Five-year outcomes of fractionated stereotactic body radiotherapy for oligometastatic prostate cancer from the TRANSFORM phase II trial.

Metastasis-directed therapy (MDT) for oligometastatic prostate cancer (PCa), including stereotactic body radiotherapy (SBRT), has shown promise but is still considered investigational. This is the 5-year analysis of the TRANSFORM trial, the largest prospective cohort of men with oligometastatic PCa treated with SBRT-based MDT. The primary endpoint was 5-year treatment escalation-free survival (TE-FS), defined as freedom from any new cancer therapy other than further SBRT. In total, 199 men received SBRT; 76.4% were hormone-naïve at baseline. The rate of 5-year TE-FS was 21.7% (95% confidence interval [CI]: 15.7%-28.7%) overall and 25.4% (95% CI: 18.1%-33.9%) in the hormone-naïve subgroup. The subgroups with International Society of Urological Pathology Grade Groups 4-5 disease (hazard ratio [HR] = 1.48, 95% CI: 1.05-2.01, p = .026), a higher baseline prostate-specific antigen (PSA) (HR = 1.06, 95% CI: 1.03-1.09, p < .001) and those who received prior androgen deprivation therapy (ADT) (HR = 2.13, 95% CI: 1.40-3.26, p < .001), were at greater risk of treatment escalation. Outcomes for participants with four or five initial lesions were comparable to those with one to three lesions. At last follow-up, 18.9% (95% CI: 13.2%-25.7%) of participants were free from treatment escalation (median follow-up of 67.9 months) and two participants had an undetectable PSA level. No treatment-related grade three or higher adverse events were reported. The findings of this study demonstrate that SBRT-based MDT is an effective option for delaying systemic treatment escalation in the context of oligometastatic PCa. Future randomised trials comparing SBRT-based MDT to standard-of-care ADT-based approaches are required to evaluate the impact of delaying ADT on survival.

Molecular classification of hormone-sensitive and castration-resistant prostate cancer, using nonnegative matrix factorization molecular subtyping of primary and metastatic specimens.

BACKGROUND: Despite the rapidly evolving therapeutic landscape, immunotherapy has demonstrated limited activity in prostate cancer. A greater understanding of the molecular landscape, particularly the expression of immune-related pathways, will inform future immunotherapeutic strategies. Consensus nonnegative matrix factorization (cNMF) is a novel model of molecular classification analyzing gene expression data, focusing on biological interpretation of metagenes and selecting meaningful clusters. OBJECTIVE: We aimed to identify molecular subtypes of prostate cancer using cNMF and correlate these with existing biomarkers to inform future immunotherapeutic strategies. METHODS: A cohort of archival tumor specimens from hormone-sensitive and castration-resistant disease was studied. Whole transcriptomic profiles were generated using TruSeq RNA Access technology and subjected to cNMF. Comprehensive genomic profiling was performed with the FoundationOne assay. NMF subtypes were characterized by gene expression pathways, genomic alterations and correlated with clinical data, then applied to The Cancer Genome Atlas data set. RESULTS: We studied 164 specimens, including 52 castration-resistant and 13 paired primary/metastatic specimens. cNMF identified four distinct subtypes. NMF1 (19%) is enriched for immune-related and stromal-related pathways with transforming growth factor ß (TGFß) signature. NMF2 (36%) is associated with FOXO-mediated transcription signature and AKT signaling, NMF3 (26%) is enriched for ribosomal RNA processing, while NMF4 (19%) is enriched for cell cycle and DNA-repair pathways. The most common gene alterations included TMPRSS22 (42%), TP53 (23%), and DNA-repair genes (19%), occurring across all subtypes. NMF4 is significantly enriched for MYC and Wnt-signaling gene alterations. TMB, CD8 density, and PD-L1 expression were low overall. NMF1 and NMF4 were NMF2 was associated with superior overall survival. CONCLUSIONS: Using cNMF, we identified four molecularly distinct subtypes which may inform treatment selection. NMF1 demonstrates the most inflammatory signature with asuppressive TGFß signature, suggesting potential benefit with immunotherapy combination strategies targeting TGFß and PD-(L)1. Prospective studies are required to evaluate the use of this novel model to molecularly stratify patients for optimal treatment selection.

