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Background: The delineation of intraprostatic lesions is vital for correct delivery of focal radiotherapy boost in patients with prostate cancer (PC). Errors in the delineation could translate into reduced tumour control and potentially increase the side effects. The purpose of this study is to compare PET-based delineation methods with histopathology., Materials and Methods: The study population consisted of 15 patients with confirmed high-risk PC intended for prostatectomy. [68Ga]-PSMA-PET/MR was performed prior to surgery. Prostate lesions identified in histopathology were transferred to the in vivo [68Ga]-PSMA-PET/MR coordinate system. Four radiation oncologists manually delineated intraprostatic lesions based on PET data. Various semi-automatic segmentation methods were employed, including absolute and relative thresholds, adaptive threshold, and multi-level Otsu threshold., Results: The gross tumour volumes (GTVs) delineated by the oncologists showed a moderate level of interobserver agreement with Dice similarity coefficient (DSC) of 0.68. In comparison with histopathology, manual delineations exhibited the highest median DSC and the lowest false discovery rate (FDR) among all approaches. Among semi-automatic approaches, GTVs generated using standardized uptake value (SUV) thresholds above 4 (SUV > 4) demonstrated the highest median DSC (0.41), with 0.51 median lesion coverage ratio, FDR of 0.66 and the 95th percentile of the Hausdorff distance (HD95%) of 8.22 mm., Interpretation: Manual delineations showed a moderate level of interobserver agreement. Compared to histopathology, manual delineations and SUV > 4 exhibited the highest DSC and the lowest HD95% values. The methods that resulted in a high lesion coverage were associated with a large overestimation of the size of the lesions.

Background: Historically, endocrine therapy was used in a range of scenarios in patients with rising PSA, both as a treatment for locally advanced non-metastatic prostate cancer and PSA recurrence following curative intended therapy. In the present study the objective was to investigate if chemotherapy added to endocrine therapy could improve progression-free survival (PFS)., Materials and Methods: Patients with hormone-naïve, non-metastatic prostate cancer and rising prostate-specific antigen (PSA), enrolled from Sweden, Denmark, the Netherlands, and Finland, were randomized to long-term bicalutamide (150 mg daily) or plus docetaxel (75 mg/m 2 , q3w, 8-10 cycles) without prednisone, after stratification for the site, prior local therapy or not, and PSA doubling time. The primary endpoint was 5-year PFS analyzed with a stratified Cox proportional hazards regression model on intention to treat basis., Results: Between 2009 and 2018, a total of 348 patients were randomized; 315 patients had PSA relapse after radical treatment, 33 patients had no prior local therapy. Median follow-up was 4.9 years (IQR 4.0-5.1). Adding docetaxel improved PFS (HR 0.68, 95% CI 0.50-0.93; p  = 0.015). Docetaxel showed an advantage for patients with PSA relapse after prior local therapy (HR 0.67, 95% CI 0.49-0.94; p  = 0.019). One event of neutropenic infection/fever occurred in 27% of the patients receiving docetaxel. Limitations were slow recruitment, lack of enrolling patients without radical local treatment, and too short follow-up for evaluation of overall survival in patients with PSA relapse., Conclusion: Docetaxel improved PFS in patients starting bicalutamide due to PSA relapse after local therapy or localized disease without local therapy. Confirmatory studies of the efficacy of docetaxel in the setting of PSA-only relapse in addition to endocrine therapies may be justified if longer follow-up will show increased metastatic-free survival.

Background: Perirectal spacers may be beneficial to reduce rectal side effects from radiotherapy (RT). Here, we present the impact of a hyaluronic acid (HA) perirectal spacer on rectal dose as well as spacer stability, long-term gastrointestinal (GI) and genitourinary (GU) toxicity and patient-reported outcome (PRO)., Methods: In this phase II study 81 patients with low- and intermediate-risk prostate cancer received transrectal injections with HA before external beam RT (78 Gy in 39 fractions). The HA spacer was evaluated with MRI four times; before (MR0) and after HA-injection (MR1), at the middle (MR2) and at the end (MR3) of RT. GI and GU toxicity was assessed by physician for up to five years according to the RTOG scale. PROs were collected using the Swedish National Prostate Cancer Registry and Prostate cancer symptom scale questionnaires., Results: There was a significant reduction in rectal V70% (54.6 Gy) and V90% (70.2 Gy) between MR0 and MR1, as well as between MR0 to MR2 and MR3. From MR1 to MR2/MR3, HA thickness decreased with 28%/32% and CTV-rectum space with 19%/17% in the middle level. The cumulative late grade ≥ 2 GI toxicity at 5 years was 5% and the proportion of PRO moderate or severe overall bowel problems at 5 years follow-up was 12%. Cumulative late grade ≥ 2 GU toxicity at 5 years was 12% and moderate or severe overall urinary problems at 5 years were 10%., Conclusion: We show that the HA spacer reduced rectal dose and long-term toxicity., (© 2023. The Author(s).)

To improve treatment of metastatic prostate cancer, the biology of metastases needs to be understood. We recently described three subtypes of prostate cancer bone metastases (MetA-C), based on differential gene expression. The aim of this study was to verify the clinical relevance of these subtypes and to explore their biology and relations to genetic drivers. Freshly-frozen metastasis samples were obtained as hormone-naive (n = 17), short-term castrated (n = 21), or castration-resistant (n = 65) from a total of 67 patients. Previously published sequencing data from 573 metastasis samples were also analyzed. Through transcriptome profiling and sample classification based on a set of predefined MetA-C-differentiating genes, we found that most metastases were heterogeneous for the MetA-C subtypes. Overall, MetA was the most common subtype, while MetB was significantly enriched in castration-resistant samples and in liver metastases, and consistently associated with poor prognosis. By gene set enrichment analysis, the phenotype of MetA was described by high androgen response, protein secretion and adipogenesis, MetB by high cell cycle activity and DNA repair, and MetC by epithelial-to-mesenchymal transition and inflammation. The MetB subtype demonstrated single nucleotide variants of RB transcriptional corepressor 1 (RB1) and loss of 21 genes at chromosome 13, including RB1, but provided independent prognostic value to those genetic aberrations. In conclusion, a distinct set of gene transcripts can be used to classify prostate cancer metastases into the subtypes MetA-C. The MetA-C subtypes show diverse biology, organ tropism, and prognosis. The MetA-C classification may be used independently, or in combination with genetic markers, primarily to identify MetB patients in need of complementary therapy to conventional androgen receptor-targeting treatments., (© 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Background: Patients with metastatic prostate cancer (PC) are treated with androgen deprivation therapy (ADT) that initially reduces metastasis growth, but after some time lethal castration-resistant PC (CRPC) develops. A better understanding of the tumor biology in bone metastases is needed to guide further treatment developments. Subgroups of PC bone metastases based on transcriptome profiling have been previously identified by our research team, and specifically, heterogeneities related to androgen receptor (AR) activity have been described. Epigenetic alterations during PC progression remain elusive and this study aims to explore promoter gene methylation signatures in relation to gene expression and tumor AR activity., Materials and Methods: Genome-wide promoter-associated CpG methylation signatures of a total of 94 tumor samples, including paired non-malignant and malignant primary tumor areas originating from radical prostatectomy samples (n = 12), and bone metastasis samples of separate patients with hormone-naive (n = 14), short-term castrated (n = 4) or CRPC (n = 52) disease were analyzed using the Infinium Methylation EPIC arrays, along with gene expression analysis by Illumina Bead Chip arrays (n = 90). AR activity was defined from expression levels of genes associated with canonical AR activity., Results: Integrated epigenome and transcriptome analysis identified pronounced hypermethylation in malignant compared to non-malignant areas of localized prostate tumors. Metastases showed an overall hypomethylation in relation to primary PC, including CpGs in the AR promoter accompanied with induction of AR mRNA levels. We identified a Methylation Classifier for Androgen receptor activity (MCA) signature, which separated metastases into two clusters (MCA positive/negative) related to tumor characteristics and patient prognosis. The MCA positive metastases showed low methylation levels of genes associated with canonical AR signaling and patients had a more favorable prognosis after ADT. In contrast, MCA negative patients had low AR activity associated with hypermethylation of AR-associated genes, and a worse prognosis after ADT., Conclusions: A promoter methylation signature classifies PC bone metastases into two groups and predicts tumor AR activity and patient prognosis after ADT. The explanation for the methylation diversities observed during PC progression and their biological and clinical relevance need further exploration.

Background: Prostate cancer (PC) metastasizes to the skeleton forming predominantly sclerotic lesions, and there is currently no cure for bone metastatic disease. The transcription factor signal transducer and activator of transcription 3 (STAT3) is implicated as a metastatic driver, but its potential as therapeutic target in bone metastasis has not been investigated. In this study, we evaluated for the first time a STAT3 inhibitor, Napabucasin, as a therapeutic option for bone metastatic PC., Methods: Effects of STAT3 inhibitors, Stattic and Napabucasin, on metastatic potential in PC cells were studied in vitro by assessment of migration capacity, self-renewal potential, and tumorsphere formation. For evaluation of the role of STAT3 in initial skeletal establishment of PC cells as well as in progressed castration-resistant PC (CRPC) in bone, human VCaP prostate cancer cells were inoculated in the tibia of mice which subsequently were treated with the STAT3 inhibitor Napabucasin. Bone specimens were analyzed using computed tomography (CT), immunohistochemistry, and quantitative polymerase chain reaction., Results: The small molecule STAT3 inhibitors Stattic and Napabucasin both effectively impaired metastatic potential of PC cells in vitro. Furthermore, treatment with Napabucasin prevented metastatic establishment in tibial bones in vivo and thereby also the tumor-induced sclerotic bone response seen in vehicle-treated VCaP xenografts. In addition, treatment with Napabucasin of established bone CRPC significantly decreased both tumor burden and tumor-induced trabecular bone volume compared with effects seen in vehicle-treated animals. Anti-mitotic effects were confirmed by decreased Ki67 staining in Napabucasin-treated xenografts compared with vehicle-treated xenografts. Alterations of gene expression in the femoral bone marrow (BM) niche toward the maintenance of hematopoietic stem cells and the myeloid lineage were demonstrated by quantitative real-time polymerase chain reaction and were further reflected by a substantial increase in the number of erythrocytes in BM of Napabucasin-treated mice. Furthermore, a unique pattern of STAT3 phosphorylation in osteoblasts/stromal cells surrounding the areas of tumor cells was demonstrated immunohistochemically in bone xenograft models using several different PC cell lines., Conclusion: Inhibition of STAT3 activity disrupts the bone metastatic niche and targets both the skeletal establishment of PC and advanced bone metastatic CRPC in mice, suggesting STAT3 as a candidate for molecular targeted therapies of skeletal metastatic disease., (© 2021 The Authors. The Prostate published by Wiley Periodicals LLC.)

