Prostate-specific Antigen Relapse Research Articles

Salvage Brachytherapy for Recurrent Prostate Cancer after Definitive Radiation Treatment and Factors That May Impact Outcomes

Salvage low-dose-rate (LDR) brachytherapy is a potential treatment option for patients with locally recurrent prostate cancer following primary radiation therapy. Here we report our single institution outcomes and toxicity when utilizing LDR brachytherapy in the salvage setting. Nineteen patients with biopsy-proven locally recurrent prostate cancer underwent salvage LDR brachytherapy under transrectal ultrasound guidance utilizing 103 Pd to 120 Gy from August 2010 through February 2018. Prostate-specific antigen (PSA) failure was determined utilizing the Phoenix (nadir+2) definition. Toxicity was graded using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 and patient reported questionnaires including the Expanded Prostate Cancer Index Composite (EPIC) and American Urological Association (AUA). Median follow-up was 41 months. The 4- and 5- year PSA relapse-free survival (RFS) following salvage treatment were 78.9% and 68.4%, respectively. Androgen deprivation therapy was utilized in conjunction with salvage treatment in 7 patients (37%). On univariate analysis, 5- year PSA relapse was associated with both patients who experienced early failures after initial definitive treatment (p=.012), or if the patient had received stereotactic body radiation treatment (SBRT) (p=.005) prior to salvage treatment. Of the four patients who were treated following a biopsy-proven recurrence after initial SBRT treatment, two patients (50%) experienced PSA failure at a median of 9 months after their salvage treatment. AUA and EPIC scores showed a significant increase at one-month follow-up after salvage brachytherapy (p = .023) and returned to baseline within six months. Three patients (16%) experienced Grade 3 acute or late urinary toxicity, five patients experienced Grade 2 acute urinary toxicity, and one patient experienced Grade 2 acute rectal toxicity. Post-implant dosimetry did not predict for toxicity. There were no Grade 4 or 5 toxicities. LDR brachytherapy is a viable treatment option in the salvage setting with minimal morbidity. While longer follow-up is needed, early failures from initial radiation treatment and prior SBRT may portend for worse outcomes following salvage LDR brachytherapy.

PSA increase after definitive treatment

Following definitive treatment with curative intent asubset of patients with prostate cancer experience biochemical recurrence. In these patients clinical parameters are mostly used to decide if a local or systemic disease recurrence is present. While salvage radiation treatment is advocated for local recurrence after radical prostatectomy, no standard recommendations exist in cases of local recurrence after primary radiation therapy although salvage prostatectomy may be considered. Imaging procedures have traditionally not routinely been recommended for the onset of prostate-specific antigen (PSA) relapse; however, prostate-specific membrane antigen (PSMA) positron emission tomography (PET) computed tomography (CT) exhibits high detection rates even at low PSA values. Thus, the current German guidelines state that PSMA PET/CT can be considered if this could result in a decisive change in further treatment management. Currently, apositive influence on oncological long-term outcome, however, has not yet been proven.

Five-Year Outcomes of a Phase 1 Dose-Escalation Study Using Stereotactic Body Radiosurgery for Patients With Low-Risk and Intermediate-Risk Prostate Cancer

To report toxicity outcomes, prostate-specific antigen (PSA) relapse, and cumulative incidence posttreatment biopsy results among patients treated on a prospective dose escalation study using ultra-hypofractionated stereotactic body radiation therapy (SBRT) for patients with low- and intermediate-risk prostate cancer. A total of 136 patients were enrolled in a phase 1 dose-escalation study to determine the tolerance of escalating radiation dose levels of SBRT for the treatment of localized prostate cancer. The initial dose level was 32.5Gy in 5 fractions, and doses were then sequentially escalated to 35Gy, 37.5Gy, and 40Gy. Eligibility criteria included only patients with low and intermediate risk, and the maximum prostate volume was 60cm3. Patients treated with neoadjuvant androgen deprivation were excluded. The median follow-up in survivors for the 4 dose levels was 5.9, 5.4, 4.1, and 3.5years, respectively. The incidence of acute grade 2 rectal toxicities for dose levels 1 to 4 were 0%, 2.9%, 2.8%, and 11.4% respectively. No grade 3 or 4 acute rectal toxicities were observed. The incidence of acute grade 2 urinary toxicities for dose levels 1 to 4 were16.7%, 22.9%, 8.3%, and 17.1%, respectively. No grade 3 or 4 acute urinary toxicities were observed. No grade 2 or higher rectal toxicities were observed. The incidence of late grade 2 urinary toxicities for dose levels 1 to 4 was 23.3%, 25.7%, 27.8%, and 31.4%, respectively. Only 1 late grade 3 urinary toxicity (urethral stricture) developed in the 40-Gy dose arm; the stricture was corrected with transurethral resection. No grade 4 late urinary toxicity was observed. The 5-year cumulative incidence of prostate-specific antigen failure for dose levels 1 to 4 was 15%, 6%, 0%, and 0%. The incidence of a 2-year positive posttreatment biopsy was 47.6%, 19.2%, 16.7%, and 7.7%, respectively for the 4 dose arms (P=.013). SBRT doses ranging from 32.5 to 40Gy in 5 fractions were well tolerated without severe urinary or rectal toxicities. Biopsy outcomes suggest improved rates of tumor clearance observed with higher doses.

