QoL. Clinical data of patients with PC were retrospectively evaluated. Patients received HR with VMAT and online image-guidance using daily CBCT. Dose was 70 Gy at 2.5 Gy/fraction. 3 target volumes were contoured: 20.3% prostate only, 17.2% prostate + seminal vesicles and 52.3 % prostate + seminal vesicles + pelvic lymph nodes. Patients filled out EORTC QLQ-C30 and PC-specific QLQ-PR25 questionnaires in two measuring points of observation. Late toxicity was assessed according to RTOG/EORTC score and International Prostate Symptom Score (IPSS) at the last consultation. The analysis included 115 PC patients (52–82 years) with 25-low-, 32 intermediate- and 58 high-risk. Median Gleason score was 7 and median PSA level of 10.25 ng/mL. Neoadjuvant androgen deprivation therapy was given to 87 patients (75.6 %) and stopped in 28 patients after 6 months; in 59 patients after 2–3 years. Median follow-up was 4.3 years (maximum: 5.5 years) The median of last PSA measurement was 0.10 ng/mL. 2 patients had PSA failure (biochemical control rate was 98.4%). No patients had local, node or metastatic relapse. Late genitourinary (GU) toxicity was observed for grades 0, 1, 2, 3 and 4 in 31.3%, 28.9%, 18%, 9.4% and 1.6%, respectively; late gastrointestinal (GI) toxicity was recorded for grades 0, 1, 2 and 3 in 75%, 5.5%, 6.3% and 0.8% patients, respectively. No grade IV late gastrointestinal toxicity was reported. IPSS score after radiotherapy was 10.5 ± 8.7 (mean ± SE). No deaths from prostate cancer but 1 due to toxicity by enterovesical fistula. Relapse-free interval was 52 months. 5-year cause-specific survival was 100% and 5-year overall survival was 90%. The questionnaires of QoL were filled out in two measuring points of observation (median 40 months after radiotherapy). Patients who received HR showed a lower degree of global health status and functional scale and increase of certain symptoms of side effects. However, emotional functioning improved and constipation decreased. The second questionnaire based on PC-specific symptoms increased, however, sexual functioning improved (questions about sexual functioning were conditional). These results are comparable to the reference date on QoL of cancer patients. HR with VMAT produces excellent rates of biochemical control for low, intermediate and high-risk PC. The long term GU and GI toxicity rates were considered low and acceptable. In addition, it is a well tolerated treatment in terms of QoL and has no negative impact on functioning and everyday life.

Long-Term Outcomes of Proton Therapy for Prostate Cancer in Japan: Retrospective Analysis of a Multi-institutional Survey

Proton therapy (PT) is spreading worldwide as a new treatment modality. Although PT provides a more focused dose distribution on the tumor compared with X-ray therapy, there remains much controversy about its routine use in prostate cancer treatment. This is the first multi-institutional retrospective survey of the long-term outcomes of PT for prostate cancer in Japan. This retrospective analysis comprises prostate cancer patients treated with PT at 7 centers between January 2008 and December 2011 and was approved by each Institutional Review Board. The NCCN classification was used. The biochemical relapse free survival (bRFS) was based on the Phoenix definition (nadir + 2.0 ng/mL). The rates of bRFS, overall survival (OS) and incidence of late gastrointestinal (GI) and genitourinary (GU) toxicities were estimated using the Kaplan-Meier methods. Toxicities were evaluated with the Common Terminology Criteria for Adverse Events version 4.0. The inclusion criteria for this analysis were as follows: (1) histologically confirmed prostate cancer, (2) no lymph node and distant metastasis, (3) Japanese men, (4) no prior radiotherapy, (5) no castration-resistant prostate cancer, (6) minimum follow-up of 6 months for surviving patients, and (7) written informed consent. The very-high risk group based on NCCN criteria was included in the high-risk group. The total number of prostate cancer patients in all institutions during this period was 1,302 and 11 patients were excluded because of above criteria. Therefore, 1,291 patients were analyzed. The number of patients in the low-risk, intermediate-risk, and high-risk groups were 215, 520, and 556, respectively. The median follow-up period of surviving patients was 69 months (range: 7-107). In total, 98.8% of patients were treated using conventional fractionation (1.8-2.0GyE) schedule (70-82 GyE/35-41 Fr) and 1.2% of patients were treated by hypofractionation schedule (63-66 GyE/ 21-22 Fr); 58.5% and 21.5 %of patients received neoadjuvant and adjuvant androgen deprivation therapy, respectively. The 5-year rates of bRFS and OS in the low-risk, intermediate-risk, and high-risk patients were 97.0%, 91.1%, 83.1% for bRFS, and 98.4%, 96.8%, 95.2% for OS, respectively. T classification, Gleason score, and NCCN classification were significant prognostic factors for bRFS in multivariate analysis. The incidence of grade 2 late GI and GU toxicities were 3.6% and 2.6%, retrospectively, but grade 3 toxicities were observed only 6 and 4 patients, respectively. This retrospective analysis of a multi-institutional survey suggested that PT is favorable and well tolerated for prostate cancer. Based on this result, multi-institutional prospective clinical trial for patients with intermediate risk group will be started to define its role in the treatment of prostate cancer in Japan.