Background: The HYPO-RT-PC trial compared conventionally fractionated radiotherapy with ultra-hypofractionated radiotherapy in patients with localised prostate cancer. Ultra-hypofractionation was non-inferior to conventional fractionation regarding 5-year failure-free survival and toxicity. We aimed to assess whether patient-reported quality of life (QOL) differs between conventional fractionation and ultra-hypofractionation up to 6 years after treatment in the HYPO-RT-PC trial., Methods: HYPO-RT-PC is a multicentre, open-label, randomised, controlled, non-inferiority, phase 3 trial done in 12 centres (seven university hospitals and five county hospitals) in Sweden and Denmark. Inclusion criteria were histologically verified intermediate-to-high-risk prostate cancer (defined as T1c-T3a with one or two of the following risk factors: stage T3a; Gleason score ≥7; and prostate-specific antigen 10-20 ng/mL with no evidence of lymph node involvement or distant metastases), age up to 75 years, and WHO performance status 0-2. Participants were randomly assigned (1:1) to conventional fractionation (78·0 Gy in 39 fractions, 5 days per week for 8 weeks) or ultra-hypofractionation (42·7 Gy in seven fractions, 3 days per week for 2·5 weeks) via a minimisation algorithm with stratification by trial centre, T-stage, Gleason score, and prostate-specific antigen. QOL was measured using the validated Prostate Cancer Symptom Scale (PCSS) and European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30) at baseline, the end of radiotherapy, months 3, 6, 12, and 24 after radiotherapy, every other year thereafter up to 10 years, and at 15 years. The primary endpoint (failure-free survival) has been reported elsewhere. Here we report QOL, a secondary endpoint analysed in the per-protocol population, up to 6 years after radiotherapy. The HYPO-RT-PC trial is registered with the ISRCTN registry, ISRCTN45905321., Findings: Between July 1, 2005, and Nov 4, 2015, 1200 patients were enrolled and 1180 were randomly assigned (conventional fractionation n=591, ultra-hypofractionation n=589); 1165 patients (conventional fractionation n=582, ultra-hypofractionation n=583) were included in this QOL analysis. 158 (71%) of 223 patients in the conventional fractionation group and 146 (66%) of 220 in the ultra-hypofractionation group completed questionnaires at 6 years. The median follow-up was 48 months (IQR 25-72). In seven of ten bowel symptoms or problems the proportion of patients with clinically relevant deteriorations at the end of radiotherapy was significantly higher in the ultra-hypofractionation group than in the conventional fractionation group (stool frequency [p<0·0001], rush to toilet [p=0·0013], flatulence [p=0·0013], bowel cramp [p<0·0001], mucus [p=0·0014], blood in stool [p<0·0001], and limitation in daily activity [p=0·0014]). There were no statistically significant differences in the proportions of patients with clinically relevant acute urinary symptoms or problems (total 14 items) and sexual functioning between the two treatment groups at end of radiotherapy. Thereafter, there were no clinically relevant differences in urinary, bowel, or sexual functioning between the groups. At the 6-year follow-up there was no difference in the incidence of clinically relevant deterioration between the groups for overall urinary bother (43 [33%] of 132 for conventional fractionation vs 33 [28%] of 120 for ultra-hypofractionation; mean difference 5·1% [95% CI -4·4 to 14·6]; p=0·38), overall bowel bother (43 [33%] of 129 vs 34 [28%] of 123; 5·7% [-3·8 to 15·2]; p=0·33), overall sexual bother (75 [60%] of 126 vs 59 [50%] of 117; 9·1% [-1·4 to 19·6]; p=0·15), or global health/QOL (56 [42%] of 134 vs 46 [37%] of 125; 5·0% [-5·0 to 15·0]; p=0·41)., Interpretation: Although acute toxicity was higher for ultra-hypofractionation than conventional fractionation, this long-term patient-reported QOL analysis shows that ultra-hypofractionation was as well tolerated as conventional fractionation up to 6 years after completion of treatment. These findings support the use of ultra-hypofractionation radiotherapy for intermediate-to-high-risk prostate cancer., Funding: The Nordic Cancer Union, the Swedish Cancer Society, and the Swedish Research Council., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: Radiotherapy is an established treatment option for prostate cancer (PCa), both as primary treatment and secondary treatment after radical prostatectomy (RP). Since 1998, detailed data on radiotherapy delivered to Swedish men with PCa (e.g. treatment modalities, absorbed doses, fractionation) have been collated within PCa data Base Sweden (PCBaSe). This study reports patterns of radical radiotherapy for PCa in Sweden over the past two decades. Materials and methods: All men with non-metastatic PCa (1998-2016) who received external beam radiotherapy (EBRT) or high or low dose-rate brachytherapy (HDR-BT/LDR-BT) were identified in PCBaSe. Analyses included: trends in radiation techniques, fractionation patterns and total doses over time; PCa-specific survival comparing treatment in 2007-2017 with 1998-2006; and regional variation in type of primary radiotherapy. Results: About 20,876 men underwent primary radiotherapy. The main treatment modalities include conventionally fractionated (2.0 Gy/fraction) EBRT (51%), EBRT with HDR-BT boost (27%) and hypofractionated (>2.4 Gy/fraction) EBRT (11%). EBRT with photon or proton boost and HDR-BT and LDR-BT monotherapies were each used minimally. Use of dose-escalated EBRT (>74 Gy) and moderate hypofractionation increased over time, while use of HDR-BT declined. Considerable regional variation in treatment modalities was apparent. Risk of PCa death following primary radiotherapy had declined for intermediate-risk (HR: 0.60; 95%CI 0.47-0.87) and high-risk PCa (HR: 0.72; 95%CI 0.61-0.86). Discussion: Increased use of dose escalation and hypofractionated EBRT has occurred in Sweden over the past two decades, reflecting current evidence and practice guidelines. Disease-specific outcomes have also improved. Data collected in PCBaSe provide an excellent resource for further research into RT use in PCa management.

Purpose: To study the relationships between absorbed dose to penile base structures and erectile dysfunction (ED) in patients treated with ultrahypofractionated (UHF) radiation therapy (RT) or conventionally fractionated (CF) RT for prostate cancer., Methods and Materials: This dose-response study comprises 673 patients (57%) of the 1180 per-protocol patients included in the HYPO-RT-PC trial (median follow-up 5, years), where patients were randomized to CF (39 × 2.0 Gy, 8 weeks) or UHF (7 × 6.1 Gy, 2.5 weeks). No androgen deprivation therapy was allowed. Only patients with erectile function sufficient for intercourse at baseline and complete RT data were included in this study. Erectile function was assessed by physician at regular follow-ups. The main endpoint was severe ED (ED s ). The penile bulb (PB) and crus were retrospectively delineated on the treatment planning computed tomography scans. Dose-volume descriptors were derived from EQD2 converted dose matrices (α/β = 3 Gy). Univariable and multivariable Cox proportional hazard regression and logistic regression were used to find predictors for ED S ., Results: No significant difference in ED s was found between CF and UHF. During the follow-up period, ED s occurred in 27% of the patients in both treatment groups. Average (median) PB mean dose, D mean, was 24.5 (20.2) in CF and 18.7 (13.1) Gy 3 in UHF. Age was the only significant predictor for ED s in Cox analyses. All dose-volume variables contributed significantly in univariable logistic regression at 2-year follow-up. Age and near maximum dose (D 2% ) were significant predictors for ED s in multivariable logistic regression analyses at both 1 and 2 years., Conclusions: The frequency of ED S was similar in the CF and UHF treatment groups. Age at radiation therapy was the strongest predictor for ED s , followed by dose to PB, and was most evident for younger patients. We propose D 2 % <50 Gy 3 and D mean <20 Gy 3 to the PB as the primary objectives to be applied in the treatment planning process., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Curative radiation therapy (RT) constitutes a cornerstone in prostate cancer (PC) treatment. We present long-term follow-up estimates for second cancer (SC) risk and overall survival (OS) in patients randomized to hormone therapy (ET) alone or combined with 70 Gy prostatic RT in the Scandinavian Prostate Cancer Group-7 (SPCG-7) study. We explored the effect of salvage RT (≥60 Gy to the ET group) and reported causes of death., Methods and Materials: The SPCG-7 study (1996-2002) was a randomized controlled trial that included 875 men with locally advanced nonmetastatic PC. In this analysis, including data from the Norwegian and Swedish Cancer and Cause of Death registries for 651 Norwegian and 209 Swedish study patients, we estimated hazard ratios (HRs) for SC and death, and cumulative incidences of SC., Results: Median follow-up of the 860 (431 ET and 429) ET + RT patients was 12.2 years for SC risk analysis and 12.6 years for the OS analysis. Eighty-three of the Norwegian ET patients received salvage RT, and median time to salvage RT was 5.9 years. We found 125 and 168 SCs in the ET and ET + RT patients, respectively. With ET alone as reference, ET + RT patients had an HR of 1.19 (95% confidence interval [CI], 0.92-1.54) for all SCs and 2.54 (95% CI, 1.14-5.69) for urinary bladder cancer (UBC). The total number of UBC was 31 (23 in ET + RT; 8 in ET), and the vast majority (85%) were superficial. The HR for SC in salvage RT patients was 0.48 (95% CI, 0.24-0.94). Median OS was 12.8 (95% CI, 11.8-13.8) and 15.3 (95%, CI 14.3-16.4) years in the ET and ET + RT groups, respectively. Compared with ET alone, the risk of death was reduced in ET + RT patients (HR, 0.73; 95% CI, 0.62-0.86) and in ET patients receiving salvage RT (HR, 0.44; 95% CI, 0.30-0.65)., Conclusions: Although the risk of UBC was increased in PC patients who received RT in addition to ET, this disadvantage is outweighed by the OS benefit of RT confirmed in our study. The risk of SC, and especially UBC, should be discussed with patients and be reflected in follow-up programs., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Taxane treatment may be a suitable therapeutic option for patients with castration-resistant prostate cancer and high expression of constitutively active androgen receptor variants (AR-Vs). The aim of the study was to compare the effects of cabazitaxel and androgen deprivation treatments in a prostate tumor xenograft model expressing high levels of constitutively active AR-V7. Furthermore, mechanisms behind acquired cabazitaxel resistance were explored., Methods: Mice were subcutaneously inoculated with 22Rv1 cells and treated with surgical castration (n = 7), abiraterone (n = 9), cabazitaxel (n = 6), castration plus abiraterone (n = 8), castration plus cabazitaxel (n = 11), or vehicle and/or sham operation (n = 23). Tumor growth was followed for about 2 months or to a volume of approximately 1000 mm 3 . Two cabazitaxel resistant cell lines; 22Rv1-CabR1 and 22Rv1-CabR2, were established from xenografts relapsing during cabazitaxel treatment. Differential gene expression between the cabazitaxel resistant and control 22Rv1 cells was examined by whole-genome expression array analysis followed by immunoblotting, immunohistochemistry, and functional pathway analysis., Results: Abiraterone treatment alone or in combination with surgical castration had no major effect on 22Rv1 tumor growth, while cabazitaxel significantly delayed and in some cases totally abolished 22Rv1 tumor growth on its own and in combination with surgical castration. The cabazitaxel resistant cell lines; 22Rv1-CabR1 and 22Rv1-CabR2, both showed upregulation of the ATP-binding cassette sub-family B member 1 (ABCB1) efflux pump. Treatment with ABCB1 inhibitor elacridar completely restored susceptibility to cabazitaxel, while treatment with AR-antagonists bicalutamide and enzalutamide partly restored susceptibility to cabazitaxel in both cell lines. The cholesterol biosynthesis pathway was induced in the 22Rv1-CabR2 cell line, which was confirmed by reduced sensitivity to simvastatin treatment., Conclusions: Cabazitaxel efficiently inhibits prostate cancer growth despite the high expression of constitutively active AR-V7. Acquired cabazitaxel resistance involving overexpression of efflux transporter ABCB1 can be reverted by bicalutamide or enzalutamide treatment, indicating the great clinical potential for combined treatment with cabazitaxel and anti-androgens., (© 2019 The Authors. The Prostate Published by Wiley Periodicals, Inc.)