Tumor Suppressor Role and Clinical Implication of the Fifth Ewing Variant (FEV) Gene, an ETS Family Gene, in Prostate Cancer

Background: Our previous study identified a 32-gene risk index model as a robust prognostic tool for disease recurrence of prostate cancer (PCa) after surgery. Among the 32 genes, the Fifth Ewing Variant (FEV) Gene was one of the top downregulated genes in the relapsed PCa. However, very little is known about FEV gene and its involvement in PCa. Methods: FEV mRNA expression was analyzed and correlated to clinical outcomes in PCa patients who underwent prostatectomy in Massachusetts General Hospital. FEV expression level was also detected in PCa cell lines and an immortalized prostate epithelial cell line BPH-1 by Western blot and qRT-PCR. Furthermore, we established stable cell lines (LNCaP and PC-3) transfected with either empty vector or the full-length FEV gene and conducted cell function assays in vitro. The role of FEV in tumor xenografts growth was also determined in vivo Finding: Of 191 patients who enrolled in this study, 77 (40.3%) and 24 (13.6%) developed prostate-specific antigen (PSA) relapse and metastasis respective after radical prostatectomy. FEV was significantly downregulated in PCa patients with PSA failure and metastasis. FEV expression was significantly reduced in all PCa cell lines compared to BPH-1 (all P<0.05). Functionally, the enforced expression of FEV markedly inhibited cell growth, migration and invasion efficacies in PCa cells and led to a significant repression of tumor xenografts growth in vivo. Interpretation: Our data indicate that FEV downregulation may be potentially associated with PSA relapse in PCa patients. Functionally, FEV may act as a tumor suppressor in PCa. Funding Statement: This work was supported by grants from National Key Basic Research Program of China (2015CB553706), National Natural Science Foundation of China (81874099, 81571 427, 81802555), the Fundamental Research Funds for the Central Universities(2018MS 18), Natural Science Foundation of Guangdong Province (2018A030313668, 2017A030 310149), Guangzhou Municipal Science and Technology Project (201710010081, 20180 3040001, 201707010291), Projects of Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou Medical University Initiation Project for PHD (201 6C12), General Research Projects of Guangzhou Science and Technology Department (201804010053). Declaration of Interests: No potential conflicts of interest were disclosed. Ethics Approval Statement: The study was approved by the human study ethics committees at Massachusetts General Hospital (MGH; Boston, MA). All specimens were handled and made anonymous according to the ethical and legal standards.

Abstract CT016: A first in man phase I/II adjuvant dendritic cell vaccine study in high-risk prostate cancer patients following radical surgery reduce the incidence of biochemical relapse

Abstract Prostate cancer patients diagnosed with high Gleason score (≥ 8) and large tumors (≥T2c) are considered high-risk patients and &amp;gt;50% will develop an early biochemical relapse following radical surgery. Presently, there is no curative therapy available for patients once when biochemical relapse occur. Based on encouraging clinical results from 6 relapsed prostate cancer patients treated under hospital exemption with dendritic cell (DC) vaccines we started an adjuvant, first in man, phase I/II study using autologous, monocyte derived DCs targeting autologous tumor antigens from primary tumor, combined with hTERT and survivin. Twenty patients were included in the study. All patients had pathological stage pT2-pT3b and Gleason score 7b-10. Following surgery prostate specific antigen (PSA) was &amp;lt; 0,2 µg/L in all patients. Fifteen patients have received 3-days DCs generated according to our standard protocol with a maturation cocktail composed of GM-CSF, IL-4, TNFα, IL1β and PgE2. Five patients were treated with a TLR 7/8 ligand containing maturation cocktail, resulting in DCs with a polarized release of IL-12p70 and no or low IL-10. The patients received 4 weekly vaccinations, then DTH vaccine at week 8 and thereafter-monthly vaccinations the first year, and every third month the second and third year. All patients except of two have completed vaccination. Of the 15 first patients using the standard DCs, three patients developed PSA relapse during vaccination (PSA measured twice &amp;gt;0,5 μg/L with minimum 4 weeks interval) and two additional patients relapsed after completed 3 years of vaccination. From the last 5 patients given the new type of DCs none have experienced PSA relapse. Seventy-five percent of the patients remain without biochemical relapse with a mean observation time of 47,5 (range 29-82) months. We confirm that the study is feasible and safe. Immune responses in the patients are under investigation. Altogether, our clinical results are promising and the use of adjuvant DC vaccines might become a new approach to prevent biochemical relapse in high-risk prostate cancer patients following radical surgery. Citation Format: Anne Merete Tryggestad, Iris Bigalke, Karol Axcrona, Bjørn Brennhovd, T Kirsti Hønnåshagen, Lisbeth Skoge, Lena Tjeldhorn, Lene Mowinckel, Stein Sæbøe-Larsen, Jens A L Jørgensen, Grete S Andreassen, Gjertrud Skorstad, Dag Josefsen, Ulrika Axcrona, Steinar Aamadal, Wolfgang Lilleby, Svein Dueland, Gunnar Kvalheim. A first in man phase I/II adjuvant dendritic cell vaccine study in high-risk prostate cancer patients following radical surgery reduce the incidence of biochemical relapse [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT016.