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

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

Subcutaneous Adipose Tissue Characteristics and Risk of Biochemical Recurrence in Men with High Risk Prostate Cancer

Obesity has become a worldwide epidemic. The interaction of obesity and excess adipose tissue on cancer biology continues to be an area of interest. The purpose of this study was to assess subcutaneous adipose tissue characteristics by computed tomography (CT) as potential imaging biomarkers in patients with high risk prostate cancer receiving radiation treatment (RT). This retrospective study included 185 men with high risk prostate cancer (PSA>20 ng/mL, Gleason score ≥ 8, or clinical extraprostatic extension) treated between 2001 and 2012. All patients received definitive, dose-escalated external beam RT along with a course of neoadjuvant, concurrent, and adjuvant androgen deprivation therapy (ADT). Each patient also had a treatment planning CT that included the L4-L5 vertebral interface and prostate specific antigen (PSA) measurements for at least 1 year following RT. The subcutaneous adipose tissue was contoured on a single axial CT slice at the level of L4-L5. The average CT attenuation, in Hounsfield units (HU), of the structure was calculated and defined as SATHU. SATAREA was defined as the cross-sectional area of the structure (in cm2) that was then normalized by the square of patient height. Biochemical failure (BF) was defined as a PSA rise of 2 ng/mL from the nadir. Freedom from BF (FFBF) was calculated from start time of ADT using the Kaplan-Meier method. Estimates of FFBF were stratified by SATHU and SATAREA quartiles. Median follow-up was 5.3 years. The mean SATHU (± standard deviation) was -99.2 HU (±6.3 HU) and the mean SATAREA was 94.7 cm2/m2 (±42.3 cm2/m2). No significant differences of SATHU and SATAREA were observed among different races or age groups. The 5 and 8-year rates of FFBF across all patients were 82.1% and 74%, respectively. Patients in the lowest quartile of SATHU experienced significantly higher FFBF compared to the other quartiles (Q4 vs. Q1, p=0.029; Q4 vs. Q2, p=0.045; Q4 vs. Q3, p=0.045). No other differences in FFBF were observed between quartiles of SATAREA or other quartiles of SATHU. Using CT imaging as a novel prognostic biomarker, low attenuation of abdominal adipose tissue was associated with a lower rate of biochemical failure in patients with high risk prostate cancer. Further research is needed to elucidate the biological underpinnings of this clinical finding and the role adipose tissue plays in modulating oncologic behavior and outcomes.

The Effect of Neoadjuvant Androgen Deprivation Therapy on Tumor Hypoxia in High-Grade Prostate Cancer: A 18F-MISO PET/MRI Imaging Study

