Klaus Brasso

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.

Socioeconomic position and participation in colorectal cancer screening.

Background:Colorectal cancer (CRC) screening with faecal occult blood test (FOBT) has the potential to reduce the incidence and mortality of CRC. Screening uptake is known to be inferior in people with low socioeconomic position (SEP) when compared with those with high position; however, the results of most previous studies have limited value because they are based on recall or area-based measures of socioeconomic position, and might thus be subject to selective participation and misclassification. In this study we investigated differences in CRC screening participation using register-based individual information on education, employment, and income to encompass different but related aspects of socioeconomic stratification. Also, the impact of ethnicity and cohabiting status was analysed.Methods:A feasibility study on CRC screening was conducted in two Danish counties in 2005 and 2006. Screening consisted of a self-administered FOBT kit mailed to 177 114 inhabitants aged 50–74 years. Information on individual socioeconomic status was obtained from Statistics Denmark.Results:A total of 85 374 (48%) of the invited returned the FOBT kits. Participation was significantly higher in women than in men (OR=1.58 (1.55–1.61)), when all socioeconomic and demographic variables were included in the statistical model. Participation also increased with increasing level of education, with OR=1.38 (1.33–1.43) in those with a higher education compared with short education. Also, participation increased with increasing income levels, with OR=1.94 (1.87–2.01) in the highest vs lowest quintile. Individuals with a disability pension, the unemployed and self-employed people were significantly less likely to participate (OR=0.77 (0.74–0.80), OR=0.83 (0.80–0.87), and OR=0.85 (0.81–0.89), respectively). Non-western immigrants were less likely to participate (OR=0.62 (0.59–0.66)) in a model controlling for age, sex, and county; however, this difference might be attributed to low SEP in these ethnic groups ((OR=0.93 (0.87–0.99), when adjusting for SEP indicators).Conclusion:This study based on individual information on several socioeconomic dimensions in a large, unselected population allowed for identification of several specific subgroups within the population with low CRC screening participation. Improved understanding is needed on the effect of targeted information and other strategies in order to reduce socioeconomic inequalities in screening.

Enzalutamide Antitumour Activity Against Metastatic Castration-resistant Prostate Cancer Previously Treated with Docetaxel and Abiraterone: A Multicentre Analysis

BACKGROUND The degree of antitumour activity of enzalutamide following disease progression on docetaxel and abiraterone remains controversial. OBJECTIVE To examine the effect of enzalutamide in patients progressing following taxane-based chemotherapy and abiraterone. DESIGN, SETTING, AND PARTICIPANTS Metastatic castration-resistant prostate cancer patients entering one of four European compassionate use programmes of enzalutamide. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The primary end point was overall survival (OS). Secondary end points were association between OS and posttreatment prostate-specific antigen (PSA) kinetics, patient characteristics, and progression-free survival, respectively. Kaplan-Meier survival analysis and Cox proportional hazard analysis were performed. RESULTS AND LIMITATIONS We identified 137 patients who prior to enzalutamide had progressed following a median of eight cycles of docetaxel and seven courses of abiraterone. The median time on enzalutamide was 3.2 mo; median OS from the time patients started enzalutamide was 8.3 mo (95% confidence interval, 6.8-9.8). Only 45 (38%) and 22 (18%) patients had PSA declines (unconfirmed) >30% and 50%, respectively. Patients who had more than 30% or 50% falls in PSA had improved survival compared with patients who had no such PSA fall (11.4 mo vs 7.1 mo; p=0.001 and 12.6 vs 7.4 mo; p=0.007, respectively). Poor performance status and low haemoglobin was negatively associated with OS. CONCLUSIONS Median OS on enzalutamide following disease progression on taxane-based chemotherapy and abiraterone was modest, but patients who experience a PSA decline >30% or 50%, respectively, with enzalutamide in this setting had longer survival. PATIENT SUMMARY Enzalutamide produces modest prostate-specific antigen (PSA) responses in patients progressing following chemotherapy and abiraterone. Despite a modest PSA response, survival may still be improved.