Image-guided radiotherapy reduces the risk of under-dosing high-risk prostate cancer extra-capsular disease and improves biochemical control

BackgroundTo determine if reduced dose delivery uncertainty is associated with daily image-guidance (IG) and Prostate Specific Antigen Relapse Free Survival (PRFS) in intensity-modulated radiotherapy (IMRT) of high-risk prostate cancer (PCa).MethodsPlanning data for consecutive PCa patients treated with IMRT (n = 67) and IG-IMRT (n = 35) was retrieved. Using computer simulations of setup errors, we estimated the patient-specific uncertainty in accumulated treatment dose distributions for the prostate and for posterolateral aspects of the gland that are at highest risk for extra-capsular disease. Multivariate Cox regression for PRFS considering Gleason score, T-stage, pre-treatment PSA, number of elevated clinical risk factors (T2c+, GS7+ and PSA10+), nomogram-predicted risk of extra-capsular disease (ECD), and dose metrics was performed.ResultsFor IMRT vs. IG-IMRT, plan dosimetry values were similar, but simulations revealed uncertainty in delivered dose external to the prostate was significantly different, due to positioning uncertainties. A patient-specific interaction term of the risk of ECD and risk of low dose to the ECD (p = 0.005), and the number of elevated clinical risk factors (p = 0.008), correlate with reduced PRFS.ConclusionsImprovements in PSA outcomes for high-risk PCa using IG-IMRT vs. IMRT without IG may be due to improved dosimetry for ECD.

Salvage radiotherapy for biochemical recurrence after radical prostatectomy: experience of a single center

Background: The purpose of this study was to report the outcomes and prognostic factors of patients who underwent salvage radiotherapy (SRT) for biochemical recurrence (BCR) following radical prostatectomy (RP) at a single center. Methods: We retrospectively reviewed 48 patients who underwent SRT for BCR after RP between January 2004 and December 2012. The Kaplan-Meier method and Cox proportional hazard regression models were used to evaluate the BCR-free survivals and the prognostic factors for BCR after SRT. Results: After a median follow-up of 68.7 months (range, 34.0–143.3 months). The BCR-free survival rates at 3 and 5 years for the 48 patients after SRT were 72.9% and 68.4%, respectively. Multivariate analysis showed that pre-RT PSA (prostate specific antigen) level >0.5 ng/mL, Gleason score at RP ≥8, and seminal vesicle invasion were significantly predictive of PSA relapse after SRT (HR: 23.29, 7.92, and 21.73). The BCR-free rate at 5 years in the pre-RT PSA level ≤0.5 and >0.5 ng/mL group was 83.4% and 52.2% (P=0.007), respectively. No grade 3 or worse acute adverse events were noted. Conclusions: SRT was an effective treatment for BCR following RP with tolerable toxicities. Lower pre-RT PSA value, low Gleason score, and non-seminal vesicle invasion were significant predictors of favorable biochemical outcomes. Our results supported the current recommendations that SRT should be initiated before PSA reaches 0.5 ng/mL.

Dose escalation of external beam radiotherapy for high-risk prostate cancer—Impact of multiple high-risk factor

ObjectiveTo retrospectively investigate the treatment outcomes of external beam radiotherapy with androgen deprivation therapy (ADT) in high-risk prostate cancer in three radiotherapy dose groups. MethodsBetween 1998 and 2013, patients with high-risk prostate cancer underwent three-dimensional conformal radiotherapy or intensity-modulated radiotherapy of 66 Gy, 72 Gy, or 78 Gy with ADT. Prostate-specific antigen (PSA) relapse was defined using the Phoenix definition. PSA relapse-free survival (PRFS) was evaluated in each radiotherapy dose group. Moreover, high-risk patients were divided into H-1 (patients with multiple high-risk factors) and H-2 (patients with a single high-risk factor) as risk subgroups. ResultsTwo hundred and eighty-nine patients with a median follow-up period of 77.3 months were analyzed in this study. The median duration of ADT was 10.1 months. Age, Gleason score, T stage, and radiotherapy dose influenced PRFS with statistical significance both in univariate and multivariate analyses. The 4-year PRFS rates in Group-66 Gy, Group-72 Gy and Group-78 Gy were 72.7%, 81.6% and 90.3%, respectively. PRFS rates in the H-1 subgroup differed with statistical significance with an increasing radiotherapy dose having a more favorable PRFS, while PRFS rates in H-2 subgroup did not differ with increase in radiotherapy dose. ConclusionDose escalation for high-risk prostate cancer in combination with ADT improved PRFS. PRFS for patients in the H-1 subgroup was poor, but dose escalation in those patients was beneficial, while dose escalation in the H-2 subgroup was not proven to be effective for improving PRFS.

Prostate-Specific Antigen (PSA) Bounce After Dose-Escalated External Beam Radiation Therapy Is an Independent Predictor of PSA Recurrence, Metastasis, and Survival in Prostate Adenocarcinoma Patients