Tumor hypoxia has been associated with a higher risk of biochemical recurrence in prostate cancer (PCa) patients treated with curative radiotherapy (RT). Fluoromisonidazole (18F-MISO) is a promising PET tracer tested in some cancer types as a tool to identify and target hypoxic areas. In this prospective study we assessed the occurrence of hypoxia and evaluated the correlation between tissue and imaging hypoxia-biomarkers before and after 3 months of neoadjuvant androgen deprivation therapy (nADT) in high-grade PCa patients treated with curative RT. Eleven non-metastatic high-risk PCa patients with a bioptic Gleason score (GS) ≥ 8 underwent two 18F-MISO hybrid PET/MRI studies before and after 3 months of nADT, respectively. In all patients, a 18F-Choline (CHO) PET/CT was realized for initial staging. 18F-MISO target–to–blood pool ratio (TBR=SUVmax/SUVmean blood) and CHO SUVmax were estimated for each patient based on a sextant repartition of the prostate gland, while the CHO metabolic tumor volume (MTV) was measured for all macroscopically visible tumor lesions. Immunohistochemistry for tissue hypoxia- and proliferation-related biomarkers (EGFR, CAIX, VEGF-A, HIF-1alpha, GLUT1 and Ki67) was performed in all the biopsies cores with the highest GS. Correlations between tissue biomarkers and 18F-MISO TBR, CHO SUVmax and MTV values, mpMRI Prostate Imaging Reporting and Data System (PIRADS) scores, and GS repartition in the whole prostate gland before nADT initiation were made using non parametric tests. The pre- and post-treatment MISO TBR was compared in all biopsy-positives areas by repeated measures ANOVA, controlling for the repeated measures in different zones of an individual patients as “between subjects” factor. A significant focal 18F-MISO uptake (SUV>1.4) was visible in 7 patients (21 zones) corresponding in 5 cases to the highest GS lesion. Among the 21 zones with a significant initial uptake, only 6 zones (in 3 cases the highest GS lesion) maintained an uptake higher than 1.4 after nADT. Mean 18F-MISO TBR before nADT (1.26±0.4) was significantly higher than after nADT (1.06±0.4) (p=0.005). A statistically significant relation was found between GS and 18F-MISO TBR (.351, p=0.018), between GS and CHO SUVmax (.570, p<0.001), between GS and PIRADS (.494, p=0.001), and between CHO SUVmax and PIRADS (.346, p=0.02). No statistically significant correlation was found between MISO imaging and tissue hypoxia biomarkers. 18F-MISO PET imaging showed variable uptake in PCa, associated with GS and lowering significantly after 3 months of nADT. These findings suggest the existence of a hypoxic microenvironment in PCa and further support the re-oxygenation role of the nADT phase and its potential role in overcoming tumor resistance in high-risk PCa.

Patient-Reported Sexual Survivorship Following Proton Therapy in Prostate Cancer

Radiation therapy affects sexual survivorship after prostate cancer treatment. To help guide individualized treatment discussions, we underwent this analysis to identify baseline predictive factors that affect long-term erectile function. From 2006 to 2010, 1,159 patients were enrolled on an institutional review board-approved outcomes tracking protocol for prostate cancer. Patients received proton radiotherapy to a median dose of 78 Gy(RBE) (range, 72-82) cobalt-gray equivalent (CGE). Patients were evaluated for sexual health-related quality of life using the Expanded Prostate Index Composite questionnaire (EPIC) before treatment, every 6 months after treatment for 2 years, and then annually. Potency was defined by the EPIC question, “How would you describe the usual quality of your erections during the last 4 weeks,” where “firm enough for intercourse” was considered potent, while any other answer was considered “impotent.” One hundred fifty-four men who received neoadjuvant androgen deprivation therapy (ADT) were excluded from the analysis. In the remaining 1,005, 676 were “potent” and 329 were “impotent” per the baseline EPIC questionnaire. EPIC questionnaires were answered by 100%, 89%, 82%, and 59% of eligible men at baseline, 6 months, 2 years, and 5 years after treatment. Univariate analysis comparing the 676 potent to 329 impotent cohorts at baseline showed that age, cardiac disease, hypertension, hyperlipidemia, and diabetes were statistically significant factors associated with impotency among the 1,005 men who had not received neoadjuvant ADT. Among the 676 men who were potent at baseline, the potency rates at follow-up time points of 6 months, 2 years, and 5 years were 81%, 68%, and 61%. Univariate analysis at each timeframe showed numerous pretreatment quality-of-life, patient, disease-specific, and treatment-specific factors potentially associated with potency. Recursive partitioning analysis showed that men with a score of “very good” on Q57 (ability to have an erection) at baseline had an 80% rate of potency at 5 years (n = 137), whereas those with a lower score and cardiac disease had a 26% chance of potency (n = 40). Among men with a score of “very good” on Q57 and no history of cardiac disease, 62% (n = 145) remained potent 5 years after treatment, compared with only 44% (n = 78) among men who reported their ability to have erections as “fair,” “poor,” or “very poor to none.” Stratification by patient-reported pretreatment sexual function and comorbidities enables prediction of erectile function at 5 years in a cohort of potent men treated with proton therapy without neoadjuvant ADT. EPIC subset questions with baseline comorbidities may potentially serve as quick and practical clinical tools for predicting sexual survivorship, but further internal and external validation is needed.

