Accuracy of gross tumour volume delineation with [68Ga]-PSMA-PET compared to histopathology for high-risk prostate cancer.

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.

The grade of individual prostate cancer lesions predicted by magnetic resonance imaging and positron emission tomography.

BACKGROUND: Multiparametric magnetic resonance imaging (mpMRI) and positron emission tomography (PET) are widely used for the management of prostate cancer (PCa). However, how these modalities complement each other in PCa risk stratification is still largely unknown. We aim to provide insights into the potential of mpMRI and PET for PCa risk stratification. METHODS: We analyzed data from 55 consecutive patients with elevated prostate-specific antigen and biopsy-proven PCa enrolled in a prospective study between December 2016 and December 2019. [68Ga]PSMA-11 PET (PSMA-PET), [11C]Acetate PET (Acetate-PET) and mpMRI were co-registered with whole-mount histopathology. Lower- and higher-grade lesions were defined by International Society of Urological Pathology (ISUP) grade groups (IGG). We used PET and mpMRI data to differentiate between grades in two cases: IGG 3 vs. IGG 2 (case 1) and IGG ≥ 3 vs. IGG ≤ 2 (case 2). The performance was evaluated by receiver operating characteristic (ROC) analysis. RESULTS: We find that the maximum standardized uptake value (SUVmax) for PSMA-PET achieves the highest area under the ROC curve (AUC), with AUCs of 0.72 (case 1) and 0.79 (case 2). Combining the volume transfer constant, apparent diffusion coefficient and T2-weighted images (each normalized to non-malignant prostatic tissue) results in AUCs of 0.70 (case 1) and 0.70 (case 2). Adding PSMA-SUVmax increases the AUCs by 0.09 (p < 0.01) and 0.12 (p < 0.01), respectively. CONCLUSIONS: By co-registering whole-mount histopathology and in-vivo imaging we show that mpMRI and PET can distinguish between lower- and higher-grade prostate cancer, using partially discriminative cut-off values.

Magnetic Resonance Imaging (MRI) and Positron Emission Tomography (PET) are two medical imaging methods commonly used to image prostate cancers. However, the relationship between images obtained with these methods and prostate cancer aggressiveness is not well understood. Here, we investigate whether MRI and PET can differentiate between lower- and higher-grade prostate tumors, where grade is an indicator of how aggressive the disease is likely to be. We find that the characteristics of prostate cancer tumors as seen on MRI and PET scans can help to predict tumor grade. This means that these imaging methods may be helpful when clinicians are predicting patient prognosis and deciding on appropriate treatments. However, further validation is necessary before these approaches are widely implemented for this purpose.

Histopathology-validated lesion detection rates of clinically significant prostate cancer with mpMRI, [ 68 Ga]PSMA-11-PET and [ 11 C]Acetate-PET.

OBJECTIVE: PET/CT and multiparametric MRI (mpMRI) are important diagnostic tools in clinically significant prostate cancer (csPC). The aim of this study was to compare csPC detection rates with [ 68 Ga]PSMA-11-PET (PSMA)-PET, [ 11 C]Acetate (ACE)-PET, and mpMRI with histopathology as reference, to identify the most suitable imaging modalities for subsequent hybrid imaging. An additional aim was to compare inter-reader variability to assess reproducibility. METHODS: During 2016-2019, all study participants were examined with PSMA-PET/mpMRI and ACE-PET/CT prior to radical prostatectomy. PSMA-PET, ACE-PET and mpMRI were evaluated separately by two observers, and were compared with histopathology-defined csPC. Statistical analyses included two-sided McNemar test and index of specific agreement. RESULTS: Fifty-five study participants were included, with 130 histopathological intraprostatic lesions >0.05 cc. Of these, 32% (42/130) were classified as csPC with ISUP grade ≥2 and volume >0.5 cc. PSMA-PET and mpMRI showed no difference in performance ( P  = 0.48), with mean csPC detection rate of 70% (29.5/42) and 74% (31/42), respectively, while with ACE-PET the mean csPC detection rate was 37% (15.5/42). Interobserver agreement was higher with PSMA-PET compared to mpMRI [79% (26/33) vs 67% (24/38)]. Including all detected lesions from each pair of observers, the detection rate increased to 90% (38/42) with mpMRI, and 79% (33/42) with PSMA-PET. CONCLUSION: PSMA-PET and mpMRI showed high csPC detection rates and superior performance compared to ACE-PET. The interobserver agreement indicates higher reproducibility with PSMA-PET. The combined result of all observers in both PSMA-PET and mpMRI showed the highest detection rate, suggesting an added value of a hybrid imaging approach.