Toevaluate the difference in prostate-specific antigen (PSA) recurrence-free, distant metastasis-free, overall, and cancer-specific survival between PSA bounce (PSA-B) and non-bounce patients treated with dose-escalated external beam radiation therapy (DE-EBRT). During 1990-2010, 1898 prostate adenocarcinoma patients were treated with DE-EBRT to ≥75Gy with ≥5years follow-up. Patients receiving neoadjuvant/concurrent androgen-deprivation therapy (n=1035) or with fewer than 4 PSA values obtained 6months or more after post-EBRT completion (n=87) were excluded. The evaluable 776 patients were treated (median, 81.0Gy). Prostate-specific antigen bounce was defined as a ≥0.2-ng/mL increase above the interval PSA nadir, followed by a decrease to nadir or below. Prostate-specific antigen relapse was defined as post-radiation therapy PSA nadir + 2ng/mL. Median follow-up was 9.2years (interquartile range, 6.9-11.3years). One hundred twenty-three patients (15.9%) experienced PSA-B after DE-EBRT at a median of 24.6months (interquartile range, 16.1-38.5months). On multivariate analysis, younger age (P=.001), lower Gleason score (P=.0003), and higher radiation therapy dose (P=.0002) independently predicted PSA-B. Prostate-specific antigen bounce was independently associated with decreased risk for PSA relapse (hazard ratio [HR] 0.53; 95% confidence interval [CI] 0.33-0.85; P=.008), distant metastatic disease (HR 0.34; 95% CI 0.12-0.94; P=.04), and all-cause mortality (HR 0.53; 95% CI 0.29-0.96; P=.04) on multivariate Cox analysis. Because all 50 prostate cancer-specific deaths in patients without PSA-B were in the non-bounce cohort, competing-risks analysis was not applicable. A nonparametric competing-risks test demonstrated that patients with PSA-B had superior cancer-specific survival compared with patients without PSA-B (P=.004). Patients treated with dose-escalated radiation therapy for prostate adenocarcinoma who experience posttreatment PSA-B have improved PSA recurrence-free survival, distant metastasis-free survival, overall survival, and cancer-specific survival outcomes.

Clinical Potential of Statins in Prostate Cancer Radiation Therapy.

Statins are cholesterol- lowering drugs that have been shown to possess anti-tumour properties. Observational studies have shown that 3-hydroxy-3-methlyglutaryl coenzyme A reductase inhibitor (statin) use may be associated with reduced prostate cancer risk. Preclinical studies suggest that statins possess anticancer and radiosensitising properties. This review aims to determine the impact of statin use in the efficacy of radiation therapy and the therapeutic window in prostate cancer. The scientific databases PubMed, Science Direct, EMBASE, Cochrane Collaboration, and Google Scholar were searched for articles identifying statin use in histologically confirmed prostate cancer treated with external beam radiation therapy. Improvement was observed in freedom from biochemical failure (91% vs. 79%), relapse free survival (72% vs. 69%), distant metastasis free survival (96% vs. 94%), and prostate-specific antigen (PSA) relapse free survival (89% vs. 83%) with statin use, however this did not translate into an overall survival benefit for patients. Conflicting data concerning clinical outcomes reduce the integrity of these findings. The literature supports the radiosensitising properties of statins and their potential antitumor effects in prostate cancer. Statin use in prostate cancer presents many obstacles yet to be overcome, which warrant attention prior to the routine implementation of statins in treatment regimes. However, there is evidence to support their beneficial use.

Salvage brachytherapy for recurrent prostate cancer after definitive radiation therapy: A comparison of low-dose-rate and high-dose-rate brachytherapy and the importance of prostate-specific antigen doubling time

BackgroundSalvage brachytherapy is a treatment option for patients with locally recurrent prostate cancer after primary radiation therapy. We reviewed our experience using low-dose-rate (LDR) or high-dose-rate (HDR) brachytherapy to compare the outcome and toxicity profiles of each approach in the salvage brachytherapy setting. Methods and MaterialsNinety-eight patients with biopsy-proven locally recurrent prostate cancer who underwent salvage brachytherapy (LDR = 37; HDR = 61) following an initial course of definitive radiotherapy between 4/2003 and 4/2015 were retrospectively reviewed. All patients underwent salvage brachytherapy using LDR or HDR. Androgen deprivation therapy was used in 45% of the patients. Prostate-specific antigen (PSA) failure was determined using the Phoenix (nadir+2) definition. Toxicity was graded using Common Terminology Criteria for Adverse Events version 4 and patient-reported questionnaires. ResultsMedian followup was 31 months. The 3-year PSA relapse-free survival (RFS) was 60.1% (95% CI, 49.6–72.5%). There was no difference between LDR and HDR brachytherapy in terms of PSA RFS (p = 0.84 by log-rank test). On multivariate analysis, only prostate-specific antigen doubling time (PSADT) <12 months was significantly associated with PSA relapse. The 3-year PSA RFS for patients with a PSADT <12 months was 39% compared with 73% for PSADT ≥12 months (p = 0.002 by long-rank test). There were no statistically significant differences in toxicity between LDR and HDR brachytherapy. There was a higher peak in urinary symptoms in LDR patients; however by 24–36 months, most patients in both groups returned to baseline. ConclusionsBoth LDR and HDR salvage brachytherapy are an excellent treatment options for appropriately selected patients with comparable outcome and toxicity. Patients with a PSADT < 12 months seem to have worse outcomes.

