Prostate Specific Antigen and Biopsy Contamination in the Göteborg-1 Randomized, Population-Based, Prostate Cancer Screening Trial.

PURPOSE: Even when a screening study has demonstrated a mortality reduction, the degree of pre-testing and contamination is of importance as it can dilute the "true" effect of screening. Our object was to describe the level of pre-testing and contamination in the Göteborg-1 prostate cancer screening trial. MATERIALS AND METHODS: A total of 20,000 men, 50-64 years old, were invited in 1994 and randomized to either a screening group (offered prostate specific antigen testing every 2 years) or to a control group. Follow-up was through December 31, 2014. Outcome measurement was overall testing in the screening group and control group. A positive prostate specific antigen test was defined as a prostate specific antigen ≥3 ng/ml. RESULTS: In the study, 4.2% in the screening group and 4.6% men in the control group were tested before study start. During follow-up, 72% in the control group took at least 1 prostate specific antigen test (contamination) compared to 87% of men in the screening group. Of all prostate specific antigens, 24% in the screening group and 39% in the control group were above threshold. In total, 66% of the men underwent prostate biopsy within 12 months from a raised prostate specific antigen in the screening group and 28% in the control group. CONCLUSIONS: Similar proportions of men were prostate specific antigen-tested in both the screening group and control group, yet only a minority of contamination prostate specific antigens led to biopsy. Also, men in the screening group started screening at a younger age. These could both be explanations for our result that organized screening is more effective in reducing prostate cancer mortality than non-organized testing. When carried out properly and compared to an unscreened population, the effects of organized screening are likely even greater than previously shown in the Göteborg screening trial.

Single institution followed by national implementation of systematic surgical quality control and feedback for radical prostatectomy: a 20-year journey.

PURPOSE: The demand for objective and outcome-based facts about surgical results after radical prostatectomy (RP) is increasing. Systematic feedback is also essential for each surgeon to improve his/her performance. METHODS: RP outcome data (e.g., pT-stage and margin status) have been registered at Sahlgrenska University Hospital (SUH) since 1988 and patient-related outcome measures (PROM) have been registered since 2001. The National Prostate Cancer Registry (NPCR) has covered all Regions in Sweden since 1998 and includes PROM-data from 2008. Initially PROM was on-paper questionnaires but due since 2018 all PROMs are collected electronically. In 2014 an on-line "dashboard" panel was introduced, showing the results for ten quality-control variables in real-time. Since 2017 all RP data on hospital, regional, and national levels are publicly accessible on-line on "www.npcr.se/RATTEN". RESULTS: The early PROM-data from SUH have been used for internal quality control. As national clinical and PROM-data from the NPCR have been made accessible on-line and in real-time we have incorporated this into our pre-existing protocol. Our data are now internally available as real-time NPCR reports on the individual surgeons' results, as well as ePROM data. We can compare the results of each surgeon internally and to other departments' aggregated data. The public can access data and compare hospital level data on "RATTEN". CONCLUSIONS: The process of quality control of RP locally at SUH, and nationally through the NPCR, has been long but fruitful. The online design, with direct real-time feedback to the institutions that report the data, is essential.

Contamination in control group led to no effect of PSA-based screening on prostate cancer mortality at 9 years follow-up: Results of the French section of European Randomized Study of Screening for Prostate Cancer (ERSPC).

INTRODUCTION: European Randomized Study of Screening for Prostate Cancer (ERSPC) mortality results were reported for 7 European countries (excluding France) and showed a significant reduction in Prostate cancer (PCa) mortality. As those results have not been part of the global ERSPC results, it is of interest to report PCa mortality at a median follow-up of 9 years for French section of ERSPC. MATERIAL AND METHODS: Two administrative departments were involved in the study. Only men after randomization in the screening group were invited by mail to be screened by PSA testing with two rounds at 4-6 year intervals. Biopsy was recommended if PSA>=3.0 ng/mL. No information other that the French Association of Urology recommandations on the use of PSA was offered to the control group (own decision of physicians and patients). Follow up was based on cancer registry database. Contamination defined as the receipt of PSA testing in control arm was measured. Poisson regression models were used to estimate the Rate Ratio (RR) of PCa mortality and incidence in the screening vs. control arm. RESULTS: Starting from 2003, 80,696 men aged 55-69 years were included. The percentage of men in the screening arm with at least one PSA test (compliance) was 31%. Compared to the control arm, PCa incidence increased by 10% in the screening arm (RR=1.10; 95% CI=[1.04-1.16], P=0.001), but PCa mortality did not differ (0.222 and 0.215 deaths/1000 person-years; RR=1.03[0.75-1.42], P=0.9). DISCUSSION: Limitations include low participation rate. PSA testing in the control arm was observed in 32% of men (contamination). CONCLUSIONS: Contamination in control group led to no effect of PSA-based screening on prostate cancer mortality at 9 years follow-up. LEVEL OF EVIDENCE: 3.

Prostate cancer: ESMO Consensus Conference Guidelines 2012.

The first ESMO Consensus Conference on prostate cancer was held in Zurich, Switzerland, on 17-19 November 2011, with the participation of a multidisciplinary panel of leading professionals including experts in methodological aspects. Before the conference, the expert panel prepared clinically relevant questions about prostate cancer in four areas for discussion as follows: diagnosis and staging, management of early localized disease, management of advanced localized disease and systemic disease. All relevant scientific literature, as identified by the experts, was reviewed in advance. During the Consensus Conference, the panel developed recommendations for each specific question. The recommendations detailed here are based on an expert consensus after careful review of published data. All participants have approved this final update.

To be screened or not to be screened? Modeling the consequences of PSA screening for the individual.