Background: Hypofractionated radiotherapy for prostate cancer has gained increased attention due to its proposed high radiation-fraction sensitivity. Recent reports from studies comparing moderately hypofractionated and conventionally fractionated radiotherapy support the clinical use of moderate hypofractionation. To date, there are no published randomised studies on ultra-hypofractionated radiotherapy. Here, we report the outcomes of the Scandinavian HYPO-RT-PC phase 3 trial with the aim to show non-inferiority of ultra-hypofractionation compared with conventional fractionation., Methods: In this open-label, randomised, phase 3 non-inferiority trial done in 12 centres in Sweden and Denmark, we recruited men up to 75 years of age with intermediate-to-high-risk prostate cancer and a WHO performance status between 0 and 2. Patients were randomly assigned to ultra-hypofractionation (42·7 Gy in seven fractions, 3 days per week for 2·5 weeks) or conventional fractionated radiotherapy (78·0 Gy in 39 fractions, 5 days per week for 8 weeks). No androgen deprivation therapy was allowed. The primary endpoint was time to biochemical or clinical failure, analysed in the per-protocol population. The prespecified non-inferiority margin was 4% at 5 years, corresponding to a critical hazard ratio (HR) limit of 1·338. Physician-recorded toxicity was measured according to the Radiation Therapy Oncology Group (RTOG) morbidity scale and patient-reported outcome measurements with the Prostate Cancer Symptom Scale (PCSS) questionnaire. This trial is registered with the ISRCTN registry, number ISRCTN45905321., Findings: Between July 1, 2005, and Nov 4, 2015, 1200 patients were randomly assigned to conventional fractionation (n=602) or ultra-hypofractionation (n=598), of whom 1180 (591 conventional fractionation and 589 ultra-hypofractionation) constituted the per-protocol population. 1054 (89%) participants were intermediate risk and 126 (11%) were high risk. Median follow-up time was 5·0 years (IQR 3·1-7·0). The estimated failure-free survival at 5 years was 84% (95% CI 80-87) in both treatment groups, with an adjusted HR of 1·002 (95% CI 0·758-1·325; log-rank p=0·99). There was weak evidence of an increased frequency of acute physician-reported RTOG grade 2 or worse urinary toxicity in the ultra-hypofractionation group at end of radiotherapy (158 [28%] of 569 patients vs 132 [23%] of 578 patients; p=0·057). There were no significant differences in grade 2 or worse urinary or bowel late toxicity between the two treatment groups at any point after radiotherapy, except for an increase in urinary toxicity in the ultra-hypofractionation group compared to the conventional fractionation group at 1-year follow-up (32 [6%] of 528 patients vs 13 [2%] of 529 patients; (p=0·0037). We observed no differences between groups in frequencies at 5 years of RTOG grade 2 or worse urinary toxicity (11 [5%] of 243 patients for the ultra-hypofractionation group vs 12 [5%] of 249 for the conventional fractionation group; p=1·00) and bowel toxicity (three [1%] of 244 patients vs nine [4%] of 249 patients; p=0·14). Patient-reported outcomes revealed significantly higher levels of acute urinary and bowel symptoms in the ultra-hypofractionation group compared with the conventional fractionation group but no significant increases in late symptoms were found, except for increased urinary symptoms at 1-year follow-up, consistent with the physician-evaluated toxicity., Interpretation: Ultra-hypofractionated radiotherapy is non-inferior to conventionally fractionated radiotherapy for intermediate-to-high risk prostate cancer regarding failure-free survival. Early side-effects are more pronounced with ultra-hypofractionation compared with conventional fractionation whereas late toxicity is similar in both treatment groups. The results support the use of ultra-hypofractionation for radiotherapy of prostate cancer., Funding: The Nordic Cancer Union, the Swedish Cancer Society, and the Swedish Research Council., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Bone metastasis is the lethal end-stage of prostate cancer (PC), but the biology of bone metastases is poorly understood. The overall aim of this study was therefore to explore molecular variability in PC bone metastases of potential importance for therapy. Specifically, genome-wide expression profiles of bone metastases from untreated patients (n = 12) and patients treated with androgen-deprivation therapy (ADT, n = 60) were analyzed in relation to patient outcome and to morphological characteristics in metastases and paired primary tumors. Principal component analysis and unsupervised classification were used to identify sample clusters based on mRNA profiles. Clusters were characterized by gene set enrichment analysis and related to histological and clinical parameters using univariate and multivariate statistics. Selected proteins were analyzed by immunohistochemistry in metastases and matched primary tumors (n = 52) and in transurethral resected prostate (TUR-P) tissue of a separate cohort (n = 59). Three molecular subtypes of bone metastases (MetA-C) characterized by differences in gene expression pattern, morphology, and clinical behavior were identified. MetA (71% of the cases) showed increased expression of androgen receptor-regulated genes, including prostate-specific antigen (PSA), and glandular structures indicating a luminal cell phenotype. MetB (17%) showed expression profiles related to cell cycle activity and DNA damage, and a pronounced cellular atypia. MetC (12%) exhibited enriched stroma-epithelial cell interactions. MetB patients had the lowest serum PSA levels and the poorest prognosis after ADT. Combined analysis of PSA and Ki67 immunoreactivity (proliferation) in bone metastases, paired primary tumors, and TUR-P samples was able to differentiate MetA-like (high PSA, low Ki67) from MetB-like (low PSA, high Ki67) tumors and demonstrate their different prognosis. In conclusion, bone metastases from PC patients are separated based on gene expression profiles into molecular subtypes with different morphology, biology, and clinical outcome. These findings deserve further exploration with the purpose of improving treatment of metastatic PC., (© 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

Purpose: Bone is the most predominant site of distant metastasis in prostate cancer, and patients have limited therapeutic options at this stage. Experimental Design: We performed a system-wide quantitative proteomic analysis of bone metastatic prostate tumors from 22 patients operated to relieve spinal cord compression. At the time of surgery, most patients had relapsed after androgen-deprivation therapy, while 5 were previously untreated. An extended cohort of prostate cancer bone metastases ( n = 65) was used for immunohistochemical validation. Results: On average, 5,067 proteins were identified and quantified per tumor. Compared with primary tumors ( n = 26), bone metastases were more heterogeneous and showed increased levels of proteins involved in cell-cycle progression, DNA damage response, RNA processing, and fatty acid β-oxidation; and reduced levels of proteins were related to cell adhesion and carbohydrate metabolism. Within bone metastases, we identified two phenotypic subgroups: BM1, expressing higher levels of AR canonical targets, and mitochondrial and Golgi apparatus resident proteins; and BM2, with increased expression of proliferation and DNA repair-related proteins. The two subgroups, validated by the inverse correlation between MCM3 and prostate specific antigen immunoreactivity, were related to disease prognosis, suggesting that this molecular heterogeneity should be considered when developing personalized therapies. Conclusions: This work is the first system-wide quantitative characterization of the proteome of prostate cancer bone metastases and a valuable resource for understanding the etiology of prostate cancer progression. Clin Cancer Res; 24(21); 5433-44. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Background: Transforming growth factor β (TGFβ) functions as a double-edged sword in prostate cancer tumorigenesis. In initial stages of the disease, TGFβ acts as a growth inhibitor upon tumor cells, whereas it in later stages of disease rather promotes invasion and metastatic potential. One well-known cellular source of TGFβ in the bone metastatic site is the bone-forming osteoblasts. Here we have studied the effects by osteoblast-derived factors on metastatic potential in several human prostate cancer cell lines., Methods: Effects on metastatic potential in prostate cancer cells by osteoblast-derived factors were studied in vitro using several methods, including Transwell migration and evaluation of formation of pro-migratory protrusions. Confocal microscopy was used to evaluate possible changes in differentiation state in tumor cells by analysis of markers for epithelial-to-mesenchymal transition (EMT). The Matrigel-on-top 3D culture method was used for further assessment of metastatic characteristics in tumor cells by analysis of formation of filopodium-like protrusions (FLPs)., Results: Osteoblast-derived factors increased migration of PC-3U cells, an effect less prominent in cells overexpressing a mutated type I TGFβ receptor (TβRI) preventing non-canonical TRAF6-dependent TGFβ signaling. Osteoblast-derived factors also increased the formation of long protrusions and loss of cell-cell contacts in PC-3U cells, suggesting induction of a more aggressive phenotype. In addition, treatment with TGFβ or osteoblast-derived factors of PC-3U cells in Matrigel-on-top 3D cultures promoted formation of FLPs, previously shown to be essential for metastatic establishment., Conclusions: These findings suggests that factors secreted from osteoblasts, including TGFβ, can induce several cellular traits involved in metastatic potential of PC-3U cells, further strengthening the role for bone cells to promote metastatic tumor cell behavior., (© 2018 Wiley Periodicals, Inc.)