Prostate-Specific Membrane Antigen Positron Emission Tomography–Computed Tomography for Prostate Cancer: Distribution of Disease and Implications for Radiation Therapy Planning

To explore the prostate-specific membrane antigen (PSMA)-avid distribution of prostate cancer (PC) on positron emission tomography (PET), both at the time of initial diagnosis and at the time of relapse after definitive local treatment. A total of 179 PSMA PET scans in patients with nil or ≤3 lesions on conventional imaging were retrospectively categorized into 3 subgroups: group A, high-risk PC with no prior definitive therapy (n=34); group B, prior prostatectomy (n=75); and group C, prior radiation therapy (n=70). The numbers and locations of the PSMA-avid lesions were mapped. The PSMA-positive lesions were identified subjectively by a nuclear medicine physician on the basis of clinical experience and taking into account the recent literature and artefacts. A total of 893 PSMA-avid lesions were identified; at least 1 lesion was detected in 80% of all scans. A high detection rate was present even at very low serum PSA levels (eg, at PSA ≤0.20ng/mL in group B, the detection rate was 46%). Thirty-eight percent of studies revealed extrapelvic disease (41%, 31%, and 46% in groups A, B, and C, respectively). Almost one-third of all studies showed only oligometastases (24%, 36%, and 31% in groups A, B, and C, respectively). A large proportion of these (40%) were a solitary lesion. Prostate-specific membrane antigen PET demonstrated a large number of otherwise unknown metastatic lesions. Therefore we recommend PSMA PET for more accurate assessment of disease burden in initial staging of high-risk PC, as well as for restaging in patients with prostate-specific antigen relapse after primary therapies. Furthermore, a high proportion of oligometastases on PSMA PET provides a prime opportunity to investigate the role of targeted local therapies for oligometastatic PCs.

68Ga-PSMA PET/CT and Volumetric Morphology of PET-Positive Lymph Nodes Stratified by Tumor Differentiation of Prostate Cancer.

68Ga-prostate-specific membrane antigen (PSMA) PET/CT is a new method to detect early nodal metastases in patients with biochemical relapse of prostate cancer. In this retrospective investigation, the dimensions, volume, localization, and SUVmax of nodes identified by 68Ga-PSMA were correlated to their Gleason score (GS) at diagnosis. Methods: All PET/CT images were acquired 60 ± 10 min after intravenous injection of 68Ga-PSMA (mean dose, 176 MBq). In 147 prostate cancer patients (mean age, 68 y; range, 44-87 y) with prostate-specific antigen relapse (mean prostate-specific antigen level, 5 ng/mL; range, 0.25-294 ng/mL), 362 68Ga-PSMA PET-positive lymph nodes (LNs) were identified. These patients were classified on the basis of their histopathology at primary diagnosis into either low- (GS ≤ 6, well differentiated), intermediate- (GS = 7, moderately differentiated), or high-GS cohorts (GS ≥ 8, poorly differentiated prostate cancer). Using semiautomated LN segmentation software (Fraunhofer MEVIS), we measured node volume and short-axis dimensions (SADs) and long-axis dimensions based on CT and compared with the SUVmax Nodes demonstrating uptake of 68Ga-PSMA with an SUVmax of 2.0 or more were considered PSMA-positive, and nodes with an SAD of 8 mm or more were considered positive by morphologic criteria. Results: Mean SUVmax was 13.5 (95% confidence interval [CI], 10.9-16.1), 12.4 (95% CI, 9.9-14.9), and 17.8 (95% CI, 15.4-20.3) within the low-, intermediate-, and high-GS groups, respectively. The morphologic assessment of the 68Ga-PSMA-positive LN demonstrated that the low-GS cohort presented with smaller 68Ga-PSMA-positive LNs (mean SAD, 7.7 mm; n = 113), followed by intermediate- (mean SAD, 9.4 mm; n = 122) and high-GS cohorts (mean SAD, 9.5 mm; n = 127). On the basis of the CT morphology criteria, only 34% of low-GS patients, 56% of intermediate-GS patients, and 53% of high-GS patients were considered CT positive. Overall, 68Ga-PSMA imaging led to a reclassification of stage in 90 patients (61%) from cN0 to cN1 over CT. Conclusion:68Ga-PSMA PET is a promising modality in biochemical recurrent prostate cancer patients for N staging. Conventional imaging underestimates LN involvement compared with PSMA molecular staging score in each GS cohort. The sensitivity of 68Ga-PSMA PET/CT enables earlier detection of subcentimeter LN metastases in the biochemical recurrence setting.

Validation of Cyclic Adenosine Monophosphate Phosphodiesterase-4D7 for its Independent Contribution to Risk Stratification in a Prostate Cancer Patient Cohort with Longitudinal Biological Outcomes