Transcriptome sequencing and multi-plex imaging of prostate cancer microenvironment reveals a dominant role for monocytic cells in progression.

BACKGROUND: Prostate cancer is caused by genomic aberrations in normal epithelial cells, however clinical translation of findings from analyses of cancer cells alone has been very limited. A deeper understanding of the tumour microenvironment is needed to identify the key drivers of disease progression and reveal novel therapeutic opportunities. RESULTS: In this study, the experimental enrichment of selected cell-types, the development of a Bayesian inference model for continuous differential transcript abundance, and multiplex immunohistochemistry permitted us to define the transcriptional landscape of the prostate cancer microenvironment along the disease progression axis. An important role of monocytes and macrophages in prostate cancer progression and disease recurrence was uncovered, supported by both transcriptional landscape findings and by differential tissue composition analyses. These findings were corroborated and validated by spatial analyses at the single-cell level using multiplex immunohistochemistry. CONCLUSIONS: This study advances our knowledge concerning the role of monocyte-derived recruitment in primary prostate cancer, and supports their key role in disease progression, patient survival and prostate microenvironment immune modulation.

The modified International Society of Urological Pathology system improves concordance between biopsy and prostatectomy tumour grade.

OBJECTIVES: To assess the concordance between biopsy and radical prostatectomy (RP) specimens using the 2005 Gleason score (GS) and the International Society of Urological Pathology (ISUP) 2014/World Health Organization 2016 modified system, accounting for the introduction of transperineal biopsy and pre-biopsy multiparametric magnetic resonance imaging (mpMRI). PATIENTS AND METHODS: Between 2002 and 2019, we identified 2431 patients with paired biopsy and RP histopathology from a prospectively recorded and maintained prostate cancer database. Biopsy specimens were graded according to the 2005 GS or ISUP 2014 modified system, according to the year of diagnosis. Multivariable logistic regression analysis was conducted to retrospectively assess the impact of prostate-specific antigen (PSA), PSA density, age, pre-biopsy mpMRI, and biopsy method, on the rate of upgraded disease. The kappa coefficient was used to establish the degree of change in concordance between groups. RESULTS: Overall, 24% of patients had upgraded disease and 8% of patients had downgraded disease when using the modified ISUP 2014 criteria. Agreement in the updated ISUP 2014 cohort was 68%, compared with 55% in the 2005 GS group, which was validated by a kappa coefficient that was good (k = 0.5 ± 0.4) and poor (k = 0.3 ± 0.1), respectively. In multivariable models, a change in grading system independently improved overall disease concordance (P = 0.02), and there were no other co-segregated patient or pathological factors such as PSA, total number of cores, maximum cancer length, biopsy route or the use of mpMRI that impacted this finding. CONCLUSION: The 2014 ISUP modifed system improves overall concordance between biopsy and surgical specimens, and thus allows more accurate prognostication and management in high-grade disease, independent of more extensive prostate sampling and the use of mpMRI.

Fractionated stereotactic body radiotherapy for up to five prostate cancer oligometastases: Interim outcomes of a prospective clinical trial.

Stereotactic body radiotherapy (SBRT) can delay escalation to systemic treatment in men with oligometastatic prostate cancer (PCa). However, large, prospective studies are still required to evaluate the efficacy of this approach in different patient groups. This is the interim analysis of a prospective, single institution study of men relapsing with up to five synchronous lesions following definitive local treatment for primary PCa. Our aim was to determine the proportion of patients not requiring treatment escalation following SBRT. In total, 199 patients were enrolled to receive fractionated SBRT (50 Gray in 10 fractions) to each visible lesion. Fourteen patients were castration resistant at enrolment. The proportion of patients not requiring treatment escalation 2 years following SBRT was 51.7% (95% CI: 44.1-59.3%). The median length of treatment escalation-free survival over the entire follow-up period was 27.1 months (95% CI; 21.8-29.4 months). Prior androgen deprivation therapy (ADT) predicted a significantly lower rate of freedom from treatment escalation at 2 years compared to no prior ADT (odds ratio = 0.21, 95% CI: 0.08-0.54, p = 0.001). There was no difference in the efficacy of SBRT when treating 4-5 vs. 1-3 initial lesions. A prostate-specific antigen (PSA) decline was induced in 75% of patients, with PSA readings falling to an undetectable level in six patients. No late grade three toxicities were observed. These interim results suggest that SBRT can be used to treat up to five synchronous PCa oligometastases to delay treatment escalation.