Impact of five-tiered Gleason grade groups on prognostic prediction in clinical stage T3 prostate cancer undergoing high-dose-rate brachytherapy.

We evaluated a five-tiered Gleason grade groups arising from the 2014 International Society of Urological Pathology consensus conference on prognostic prediction in clinical stage T3a (extracapsular invasion) and T3b (seminal vesicle involvement) prostate cancer undergoing high-dose-rate brachytherapy (HDR-BT). From November 2003 to December 2012, 283 patients with stage T3 prostate cancer received HDR-BT and external beam radiation therapy (EBRT) with long-term androgen deprivation therapy (ADT). Of these, 203 (72%) and 80 (28%) patients had stage T3a and T3b disease, respectively. The mean dose to 90% of the planning target volume was 7.5 Gy/fraction of HDR-BT. After five fractions, EBRT with 10 fractions of 3 Gy was administered. All patients first underwent ≥6 months of neoadjuvant ADT, and adjuvant ADT continued for 36 months. Median follow-up was 74 months from the start of radiotherapy. The 10-year biochemical recurrence (BCR) -free rate for stage T3a and T3b disease was 79% and 64%, respectively (P = 0.0083). The 10-year cancer-specific survival (CSS) rate for stage T3a and T3b was 96% and 91%, respectively (P = 0.0305). Although grade groups ≥4 were independent predictors for BCR in cT3a patients (P = 0.0270), they failed to significantly predict prostate cancer-specific mortality (PCSM) among cT3a patients. Among cT3b patients, grade group 5 was a significant predictor of both BCR (P = 0.0017) and PCSM (P = 0.0233). Among stage T3a patients, no significant difference existed in 10-year CSS between grade groups 5 and 4 (94% vs 97%, P = 0.3960). In contrast, grade group 5 had a significantly worse outcome in 10-year CSS than grade group 4 among stage T3b patients (74% vs 100%, P = 0.0350). Stage T3a patients with grade groups 4/5 and stage T3b with grade group 4 had fairly low PCSM risk. Approximately one of four patients among stage T3b patients with grade group 5 showed PCSM after combined HDR-BT and EBRT with long-term ADT. Stage T3b patients with grade group 5 may have a greater risk for PCSM.

Long‐term outcomes in patients treated with proton therapy for localized prostate cancer

The aim of this retrospective study was to report long‐term clinical outcomes in patients treated with proton therapy (PT) for localized prostate cancer. Between 2001 and 2014, 1375 consecutive patients were treated with PT. Patients were classified into prognostic risk groups based on the National Comprehensive Cancer Network criteria. Freedom from biochemical relapse (FFBR), cancer‐specific survival (CSS) and incidence of late gastrointestinal (GI)/genitourinary (GU) toxicities were calculated. Multivariate analysis was performed to identify clinical prognostic factors for FFBR and late toxicities. The median follow‐up period was 70 months (range, 4–145 months). In total, 99% of patients received 74 Gy (relative biologic effectiveness [RBE]); 56% of patients received neoadjuvant androgen deprivation therapy. For the low‐, intermediate‐, high‐, and very high‐risk groups, 5‐year FFBR was 99% (95% confidence intervals [CI], 96–100%), 91% (95% CI, 88–93%), 86% (95% CI, 82–89%), and 66% (95% CI, 53–76%), respectively, and 5‐year CSS was 100% (95% CI, 100–100%), 100% (95% CI, 100–100%) , 99% (95% CI, 97–100%), and 95% (95% CI, 94–98%), respectively. Patient age, T classification, Gleason score, prostate‐specific antigen, and percentage of positive cores were significant prognostic factors for FFBR. Grade 2 or higher GI and GU toxicities were 3.9% and 2.0%. Patient age was a prognostic factor for both late GI and GU toxicities. This study represents the largest cohort of patients treated with PT for localized prostate cancer, with the longest follow‐up to date. Our results demonstrate that the biochemical control of PT is favorable particularly for high‐ and very high‐risk patients with lower late genitourinary toxicity and indicates the necessity of considering patient age in the treatment protocols.