Advanced prostate cancer frequently metastasizes to bone and induces a mixed osteoblastic/osteolytic bone response. Standard treatment for metastatic prostate cancer is androgen-deprivation therapy (ADT) that also affects bone biology. Treatment options for patients relapsing after ADT are limited, particularly in cases where castration-resistance does not depend on androgen receptor (AR) activity. Patients with non-AR driven metastases may, however, benefit from therapies targeting the tumor microenvironment. Therefore, the current study specifically investigated bone cell activity in clinical bone metastases in relation to tumor cell AR activity, in order to gain novel insight into biological heterogeneities of possible importance for patient stratification into bone-targeting therapies. Metastasis tissue obtained from treatment-na&iuml;ve ( n = 11) and castration-resistant ( n = 28) patients was characterized using whole-genome expression analysis followed by multivariate modeling, functional enrichment analysis, and histological evaluation. Bone cell activity was analyzed by measuring expression levels of predefined marker genes representing osteoclasts ( ACP5 , CTSK , MMP9 ), osteoblasts ( ALPL , BGLAP , RUNX2 ) and osteocytes ( SOST ). Principal component analysis indicated a positive correlation between osteoblast and osteoclast activity and a high variability in bone cell activity between different metastases. Immunohistochemistry verified a positive correlation between runt-related transcription factor 2 (RUNX2) positive osteoblasts and tartrate-resistant acid phosphatase (TRAP, encoded by ACP5 ) positive osteoclasts lining the metastatic bone surface. No difference in bone cell activity was seen between treatment-na&iuml;ve and castration-resistant patients. Importantly, bone cell activity was inversely correlated to tumor cell AR activity (measured as AR , FOXA1 , HOXB13 , KLK2 , KLK3 , NKX3-1 , STEAP2 , and TMPRSS2 expression) and to patient serum prostate-specific antigen (PSA) levels. Functional enrichment analysis indicated high bone morphogenetic protein (BMP) signaling in metastases with high bone cell activity and low tumor cell AR activity. This was confirmed by BMP4 immunoreactivity in tumor cells of metastases with ongoing bone formation, as determined by histological evaluation of van Gieson-stained sections. In conclusion, the inverse relation observed between bone cell activity and tumor cell AR activity in prostate cancer bone metastasis may be of importance for patient response to AR and/or bone targeting therapies, but needs to be evaluated in clinical settings in relation to serum markers for bone remodeling, radiography and patient response to therapy. The importance of BMP signaling in the development of sclerotic metastasis lesions deserves further exploration.

Background: There are no conclusive results from randomized trials on radiotherapy (RT) versus radical prostatectomy (RP) for prostate cancer. Numerous observational studies have suggested that RP is associated with a lower risk of prostate cancer death, but whether results have been biased due to limited adjustments for confounding factors is unknown., Objective: To compare the risk of prostate cancer death after RT versus RP., Design, Setting, and Participants: Nationwide population-based observational study of men in the Prostate Cancer data Base Sweden 3.0 who had undergone RT or RP between 1998 and 2012., Outcome Measurements and Statistical Analysis: Prostate cancer deaths were compared. Hazard ratios (HRs) were calculated in Cox regression models, including clinical T stage, M stage, Gleason grade group, serum levels of prostate-specific antigen, proportion of biopsy cores with cancer, mode of detection, comorbidity, age, educational level, and civil status. Period analysis with left truncation was performed., Results and Limitations: Primary treatment was RT or RP for 41 503 men. Treatment effect was associated with disease severity. In univariate analysis of RT versus RP, risk of prostate cancer death was higher after RT-low- and intermediate-risk cancer, HR 1.82 (95% confidence interval [CI]: 1.53-2.16), and high-risk cancer, HR 1.57 (95% CI: 1.33-1.85). After full adjustment in period analysis, this difference between the treatments was attenuated-low- and intermediate-risk cancer, HR 1.24 (95% CI: 0.97-1.58), and high-risk cancer, HR 1.03 (95% CI: 0.81-1.31). Confounding remained due to nonrandom allocation to treatment., Conclusions: In comparison with previous studies, the difference in prostate cancer mortality after RT and RP was much smaller., Patient Summary: The difference in prostate cancer mortality after contemporary radiotherapy and radical prostatectomy was small in contrast to previous studies, indicating that potential side effects should be more emphasized when selecting treatment., (Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: There is increasing low-quality evidence rationalizing the use of radical therapy for men at high risk of disseminated prostate cancer., Objective: To investigate, using high-quality epidemiologic data, whether initial radical therapy in men at high risk of disseminated prostate cancer improves survival., Design, Setting, and Participants: An observational population-based Swedish study from 1996 to 2010 of men at high risk of disseminated prostate cancer (prostate-specific antigen [PSA] >50) initially treated by radical therapy (radiation therapy [n=630] or radical prostatectomy [n=120]) or androgen deprivation therapy (n=17 602), and followed for up to 15 yr., Outcome Measurements and Statistical Analysis: Prostate-cancer and other-cause mortality was estimated for the treatment groups. We also matched the two cohorts for grade, T stage, M stage, Charlson score, year of diagnosis, age, and PSA, and found androgen deprivation therapy patient matches for 575 of the radical therapy patients, and then repeated comparative effectiveness analyses., Results and Limitation: Prostate-cancer mortality was substantially greater in the androgen deprivation therapy group compared with the radically treated one, in unmatched (9062/17 602 vs 86/750) and matched (177/575 vs 71/575) cohorts. Among matched cohorts, initial androgen deprivation therapy was associated with nearly three-fold higher hazard of prostate-cancer death compared with initial radical therapy (2.87; 95% confidence interval 2.16-3.82). Multiple sensitivity analyses suggested that the findings were robust, although the general limitations of nonrandomized studies remain. Further, the study cohort may have included men with both systemic and nonsystemic disease, as a sole eligibility criterion of PSA >50 was used., Conclusions: This large and comprehensive population-based study suggests that initial radical therapy in men at high risk of disseminated prostate cancer improves survival., Patient Summary: This large Swedish study suggests that men with prostate cancer that has spread beyond the prostate benefit from treating the prostate itself with radiation therapy or surgery rather than treating the disease with hormones alone., (Copyright © 2017 European Association of Urology. All rights reserved.)

Prostate cancer (PCa) patients with bone metastases are primarily treated with androgen deprivation therapy (ADT). Less pronounced ADT effects are seen in metastases than in primary tumors. To test if acute effects of ADT was enhanced by concurrent inhibition of pro-survival insulin-like growth factor 1 (IGF-1), rats were inoculated with Dunning R3327-G tumor cells into the tibial bone marrow cavity and established tumors were treated with castration in combination with IGF-1 receptor (IGF-1R) inhibitor NVP-AEW541, or by each treatment alone. Dunning R3327-G cells were stimulated by androgens and IGF-1 in vitro. In rat tibia, Dunning R3327-G cells induced bone remodeling, identified through increased immunoreactivity of osteoblast and osteoclast markers. Tumor cells occasionally grew outside the tibia, and proliferation and apoptotic rates a few days after treatment were evaluated by scoring BrdU- and caspase-3-positive tumor cells inside and outside the bone marrow cavity, separately. Apoptosis was significantly induced outside, but unaffected inside, the tibial bone by either castration or NVP-AEW541, and the maximum increase (2.7-fold) was obtained by the combined treatment. Proliferation was significantly reduced by NVP-AEW541, independently of growth site, although the maximum decrease (24%) was observed when NVP-AEW541 was combined with castration. Tumor cell IGF-1R immunoreactivity was evaluated in clinical PCa bone metastases (n = 61), and positive staining was observed in most cases (74%). In conclusion, IGF-1R inhibition may be evaluated in combination with ADT in patients with metastatic PCa, or in combination with therapies for the subsequent development of castration-resistant disease, although diverse responses could be anticipated depending on metastasis site.

Purpose: To investigate the risk of thromboembolic disease (TED) after radiation therapy (RT) with curative intent for prostate cancer (PCa)., Patients and Methods: We identified all men who received RT as curative treatment (n=9410) and grouped according to external beam RT (EBRT) or brachytherapy (BT). By comparing with an age- and county-matched comparison cohort of PCa-free men (n=46,826), we investigated risk of TED after RT using Cox proportional hazard regression models. The model was adjusted for tumor characteristics, demographics, comorbidities, PCa treatments, and known risk factors of TED, such as recent surgery and disease progression., Results: Between 2006 and 2013, 6232 men with PCa received EBRT, and 3178 underwent BT. A statistically significant association was found between EBRT and BT and risk of pulmonary embolism in the crude analysis. However, upon adjusting for known TED risk factors these associations disappeared. No significant associations were found between BT or EBRT and deep venous thrombosis., Conclusion: Curative RT for prostate cancer using contemporary methodologies was not associated with an increased risk of TED., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Skeletal metastatic disease is a deleterious consequence of dissemination of tumor cells from numerous primary sites, such as prostate, lung and breast. Skeletal metastases are still incurable, resulting in development of clinical complications and decreased survival for cancer patients with metastatic disease. During the last decade, tumor cell-derived microvesicles have been identified and suggested to be involved in cancer disease progression. Whether cancer exosomes are involved in tumor and bone cell interactions in the metastatic site is still, however, a rather unexplored field. Here we show that exosomes isolated from the murine prostate cancer cell line TRAMP-C1 dramatically decrease fusion and differentiation of monocytic osteoclast precursors to mature, multinucleated osteoclasts. The presence of tumor cell-derived exosomes also clearly decreased the expression of established markers for osteoclast fusion and differentiation, including DC-STAMP, TRAP, cathepsin K, and MMP-9. In contrast, exosomes derived from murine fibroblastic cells did not affect osteoclast formation. Our findings suggest that exosomes released from tumor cells in the tumor-bone interface are involved in pathological regulation of bone cell formation in the metastatic site. This further strengthens the role of tumor cell-derived microvesicles in cancer progression and disease aggressiveness., Competing Interests: The authors have declared that no competing interests exist.