Late biochemical recurrence after radical prostatectomy is associated with a slower rate of progression.

OBJECTIVE: To characterise the pattern of late biochemical recurrence (BCR) in the largest contemporary cohort of patients with localised prostate cancer treated with radical prostatectomy (RP) in the active surveillance era. PATIENTS AND METHODS: Consecutive patients who underwent RP for localised prostate cancer between 2003 and 2017 were identified from a prospectively recorded, dedicated prostate cancer database. Patients who received neoadjuvant androgen-deprivation therapy were excluded. These patients were categorised into the following groups: no BCR, BCR at <12 months (early), BCR at 12-60 months (intermediate), and BCR at >60 months (late), after RP. Clinicopathological characteristics were analysed using the Student's t-test, Mann-Whitney U-test, or chi-squared test where appropriate. Multivariable binomial logistic regression models were used to assess predictors of BCR at various time-points. RESULTS: In all, 2312 patients were included in the final analysis with up to 12 years of follow-up data. The average patient had clinically localised prostate cancer, an elevated PSA level, and International Society of Urological Pathology (ISUP) Grade Group 2 on biopsy. In all, 88.7% of patients had ISUP Grade Group ≥2 at RP. A subgroup of 446 patients had undetectable PSA levels at 5 years after RP; 11.7% of them progressed to experience BCR. In this subgroup, late recurrers had significantly higher-grade tumours on ISUP and Gleason sum (P <0.001 and P = 0.001, respectively), higher rates of extraprostatic extension (P = 0.022), and larger tumour volumes (P = 0.032). Logistic regression showed that RP ISUP Grade Group was a significant predictor of BCR (odds ratio 2.14, 95% confidence interval 1.43-3.20; P <0.001). CONCLUSION: This study characterises the pattern of late BCR in the largest contemporary active surveillance era cohort. We have identified that RP ISUP Grade Group is a strong predictive indicator for late BCR. We also propose that timing of BCR resides on a continuum of risk and that the potential concept of dormant micrometastatic involvement requires further research and evaluation.

Routinely reported 'equivocal' lymphovascular invasion in prostatectomy specimens is associated with adverse outcomes.

OBJECTIVE: To evaluate the significance of routinely reported 'equivocal' lymphovascular invasion (LVI) in prostatectomy specimens of patients with clinically localized prostate cancer. MATERIALS AND METHODS: Prospectively collected data from men who underwent prostatectomy for clinically localized prostate cancer were retrospectively reviewed. Rates of adverse pathological features and biochemical recurrence (BCR) were compared between tumours positive, negative or 'equivocal' for LVI. Multivariable Cox regression analysis was performed to identify independent predictors of BCR. RESULTS: Of 1 310 consecutive cases, LVI was present definitively in 82 (6.3%) and equivocally in 43 (3.3%) cases. Similar to definitive LVI, equivocal LVI was significantly associated with other adverse pathological features, including advanced stage, higher Gleason grade and positive surgical margins. BCR occurred more frequently in patients with tumours that were equivocal (61%) or positive for LVI (71%) than in patients with negative results (14.7%). In addition, patients with both definitive and equivocal LVI had a significantly shorter BCR-free survival time compared with those with negative LVI. Multivariable Cox regression analysis indicated that the presence of either definitive or equivocal LVI were independent predictors of disease recurrence (hazard ratio [HR] 3.32, 95% confidence interval [CI] 2.3-4.8; P <0.001 vs HR 1.66, 95% CI 1.05-2.65; P = 0.032, respectively). CONCLUSION: In this single-institution study, equivocal LVI had a similar association with adverse pathological features and rate of BCR to that of definitive LVI. If our observations are validated in an independent cohort, consideration should be given to the inclusion of equivocal LVI as part of routine pathological reporting.

An online psychological intervention can improve the sexual satisfaction of men following treatment for localized prostate cancer: outcomes of a Randomised Controlled Trial evaluating My Road Ahead.