Subcutaneous adipose tissue characteristics and the risk of biochemical recurrence in men with high-risk prostate cancer

Purpose/objective(s)To assess subcutaneous adipose tissue characteristics by computed tomography (CT) as potential imaging biomarkers predictive of biochemical recurrence in men with high-risk prostate cancer receiving radiotherapy (RT). Materials and methodsThis retrospective study included men with high-risk prostate cancer (PSA>20ng/ml, Gleason score ≥8, or clinical extraprostatic extension) treated between 2001 and 2012. All patients received definitive, dose-escalated external beam RT along with a course of neoadjuvant, concurrent, and adjuvant androgen deprivation therapy (ADT). Each patient also had a treatment planning CT that included the L4-L5 vertebral interface and prostate specific antigen (PSA) measurements for at least 2 years following RT. The subcutaneous adipose tissue was contoured on a single axial CT slice at the level of L4-L5. The average CT attenuation, in Hounsfield units (HU), of the structure was calculated and defined as SATHU. SATAREA was defined as the cross-sectional area of the structure (in cm2) that was then normalized by the square of patient height. Biochemical failure (BF) was defined as a PSA rise of 2ng/ml from the nadir. Freedom from BF (FFBF) was calculated from start time of ADT using the Kaplan-Meier method. Estimates of FFBF were stratified by SATHU and SATAREA quartiles. ResultsA total of 171 men met the inclusion criteria with a median follow-up of 5.6 years. The mean SATHU (±standard deviation) was −99.2HU (±6.1HU), and the mean SATAREA was 93.2cm2/m2 (±39.4cm2/m2). The 5- and 8-year rates of FFBF across all patients were 81.5% and 73.5%, respectively. Patients in the lowest quartile of SATHU experienced significantly higher FFBF compared to the other quartiles (Q4 vs. Q1, P = 0.017; Q4 vs. Q2, P = 0.045; Q4 vs. Q3, P = 0.044). No other differences in FFBF were observed between quartiles of SATAREA or other quartiles of SATHU. ConclusionLower subcutaneous adipose tissue density was associated with a lower rate of BF following RT with ADT for men with high-risk prostate cancer. Further research is needed to elucidate the biological underpinnings of this clinical finding and the role adipose tissue plays in modulating oncologic behavior and outcomes.

Pathological and oncological features of Korean prostate cancer patients eligible for active surveillance: analysis from the K-CaP registry.

A web-based multicenter Korean Prostate Cancer Database (K-CaP) was established to provide urologists with information on Korean prostate cancer (PCa) patients treated with radical prostatectomy (RP). We utilized the K-CaP registry to identify pathological features and oncological outcomes of Korean PCa patients eligible for active surveillance (AS). The K-CaP registry consisted of 6415 patients who underwent RP from May 2001 to April 2013 at five institutions. Preoperative clinicopathological data were collected to identify patients who were eligible for at least one contemporary AS protocol. Patients who had received neoadjuvant androgen deprivation therapy or a 5α-reductase inhibitor, who had <10 total biopsy cores, or who had incomplete data were excluded. Biochemical recurrence (BCR) was defined as prostate-specific antigen (PSA) level ≥0.2 ng/ml following RP. A total of 560 patients were identified, and the median follow-up period was 52.0 (interquartile range, 39.0-67.3) months. Pathologically insignificant PCa, defined as organ-confined disease with Gleason score ≤6 was observed in 314 (56.1%) patients. Pathological upgrading (Gleason score ≥7) and upstaging (≥pT3) were observed in 237 (42.3%) and 75 (13.4%) patients, respectively. Unfavorable disease (extracapsular extension, seminal vesicle invasion, or Gleason score ≥8) was observed in 85 (15.2%) patients. PSA density ≤0.2 ng/ml/cc and maximal single core involvement ≤20% were revealed as independent preoperative predictors of pathologically insignificant PCa. Contemporary Western AS protocols unreliably predict pathologically insignificant PCa in Korean men. Korean men may harbor more aggressive PCa features than Western men, and thus, a more stringent AS protocol is needed.