BackgroundThe clinical metrics used to date to assess the progression risk of newly diagnosed prostate cancer patients only partly represent the true biological aggressiveness of the underlying disease. ObjectiveValidation of the prognostic biomarker phosphodiesterase-4D7 (PDE4D7) in predicting longitudinal biological outcomes in a historical surgery cohort to improve postsurgical risk stratification. Design, patients, and methodsRNA was extracted from biopsy punches of resected tumors from 550 patients. PDE4D7 was quantified using one-step quantitative reverse transcription-polymerase chain reaction. PDE4D7 scores were calculated by normalization of PDE4D7 to reference genes. Multivariate analyses were adjusted for clinical prognostic variables. Outcomes tested were: prostate-specific antigen relapse, start of salvage treatment, progression to metastases, overall mortality, and prostate cancer-specific mortality. The PDE4D7 score was combined with the clinical risk model Cancer of the Prostate Risk Assessment Postsurgical Score (CAPRA-S) using multivariate regression modeling; the combined score was tested in post-treatment progression free survival prediction. Outcome measurements and statistical analysisCorrelations with outcomes were analyzed using multivariate Cox regression and logistic regression statistics. Results and limitationsThe PDE4D7 score was significantly associated with time-to-prostate specific antigen failure after prostatectomy (hazard ratio [HR]: 0.53, 95% confidence interval [CI]: 0.41–0.67 for each unit increase, p<0.0001). After adjustment for postsurgical prognostic variables the HR was 0.56 (95% CI: 0.43–0.73, p<0.0001). The PDE4D7 score remained significant after adjusting the multi-variate analysis for the CAPRA-S model categories (HR=0.54, 95% CI=0.42–0.69, p<0.0001). Combination of the PDE4D7 score with the CAPRA-S demonstrated a significant incremental value of 4–6% in 2-yr (p=0.004) or 5-yr (p=0.003) prediction of progression free survival after surgery. The combined model of PDE4D7 and CAPRA-S improves patient selection with very high risk of fast disease relapse after primary intervention. ConclusionsThe PDE4D7 score has the potential to provide independent risk information and to restratify patients with clinical intermediate- to high-risk characteristics to a very low-risk profile. Patient summaryIn this report, we studied the potential of a novel biomarker to predict outcomes of a cohort of prostate cancer patients who underwent surgery more than 10 yr ago. We found that a gene called phosphodiesterase-4D7 added extra information to the available clinical data. We conclude that the measurement of this gene in tumor tissue may contribute to more effective treatment decisions.

MP53-02 SERUM TESTOSTERONE LEVEL IS A USEFUL BIOMARKER TO AID OPTIMAL TREATMENT SELECTION IN MEN WITH CASTRATION-RESISTANT PROSTATE CANCER

You have accessJournal of UrologyProstate Cancer: Advanced (including Drug Therapy) III1 Apr 2017MP53-02 SERUM TESTOSTERONE LEVEL IS A USEFUL BIOMARKER TO AID OPTIMAL TREATMENT SELECTION IN MEN WITH CASTRATION-RESISTANT PROSTATE CANCER Kohei Hashimoto, Tetsuya Shindo, Hidetoshi Tabata, Toshiaki Tanaka, Jiro Hashimoto, Ryuta Inoue, Takashi Shimizu, Takashi Muranaka, Hiroshi Hotta, Atsushi Takahashi, Masahiro Yanase, and Naoya Masumori Kohei HashimotoKohei Hashimoto More articles by this author , Tetsuya ShindoTetsuya Shindo More articles by this author , Hidetoshi TabataHidetoshi Tabata More articles by this author , Toshiaki TanakaToshiaki Tanaka More articles by this author , Jiro HashimotoJiro Hashimoto More articles by this author , Ryuta InoueRyuta Inoue More articles by this author , Takashi ShimizuTakashi Shimizu More articles by this author , Takashi MuranakaTakashi Muranaka More articles by this author , Hiroshi HottaHiroshi Hotta More articles by this author , Atsushi TakahashiAtsushi Takahashi More articles by this author , Masahiro YanaseMasahiro Yanase More articles by this author , and Naoya MasumoriNaoya Masumori More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.1653AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Enzalutamide and abiraterone are frequently used for castration-resistant prostate cancer (CRPC), because of improved tolerability of them compared to taxanes. However, there are no predictive biomarkers to make a decision of how to best use abiraterone or enzalutamide. The aim of this study was to clarify the impact of serum testosterone in a decision-making of treatment selections (enzalutamide or abiraterone) for CRPC. METHODS We retrospectively evaluated consecutive CRPC patients treated at our institution and other satellite hospitals between 2013 and May 2016. A total of 115 patients received enzalutamide or abiraterone for CRPC and had serum testosterone measure at the initiation of the treatment were included in this study. The patients were divided into two groups by serum testosterone before enzalutamide or abiraterone: 54 in the testosterone <5 ng/dl group and 61 in the testosterone ≥5 ng/dl group. Prostate-specific antigen (PSA) response rates (defined as ≥50% PSA declines), PSA progression-free survival (PSA-PFS), and overall survival (OS) were compared between groups. RESULTS A total of 72 patients were treated with enzalutamide and 43 with abiraterone. In the testosterone <5 ng/dl group, the PSA response rates were significantly lower with enzalutamide than that with abiraterone (32% vs. 62%, p=0.033), whereas there was no difference in the testosterone ≥5 ng/dl group (81% vs. 93%, p=0.429). During the median follow-up period of 12 months, 68 men (59%) had PSA relapse. In the testosterone <5 ng/dl group, the median PSA-PFS was significantly lower with enzalutamide than that with abiraterone (2.8 months vs. 6.4 months, p=0.004) (Figure). Likewise, it was significantly lower with enzalutamide than that with abiraterone in the testosterone ≥5 ng/dl group (7.6 months vs. no available, p=0.004) (Figure). Multivariate analysis reveals that testosterone ≥5 ng/dl was an independent predictive factor for PSA-PFS (HR 3.1, p<0.001). However, there was no significant difference in the median OS according to the different testosterone groups. CONCLUSIONS This result suggests that serum testosterone level is a useful biomarker in a decision-making of treatment selections in the novel hormonal therapy for CRPC. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e713 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Kohei Hashimoto More articles by this author Tetsuya Shindo More articles by this author Hidetoshi Tabata More articles by this author Toshiaki Tanaka More articles by this author Jiro Hashimoto More articles by this author Ryuta Inoue More articles by this author Takashi Shimizu More articles by this author Takashi Muranaka More articles by this author Hiroshi Hotta More articles by this author Atsushi Takahashi More articles by this author Masahiro Yanase More articles by this author Naoya Masumori More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Diffusion-weighted MRI treatment monitoring of primary hypofractionated proton and carbon ion prostate cancer irradiation using raster scan technique.