BACKGROUND: Prostate cancer treatment often results in significant psycho-sexual challenges for men following treatment; however, many men report difficulty in accessing appropriate care. METHODS: A randomized controlled trial was undertaken to assess the efficacy of a 10-week self-guided online psychological intervention called My Road Ahead (MRA) for men with localized prostate cancer in improving sexual satisfaction. Participants were randomized to 1 of 3 conditions MRA alone or MRA plus online forum, or forum access alone. Pre, post, and follow-up assessments of overall sexual satisfaction were conducted. Mixed models and structural equation modeling were used to analyze the data. RESULTS: One hundred forty-two men (mean age 61 y; SD = 7) participated. The majority of participants had undergone radical prostatectomy (88%) and all men had received treatment for localized prostate cancer. Significant differences were obtained for the 3 groups (P = .026) and a significant improvement in total sexual satisfaction was observed only for participants who were allocated to MRA + forum with a large effect size (P = .004, partial η2  = 0.256). Structural equation modeling indicated that increases in sexual function, masculine self-esteem, and sexual confidence contributed significantly to overall sexual satisfaction for the MRA + forum plus forum condition. CONCLUSIONS: This study is the first, to our knowledge, that has evaluated a self-guided online psychological intervention tailored to the specific needs of men with prostate cancer. The findings indicate the potential for MRA to deliver support that men may not otherwise receive and also highlight the importance of psychological intervention to facilitate improved sexual outcomes.

A urinary microRNA signature can predict the presence of bladder urothelial carcinoma in patients undergoing surveillance.

BACKGROUND: The objective of this study was to determine whether microRNA (miRNA) profiling of urine could identify the presence of urothelial carcinoma of the bladder (UCB) and to compare its performance characteristics to that of cystoscopy. METHODS: In the discovery cohort we screened 81 patients, which included 21 benign controls, 30 non-recurrers and 30 patients with active cancer (recurrers), using a panel of 12 miRNAs. Data analysis was performed using a machine learning approach of a Support Vector Machine classifier with a Student's t-test feature selection procedure. This was trained using a three-fold cross validation approach and performance was measured using the area under the receiver operator characteristic curve (AUC). The miRNA signature was validated in an independent cohort of a further 50 patients. RESULTS: The best predictor to distinguish patients with UCB from non-recurrers was achieved using a combination of six miRNAs (AUC=0.85). This validated in an independent cohort (AUC=0.74) and detected UCB with a high sensitivity (88%) and sufficient specificity (48%) with all significant cancers identified. The performance of the classifier was best in detecting clinically significant disease such as presence of T1 Stage disease (AUC=0.92) and high-volume disease (AUC=0.81). Cystoscopy rates in the validation cohort would have been reduced by 30%. CONCLUSIONS: Urinary profiling using this panel of miRNAs shows promise for detection of tumour recurrence in the surveillance of UCB. Such a panel may be useful in reducing the morbidity and costs associated with cystoscopic surveillance, and now merits prospective evaluation.

Patterns-of-care and health economic analysis of robot-assisted radical prostatectomy in the Australian public health system.