Abstract 2415: Genome-wide alterations in gene expression of prostate cancer (PC) cells surviving neo-adjuvant androgen deprivation therapy

Abstract Background: Although androgen deprivation therapy initially decreases PC tumor burden, resistance to further androgen receptor (AR)-directed treatments or chemotherapy is inevitable once CRPC is established. We postulated that the stress of ADT triggers widespread alterations in expression that renders a metastable physiologic state conditioned by epigenetic changes that might be initially reversible by targeting non-androgen pathways. We conducted a pilot study to explore genome-wide expression alterations in PC foci surviving 3 months ADT (eADT). Methods: mRNA from 7 frozen microdissected PC foci and normal counterparts (NC) were processed for RNA-seq. RNA-seq changes in eADT specimens were compared first with NC and the untreated PC in the TCGA PRAD (TCGA) database to castrate resistant (mCRPC) specimens in the dbGAP study phs000915.v1.p1database. The raw data (fastq files) was quantified using kallisto, normalized by TMM using R package edgeR, batch effects corrected using R package SVA. Analysis of differential gene expression by R package sleuth. Pathway and gene set by GSEA, GAGE/pathview packages for Gene Ontology (GO) and KEGG. Results: TMPRSS2-ERG+, 5/7. Highest DEG in eADT vs. TCGA vs mCRPC were non-coding RNA’s. Among 17431 differentially regulated paths; GSEA of eADT vs TCGA or mCRPC: 341 (1.95%) and 1366 (7.84%) up- vs 46 (0.26%) and 59 (0.34%) down-regulated. KEGG paths, eADT vs. TCGA or mCRPC, 11 and 53 up vs. 2 and 3 down- respectively. Highly down- path in eADT vs TCGA (log q&amp;lt;10-17) was ribosomal vs. cell cycle and DNA replication in mCRPC. Six paths significantly up- in eADT vs TCGA or mCRPC: Wnt, adherence junction, steroid biosynthesis, unsaturated fatty acids, citrate cycle, ErbB. Calcium, MAPK, insulin, GnRH and Hedgehog were also up- in eADT vs mCRPC. AR full-length was marginally higher in eADT than TCGA and lower than mCRPC, no differences in gene targets. Conclusions: This pilot data shows that ADT triggers a wide range of gene expression alterations that support PC cell survival and may be vulnerable to therapeutic targeting in addition to the androgen pathway. Validation of these findings is planned in a larger set of samples from the same bank. Citation Format: Anna C. Ferrari, Hatem Sabaawy, Mark Stein, David Foran, Ying Chen, Srinivasan Yegnasubramanian. Genome-wide alterations in gene expression of prostate cancer (PC) cells surviving neo-adjuvant androgen deprivation therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2415. doi:10.1158/1538-7445.AM2017-2415

Testicular vs adrenal sources of hydroxy-androgens in prostate cancer

Neoadjuvant androgen deprivation therapy (NADT) is one strategy for the treatment of early-stage prostate cancer; however, the long-term outcomes of NADT with radical prostatectomy including biochemical failure-free survival are not promising. One proposed mechanism is incomplete androgen ablation. In this study, we aimed to evaluate the efficiency of serum hydroxy-androgen suppression in patients with localized high-risk prostate cancer under NADT (leuprolide acetate plus abiraterone acetate and prednisone) and interrogate the primary sources of circulating hydroxy-androgens using our recently described stable isotope dilution liquid chromatography mass spectrometric method. For the first time, three androgen diols including 5-androstene-3β,17β-diol (5-adiol), 5α-androstane-3α,17β-diol (3α-adiol), 5α-androstane-3β,17β-diol (3β-adiol), the glucuronide or sulfate conjugate of 5-adiol and 3α-adiol were measured and observed to be dramatically reduced after NADT. By comparing patients that took leuprolide acetate alone vs leuprolide acetate plus abiraterone acetate and prednisone, we were able to distinguish the primary sources of these androgens and their conjugates as being of either testicular or adrenal in origin. We find that testosterone, 5α-dihydrotestosterone (DHT), 3α-adiol and 3β-adiol were predominately of testicular origin. By contrast, dehydroepiandrosterone (DHEA), epi-androsterone (epi-AST) and their conjugates, 5-adiol sulfate and glucuronide were predominately of adrenal origin. Our findings also show that NADT failed to completely suppress DHEA-sulfate levels and that two unappreciated sources of intratumoral androgens that were not suppressed by leuprolide acetate alone were 5-adiol-sulfate and epi-AST-sulfate of adrenal origin.