Investigating microRNA Profiles in Prostate Cancer Bone Metastases and Functional Effects of microRNA-23c and microRNA-4328.

MicroRNAs (miRNAs) are aberrantly expressed in prostate cancer (PC), but comprehensive knowledge about their levels and function in metastatic PC is lacking. Here, we explored the differential expression of miRNA profiles during PC progression to bone metastasis, and further focused on the downregulation of miRNA-23c and -4328 and their impact on PC growth in experimental models. Using microarray screening, the levels of 1510 miRNAs were compared between bone metastases (n = 14), localized PC (n = 7) and benign prostate tissue (n = 7). Differentially expressed miRNAs (n = 4 increased and n = 75 decreased, p < 0.05) were identified, of which miRNA-1, -23c, -143-3p, -143-5p, -145-3p, -205-5p, -221-3p, -222-3p and -4328 showed consistent downregulation during disease progression (benign > localized PC > bone metastases). The downregulation of miRNA-23c and -4328 was confirmed by reverse transcription and quantitative polymerase chain reaction analysis of 67 metastasis, 12 localized PC and 12 benign prostate tissue samples. The stable overexpression of miRNA-23c and -4328 in the 22Rv1 and PC-3 cell lines resulted in reduced PC cell growth in vitro, and in the secretion of high levels of miRNA-23c (but not -4328) in extracellular vesicles. However, no tumor suppressive effects were observed from miRNA-23c overexpression in PC-3 cells subcutaneously grown in mice. In conclusion, bone metastases display a profound reduction of miRNA levels compared to localized PC and benign disease. The downregulation of those miRNAs, including miRNA-23c and -4328, may lead to a loss of tumor suppressive effects and provide biomarker and therapeutic possibilities that deserve to be further explored.

Effect of docetaxel added to bicalutamide in Hormone-Naïve non-metastatic prostate cancer with rising PSA, a randomized clinical trial (SPCG-14).

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/m2, 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.

Hyaluronic acid spacer in prostate cancer radiotherapy: dosimetric effects, spacer stability and long-term toxicity and PRO in a phase II study.

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.

Epithelial and Stromal Characteristics of Primary Tumors Predict the Bone Metastatic Subtype of Prostate Cancer and Patient Survival after Androgen-Deprivation Therapy.

Prostate cancer (PC) bone metastases can be divided into transcriptomic subtypes, by us termed MetA-C. The MetB subtype, constituting about 20% of the cases, is characterized by high cell cycle activity, low androgen receptor (AR) activity, and a limited response to standard androgen deprivation therapy (ADT). Complementary treatments should preferably be introduced early on if the risk of developing metastases of the MetB subtype is predicted to behigh. In this study, we therefore examined if the bone metastatic subtype and patient outcome after ADT could be predicted by immunohistochemical analysis of epithelial and stromal cell markers in primary tumor biopsies obtained at diagnosis (n = 98). In this advanced patient group, primary tumor International Society of Urological Pathology (ISUP) grade was not associated with outcome or metastasis subtype. In contrast, high tumor cell Ki67 labeling (proliferation) in combination with low tumor cell immunoreactivity for PSA, and a low fraction of AR positive stroma cells in the primary tumors were prognostic for poor survival after ADT. Accordingly, the same tissue markers were associated with developing metastases enriched for the aggressive MetB subtype. The development of the contrasting MetA subtype, showing the best response to ADT, could be predicted by the opposite staining pattern. We conclude that outcome after ADT and metastasis subtype can, at least to some extent, be predicted by analysis of primary tumor characteristics, such as tumor cell proliferation and PSA expression, and AR expression in stromal cells.