OBJECTIVES: To compare patterns of care and peri-operative outcomes of robot-assisted radical prostatectomy (RARP) with other surgical approaches, and to create an economic model to assess the viability of RARP in the public case-mix funding system. PATIENTS AND METHODS: We retrospectively reviewed all radical prostatectomies (RPs) performed for localized prostate cancer in Victoria, Australia, from the Victorian Admitted Episode Dataset, a large administrative database that records all hospital inpatient episodes in Victoria. The first database, covering the period from July 2010 to April 2013 (n = 5 130), was used to compare length of hospital stay (LOS) and blood transfusion rates between surgical approaches. This was subsequently integrated into an economic model. A second database (n = 5 581) was extracted to cover the period between July 2010 and June 2013, three full financial years, to depict patterns of care and make future predictions for the 2014-2015 financial year, and to perform a hospital volume analysis. We then created an economic model to evaluate the incremental cost of RARP vs open RP (ORP) and laparoscopic RP (LRP), incorporating the cost-offset from differences in LOS and blood transfusion rate. The economic model constructs estimates of the diagnosis-related group (DRG) costs of ORP and LRP, adds the gross cost of the surgical robot (capital, consumables, maintenance and repairs), and manipulates these DRG costs to obtain a DRG cost per day, which can be used to estimate the cost-offset associated with RARP in comparison with ORP and LRP. Economic modelling was performed around a base-case scenario, assuming a 7-year robot lifespan and 124 RARPs performed per financial year. One- and two-way sensitivity analyses were performed for the four-arm da Vinci SHD, Si and Si dual surgical systems (Intuitive Surgical Ltd, Sunnyvale, CA, USA). RESULTS: We identified 5 581 patients who underwent RP in 20 hospitals in Victoria with an open, laparoscopic or robot-assisted surgical approach in the public and private sector. The majority of RPs (4 233, 75.8%), in Victoria were performed in the private sector, with an overall 11.5% decrease in the total number of RPs performed over the 3-year study period. In the most recent financial year, 820 (47%), 765 (44%) and 173 patients (10%) underwent RARP, ORP and LRP, respectively. In the same timeframe, RARP accounted for 26 and 53% of all RPs in the public and private sector, respectively. Public hospitals in Victoria perform a median number of 14 RPs per year and 40% of hospitals perform <10 RPs per year. In the public system, RARP was associated with a mean (±sd) LOS of 1.4 (±1.3) days compared with 3.6 (±2.7) days for LRP and 4.8 (±3.5) days for ORP (P < 0.001). The mean blood transfusion rates were 0, 6 and 15% for RARP, LRP and ORP, respectively (P < 0.001). The incremental cost per RARP case compared with ORP and LRP was A$442 and A$2 092, respectively, for the da Vinci S model, A$1 933 and A$3 583, respectively, for the da Vinci Si model and A$3 548 and A$5 198, respectively for the da Vinci Si dual. RARP can become cost-equivalent with ORP where ~140 cases per year are performed in the base-case scenario. CONCLUSIONS: Over the period studied, RARP has become the dominant approach to RP, with significantly shorter LOS and lower blood transfusion rate. This translates to a significant cost-offset, which is further enhanced by increasing the case volume, extending the lifespan of the robot and reductions in the cost of consumables and capital.

The urologist's role in multidisciplinary management of placenta percreta.

OBJECTIVE: To evaluate urological interventions in patients with placental adhesive disorders in our collaborative experience at a tertiary referral centre. PATIENTS AND METHODS: We performed a retrospective analysis of a prospectively collected data set, consisting of all women that presented with placental adhesive disorders at the Royal Women's Hospital from August 2009 to September 2013. Patients who required urological intervention were identified and perioperative details were retrieved. RESULTS: Of the 49 women that presented with placental adhesive disorders, 36 (73.5%) underwent urological interventions. The patients were divided into three groups: planned hysterectomy (37 patients), planned conservative management (five) and undiagnosed placenta percreta (seven). In the planned hysterectomy group, 29 patients underwent preoperative cystoscopy and ureteric catheter placement. In 10 patients (34%), the placenta partially invaded the bladder and/or ureter, requiring urological repair. In the conservative management group, four underwent preoperative cystoscopy and ureteric catheter placement, and one case required closure of a cystotomy. Of the seven patients with undiagnosed percreta, two were noted to have bladder involvement requiring repair at the time of Caesarean hysterectomy. CONCLUSION: Patients with placental adhesive disorders frequently require urological intervention to prevent or repair injury to the urinary tract. These cases are best managed in specialist centres with multidisciplinary expertise including urologists and interventional radiologists.

Identification of candidates for observation.

PURPOSE OF REVIEW: The clinical value of active surveillance may still be limited due to acceptance and considerable misclassification rates, and inadequate follow-up criteria. This review focuses on the most recent developments in the use of active surveillance and patient-specific factors that may be used to identify patients suitable for this strategy. RECENT FINDINGS: The number of patients diagnosed with low-risk prostate cancer has risen. Active surveillance acceptance rates are increasing, but still limited and varying importantly (2-49%). Misclassification is inevitable in all currently used protocols, although most of these patients still have relatively favorable-risk prostate cancer. African-American race, obese, and older-aged patients show more unfavorable intermediate results in an active surveillance situation. These are unlikely to be explained by the small differences in preoperative characteristics only. Psychological profiling may also be added to the selection process. Most studies report intermediate endpoints only. SUMMARY: Patient-specific factors may be incorporated when identifying patients for active surveillance. This does not imply that active surveillance is not justified in specific groups, but may suggest the need for an intensified and personalized selection, instead of a one-size-fits-all approach.