To investigate parametric changes in the apparent diffusion coefficient (ADC) at multiple timepoints during and after completion of primary proton and carbon ion irradiation of prostate cancer (PCa) as compared with normal-appearing prostate parenchyma. In all, 92 patients with histologically confirmed PCa received either proton or carbon ion hypofractionated radiotherapy (RT). All were prospectively evaluated with diffusion-weighted magnetic resonance imaging (DWI-MRI) at five timepoints: baseline, day 10 during therapy and 6 weeks, 6 months, and 18 months after treatment. Linear mixed models (LMM) were used to evaluate the effects of radiation, antihormonal therapy, time, and type of particle irradiation on manual ADC measurements. ADC differences related to prostate-specific antigen (PSA) relapse according to PSA thresholds and to Vancouver rules and Phoenix criteria were examined using LMM and unpaired Student's t-test. A measurable and continuous increase of tumor ADC measurements from baseline (1.194 × 10-3 mm2 /s) during (1.350 × 10-3 mm2 /s, day 10, P = 0.006) and after treatment (1.355/1.430/1.490 × 10-3 mm2 /s, week 6 / month 6 / month 18, P = 0.001/<0.001/<0.001) was found. ADC values of normal-appearing control tissue remained unchanged. Androgen deprivation (P ≥ 0.320), different PSA thresholds (P = 0.634), and PSA relapse criteria according to Vancouver rules (P ≥ 0.776) had no effect. A weak association between 18-month measurements and Phoenix criteria (P = 0.046) was found. ADC parametric changes were distinct in tumor tissue, highlighting the ability of diffusion MRI to evaluate different aspects of the microscopic pathophysiology. Although promising, their use as noninvasive imaging biomarkers requires further validation. 1 Technical Efficacy: Stage 1 J. MAGN. RESON. IMAGING 2017;46:850-860.

Treatment of locally advanced prostate cancer (Stage T3).

Formerly, locally advanced prostate cancer exhibited poorly prognosis. In the late 1990s, new surgical and radiation technologies were introduced in combination with androgen deprivation. To evaluate respective strategies, outcomes were examined. Between 2001 and 2010, 224 patients with T3N0M0 (10.9% of all prostate cancer cases) were treated with prostatectomy, external beam radiation therapy with/without androgen deprivation or hormone alone. Complete records were obtained by the end of 2015. Operation group first started without adjuvant treatment and prostate-specific antigen (PSA) relapse occurred in 39% of cases. Radiation therapy group was alternatively divided into two subgroups, that received either monotherapy or combination with androgen deprivation, and PSA relapse rates were 65 and 16%, respectively. High rates of PSA relapse inboth the operation and radiation therapy groups were observed in patients without adjuvant therapy, but after relapse androgen deprivation proceeded favorable outcomes. In the radiation subgroups, PSA relapse rates were different, but both subsequent survival rates were the same. This may be due to the effect of androgen deprivation after relapse, indicating effect of delayed therapy. PSA relapse rate in the hormone therapy group was 25% and after relapse, patients applied to treatment with other hormonal and anticancer drugs. Overall survival rates were 91, 88 and 67% in the operation, radiation therapy and hormone therapy groups, respectively. Aggressive treatment with short-term androgen deprivation for locally advanced prostate cancer could be beneficial and not harmful when suitable candidates are selected. Delayed androgen deprivation was effective for no adjuvant patients after PSA relapse.

11C-acetate positron-emission tomography/computed tomography imaging for detection of recurrent disease after radical prostatectomy or radiotherapy in patients with prostate cancer.

To evaluate, in a prospective study, the effectiveness of computed tomography (CT)-matched 11C-acetate (AC) positron-emission tomography (PET) in patients with prostate cancer (PCa) who had prostate-specific antigen (PSA) relapse after radical prostatectomy (RP) or radiotherapy (RT). In 103 relapsing patients after RP (n = 97) or RT (n = 6) AC-PET images and CT scans were obtained. In patients with AC-PET-positive results with localized PCa recurrence, detected lesions were resected and histologically verified or, after local RT, followed-up by PSA testing. Patients with distant disease on AC-PET were treated with androgen deprivation/chemotherapy. Of 103 patients, 42 were AC-PET-positive. PSA levels were <1.0, <2.0 and <4.0 ng/mL in six, 16 and 20 patients, respectively. In 25/42 patients AC-PET suggested lymph node metastases: 16/25 patients underwent surgery (10/16 metastasis, 6/16 inflammation); 9/25 patients underwent RT of lymph node metastases, which was followed by decreasing PSA level. In 17/42 patients who had distant disease, systemic treatment was commenced. Combining patients who underwent surgery and those who underwent RT, 19/25 patients were true-positive in terms of AC-PET (positive predictive value 76%). In 5/19 patients, PSA level was <2.0 ng/mL, in 2/19 patients it was <1.0 ng/mL and in 14/19 patients it was 5.4-23.1 ng/mL. In AC-PET-positive patients after surgery or RT (without androgen deprivation), median (range) time to renewed PSA increase was 6 (5-9) months. Only a minority of patients with relapsing PCa appear to benefit from AC-PET for guiding potential local treatment. False-positive results show that factors other than tumour metabolism induce increased AC uptake. The time free of recurrence after local treatment was shorter than expected.