Background: In high-risk prostate cancer (PCa), no study with observation times beyond 10 yr has demonstrated survival improvement after addition of prostatic radiotherapy (RAD) to endocrine treatment (ET) alone., Objective: To compare mortality rates in patients receiving ET alone versus ET + RAD., Design, Settings, and Participants: From 1996 to 2002, 875 Scandinavian patients with high-risk (90%) or intermediate PCa were randomized to ET or ET + RAD (The Scandinavian Prostate Cancer Group-7). After 3 mo with total androgen blockade in all patients, all individuals continued lifelong antiandrogen monotherapy. Those randomized to ET + RAD started prostate radiotherapy (70Gy) at 3 mo., Outcome, Measurements and Statistical Analysis: PCa-specific 15-yr mortality represented the primary endpoint. Assessment of the combination treatment effect and prognostic factors was performed in competing risk analyses and Cox proportional-hazard models., Intervention: RAD added to ET., Results and Limitations: With a median observation time of 12 yr, the 15-yr PCa-specific mortality rates were 34% (95% confidence interval, 29-39%) and 17% (95% confidence interval, 13-22%) in the ET and ET + RAD arms respectively (p<0.001). Compared with the ET arm, the median overall survival in the ET + RAD arm was prolonged by 2.4 yr. Treatment with ET alone, age ≥65 yr and increasing histology grade independently increased the risk of PCa-specific and overall mortality. Limitations include nonformal evaluation of comorbidity, the inability to calculate progression-free survival, and lack of information about salvage therapy and toxicity., Conclusions: In patients with nonmetastatic locally advanced or aggressive PCa, ET + RAD reduces the absolute risk of PCa-specific death by 17% at 15 yr compared with ET alone; the comparable 15-yr PCa-specific mortality rates being 17% and 34%. The results warrant a phase 3 study comparing ET + RAD with radical prostatectomy in high-risk PCa., Patient Summary: Adding prostatic therapy to lifelong antiandrogen therapy halves the absolute risk of death from prostate cancer from 34% to 17% 15 yr after diagnosis., (Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objective: The aim of this study was to assess the risk of serious adverse effects after radiotherapy (RT) with curative intention and radical prostatectomy (RP)., Materials and Methods: Men who were diagnosed with prostate cancer between 1997 and 2012 and underwent curative treatment were selected from the Prostate Cancer data Base Sweden. For each included man, five prostate cancer-free controls, matched for birth year and county of residency, were randomly selected. In total, 12,534 men underwent RT, 24,886 underwent RP and 186,624 were controls. Adverse effects were defined according to surgical and diagnostic codes in the National Patient Registry. The relative risk (RR) of adverse effects up to 12 years after treatment was compared to controls and the risk was subsequently compared between RT and RP in multivariable analyses., Results: Men with intermediate- and localized high-risk cancer who underwent curative treatment had an increased risk of adverse effects during the full study period compared to controls: the RR of undergoing a procedures after RT was 2.64 [95% confidence interval (CI) 2.56-2.73] and after RP 2.05 (95% CI 2.00-2.10). The risk remained elevated 10-12 years after treatment. For all risk categories of prostate cancer, the risk of surgical procedures for urinary incontinence was higher after RP (RR 23.64, 95% CI 11.71-47.74), whereas risk of other procedures on the lower urinary tract and gastrointestinal tract or abdominal wall was higher after RT (RR 1.67, 95% CI 1.44-1.94, and RR 1.86, 95% CI 1.70-2.02, respectively)., Conclusion: The risk of serious adverse effects after curative treatment for prostate cancer remained significantly elevated up to 12 years after treatment.

Purpose: To investigate long-term changes in the rectal mucosa after curative external beam radiation therapy in the treatment of prostate cancer., Methods and Materials: In the Scandinavian Prostate Cancer Group 7 trial, 880 men with locally advanced prostate cancer were randomized to hormonal therapy alone versus hormonal therapy plus radiation therapy to 70 Gy. A subcohort from this trial being randomized at our center (n=178) was invited to a study on late anorectal side effects during 2003-2005, approximately 5 years after treatment, including measuring health-reported quality of life and physician-assessed toxicity score by the Late Effects Normal Tissue Task Force/Subjective, Objective, Management, Analytic (LENT/SOMA) and European Organization for Research and Treatment of Cancer/Radiation Therapy Oncology Group score. Sixty-seven patients had a rectal mucosa biopsy. Sixty-four biopsies were included in the final analysis, of which 33 patients were randomized to hormonal treatment and 31 to hormonal treatment plus radiation therapy. The presence of fibrosis, number of capillaries, and lymphocyte infiltration was then evaluated by light microscopy., Results: The group receiving radiation therapy had significantly higher LENT/SOMA and function/bother scale scores than the group that only received hormonal treatment, but there was no significant difference in the presence of fibrosis, ectasia, number of capillaries in the lamina propria, or lymphocyte infiltration between the groups., Conclusion: Radiation therapy to 70 Gy to the prostate does not induce long-term microscopic mucosal changes in the rectum 5 years after treatment. This is in contrast to the general assumption that structural changes, including fibrosis, seen after radiation therapy include the mucosa. We speculate that the main late effects of radiation therapy on the structure of the rectum are located in the deeper layers of the rectal wall than the mucosa., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Aggressive tumors induce tumor-supporting changes in the benign parts of the prostate. One factor that has increased expression outside prostate tumors is hemoxygenase-1 (HO-1). To investigate HO-1 expression in more detail, we analyzed samples of tumor tissue and peritumoral normal prostate tissue from rats carrying cancers with different metastatic capacity, and human prostate cancer tissue samples from primary tumors and bone metastases. In rat prostate tumor samples, immunohistochemistry and quantitative RT-PCR showed that the main site of HO-1 synthesis was HO-1+ macrophages that accumulated in the tumor-bearing organ, and at the tumor-invasive front. Small metastatic tumors were considerably more effective in attracting HO-1+ macrophages than larger non-metastatic ones. In clinical samples, accumulation of HO-1+ macrophages was seen at the tumor invasive front, almost exclusively in high-grade tumors, and it correlated with the presence of bone metastases. HO-1+ macrophages, located at the tumor invasive front, were more abundant in bone metastases than in primary tumors. HO-1 expression in bone metastases was variable, and positively correlated with the expression of macrophage markers but negatively correlated with androgen receptor expression, suggesting that elevated HO-1 could be a marker for a subgroup of bone metastases. Together with another recent observation showing that selective knockout of HO-1 in macrophages reduced prostate tumor growth and metastatic capacity in animals, the results of this study suggest that extratumoral HO-1+ macrophages may have an important role in prostate cancer.

Objective: To evaluate long-term urinary, sexual and bowel functional outcomes after prostate cancer treatment at a median (interquartile range) follow-up of 12 (11-13) years., Patients and Methods: In this nationwide, population-based study, we identified 6 003 men diagnosed with localized prostate cancer (clinical local stage T1-2, any Gleason score, prostate-specific antigen <20 ng/mL, NX or N0, MX or M0) between 1997 and 2002 from the National Prostate Cancer Register, Sweden. The men were aged ≤70 years at diagnosis. A control group of 1 000 men without prostate cancer were also selected, matched for age and county of residence. Functional outcomes were evaluated with a validated self-reported questionnaire., Results: Responses were obtained from 3 937/6 003 cases (66%) and 459/1 000 (46%) controls. At 12 years after diagnosis and at a median age of 75 years, the proportion of cases with adverse symptoms was 87% for erectile dysfunction/sexual inactivity, 20% for urinary incontinence and 14% for bowel disturbances. The corresponding proportions for controls were 62, 6 and 7%, respectively. Men with prostate cancer, except those on surveillance, had an increased risk of erectile dysfunction compared with the men in the control group. Radical prostatectomy was associated with an increased risk of urinary incontinence (odds ratio [OR] 1.89, 95% confidence interval [CI] 1.36-2.62) and radiotherapy increased the risk of bowel dysfunction (OR 2.46, 95% CI 1.73-3.49) compared with men in the control group. Multi-modal treatment, in particular treatment including androgen deprivation therapy (ADT), was associated with the highest risk of adverse effects; for instance, radical prostatectomy followed by radiotherapy and ADT was associated with an OR of 3.74 (95% CI 1.76-7.95) for erectile dysfunction and an OR of 3.22 (95% CI 1.93-5.37) for urinary incontinence., Conclusion: The proportion of men who experienced a long-term impact on functional outcomes after prostate cancer treatment was substantial., (© 2015 The Authors BJU International © 2015 BJU International Published by John Wiley & Sons Ltd.)

Background: Clinical management of the prostate needs improved prognostic tests and treatment strategies. Because proteins are the ultimate effectors of most cellular reactions, are targets for drug actions and constitute potential biomarkers; a quantitative systemic overview of the proteome changes occurring during prostate cancer (PCa) initiation and progression can result in clinically relevant discoveries., Objectives: To study cellular processes altered in PCa using system-wide quantitative analysis of changes in protein expression in clinical samples and to identify prognostic biomarkers for disease aggressiveness., Design, Setting, and Participants: Mass spectrometry was used for genome-scale quantitative proteomic profiling of 28 prostate tumors (Gleason score 6-9) and neighboring nonmalignant tissue in eight cases, obtained from formalin-fixed paraffin-embedded prostatectomy samples. Two independent cohorts of PCa patients (summing 752 cases) managed by expectancy were used for immunohistochemical evaluation of proneuropeptide-Y (pro-NPY) as a prognostic biomarker., Results and Limitations: Over 9000 proteins were identified as expressed in the human prostate. Tumor tissue exhibited elevated expression of proteins involved in multiple anabolic processes including fatty acid and protein synthesis, ribosomal biogenesis and protein secretion but no overt evidence of increased proliferation was observed. Tumors also showed increased levels of mitochondrial proteins, which was associated with elevated oxidative phosphorylation capacity measured in situ. Molecular analysis indicated that some of the proteins overexpressed in tumors, such as carnitine palmitoyltransferase 2 (CPT2, fatty acid transporter), coatomer protein complex, subunit alpha (COPA, vesicle secretion), and mitogen- and stress-activated protein kinase 1 and 2 (MSK1/2, protein kinase) regulate the proliferation of PCa cells. Additionally, pro-NPY was found overexpressed in PCa (5-fold, p<0.05), but largely absent in other solid tumor types. Pro-NPY expression, alone or in combination with the ERG status of the tumor, was associated with an increased risk of PCa specific mortality, especially in patients with Gleason score ≤ 7 tumors., Conclusions: This study represents the first system-wide quantitative analysis of proteome changes associated to localized prostate cancer and as such constitutes a valuable resource for understanding the complex metabolic changes occurring in this disease. We also demonstrated that pro-NPY, a protein that showed differential expression between high and low risk tumors in our proteomic analysis, is also a PCa specific prognostic biomarker associated with increased risk for disease specific death in patients carrying low risk tumors., Patient Summary: The identification of proteins whose expression change in prostate cancer provides novel mechanistic information related to the disease etiology. We hope that future studies will prove the value of this proteome dataset for development of novel therapies and biomarkers., (Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objective: The aim of this study was to prospectively assess the development of 24 urinary, gastrointestinal and sexual symptoms in patients with prostate cancer (PCa) during and after image-guided volumetric modulated arc therapy (IG-VMAT)., Material and Methods: A total of 87 patients with PCa participated in this study. The patients were asked to complete a modified version of the Prostate Cancer Symptom Scale (PCSS) questionnaire before radiotherapy (RT) (baseline), at the start of RT, at the end of RT and 1 year after RT. Changes in symptoms at the start of RT, at the end of RT and 1 year after RT compared to baseline were analysed by a mixed model analysis of repeated measurements with the following covariates: age, comorbidity, smoking and androgen deprivation therapy (ADT)., Results: All urinary problems except for haematuria increased significantly at the end of RT compared to baseline. One year after RT, there was no longer any difference compared to baseline for any of the urinary symptoms. All gastrointestinal symptoms except for nausea increased significantly at the end of RT. One year after RT, patients also reported slightly higher degrees of stool frequency, bowel leakage, planning of toilet visits, flatulence, mucus, gastrointestinal bleeding and impact of gastrointestinal bother on daily activities compared to baseline. All sexual symptoms increased significantly at all times compared to baseline. The use of ADT was associated with worse sexual symptoms., Conclusions: IG-VMAT is a safe treatment for PCa, with few and mild changes in urinary and gastrointestinal symptoms 1 year after RT compared to baseline. Sexual symptoms deteriorated both during and after RT. The use of ADT was associated with worse sexual symptoms.