My Road Ahead study protocol: a randomised controlled trial of an online psychological intervention for men following treatment for localised prostate cancer.

BACKGROUND: There is a need for psychosocial interventions for men with prostate cancer to promote adaptive coping with the challenges and distress associated with diagnosis, treatment and recovery. In addition, interventions are needed that help to overcome barriers to psychosocial treatment such as limited face-to-face psychosocial support services, a shortage of adequately trained professionals, geographical distance, perceived and personal stigma and a preference for consumer-centric and self-directed learning. My Road Ahead is an online cognitive behaviour therapy (CBT) intervention for prostate cancer. This protocol describes a randomised controlled trial (RCT) that will evaluate the efficacy of this online intervention alone, the intervention in combination with a moderated online forum, and the moderated online forum alone. METHODS/DESIGN: This study utilises a RCT design with three groups receiving: 1) the 6-module My Road Ahead intervention alone; 2) the My Road Ahead intervention plus a moderated online forum; and 3) the moderated online forum alone. It is expected that 150 men with localised prostate cancer will be recruited into the RCT. Online measures will assess men's psychological distress as well as sexual and relationship adjustment at baseline, post-intervention, 3 month follow-up and 6 month follow-up. The study is being conducted in Australia and participants will be recruited from April 2012 to Feb 2014. The primary aim of this study is to evaluate the efficacy of My Road Ahead in reducing psychological distress. DISCUSSION: To our knowledge, My Road Ahead is the first self-directed online psychological intervention developed for men who have been treated for localised prostate cancer. The RCT will assess the efficacy of this intervention in improving psychological well-being, sexual satisfaction, relationship satisfaction and overall quality of life. If successful, this intervention could provide much needed support to men receiving treatment for localised prostate cancer in a highly accessible manner. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry Identifier: ACTRN12611000278932.

The Melbourne Consensus Statement on the early detection of prostate cancer.

Various conflicting guidelines and recommendations about prostate cancer screening and early detection have left both clinicians and their patients quite confused. At the Prostate Cancer World Congress held in Melbourne in August 2013, a multidisciplinary group of the world's leading experts in this area gathered together and generated this set of consensus statements to bring some clarity to this confusion. The five consensus statements provide clear guidance for clinicians counselling their patients about the early detection of prostate cancer.

Positive surgical margins: rate, contributing factors and impact on further treatment: findings from the Prostate Cancer Registry.