Clinical and biological relevance of the transcriptomic-based prostate cancer metastasis subtypes MetA-C.

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.

Paediatric diagnostic reference levels for common radiological examinations using the European guidelines.

OBJECTIVE: The purpose of this study was to explore the feasibility to determine regional diagnostic reference levels (RDRLs) for paediatric conventional and CT examinations using the European guidelines and to compare RDRLs derived from weight and age groups, respectively. METHODS: Data were collected from 31 hospitals in 4 countries, for 7 examination types for a total of 2978 patients. RDRLs were derived for each weight and age group, respectively, when the total number of patients exceeded 15. RESULTS: It was possible to derive RDRLs for most, but not all, weight-based and age-based groups for the seven examinations. The result using weight-based and age-based groups differed substantially. The RDRLs were lower than or equal to the European and recently published national DRLs. CONCLUSION: It is feasible to derive RDRLs. However, a thorough review of the clinical indications and methodologies has to be performed previous to data collection. This study does not support the notion that DRLs derived using age and weight groups are exchangeable. ADVANCES IN KNOWLEDGE: Paediatric DRLs should be derived using weight-based groups with access to the actual weight of the patients. DRLs developed using weight differ markedly from those developed with the use of age. There is still a need to harmonize the method to derive solid DRLs for paediatric radiological examinations.

Registration of histopathology to magnetic resonance imaging of prostate cancer.

BACKGROUND AND PURPOSE: The diagnostic accuracy of new imaging techniques requires validation, preferably by histopathological verification. The aim of this study was to develop and present a registration procedure between histopathology and in-vivo magnetic resonance imaging (MRI) of the prostate, to estimate its uncertainty and to evaluate the benefit of adding a contour-correcting registration. MATERIALS AND METHODS: For twenty-five prostate cancer patients, planned for radical prostatectomy, a 3D-printed prostate mold based on in-vivo MRI was created and an ex-vivo MRI of the specimen, placed inside the mold, was performed. Each histopathology slice was registered to its corresponding ex-vivo MRI slice using a 2D-affine registration. The ex-vivo MRI was rigidly registered to the in-vivo MRI and the resulting transform was applied to the histopathology stack. A 2D deformable registration was used to correct for specimen distortion concerning the specimen's fit inside the mold. We estimated the spatial uncertainty by comparing positions of landmarks in the in-vivo MRI and the corresponding registered histopathology stack. RESULTS: Eighty-four landmarks were identified, located in the urethra (62%), prostatic cysts (33%), and the ejaculatory ducts (5%). The median number of landmarks was 3 per patient. We showed a median in-plane error of 1.8 mm before and 1.7 mm after the contour-correcting deformable registration. In patients with extraprostatic margins, the median in-plane error improved from 2.1 mm to 1.8 mm after the contour-correcting deformable registration. CONCLUSIONS: Our registration procedure accurately registers histopathology to in-vivo MRI, with low uncertainty. The contour-correcting registration was beneficial in patients with extraprostatic surgical margins.

A novel DNA methylation signature is associated with androgen receptor activity and patient prognosis in bone metastatic prostate cancer.

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.

High Monocyte Count and Expression of S100A9 and S100A12 in Peripheral Blood Mononuclear Cells Are Associated with Poor Outcome in Patients with Metastatic Prostate Cancer.