Tumor-derived exosomes, which are nanometer-sized extracellular vesicles of endosomal origin, have emerged as promoters of tumor immune evasion but their role in prostate cancer (PC) progression is poorly understood. In this study, we investigated the ability of prostate tumor-derived exosomes to downregulate NKG2D expression on natural killer (NK) and CD8+ T cells. NKG2D is an activating cytotoxicity receptor whose aberrant loss in cancer plays an important role in immune suppression. Using flow cytometry, we found that exosomes produced by human PC cells express ligands for NKG2D on their surface. The NKG2D ligand-expressing prostate tumor-derived exosomes selectively induced downregulation of NKG2D on NK and CD8+ T cells in a dose-dependent manner, leading to impaired cytotoxic function in vitro. Consistent with these findings, patients with castration-resistant PC (CRPC) showed a significant decrease in surface NKG2D expression on circulating NK and CD8+ T cells compared to healthy individuals. Tumor-derived exosomes are likely involved in this NKG2D downregulation, since incubation of healthy lymphocytes with exosomes isolated from serum or plasma of CRPC patients triggered downregulation of NKG2D expression in effector lymphocytes. These data suggest prostate tumor-derived exosomes as down-regulators of the NKG2D-mediated cytotoxic response in PC patients, thus promoting immune suppression and tumor escape.

Background: Hypo-fractionated external beam radiotherapy with narrow CTV-PTV margins is increasingly applied for prostate cancer. This demands a precise target definition and knowledge on target location and extension during treatment. It is unclear how increase in fraction size affects changes in prostate volume during treatment. Our aim was to study prostate volume changes during extreme hypo-fractionation (7 × 6.1 Gy) by using sequential MRIs., Methods: Twenty patients treated with extreme hypo-fractionation were recruited from an on-going prospective randomized phase III trial. An MRI scan was done before start of treatment, at mid treatment and at the end of radiotherapy. The prostate was delineated at each MRI and the volume and maximum extension in left-right, anterior-posterior and cranial-caudal directions were measured., Results: There was a significant increase in mean prostate volume (14%) at mid treatment as compared to baseline. The prostate volume remained enlarged (9%) at the end of radiotherapy. Prostate swelling was most pronounced in the anterior-posterior and cranial-caudal directions., Conclusions: Extreme hypo-fractionation induced a significant prostate swelling during treatment that was still present at the time of last treatment fraction. Our results indicate that prostate swelling is an important factor to take into account when applying treatment margins during short extreme hypo-fractionation, and that tight margins should be applied with caution.

Background: Intra-tumoral steroidogenesis and constitutive androgen receptor (AR) activity have been associated with castration-resistant prostate cancer (CRPC). This study aimed to examine if CRPC bone metastases expressed higher levels of steroid-converting enzymes than untreated bone metastases. Steroidogenic enzyme levels were also analyzed in relation to expression of constitutively active AR variants (AR-Vs) and to clinical and pathological variables., Methodology/principal Findings: Untreated, hormone-naïve (HN, n = 9) and CRPC bone metastases samples (n = 45) were obtained from 54 patients at metastasis surgery. Non-malignant and malignant prostate samples were acquired from 13 prostatectomy specimens. Transcript and protein levels were analyzed by real-time RT-PCR, immunohistochemistry and immunoblotting. No differences in steroidogenic enzyme levels were detected between CRPC and HN bone metastases. Significantly higher levels of SRD5A1, AKR1C2, AKR1C3, and HSD17B10 mRNA were however found in bone metastases than in non-malignant and/or malignant prostate tissue, while the CYP11A1, CYP17A1, HSD3B2, SRD5A2, and HSD17B6 mRNA levels in metastases were significantly lower. A sub-group of metastases expressed very high levels of AKR1C3, which was not due to gene amplification as examined by copy number variation assay. No association was found between AKR1C3 expression and nuclear AR staining, tumor cell proliferation or patient outcome after metastases surgery. With only one exception, high AR-V protein levels were found in bone metastases with low AKR1C3 levels, while metastases with high AKR1C3 levels primarily contained low AR-V levels, indicating distinct mechanisms behind castration-resistance in individual bone metastases., Conclusions/significance: Induced capacity of converting adrenal-gland derived steroids into more potent androgens was indicated in a sub-group of PC bone metastases. This was not associated with CRPC but merely with the advanced stage of metastasis. Sub-groups of bone metastases could be identified according to their expression levels of AKR1C3 and AR-Vs, which might be of relevance for patient response to 2(nd) line androgen-deprivation therapy.

In 1987, the first Regional Prostate Cancer Register was set up in the South-East health-care region of Sweden. Other health-care regions joined and since 1998 virtually all prostate cancer (PCa) cases are registered in the National Prostate Cancer Register (NPCR) of Sweden to provide data for quality assurance, bench marking and clinical research. NPCR includes data on tumour stage, Gleason score, serum level of prostate-specific antigen (PSA) and primary treatment. In 2008, the NPCR was linked to a number of other population-based registers by use of the personal identity number. This database named Prostate Cancer data Base Sweden (PCBaSe) has now been extended with more cases, longer follow-up and a selection of two control series of men free of PCa at the time of sampling, as well as information on brothers of men diagnosed with PCa, resulting in PCBaSe 2.0. This extension allows for studies with case-control, cohort or longitudinal case-only design on aetiological factors, pharmaceutical prescriptions and assessment of long-term outcomes. The NPCR covers >96% of all incident PCa cases registered by the Swedish Cancer Register, which has an underreporting of <3.7%. The NPCR is used to assess trends in incidence, treatment and outcome of men with PCa. Since the national registers linked to PCBaSe are complete, studies from PCBaSe 2.0 are truly population based.

Background: Spinal cord compression is an oncological and surgical emergency. Delays in referral and diagnosis may influence functional outcome. It is therefore important to identify patients who will regain or maintain the ability to walk after surgery. The aim of the present study was to examine current practice for referral and diagnosis of prostate cancer patients with spinal cord compression and to identify prognostic factors for neurological outcome after surgery., Patients and Methods: The study includes 68 consecutive patients with prostate cancer who underwent surgery due to neurological compromise. Intervals from onset of neurological symptoms to referral, diagnosis, and treatment were analyzed in relation to functional outcome. The prognostic significance of preoperative clinical parameters on gait function one month after surgery was evaluated., Results: Patients who were referred from local hospitals had longer delay to surgery than those who directly presented to the cancer center (p = 0.004). The rate of diagnosis with MRI increased through the week and peaked on Friday, with few patients being diagnosed during weekends. The ability to walk before surgery, hormone-naive prostate cancer, and/or shorter time from loss of ambulation were associated with more favorable neurological outcome. In patients with hormone-refractory disease who were unable to walk before surgery regaining ambulation was associated with: duration of paresis < 48 hours (p = 0.005), good preoperative performance status (p = 0.04), preoperative PSA serum level < 200 ng/ml (p = 0.03), and surgery with posterior decompression and stabilization (p = 0.03)., Conclusion: Early diagnosis and rapid treatment of spinal cord compression in prostate cancer patients is crucial for neurological recovery. Raising awareness of the condition among patients at risk and among physicians is of outmost importance as well as improving local and regional guidelines for treatment.

Background: The Late Effects Normal Tissue/Subjective Objective Management Analytic (LENT/SOMA) system for grading of side effects after radiotherapy was proposed several years ago. Only a few studies have previously been performed on the validity of the LENT/SOMA. The aim of the present study was to validate the LENT/SOMA scoring system for recto-anal side effects after treatment for prostate cancer in a randomized trial., Material and Methods: A total of 875 patients with locally advanced prostate cancer were randomized to either hormonal treatment alone or hormonal treatment plus radiotherapy in the Scandinavian Prostate Cancer Group 7 (SPCG-7) study. At least three years after treatment was started, the 178 patients that were randomized at St. Olavs Hospital were approached. One hundred and three patients of these accepted inclusion. The side effects according to LENT/SOMA were graded by oncologist and nurse. In addition, side effects were graded according to the European Organisation for Research and Treatment of Cancer and the Radiation Therapy Oncology Group (EORTC/RTOG) toxicity scale and patient-reported health-related quality of life (HRQOL) questionnaires. Content/face validity, sensitivity and inter-rater reliability of the LENT/SOMA tables for rectum were analyzed., Results: Content/face analysis of LENT/SOMA revealed serious problems. Significant correlations (Spearman's rho > 0.4) were found between three of 15 LENT/SOMA items and similar HRQOL items. LENT/SOMA score made it possible to detect significant differences between the two groups of patients (p < 0.001), EORTC/RTOG toxicity score did not (p = 0.138). Inter-rater reliability was acceptable., Conclusions: LENT/SOMA scoring system for recto-anal side effects after radiotherapy for prostate cancer displays serious difficulties in the present study. Replacement of LENT/SOMA tables for rectum by a combination of patient-reported HRQOL questionnaires, clinical examination and objective physiological measurements might be called for.

Unlabelled: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: There are two randomized controlled trials showing that radiotherapy can be beneficial for men with locally advanced prostate cancer. The present study confirms the importance of curative treatment for men with high-risk prostate cancer., Objective: To investigate the influence of curative treatment on cause-specific mortality in men diagnosed with prostate cancer (PCa) with serum prostate-specific antigen (PSA) levels between 20 and 100 ng/mL., Materials and Methods: Patients with PCa (T1-4, N0/N1/NX, M0/MX), PSA 20-100 ng/mL and age ≤75 years were identified in the National Prostate Cancer Register of Sweden. Data on co-morbidity diagnoses were obtained from the National Patient Register and cause of death from the Cause of Death Register. Following adjustment for age at diagnosis, co-morbidity burden, Gleason score, T-category, PSA level and cause-specific mortality in relation to treatment were estimated using Cox regression analysis., Result: A total of 11 380 men were diagnosed with PCa between 1996 and 2008 and fulfilled the inclusion criteria. The cumulative 10-year PCa-specific mortality was 36% for patients receiving only palliative treatment and 13% for those treated with curative intent. For the 8462 (74%) patients with PSA levels from 20 to 50 ng/mL at diagnosis, the hazard ratio for death from PCa was 0.23 (95% confidence interval 0.19-0.27) for those treated with curative intent compared with those given palliative treatment after adjusting for age, co-morbidity, T category, PSA level and Gleason score. The corresponding hazard ratio was 0.22 (95% confidence interval 0.17-0.30) for patients with PSA levels from 51 to 100 ng/mL., Conclusion: Treatment with curative intent for men with high-risk PCa was associated with reduced cause-specific mortality and should be considered even when serum PSA exceeds 20 ng/mL., (© 2012 BJU International.)