OBJECTIVE: To describe the characteristics of patients with and without positive surgical margins (PSMs) and to analyse the impact of PSMs on secondary cancer treatment after radical prostatectomy (RP), with short-term follow-up. PATIENTS AND METHODS: We analysed data from 2385 consecutive patients treated using RP, who were notified to the Prostate Cancer Registry by 37 hospitals in Victoria, Australia between August 2008 and February 2012. Independent and multivariate models were constructed to predict the likelihood of PSMs. Independent and multivariate predictors of secondary treatment after RP in the initial 12 months after diagnosis were also assessed. RESULTS: Data on PSM status were collected for 2219/2385 (93%) patients. In total 592/2175 (27.2%) RPs resulted in PSMs; 102/534 (19.1%) in the low-risk group, 317/1218 (26.0%) in the intermediate-risk group, 153/387 (39.5%) in the high-risk group, and 9/11 (81.8%) in the very-high-risk disease group of patients. Patients having surgery in a hospital where <10 RPs occur each year were significantly more likely to have a PSM (incidence rate ratio [IRR] 1.44, 95% confidence interval [CI] 1.07-1.93) and those in the intermediate-, high- or very-high-risk groups (IRR 1.34, 95% CI 1.09-1.65, P = 0.007, IRR 1.96, 95% CI 1.57-2.45, P < 0.001 and IRR 3.81, 95% CI 2.60-5.60, P < 0.001, respectively) were significantly more likely to have a PSM than those in the low-risk group (IRR 2.50, 95% CI 1.23-5.11, P = 0.012). Patients with PSMs were significantly less likely to have been treated at a private hospital than a public hospital (IRR 0.76, 95% CI 0.63-0.93, P = 0.006) or to have undergone robot-assisted RP (IRR 0.69, 95% CI 0.55-0.87; P = 0.002) than open RP. Of the 2182 patients who underwent RP in the initial 12 months after diagnosis, 1987 (91.1%) received no subsequent treatment, 123 (5.6%) received radiotherapy, 47 (2.1%) received androgen deprivation therapy (ADT) and 23 (1.1%) received a combination of radiotherapy and ADT. Two patients (0.1%) received chemotherapy combined with another treatment. At a multivariate level, predictors of additional treatment after RP in the initial 12 months included having a PSM compared with a negative surgical margin (odds ratio [OR] 5.61, 95% CI 3.82-8.22, P < 0.001); pT3 compared with pT2 disease (OR 4.72, 95% CI 2.69-8.23, P < 0.001); and having high- or very-high-risk disease compared with low-risk disease (OR 4.36, 95% CI 2.24-8.50, P < 0.001 and OR 4.50, 95% CI 1.34-15.17, P = 0.015, respectively). Patient age, hospital location and hospital type were not associated with secondary treatment. Patients undergoing robot-assisted RP were significantly less likely to receive additional treatment than those receiving open RP (OR 0.59, 95% CI 0.39-0.88, P = 0.010). CONCLUSIONS: These data indicate an important association between hospital status and PSMs, with patients who underwent RP in private hospitals less likely than those in public hospitals to have a PSM. Patients treated in lower-volume hospitals were more likely to have a PSM and less likely to receive additional treatment after surgery in the initial 12 months, and robot-assisted RP was associated with fewer PSMs than was open RP in this non-randomized observational study. PSM status and pathological T3 disease are both important and independent predictors of secondary cancer treatment for patients undergoing RP. A robot-assisted RP approach appears to decrease the likelihood of subsequent treatment, when compared with the open approach.

Genomic evolution shapes prostate cancer disease type.

The development of cancer is an evolutionary process involving the sequential acquisition of genetic alterations that disrupt normal biological processes, enabling tumor cells to rapidly proliferate and eventually invade and metastasize to other tissues. We investigated the genomic evolution of prostate cancer through the application of three separate classification methods, each designed to investigate a different aspect of tumor evolution. Integrating the results revealed the existence of two distinct types of prostate cancer that arise from divergent evolutionary trajectories, designated as the Canonical and Alternative evolutionary disease types. We therefore propose the evotype model for prostate cancer evolution wherein Alternative-evotype tumors diverge from those of the Canonical-evotype through the stochastic accumulation of genetic alterations associated with disruptions to androgen receptor DNA binding. Our model unifies many previous molecular observations, providing a powerful new framework to investigate prostate cancer disease progression.

Extraprostatic extension into periprostatic fat is a more important determinant of prostate cancer recurrence than an invasive phenotype.

PURPOSE: Although micrometastasis development correlates closely with the depth of invasion of many tumor types, it is unclear whether invasion into but not through the prostatic pseudocapsule has a negative impact on prognosis, similar to extraprostatic extension. We defined the impact of pseudocapsular invasion on the risk of post-prostatectomy biochemical recurrence. MATERIALS AND METHODS: Patients with pT2-3a prostate cancer were identified from a prospectively recorded database. Those with pT2 disease were categorized according to pseudocapsular invasion presence or absence. The impact of pseudocapsular invasion on biochemical recurrence was determined by univariable and multivariable Cox regression analysis. RESULTS: In a cohort of 1,338 patients we identified 595 with organ confined cancer positive for pseudocapsular invasion. Compared to tumors without evidence of invasion, pseudocapsular invasion was positively associated with higher Gleason grade and tumor volume (1.2 vs 1.9 cc, each p<0.001). On univariable analysis there was no difference in biochemical recurrence-free survival between patients with vs without pseudocapsular invasion, although those with extraprostatic extension had significantly lower biochemical recurrence-free survival (p<0.001). This was confirmed on multivariable analysis, which revealed that extraprostatic extension was a significant independent predictor of biochemical recurrence (HR 1.53, p=0.018). The presence of pseudocapsular invasion had no effect (HR 0.81, p=0.33). CONCLUSIONS: Pseudocapsular invasion is not a pathological feature associated with an adverse outcome after prostatectomy. Thus, the depth of tumor invasion is not a continuum of risk and access to periprostatic adipose tissue is a more important determinant of disease behavior than an invasive phenotype.