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.

Enzalutamide treatment in patients with metastatic castration-resistant prostate cancer progressing after chemotherapy and abiraterone acetate

Abstract Objective. The aim of this study was to record prostate-specific antigen (PSA) response and overall survival (OS) for a group of metastatic castration-resistant prostate cancer (mCRPC) patients treated with enzalutamide following progression after abiraterone treatment in the post-chemotherapy setting. Material and methods. Twenty-four mCRPC patients with progression after abiraterone treatment following primary docetaxel therapy received enzalutamide 160 mg/day. The percentage PSA response was recorded following first line docetaxel, abiraterone and enzalutamide treatment. Fischers exact test, Mann–Whitney U test and linear regression model were used to test for differences in PSA response. Results. All patients had a follow-up of at least 3 months. The median PSA response following 1 month of enzalutamide was –12% (range –56% to 76%), while the median best PSA response was –22% (–76% to 76%). Forty-six percent had a greater than 30% decrease in PSA. The PSA response to enzalutamide did not correlate with the number of prior cancer treatments (p = 0.57), time from diagnosis to mCRPC (p = 0.11) or prior response to docetaxel (p = 0.67). However, patients treated with second line cabazitaxel had an inferior PSA response to enzalutamide (p = 0.03), and there was a trend for the PSA response to abiraterone to correlate with the PSA response to the succeeding enzalutamide (B = 0.22, p = 0.05). The median OS was 4.8 months. Conclusions. Previous abiraterone therapy is associated with a less marked fall in PSA following enzalutamide therapy in post-chemotherapy mCRPC patients compared with reported results in randomized trials. Larger prospective studies of sequencing are warranted.

Testicular torsion: a follow-up study.

Thirty-five patients were examined 6-11 years after operation for torsion of the testis. Loss of testicular tissue was significantly associated with long preoperative duration of symptoms and with low postoperative sperm counts. The sex hormones were normal in the majority of patients but there were significantly higher levels of both FSH and LH in the group of patients with symptoms exceeding 8 hours. There was also a higher prevalence of abnormal semen quality in the same group. Furthermore, FSH and LH levels correlated significantly to the duration of symptoms and correlated inversely to the sperm count and concentration. Measurement of carnitine levels in seminal plasma, as a sign of vas deferens obstruction or dysfunction of epididymis, and of autoantibodies against spermatozoa revealed no significant findings.

Changes of Biochemical Markers of Bone Turnover and YKL-40 Following Hormonal Treatment for Metastatic Prostate Cancer Are Related to Survival

Purpose: Elevated serum levels of biochemical markers of bone turnover and YKL-40 in patients with metastatic prostate cancer (PC) at the time of diagnosis are associated to poor prognosis. In this study, we evaluated the value of these biomarkers in monitoring the patients during hormonal treatment. Experimental Design: Serum procollagen type I N-terminal propeptide (PINP), bone-specific alkaline phosphatase (BAP), CTX-I, and YKL-40 were determined by ELISA in a longitudinal study of 106 patients with metastatic PC during treatment with total androgen ablation or parenteral estrogen. Serum samples were collected with 3 months interval. Median observation time was 4.9 years (range, 3.6-6.2). A total of 78 patients died (64 within 7 months following the last blood sampling). Results: After 6 months treatment, serum PINP, BAP, and YKL-40 decreased (P < 0.0001), but not serum CTX-I compared with baseline values. Univariate Cox analysis showed that serum PINP at 6 months [log transformed and treated as a continuous variable; hazard ratio (HR), 2.2; P < 0.0001], serum BAP (HR, 1.8; P < 0.0001), and serum CTX-I (HR, 2.4; P < 0.0001), but not serum YKL-40 (HR, 1.4; P = 0.16) were associated with survival. Multivariate Cox analysis including the biomarkers 6 months after the start of treatment showed that Soloway score (HR, 3.9; P = 0.013), WHO tumor grade (HR, 3.9; P = 0.004), and serum PINP (HR, 2.2; P < 0.0001) were independent prognostic variables of survival. Scoring the biomarkers during treatment as time-dependent covariates in univariate Cox regression analysis showed that increases in serum PINP (HR, 2.0; P < 0.0001), BAP (HR, 2.1; P < 0.0001), and YKL-40 (HR, 2.1; P < 0.0001) were predictors of early death. Conclusions: Serial monitoring of serum PINP, BAP, CTX-I, and YKL-40 in metastatic PC patients during hormonal treatment provided information of prognosis.

