Kasper Drimer Berg

Active surveillance for clinically localized prostate cancer––A systematic review

Active surveillance (AS) has been introduced as an observational strategy to delay or avoid curative treatment without compromising long‐term cancer‐specific survival. The 10 studies included in this review, published between 2008 and 2013, generally agreed upon patients selection for the AS strategy and how they should be managed within the program. However, uncertainties persists concerning optimal patient selection and reliable progression criteria, as well as the long‐term safety of AS. J. Surg. Oncol. 2014 109:830–835.

ERG Protein Expression in Diagnostic Specimens Is Associated with Increased Risk of Progression During Active Surveillance for Prostate Cancer

BACKGROUND Compelling biomarkers identifying prostate cancer patients with a high risk of progression during active surveillance (AS) are needed. OBJECTIVE To examine the association between ERG expression at diagnosis and the risk of progression during AS. DESIGN, SETTING, AND PARTICIPANTS This study included 265 patients followed on AS with prostate-specific antigen (PSA) measurements, clinical examinations, and 10-12 core rebiopsies from 2002 to 2012 in a prospectively maintained database. ERG immunohistochemical staining was performed on diagnostic paraffin-embedded formalin-fixed sections with a ready-to-use kit (anti-ERG, EPR3864). Men were characterised as ERG positive if a minimum of one tumour focus demonstrated ERG expression. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Overall AS progression was defined as clinical progression: increased clinical tumour category ≥cT2b by digital rectal examination and ultrasound, and/or histopathologic progression: upgrade of Gleason score, more than three positive cores or bilateral positive cores, and/or PSA progression: PSA doubling time <3 yr. Risk of progression was analysed using multiple cause-specific Cox regression and stratified cumulative incidences (Aalen-Johansen method). Curatively intended treatment, watchful waiting, and death without progression were treated as competing events. RESULTS AND LIMITATIONS A total of 121 of 142 ERG-negative and 96 of 123 ERG-positive patients had complete diagnostic information. In competing risk models, the ERG-positive group showed significantly higher incidences of overall AS progression (p<0.0001) and of the subgroups PSA progression (p<0.0001) and histopathologic progression (p<0.0001). The 2-yr cumulative incidence of overall AS progression was 21.7% (95% confidence interval [CI], 14.3-29.1) in the ERG-negative group compared with 58.6% (95% CI, 48.7-68.5) in the ERG-positive group. ERG positivity was a significant predictor of overall AS progression in multiple Cox regression (hazard ratio: 2.45; 95% CI, 1.62-3.72; p<0.0001). The main limitation of this study is its observational nature. CONCLUSIONS In our study, ERG positivity at diagnosis can be used to estimate the risk of progression during AS. If confirmed, ERG status can be used to individualise AS programmes. PATIENT SUMMARY The tissue biomarker ERG identifies active surveillance patients with an increased risk of disease progression.

Serum testosterone level as a predictor of biochemical failure after radical prostatectomy for localized prostate cancer

Study Type – Aetiology (individual cohort)

Prostate needle biopsies: interobserver variation and clinical consequences of histopathological re-evaluation

Berg KD, Toft BG, Røder MA, Brasso K, Vainer B, Iversen P. Prostate needle biopsies: interobserver variation and clinical consequences of histopathological re‐evaluation. APMIS 2011; 119: 239–46.

Does Cytoreductive Prostatectomy Really Have an Impact on Prognosis in Prostate Cancer Patients with Low-volume Bone Metastasis? Results from a Prospective Case-Control Study

The impact of cytoreductive radical prostatectomy (CRP) on oncological outcomes in patients with prostate cancer (PCa) and distant metastases has been demonstrated by retrospective data with their potential selection bias. Using prospective institutional data, we compared the outcomes between 43 PCa patients with low-volume bone metastases (1-3 lesions) undergoing CRP (median follow-up 32.7 mo) and 40 patients receiving best systemic therapy (BST; median follow-up 82.2 mo). The inclusion criteria for both cohorts were identical. So far, no significant difference in castration resistant-free survival (p=0.92) or overall survival (p=0.25) has been detected. Compared to recent reports, the outcomes for our control group are more favorable, indicating a potential selection bias in the previous retrospective studies. Therefore, the unclear oncological effect has to be weighed against the potential risks of CRP. However, patients benefit from a significant reduction in locoregional complications (7.0% vs 35%; p<0.01) when undergoing CRP. PATIENT SUMMARY In this study we analyzed the impact of surgery in patients with prostate cancer and bone metastases. Using prospective data, we could not show a significant benefit of surgery on survival, but the rate of locoregional complications was lower. Therefore, patients should be treated within prospective trials evaluating the role of cytoreductive prostatectomy in low-volume, bone metastatic prostate cancer.

Is it possible to predict low-volume and insignificant prostate cancer by core needle biopsies?