Presence or absence of a positive pathological margin outperforms any other margin-associated variable in predicting clinically relevant biochemical recurrence in Gleason 7 prostate cancer.

UNLABELLED: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: The presence of a positive pathological margin is an independent risk factor for clinically significant disease recurrence only in intermediate-risk disease when the a priori risk of micrometastatic disease is accounted for. The study examines patients with Gleason 7 prostate cancer to assess the relative importance of various margin-related variables (focality, linear length, tumour grade at margin, presence of diathermy artifact and plane of tumour) with regard to biochemical recurrence. We found that the presence or absence of a positive pathological margin outperforms any other margin-associated variable in predicting significant disease recurrence. OBJECTIVE: To determine the influence of pathological margin variables on the risk of clinically significant biochemical recurrence in Gleason 7 prostate cancer. MATERIALS AND METHODS: Patients with Gleason 7 prostate cancer with complete clinical and pathological data and detailed follow-up were identified from a prospectively recorded prostatectomy database. Slides from all patients with positive pathological margins were reviewed by a single expert uropathologist and the following information recorded: multifocality, linear length, predominant Gleason grade at the margin, diathermy artifact and margin plane. Cox regression models were generated to determine the impact of positive pathological margins on the risk of biochemical recurrence (using various definitions thereof). RESULTS: Of 1048 patients with Gleason 7 prostate cancer, 238 (23%) patients had positive margins. With a median follow-up of 11 months, biochemical recurrence occurred in 9.7% of patients with negative surgical margins and 28.4% of patients with positive margins. Positive margins were significantly associated with higher serum prostate-specific antigen (PSA) level, tumour grade, stage and volume. In patients with positive pathological margins, controlling for other factors, no margin-derived variable (focality, linear length, tumour grade at margin, diathermy artifact or plane of tumour) was a consistent predictor of biochemical recurrence, although the presence of Gleason score 4 or tertiary Gleason score 5 tumour at the margin edge was an independent predictor of recurrence with PSA doubling times ≤ 6 and ≤9 months. Similarly, in the cohort as a whole, the pathological margin status was a more important predictor of recurrence than any other margin-derived variable. CONCLUSIONS: In Gleason 7 prostate cancer, positive pathological margin status was the only consistent margin-derived variable determining biochemical failure. The presence of high-grade disease at the margin may also have an impact on the development of clinically significant biochemical recurrence.

A randomised, wait-list controlled trial: evaluation of a cognitive-behavioural group intervention on psycho-sexual adjustment for men with localised prostate cancer.

OBJECTIVE: To examine the effectiveness of a cognitive-behavioural therapy (CBT) group intervention to facilitate improved psycho-sexual adjustment to treatment side effects in prostate cancer survivors post-radical prostatectomy. METHODS: A randomised, wait-list controlled trial was conducted with a total of 60 men who participated in a manualised 8-week cognitive-behavioural group intervention 6 months to 5 years post-radical prostatectomy for localised prostate cancer. Participants completed standardised questionnaires pre-intervention and post-intervention, which assessed mood state, stress, general and prostate cancer anxiety, quality of life and areas of sexual functioning. RESULTS: Paired samples t-tests identified a significant improvement in sexual confidence, masculine self-esteem, sexual drive/relationship and a significant decline in sexual behaviour from pre-intervention to post-intervention. Hierarchical regression analyses revealed that after controlling for covariates, participation in the group intervention significantly improved sexual confidence, sexual intimacy, masculine self-esteem and satisfaction with orgasm. CONCLUSIONS: This group-based CBT intervention for men post-radical prostatectomy for localised prostate cancer shows promising results in terms of improving quality of life.