Increasing evidence indicates calcium-binding S100 protein involvement in inflammation and tumor progression. In this prospective study, we evaluated the mRNA levels of two members of this family, S100A9 and S100A12, in peripheral blood mononuclear cells (PBMCs) in a cohort of 121 prostate cancer patients using RT-PCR. Furthermore, monocyte count was determined by flow cytometry. By stratifying patients into different risk groups, according to TNM stage, Gleason score and PSA concentration at diagnosis, expression of S100A9 and S100A12 was found to be significantly higher in patients with metastases compared to patients without clinically detectable metastases. In line with this, we observed that the protein levels of S100A9 and S100A12 in plasma were higher in patients with advanced disease. Importantly, in patients with metastases at diagnosis, high monocyte count and high levels of S100A9 and S100A12 were significantly associated with short progression free survival (PFS) after androgen deprivation therapy (ADT). High monocyte count and S100A9 levels were also associated with short cancer-specific survival, with monocyte count providing independent prognostic information. These findings indicate that circulating levels of monocytes, as well as S100A9 and S100A12, could be biomarkers for metastatic prostate cancer associated with particularly poor prognosis.

Establishing paediatric diagnostic reference levels using reference curves - A feasibility study including conventional and CT examinations.

PURPOSE: To derive Regional Diagnostic Reference Levels (RDRL) for paediatric conventional and CT examinations using weight-based DRL curves and compare the outcome with DRL derived using the weight groups. METHODS: Data from 1722 examinations performed at 29 hospitals in four countries were included. DRL was derived for four conventional x-ray (chest, abdomen, pelvis, hips/joints) and two types of CT examinations (thorax, abdomen). DRL curves were derived using an exponential fit to the data using weight as an independent variable and the respective radiation dose indices (PKA, CTDIvol, DLP) as dependent variables. DRL was also derived for weight groups for comparison. The result was compared with national diagnostic reference level (NDRL) curves. RESULTS: The derived curves show similarities with the NDRL curves available and corresponded sufficiently well with DRL for weight groups using the same data set, if sufficient number of data was available. CONCLUSIONS: We conclude that weight-based DRL curves are a feasible approach and could be used together with DRL for weight groups. The main advantage of DRL curves is its application in the clinic. When the examination frequency is low, time to collect enough data to establish typical values for one or several weight groups may be unreasonably long. The curve provides the means to compare dose level faster and with fewer data points.

Inhibition of STAT3 prevents bone metastatic progression of prostate cancer in vivo.

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.

Ultra-hypofractionated versus conventionally fractionated radiotherapy for prostate cancer (HYPO-RT-PC): patient-reported quality-of-life outcomes of a randomised, controlled, non-inferiority, phase 3 trial.

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.

Comparative Effectiveness of Different Radical Radiotherapy Treatment Regimens for Prostate Cancer: A Population-Based Cohort Study.

BACKGROUND: It is unclear which radiotherapy technique and dose fractionation scheme is most effective in decreasing the risk of prostate cancer death. METHODS: We conducted a population-based cohort study among 15 164 men in the Prostate Cancer database Sweden (version 4.0) treated with primary radical radiotherapy for prostate cancer in Sweden from 1998 to 2016. We calculated hazard ratios with 95% confidence intervals (CIs) of the association between the following exposure groups and outcome: conventionally fractionated external beam radiotherapy (EBRT) to 78 Gy (39 × 2 Gy), EBRT combined with high dose-rate brachytherapy (HDR-BT) (25 × 2 Gy + 2 × 10 Gy), conventionally fractionated EBRT to 70 Gy (35 × 2 Gy), and moderately hypofractionated (M-HF) dose-escalated EBRT (29 × 2.5 Gy or 22 × 3 Gy). RESULTS: Of the men, 7296 received conventionally fractionated EBRT to 78 Gy, 4657 EBRT combined with HDR-BT, 1672 conventionally fractionated EBRT to 70 Gy, and 1539 M-HF EBRT. Using EBRT to 78 Gy as the reference, the multivariable hazard ratios (95% CIs) of prostate cancer death was 0.64 (0.53 to 0.78) for EBRT combined with HDR-BT, 1.00 (0.80 to 1.27) for EBRT to 70 Gy, and 1.51 (0.99 to 2.32) for M-HF EBRT. The multivariable hazard ratios (95% CIs) for death from any cause were 0.79 (0.71 to 0.88), 0.99 (0.87 to 1.14), and 1.12 (0.88 to 1.42), respectively. The lower risk of prostate cancer death comparing EBRT combined with HDR-BT with conventionally fractionated EBRT to 78 Gy was more pronounced for men with high-risk or poorly differentiated tumors. CONCLUSIONS: In this study, EBRT combined with HDR-BT was the most effective radiotherapy treatment regimen, especially for poorly differentiated tumors. Randomized trials comparing EBRT combined with HDR-BT with dose-escalated EBRT should be a priority.