Long-term Impact of Adjuvant Versus Early Salvage Radiation Therapy in pT3N0 Prostate Cancer Patients Treated with Radical Prostatectomy: Results from a Multi-institutional Series

BackgroundThree prospective randomised trials reported discordant findings regarding the impact of adjuvant radiation therapy (aRT) versus observation for metastasis-free survival (MFS) and overall survival (OS) among patients with pT3N0 prostate cancer treated with radical prostatectomy (RP). None of these trials systematically included patients who underwent early salvage radiation therapy (esRT). ObjectiveTo test the hypothesis that aRT was associated with better cancer control and survival compared with observation followed by esRT. Design, setting, and participantsUsing a multi-institutional cohort from seven tertiary referral centres, we retrospectively identified 510 pT3pN0 patients with undetectable prostate-specific antigen (PSA) after RP between 1996 and 2009. Patients were stratified into two groups: aRT (group 1) versus observation followed by esRT in case of PSA relapse (group 2). Specifically, esRT was administered at a PSA level ≤0.5ng/ml. InterventionWe compared aRT versus observation followed by esRT. Outcome measurements and statistical analysisThe evaluated outcomes were MFS and OS. Multivariable Cox regression analyses tested the association between groups (aRT vs observation followed by esRT) and oncologic outcomes. Covariates consisted of pathologic stage (pT3a vs pT3b or higher), pathologic Gleason score (≤6, 7, or ≥8), surgical margin status (negative vs positive), and year of surgery. An interaction with groups and baseline patient risk was tested for the hypothesis that the impact of aRT versus observation followed by esRT was different by pathologic characteristics. The nonparametric curve fitting method was used to explore graphically the relationship between MFS and OS at 8 yr and baseline patient risk (derived from the multivariable analysis). Results and limitationsOverall, 243 patients (48%) underwent aRT, and 267 (52%) underwent initial observation. Within the latter group, 141 patients experienced PSA relapse and received esRT. Median follow-up after RP was 94 mo (interquartile range [IQR]: 53–126) and 92 mo (IQR: 70–136), respectively (p=0.2). MFS (92% vs 91%; p=0.9) and OS (89% vs 92%; p=0.9) at 8 yr after surgery were not significantly different between the two groups. These results were confirmed in multivariable analysis, in which observation followed by esRT was not associated with a significantly higher risk of distant metastasis (hazard ratio [HR]: 1.35; p=0.4) and overall mortality (HR: 1.39; p=0.4) compared with aRT. Using the nonparametric curve fitting method, a comparable proportion of MFS and OS at 8 yr among groups was observed regardless of pathologic cancer features (p=0.9 and p=0.7, respectively). Limitations consisted of the retrospective nature of the study and the relatively small size of the patient population. ConclusionsAt long-term follow-up, no significant differences between aRT and esRT were observed for MFS and OS. Our study, although based on retrospective data, suggests that esRT does not compromise cancer control and potentially reduces overtreatment associated with aRT. Patient summaryAt long-term follow-up, no significant differences in terms of distant metastasis and mortality were observed between immediate postoperative adjuvant radiation therapy (aRT) and initial observation followed by early salvage radiation therapy (esRT) in case of prostate-specific antigen relapse. Our study suggests that esRT does not compromise cancer control and potentially reduces overtreatment associated with aRT.

Contemporary Mapping of Post-Prostatectomy Prostate Cancer Relapse with 11C-Choline Positron Emission Tomography and Multiparametric Magnetic Resonance Imaging

We identify sites and patterns of cancer recurrence in patients with post-prostatectomy biochemical relapse using 11C-choline positron emission tomography/computerized tomography and endorectal coil multiparametric magnetic resonance imaging. Between January 2008 and June 2015, 2,466 men underwent choline positron emission tomography for suspected prostate cancer relapse at our institution. Of these men 202 did not receive hormone or radiation therapy, underwent imaging with choline positron emission tomography and multiparametric magnetic resonance imaging, and were found to have disease recurrence. Overall patterns of recurrence were described, and factors associated with local only recurrence were evaluated using univariable and multivariable logistic regression. Median prostate specific antigen at positive scan was 2.3 ng/ml (IQR 1.4-5.5) with a median time from prostate specific antigen relapse to lesion visualization of 15 months (IQR 4.8-34.2). Of these 202 men 68 (33%) exhibited local only, 45 (22%) local plus metastatic and 89 (45%) metastatic only relapse. Pelvic node only relapse was observed in 39 (19%) men. Median prostate specific antigen at positive imaging for patients with local only, metastatic only and local plus metastatic relapse was 2.3, 2.7 and 2.2 ng/ml (p=0.46), with a median interval from biochemical recurrence to positive scan of 33.5, 7.0 and 15.0 months, respectively (p <0.001). On multivariable analysis time from biochemical recurrence to positive imaging was independently associated with local only recurrence (OR 1.10 for every 6-month increase, p=0.012). Combined choline positron emission tomography and multiparametric magnetic resonance imaging evaluation of biochemical recurrence after prostatectomy reveals an anatomically diverse pattern of recurrence. These findings have implications for optimizing the salvage treatment of patients with prostate cancer with relapse following surgery.