Prognostic and predictive value of intact and cleaved forms of the urokinase plasminogen activator receptor in metastatic prostate cancer

The purpose of this study was to investigate the prognostic value of different forms of the urokinase receptor, uPAR, in serum from prostate cancer (PC) patients.

MORTALITY OF PATIENTS WITH CLINICALLY LOCALIZED PROSTATE CANCER TREATED WITH OBSERVATION FOR 10 YEARS OR LONGER: A POPULATION BASED REGISTRY STUDY

PURPOSE We studied the outcome in patients with early and probably organ confined prostate cancer who were considered candidates for curative therapy and treated expectantly. MATERIALS AND METHODS The study included 2,570 patients with newly diagnosed prostate cancer reported to the Danish Cancer Registry from 1943 to 1986 and surviving for 10 years or longer. Mortality and causes of death were analyzed and stratified by stage, age and time of diagnosis. Excess mortality was calculated from life expectancy tables for the general population. RESULTS An overall excess mortality (standard mortality ratio 1.58, 95% confidence interval [95% CI] 1.51 to 1.65) was found. Young age and advanced clinical stage at diagnosis entailed a higher risk of death from prostate cancer. Overall 42.7 and 19.1% of the patients who died had prostate cancer as the direct or contributing cause of death, respectively. Of the annual deaths 13% were attributable to prostate cancer. In 1,326 patients 55 to 64 and 65 to 74 years old with clinically localized prostate cancer at diagnosis the excess mortality was still significant (standard mortality ratio 1.72, 95% CI 1.54 to 1.93 and 1.50, 95% CI 1.39 to 1.62, respectively). Prostate cancer was the primary or contributing cause of death in 42.9% of the younger group and 21.5% of the older group. In these patients 15% of the annual deaths were related to prostate cancer. CONCLUSIONS Patients with clinically localized prostate cancer for 10 years or longer, who were likely candidates for curative therapy when diagnosed, had significant excess mortality when treated expectantly.

Lower urinary tract symptoms : A population survey using the Danish Prostatic Symptom Score (DAN-PSS) questionnaire

OBJECTIVE To describe voiding problems and the trouble they cause in a Danish population. Furthermore, to find symptoms specific for the ageing man, and thereby symptoms that might relate to an enlarged prostate. MATERIAL AND METHODS The DAN-PSS questionnaire was mailed to a gender- and age-stratified random sample of 500 inhabitants in Herlev municipality. Prevalence of the symptoms and the trouble they cause were calculated and related to age and gender by the x2 test for trend and the chi2 test, respectively. RESULTS The response rate was 73.6%. In total, 84.5% of the subjects had experienced at least one symptom within the previous fortnight. The various symptom prevalences ranged from 3.8-67.1%. Although many subjects experienced symptoms, they were not always bothered by them, and women were generally more bothered than men. Weak stream, hesitancy and dribbling occurred more often among men, whereas incontinence (stress, mixed) occurred more often among women. Nocturia and mixed incontinence increased in prevalence with increasing age among both men and women. Weak stream, incomplete emptying, stress and urge incontinence showed an age-related increase in prevalence among men, but not among women. These might therefore be symptoms of an enlarged prostate. CONCLUSION Lower urinary tract symptoms occur with high prevalence in the background population, but they do not always cause trouble. Weak stream, incomplete emptying, stress and urge incontinence seem to be symptoms of an enlarged prostate.