MP05-04 EFFECTIVENESS OF COMBINATION THERAPY OF EXTERNAL-BEAM RADIATION AND HIGH DOSE-RATE BRACHYTHERAPY FOR HIGH-RISK PROSTATE CARCINOMA

You have accessJournal of UrologyProstate Cancer: Localized: Radiation Therapy I1 Apr 2017MP05-04 EFFECTIVENESS OF COMBINATION THERAPY OF EXTERNAL-BEAM RADIATION AND HIGH DOSE-RATE BRACHYTHERAPY FOR HIGH-RISK PROSTATE CARCINOMA Kenjiro Suzuki, Suguru Shirotake, Koshiro Nishimoto, Soichi Makino, Hideyuki Kondo, Takashi Okabe, Yota Yasumizu, Kiichiro Kodaira, Shingo Kato, and Masafumi Oyama Kenjiro SuzukiKenjiro Suzuki More articles by this author , Suguru ShirotakeSuguru Shirotake More articles by this author , Koshiro NishimotoKoshiro Nishimoto More articles by this author , Soichi MakinoSoichi Makino More articles by this author , Hideyuki KondoHideyuki Kondo More articles by this author , Takashi OkabeTakashi Okabe More articles by this author , Yota YasumizuYota Yasumizu More articles by this author , Kiichiro KodairaKiichiro Kodaira More articles by this author , Shingo KatoShingo Kato More articles by this author , and Masafumi OyamaMasafumi Oyama More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.163AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Our institution is a high volume center of radiotherapy for prostate cancer patients (PCaPts). We have performed either neoadjuvant androgen deprivation therapy (NADT), followed by external-beam radiation therapy (total 39 Gray) and high dose-rate brachytherapy (HDR-B, total 18 Gray) (NEH) or radical prostatectomy (RP) on high-risk PCaPts, as defined by prostate specific antigen (PSA) level (>20ng/mL), pathology of biopsy specimen (Gleason score [GS]: ≥8), and/or clinical staging (≥T3). No comparative studies have been reported for NEH and RP. In order to determine if NEH is a better therapy than RP, we compared biochemical recurrence-free survival (bRFS, i.e., post therapeutic PSA elevation) and overall survival (OS) between NEH and RP on high-risk PCaPts. METHODS Between 2007 and 2012, 192 and 167 high-risk PCaPts were treated by NEH and RP, respectively. Biochemical failure (BF) for NEH was defined using Phoenix definition: any PSA increase of >2 ng/mL higher than the PSA nadir value, regardless of the PSA nadir value. Whereas BF for RP was defined as PSA values of >0.2 ng/mL. Of note, PSA of 18 RP-cases (10.8 %) did not decrease to less than 0.2 ng/mL. In these cases, the day of PSA nadir was defined as BF date. Difference between bRFS and OS were calculated using Kaplan-Meier method and log-rank tests. RESULTS The median follow-up duration was 58.7 months. Age was significantly older in NEH group (median [interquartile range] = 71.9 [67.3-75.3] years) than in RP group (69.0 [64.9-72.3] years, p< 0.001, Mann-Whitney U test [MWU]). Initial PSA was higher in NEH (20.0 [10.1-43.6]) than RP group (15.9 [8.1-24.7] ng/dL, p<0.01, MWU). RP group had a trend of higher GS (72.1%) than NEH group (62.5%, p=0.07, chi square test). T stage was similar (NEH [66.1 %] vs RP [66.4 %], p=0.928, chi square test). The 5- and 7-year bRFS rates in NEH group (0.79 and 0.76, respectively) were significantly higher than those in RP group (0.51 and 0.41, respectively, p<0.001 each, Fig. 1A). However, in OS, no significant difference was found (p=0.838). CONCLUSIONS We retrospectively compared clinical outcomes of NEH and RP, and found that NEH might be as effective as RP for high-risk PCaPts. Currently, we are preparing prospective randomized case study comparing NEH and RP by adjusting age, GS, PSA, and T stage. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e38-e39 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Kenjiro Suzuki More articles by this author Suguru Shirotake More articles by this author Koshiro Nishimoto More articles by this author Soichi Makino More articles by this author Hideyuki Kondo More articles by this author Takashi Okabe More articles by this author Yota Yasumizu More articles by this author Kiichiro Kodaira More articles by this author Shingo Kato More articles by this author Masafumi Oyama More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...