Study Design: We retrospectively analyzed prognostic factors for survival in patients with prostate cancer operated for metastatic spinal cord compression., Objective: The aim was to obtain a clinical score for prediction of survival after surgery., Summary of Background Data: Survival prognosis is important when deciding about treatment of patients with metastatic spinal cord compression. The criteria for identifying patients with prostate cancer who may benefit from surgical treatment are unclear., Methods: The study comprised 68 consecutive patients with prostate cancer operated for metastatic spinal cord compression at Umeå University Hospital, Sweden. The indication for surgery was neurological deficit; 53 patients had hormone-refractory prostate cancer and 15 patients had previously untreated, hormone-naïve prostate cancer. In 42 patients, posterior decompression was performed and 26 patients were operated with posterior decompression and stabilization., Results: A new score for prediction of survival was developed on the basis of the results of survival analyses. The score includes hormone status of prostate cancer, Karnofsky performance status, evidence of visceral metastasis, and preoperative serum prostate-specific antigen (PSA). The total scores ranged from 0 to 6. Three prognostic groups were formulated: group A (n = 32) with scores 0-1; group B (n = 23) with scores 2-4, and group C (n = 12) with scores 5-6. The median overall survival was 3 (0.3-20) months in group A, 16 (1.8-59) months in group B, and more than half (7 of 12) of patients were still alive in group C., Conclusion: We present a new prognostic score for predicting survival of patients with prostate cancer after surgery for metastatic spinal cord compression. The score is easy to apply in clinical practice and may be used as additional support when making decision about treatment.

Background and Purpose: The criteria for selecting patients who may benefit from surgery of spinal cord compression in metastatic prostate cancer are poorly defined. We therefore studied patients operated for metastatic spinal cord compression in order to evaluate outcome of surgery and to find predictors of survival., Patients and Methods: We reviewed the records of 54 consecutive patients with metastatic prostate cancer who were operated for spinal cord compression at Umeå University Hospital. The indication for surgery was neurological deficit due to spinal cord compression. 41 patients had hormone-refractory cancer and 13 patients had previously untreated, hormone-naïve prostate cancer. 29 patients were operated with posterior decompression only, and in 25 patients posterior decompression and stabilization was performed., Results: Preoperatively, 6/54 of patients were able to walk. 1 month after surgery, 33 patients were walking, 15 were non-ambulatory, and 6 had died. Mortality rate was 11% at 1 month, 41% at 6 months, and 59% at 1 year. In the hormone-naïve group, 8/13 patients were still alive with a median postoperative follow-up of 26 months. In the hormone-refractory group, median survival was 5 months. Patients with hormone-refractory disease and Karnofsky performance status (KPS) of ≤ 60% had median survival of 2.5 months, whereas those with KPS of 70% and KPS of ≥ 80% had a median survival of 7 months and 18 months, respectively (p < 0.001). Visceral metastases were present in 12/41 patients with hormone-refractory tumor at the time of spinal surgery, and their median survival was 4 months-as compared to 10 months in patients without visceral metastases (p = 0.003). Complications within 30 days of surgery occurred in 19/54 patients., Interpretation: Our results indicate that patients with hormone-naive disease, and those with hormone-refractory disease with good performance status and lacking visceral metastases, may be helped by surgery for metastatic spinal cord compression.

Context: Prostate cancer (PCa) patients have many options within the realms of surgery or radiation therapy (RT). Technical advancements in RT planning and delivery have yielded different approaches, such as external beam, brachytherapy, and newer approaches such as image-guided tomotherapy or volumetric-modulated arc therapy. The selection of the optimal RT treatment for the individual is still a point of discussion, and the debate centres on two important outcomes-namely, cancer control and reduction of side-effects., Objective: To critically review and summarise the available literature on functional outcomes and rectal sequelae following RT for PCa treatment., Evidence Acquisition: A review of the literature published between 1999 and 2010 was performed using Medline and Scopus search. Relevant reports were identified using the terms prostate cancer, radiotherapy, functional outcomes, external beam radiation, brachytherapy, IMRT, quality of life, and tomotherapy and were critically reviewed and summarised., Evidence Synthesis: Related to nonuniform definition of their assessed functional end points and uneven standards of reporting, only a minority of series retrieved could be selected for analyses. Moreover, patterns of patient selection for different types of RT, inherent differences in the RT modalities, and the presence or absence of hormonal treatment also limit the ability to synthesise results from different publications or perform meta-analyses across the different treatment types. Nonetheless, several studies agree that recent technical improvements in the field of RT planning and delivery enable the administration of higher doses with equal or less toxicity. Regardless of the type of RT, the most frequently considered functional end points in the published analyses are gastrointestinal (GI) complications and rectal bleeding. Established risk factors for acute or late toxicities after RT include advanced age, larger rectal volume, a history of prior abdominal surgery, the concomitant use of androgen deprivation, preexisting diabetes mellitus, haemorrhoids, and inflammatory bowel disease (IBD). Similarly, mild acute irritative urinary symptoms are reported in several studies, whereas total urinary incontinence and other severe urinary symptoms are rare. Pretreatment genitourinary complaints, prior transurethral resection of the prostate (TURP), and the presence of acute genitourinary toxicity are suggested as contributing to long-term urinary morbidity. Erectile dysfunction (ED) is not an immediate side-effect of RT, and the occurrence of spontaneous erections before treatment is the best predictor for preserving erections sufficient for intercourse. In addition, the use of magnetic resonance imaging (MRI) permits a reduction in the dose delivered to vascular structures critical for erectile function., Conclusions: In the future, further improvement in RT planning and delivery will decrease side-effects and permit administration of higher doses. Related to the anatomy of the prostate, these higher doses may favour rectal sparing while not readily sparing the urethra and bladder neck. As a consequence, there may be a future shift from dose-limiting long-term rectal morbidity towards long-term urinary morbidity. In the absence of prospective randomised trials comparing different types of surgical and RT-based treatments in PCa, the introduction of validated tools for reporting functional and clinical outcomes is crucial for evaluating and identifying each individual's best treatment choice., (Copyright © 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objective: Post-treatment prostate biopsy side-effects were evaluated in patients with locally advanced prostate cancer on endocrine therapy alone or combined with radiotherapy in the Scandinavian Prostate Cancer Group-7 randomized trial., Material and Methods: One-hundred and twenty patients underwent transrectalultrasound-guided biopsy, and were requested to complete a questionnaire on side-effects occurring within 7 days' follow-up., Results: The questionnaire was returned by 109 patients (91%) (endocrine therapy only 52%, combined endocrine therapy and radiotherapy 48%). Previous therapy had no significant influence on pain, urinary flow, haematuria or haematospermia. Pain at biopsy was reported in 63% (mild, 57%; moderate, 5.6%; severe, one patient) and pain at follow-up in 31% (mild, 27%; moderate, four patients). Haematuria (mean duration 2.2 days) was reported in 41%, and reduced urinary flow in 20% (mild, 18%; severe: four patients; no patient had urinary retention). Haematospermia was scarce. No patient reported urinary tract infection. Rectal bleeding occurred in 18% in the endocrine and 35% in the combined therapy group (p = 0.047), with a mean duration of 1.6 and 2.2 days, respectively (p = 0.031). In logistic regression analysis, a trend towards increased rectal bleeding was found in patients on combined endocrine therapy and radiotherapy (odds ratio 2.4, p = 0.050)., Conclusion: Patient-reported post-treatment prostate biopsy side-effects were mild and self-limiting.

Radiotherapy has experienced an extremely rapid development in recent years. Important improvements such as the introduction of multileaf collimators and computed tomography (CT)-based treatment planning software have enabled three dimensional conformal external beam radiation therapy (3DCRT). The development of treatment planning systems and technology for brachytherapy has been very rapid as well. Development of accelerators with integrated on-board imaging equipment and technology, for example image-guided radiation therapy (IGRT) has further improved the precision with reduced margins to adjacent normal tissues. This has, in turn, led to the possibility to administer even higher doses to the prostate than previously. Although radiotherapy and radical prostatectomy have been used for the last decades as curative treatment modalities, still there are no randomized trials published comparing these two options. Outcome data show that the two treatment modalities are highly comparable when used for low- and intermediate-risk prostate cancer.

Purpose: The Scandinavian Prostate Cancer Group-7 randomized trial demonstrated a survival benefit of combined endocrine therapy and external-beam radiotherapy over endocrine therapy alone in patients with high-risk prostate cancer. In a subset of the study population, the incidence and clinical implications of residual prostate cancer in posttreatment prostate biopsy specimens was evaluated., Methods and Materials: Biopsy specimens were obtained from 120 of 875 men in the Scandinavian Prostate Cancer Group-7 study., Results: Biopsies were performed at median of 45 months follow-up. In 63 patients receiving endocrine treatment only and 57 patients receiving combined treatment, residual cancer was found in 66% (n = 41) and 22% (n = 12), respectively (p < 0.0001). The vast majority of residual tumors were poorly differentiated (Gleason score ≥ 8). Endocrine therapy alone was predictive of residual prostate cancer: odds ratio 7.49 (3.18-17.7), p < 0.0001. In patients with positive vs. negative biopsy the incidences of clinical events were as follows: biochemical recurrence 74% vs. 27% (p < 0.0001), local progression 26% vs. 4.7% (p = 0.002), distant recurrence 17% vs. 9.4% (p = 0.27), clinical recurrence 36% vs. 13% (p = 0.006), cancer-specific death 19% vs. 9.7% (p = 0.025). In multivariable analysis, biochemical recurrence was significantly associated with residual cancer: hazard ratio 2.69 (1.45-4.99), p = 0.002, and endocrine therapy alone hazard ratio 3.45 (1.80-6.62), p < 0.0001., Conclusions: Radiotherapy combined with hormones improved local tumor control in comparison with endocrine therapy alone. Residual prostate cancer was significantly associated with serum prostate-specific antigen recurrence, local tumor progression, clinical recurrence, and cancer-specific death in univariable analysis. Residual cancer was predictive of prostate-specific antigen recurrence in multivariable analysis., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Constitutively active androgen receptor variants (AR-V) lacking the ligand binding domain (LBD) may promote the development of castration-resistant prostate cancer (CRPC). The expression of AR-Vs in the clinically most important metastatic site, the bone, has, however, not been well documented. Our aim was therefore to compare levels of AR-Vs in hormone-naive (HN) and CRPC bone metastases in comparison to primary PC and non-malignant prostate tissue, as well as in relation to AR protein expression, whole-genome transcription profiles and patient survival., Methodology/principal Findings: Hormone-naïve (n = 10) and CRPC bone metastases samples (n = 30) were obtained from 40 patients at metastasis surgery. Non-malignant and malignant prostate samples were acquired from 13 prostatectomized men. Levels of full length AR (ARfl) and AR-Vs termed AR-V1, AR-V7, and AR-V567es mRNA were measured with RT-PCR and whole-genome transcription profiles with an Illumina Beadchip array. Protein levels were examined by Western blotting and immunohistochemistry. Transcripts for ARfl, AR-V1, and AR-V7 were detected in most primary tumors and metastases, and levels were significantly increased in CRPC bone metastases. The AR-V567es transcript was detected in 23% of the CRPC bone metastases only. A sub-group of CRPC bone metastases expressed LBD-truncated AR proteins at levels comparable to the ARfl. Detectable AR-V567es and/or AR-V7 mRNA in the upper quartile, seen in 1/3 of all CRPC bone metastases, was associated with a high nuclear AR immunostaining score, disturbed cell cycle regulation and short survival., Conclusions/significance: Expression of AR-Vs is increased in CRPC compared to HN bone metastases and associated with a particularly poor prognosis. Further studies are needed to test if patients expressing such AR-Vs in their bone metastases benefit more from drugs acting on or down-stream of these AR-Vs than from therapies inhibiting androgen synthesis.