Radical radiotherapy for prostate cancer: patterns of care in Sweden 1998-2016.

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.

Erectile Dysfunction and Absorbed Dose to Penile Base Structures in a Randomized Trial Comparing Ultrahypofractionated and Conventionally Fractionated Radiation Therapy for Prostate Cancer.

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 (EDs). 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/ß = 3 Gy). Univariable and multivariable Cox proportional hazard regression and logistic regression were used to find predictors for EDS. RESULTS: No significant difference in EDs was found between CF and UHF. During the follow-up period, EDs occurred in 27% of the patients in both treatment groups. Average (median) PB mean dose, Dmean, was 24.5 (20.2) in CF and 18.7 (13.1) Gy3 in UHF. Age was the only significant predictor for EDs in Cox analyses. All dose-volume variables contributed significantly in univariable logistic regression at 2-year follow-up. Age and near maximum dose (D2%) were significant predictors for EDs in multivariable logistic regression analyses at both 1 and 2 years. CONCLUSIONS: The frequency of EDS was similar in the CF and UHF treatment groups. Age at radiation therapy was the strongest predictor for EDs, followed by dose to PB, and was most evident for younger patients. We propose D2 % <50 Gy3 and Dmean <20 Gy3 to the PB as the primary objectives to be applied in the treatment planning process.

Assessing Radiographic Response to 223Ra with an Automated Bone Scan Index in Metastatic Castration-Resistant Prostate Cancer Patients.

For effective clinical management of patients being treated with 223Ra, there is a need for radiographic response biomarkers to minimize disease progression and to stratify patients for subsequent treatment options. The objective of this study was to evaluate an automated bone scan index (aBSI) as a quantitative assessment of bone scans for radiographic response in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods: In a multicenter retrospective study, bone scans from patients with mCRPC treated with monthly injections of 223Ra were collected from 7 hospitals in Sweden. Patients with available bone scans before treatment with 223Ra and at treatment discontinuation were eligible for the study. The aBSI was generated at baseline and at treatment discontinuation. The Spearman rank correlation was used to correlate aBSI with the baseline covariates: alkaline phosphatase (ALP) and prostate-specific antigen (PSA). The Cox proportional-hazards model and Kaplan-Meier curve were used to evaluate the association of covariates at baseline and their change at treatment discontinuation with overall survival (OS). The concordance index (C-index) was used to evaluate the discriminating strength of covariates in predicting OS. Results: Bone scan images at baseline were available from 156 patients, and 67 patients had both a baseline and a treatment discontinuation bone scan (median, 5 doses; interquartile range, 3-6 doses). Baseline aBSI (median, 4.5; interquartile range, 2.4-6.5) was moderately correlated with ALP (r = 0.60, P < 0.0001) and with PSA (r = 0.38, P = 0.003). Among baseline covariates, aBSI (P = 0.01) and ALP (P = 0.001) were significantly associated with OS, whereas PSA values were not (P = 0.059). After treatment discontinuation, 36% (24/67), 80% (54/67), and 13% (9/67) of patients demonstrated a decline in aBSI, ALP, and PSA, respectively. As a continuous variable, the relative change in aBSI after treatment, compared with baseline, was significantly associated with OS (P < 0.0001), with a C-index of 0.67. Median OS in patients with both aBSI and ALP decline (median, 134 wk) was significantly longer than in patients with ALP decline only (median, 77 wk; P = 0.029). Conclusion: Both aBSI at baseline and its change at treatment discontinuation were significant parameters associated with OS. The study warrants prospective validation of aBSI as a quantitative imaging response biomarker to predict OS in patients with mCRPC treated with 223Ra.