In an attempt to minimize overtreatment of localized prostate cancer (PCa) active surveillance (AS) and minor invasive procedures have received increased attention. We investigated the accuracy of pre‐operative findings in defining insignificant disease and distinguishing between unilateral/unifocal and bilateral/multifocal PCa. One‐hundred and sixty patients undergoing radical prostatectomy were included. Histology reports from the biopsies and matching prostatectomies were compared. Three definitions of insignificant cancer were used: InsigE: tumour volume ≤0.5 mL; InsigW: tumour volume ≤1.3 mL; InsigM: tumour ≤5% of total prostate volume and prostate‐specific antigen (PSA) ≤10 ng/mL. In all definitions, Gleason score (GS) was ≤6 and the tumour was organ confined. Biopsies alone performed poorly as a predictor of unifocal and unilateral cancer in the prostatectomy specimens with positive predictive values of 17.8% and 18.9% respectively. Inclusion of other clinical and biochemical parameters did not significantly increase the predictive value. However, the combination of GS ≤ 6, PSA ≤ 10 ng/mL and unifocal or unilateral cancer in biopsy cores resulted in a positive predictive value of 61.1%, 38.9% and 12.0%, respectively, for identifying InsigM, InsigW and InsigE in the prostate specimen. Conclusively, routine prostate biopsies cannot predict unifocal and unilateral PCa, and must be regarded insufficient to select patients for focal therapy. Although candidates for AS may be identified using standard biopsies, a considerable fraction of patients will be understaged. There is a need for more precise diagnostic tools to assess intraprostatic tumour growth.

The impact of the 2005 International Society of Urological Pathology consensus guidelines on Gleason grading – a matched‐pair analysis

To investigate whether the International Society of Urological Pathology (ISUP) 2005 revision of the Gleason grading system has influenced the risk of biochemical recurrence (BCR) after radical prostatectomy (RP), as the new guideline implies that some prostate cancers previously graded as Gleason score 6 (3 + 3) are now considered as 7 (3 + 4).

Repeated biopsies in patients with prostate cancer on active surveillance: clinical implications of interobserver variation in histopathological assessment

To investigate the clinical implications of interobserver variation in the assessment of re‐biopsies obtained during active surveillance (AS) of prostate cancer.

Active surveillance for localized prostate cancer: An analysis of patient contacts and utilization of healthcare resources

Abstract Objective. Evidence supports active surveillance (AS) as a means to reduce overtreatment of low-risk prostate cancer (PCa). The consequences of close and long-standing follow-up with regard to outpatient visits, tests and repeated biopsies are widely unknown. This study investigated the trajectory and costs of AS in patients with localized PCa. Materials and methods. In total, 317 PCa patients were followed in a prospective, single-arm AS cohort. The primary outcomes were number of patient contacts, prostate-specific antigen (PSA) tests, biopsies, hospital admissions due to biopsy complications and patients eventually undergoing curative treatment. The secondary outcome was cost. Results. The 5 year cumulative incidence of discontinued AS in a competing-risk model was 40%. During the first 5 years of AS patients underwent a median of two biopsy sets, and patients were seen in an outpatient clinic including PSA testing three to four times annually. In total, 38 of the 406 biopsy sessions led to hospital admission and 87 of the 317 patients required treatment for bladder outlet obstruction (BOO). With a median of 3.7 years’ follow-up, the total cost of AS was euro (€) 1,240,286. Assuming all patients had otherwise undergone primary radical prostatectomy, the cost difference favoured AS with a net benefit of €662,661 (35% reduction). Conclusions. AS entails a close clinical follow-up with a considerable risk of rebiopsy complication, treatment of BOO and subsequent delayed definitive therapy. This risk should be weighed against a potential economic benefit and reduction in the risk of overtreatment compared to immediate radical treatment.

Systematic review: does endocrine therapy prolong survival in patients with prostate cancer?

Abstract Objective Primary androgen deprivation therapy (ADT) remains the gold standard in the management of patients with advanced prostate cancer (PCa). ADT relieves symptoms and reduces tumor burden, but it has never been demonstrated to increase either PCa-specific or overall survival per se. Several trials have challenged this dogma. The aim of this study was to evaluate how endocrine therapy (ET) affects survival in different clinical settings of PCa. Materials and methods A review of published phase II, III and IV studies evaluating the effect of ET on survival was performed. Results In localized and locally advanced non-metastatic PCa, neoadjuvant ET before radical prostatectomy has no effect on survival. Neoadjuvant and adjuvant ET in combination with curatively intended radiotherapy results in PCa-specific and overall survival benefit, although the duration of ET remains under debate. In N + disease, the timing of ET is under debate, although data suggest that early ET is associated with decreased PCa-specific and overall mortality. In M + disease, no proper randomized trials have been performed in patients with newly diagnosed M1 disease. In metastatic castration-resistant PCa, two novel endocrine agents have been proven to increase overall survival significantly compared to placebo. Conclusions ET has never been proven to increase survival in newly diagnosed metastatic PCa in a randomized clinical trial. Nonetheless, a number of trials supports that ET with proper timing, sequencing and in combination with other therapeutic modalities increases survival in several stages of PCa.