Purpose: This study explores the implications for cancer induction of treatment details such as fractionation, planning target volume (PTV) definition, and interpatient variations, which are relevant for the radiation treatment of prostate carcinomas., Methods and Materials: Treatment planning data from 100 patients have been analyzed with a risk model based on the United Nations Scientific Committee on the Effects of Atomic Radiation competition model. The risk model can account for dose heterogeneity and fractionation effects characteristic for modern radiotherapy. Biologically relevant parameters from clinical and experimental data have been used with the model., Results: The results suggested that changes in prescribed dose could lead to a modification of the risks for individual organs surrounding the clinical target volume (CTV) but that the total risk appears to be less affected by changes in the target dose. Larger differences are observed for modifications of the margins between the CTV and the PTV because these have direct impact onto the dose level and dose heterogeneity in the healthy tissues surrounding the CTV. Interpatient anatomic variations also have to be taken into consideration for studies of the risk for cancer induction from radiotherapy., Conclusions: The results have shown the complex interplay between the risk for secondary malignancies, the details of the treatment delivery, and the patient heterogeneity that may influence comparisons between the long-term effects of various treatment techniques. Nevertheless, absolute risk levels seem very small and comparable to mortality risks from surgical interventions, thus supporting the robustness of radiation therapy as a successful treatment modality for prostate carcinomas., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background and Purpose: We previously published research on 4- and 8-year follow-ups of patient-reported sexual function after conventional external beam radiotherapy (EBRT) for localized prostate cancer (LPC) compared with age-matched controls. The current study is a prolonged 15-year follow-up with the same cohorts., Material and Methods: The cohort consisted of 29 men surviving from a group of 181 men treated between 1986 and 1989, and who were reported on previously. Of the originally reported 141 controls, 62 were eligible and 34 completed the questionnaires. Sexual function was assessed using two questionnaires, Prostate Cancer Symptom Scale (PCSS) and International Index of Erectile Function (IIEF-5)., Results: Twenty-three patients (78%) and 13 controls (38%) were not sexually active. None of the patients and 14 controls had enough of an erection to perform intercourse. Seventeen patients (94%) and 14 controls (64%) had severe erectile dysfunction. Patients with clinical progression and who had received hormone treatment had decreased sexual desire. No significant differences were measured between patients without progression/hormone treatment and the controls., Conclusion: The sexual activity 15 years after EBRT for LPC was very low, as was the probability of achieving an erection. Patients with a progressive disease and treated with hormones reported worse sexual and erectile function. The LPC free men showed higher sexual activity, lower sexual bother, and better erectile function than the patients., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: Previous cross-sectional studies show considerable discrepancies between patient and physician ratings of adverse events after prostate cancer treatment. We used data from a randomized, controlled trial to examine such discrepancies., Material and Methods: The Scandinavian Prostate Cancer Groups Study 7 randomized men with locally advanced prostate cancer to antiandrogen monotherapy or to the same hormone treatment combined with external beam radiotherapy after 3 months of total androgen blockade. We selected a subsample of 333 men with valid ratings at baseline, and at 12 and 24-month followup for this prospective substudy. We also examined a cross-sectional sample of 305 men at the end of radiotherapy. We compared patient and physician ratings of frequency of daytime and nighttime urination, urinary incontinence, erectile dysfunction, bowel problems, nausea/vomiting, breast tenderness and gynecomastia., Results: Perfect agreement between patient and physician ratings was observed in 70% to 100% of cases at baseline, in 73% to 98% at 12 months and in 65% to 97% at 24 months. There were 1% to 20% changes in perfect agreement with time. With patient ratings as the gold standard physicians more often underrated than overrated adverse events, except bowel problems, which were overrated at all posttreatment points., Conclusions: In a randomized, controlled trial of external beam radiotherapy and hormone manipulation physicians recorded pelvis related adverse events in acceptable accordance with their patients with prostate cancer. The oncologist tendency to overestimate bowel problems after radiotherapy needs further investigation. Our positive findings from a formal trial should not be transferred to daily clinical practice without further studies of discrepancies in routine clinical practice., (Copyright (c) 2010 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: Several treatment options are available for patients with prostate cancer. Applicable and valid self-assessment instruments for assessing health-related quality of life (HRQOL) are of paramount importance. The aim of this study was to explore the validity and responsiveness of the intestinal part of the prostate cancer-specific questionnaire QUFW94., Methods and Materials: The content of the intestinal part of QUFW94 was examined by evaluation of experienced clinicians and reviewing the literature. The psychometric properties and responsiveness were assessed by analyzing HRQOL data from the randomized study Scandinavian Prostate Cancer Group 7 (SPCG)/Swedish Association for Urological Oncology 3 (SFUO). Subscales were constructed by means of exploratory factor analyses. Internal consistency was assessed by Cronbach's alpha. Responsiveness was investigated by comparing baseline scores with the 4-year posttreatment follow-up., Results: The content validity was found acceptable, but some amendments were proposed. The factor analyses revealed two symptom scales. The first scale comprised five items regarding general stool problems, frequency, incontinence, need to plan toilet visits, and daily activity. Cronbach's alpha at 0.83 indicated acceptable homogeneity. The second scale was less consistent with a Cronbach's alpha at 0.55. The overall responsiveness was found to be very satisfactory., Conclusion: Two scales were identified in the bowel dimension of the QUFW94; the first one had good internal consistency. The responsiveness was excellent, and some modifications are suggested to strengthen the content validity., ((c) 2010 Elsevier Inc. All rights reserved.)

Vandetanib (ZACTIMA) is a once-daily oral anticancer drug that selectively inhibits vascular endothelial growth factor receptor, epidermal growth factor receptor, and rearranged during transfection signaling. This randomized (1:1), double-blind study evaluated vandetanib (100 mg/day) or placebo in combination with docetaxel (D; 75 mg/m(2) every 3 weeks) and prednisolone (P; 2 x 5 mg/day) in 86 patients with metastatic hormone-refractory prostate cancer (mHRPC). The primary assessment was prostate-specific antigen (PSA) response (confirmed reduction of >or=50% from baseline) and a greater number of patients showed a PSA response with placebo + DP (67%) versus vandetanib + DP (40%); hazard ratio = 2.23 (one-sided 80% confidence limit = 2.90; one-sided p = 0.99). More patients experienced progression events (disease progression or death from any cause) with vandetanib + DP (65%) versus placebo + DP (60%); hazard ratio = 1.13 (one-sided 80% confidence limit = 1.44; one-sided p = 0.67). The overall incidence of adverse events was similar in both groups, although more patients experienced adverse events, leading to permanent discontinuation with vandetanib + DP (28%) versus placebo + DP (12%). However, the safety and tolerability profile for vandetanib was similar to that previously reported; adverse events that occurred more frequently in the vandetanib + DP arm were hypertension (14% vs. 2%), erythematous rash (14% vs. 2%), and exfoliative rash (12% vs. 2%). In this study of patients with mHRPC, vandetanib + DP did not demonstrate any efficacy benefit, compared with placebo + DP.

Background: Androgen treatment for prostate cancer can adversely affect functional domains of quality of life. We aimed to assess quality of life in men with locally advanced prostate cancer in an open-label phase III randomised comparison between lifelong endocrine treatment with and without radiotherapy., Methods: We obtained quality-of-life information from 872 (99%) of 875 eligible men with locally advanced prostate cancer (T3; 78%) who were randomly assigned, between 1996 and 2002, to 3 months of total androgen blockade followed by continuous endocrine treatment (439 patients) or the same hormonal treatment with radiotherapy 3 months after randomisation (436 patients). Prospective outcomes included patient-reported symptoms and quality of life assessed with questionnaires from baseline to 4 years after randomisation. Analysis was by intention to treat. This study is registered as an international standard randomised controlled trial, number ISRCTN01534787., Findings: 438 of 439 men assigned endocrine treatment and 434 of 436 assigned endocrine plus radiotherapy completed at least one questionnaire. Missing data at baseline and during follow-up was equally distributed between groups. At 4 years, 64 (18%) of 353 patients on combined therapy and 39 (12%) of 337 on endocrine-alone therapy had moderate to severe urinary bother (p=0.005), and 16 (4%) of 355 on combined therapy and five (2%) of 338 on endocrine treatment alone had pain while urinating (p=0.024). 37 (11%) of 350 in the combined group and 23 (7%) of 35 in the endocrine-only group had overall bother from all bowel symptoms (p=0.022). 281 (85%) of 332 in the combined-treatment group and 227 (72%) of 313 in the endocrine-only group had erectile dysfunction (p=0.0002). Quality of life at 4 years was similar, with the exception of decreased social function in patients receiving endocrine treatment plus radiotherapy., Interpretation: Although addition of radiotherapy to endocrine treatment significantly increased some treatment-related symptoms, none were serious. Given the substantial survival benefit of combined treatment, the increase of symptoms seems acceptable and has little extra effect on quality of life after 4 years compared with endocrine treatment alone.