BACKGROUND: Screening with prostate-specific antigen (PSA) can reduce prostate cancer mortality, but may advance diagnosis and treatment in time and lead to overdetection and overtreatment. We estimated benefits and adverse effects of PSA screening for individuals who are deciding whether or not to be screened. METHODS: Using a microsimulation model, we estimated lifetime probabilities of prostate cancer diagnosis and death, overall life expectancy and expected time to diagnosis, both with and without screening. We calculated anticipated loss in quality of life due to prostate cancer diagnosis and treatment that would be acceptable to decide in favour of screening. RESULTS: Men who were screened had a gain in life expectancy of 0.08 years but their expected time to diagnosis decreased by 1.53 life-years. Of the screened men, 0.99% gained on average 8.08 life-years and for 17.43% expected time to diagnosis decreased by 8.78 life-years. These figures imply that the anticipated loss in quality of life owing to diagnosis and treatment should not exceed 4.8%, for screening to have a positive effect on quality-adjusted life expectancy. CONCLUSION: The decision to be screened should depend on personal preferences. The negative impact of screening might be reduced by screening men who are more willing to accept the side effects from treatment.

Risk of hernia formation after radical prostatectomy: a comparison between open and robot-assisted laparoscopic radical prostatectomy within the prospectively controlled LAPPRO trial.

PURPOSE: In addition to incisional hernia, inguinal hernia is a recognized complication to radical retropubic prostatectomy. To compare the risk of developing inguinal and incisional hernias after open radical prostatectomy compared to robot-assisted laparoscopic prostatectomy. METHOD: Patients planned for prostatectomy were enrolled in the prospective, controlled LAPPRO trial between September 2008 and November 2011 at 14 hospitals in Sweden. Information regarding patient characteristics, operative techniques and occurrence of postoperative inguinal and incisional hernia were retrieved using six clinical record forms and four validated questionnaires. RESULTS: 3447 patients operated with radical prostatectomy were analyzed. Within 24 months, 262 patients developed an inguinal hernia, 189 (7.3%) after robot-assisted laparoscopic prostatectomy and 73 (8.4%) after open radical prostatectomy. The relative risk of having an inguinal hernia after robot-assisted laparoscopic prostatectomy was 18% lower compared to open radical retropubic prostatectomy, a non-significant difference. Risk factors for developing an inguinal hernia after prostatectomy were increased age, low BMI and previous hernia repair. The incidence of incisional hernia was low regardless of surgical technique. Limitations are the non-randomised setting. CONCLUSIONS: We found no difference in incidence of inguinal hernia after open retropubic and robot-assisted laparoscopic radical prostatectomy. The low incidence of incisional hernia after both procedures did not allow for statistical analysis. Risk factors for developing an inguinal hernia after prostatectomy were increased age and BMI.

Salvage radiation therapy in prostate cancer: relationship between rectal dose and long-term, self-reported rectal bleeding.

PURPOSE: To quantify the relationship between the rectal dose distribution and the prevalence of self-reported rectal bleeding among men treated with salvage radiotherapy (ST) delivered by three-dimensional conformal radiotherapy (3DCRT) for prostate cancer. To use this relationship to estimate the risk of rectal bleeding for a contemporary cohort of patients treated with volumetric modulated arc therapy (VMAT) ST. METHODS AND PATIENTS: Rectal bleeding of any grade was reported by 56 (22%) of 255 men in a PROM-survey at a median follow-up of 6.7 years after 3DCRT ST. Treatment plan data were extracted and dose-response relationships for the rectal volumes receiving at least 35 Gy (V35Gy) or 63 Gy (V63Gy) were calculated with logistic regression. These relationships were used to estimate the risk of rectal bleeding for a cohort of 253 patients treated with VMAT ST. RESULTS: In the dose-response analysis of patients in the 3DCRT ST cohort, both rectal V35Gy and V63Gy were statistically significant parameters in univariable analysis (p = 0.005 and 0.003, respectively). For the dose-response models using either rectal V35Gy or V63Gy, the average calculated risk of rectal bleeding was 14% among men treated with VMAT ST compared to a reported prevalence of 22% for men treated with 3DCRT ST. CONCLUSIONS: We identified dose-response relationships between the rectal dose distribution and the risk of self-reported rectal bleeding of any grade in a long-term perspective for men treated with 3DCRT ST. Furthermore, VMAT ST may have the potential to decrease the prevalence of late rectal bleeding.

Germline variants in IL4, MGMT and AKT1 are associated with prostate cancer-specific mortality: An analysis of 12,082 prostate cancer cases.

BACKGROUND: Prostate cancer (PCa) is a leading cause of mortality and genetic factors can influence tumour aggressiveness. Several germline variants have been associated with PCa-specific mortality (PCSM), but further replication evidence is needed. METHODS: Twenty-two previously identified PCSM-associated genetic variants were genotyped in seven PCa cohorts (12,082 patients; 1544 PCa deaths). For each cohort, Cox proportional hazards models were used to calculate hazard ratios and 95% confidence intervals for risk of PCSM associated with each variant. Data were then combined using a meta-analysis approach. RESULTS: Fifteen SNPs were associated with PCSM in at least one of the seven cohorts. In the meta-analysis, after adjustment for clinicopathological factors, variants in the MGMT (rs2308327; HR 0.90; p-value = 3.5 × 10-2) and IL4 (rs2070874; HR 1.22; p-value = 1.1 × 10-3) genes were confirmed to be associated with risk of PCSM. In analyses limited to men diagnosed with local or regional stage disease, a variant in AKT1, rs2494750, was also confirmed to be associated with PCSM risk (HR 0.81; p-value = 3.6 × 10-2). CONCLUSIONS: This meta-analysis confirms the association of three genetic variants with risk of PCSM, providing further evidence that genetic background plays a role in PCa-specific survival. While these variants alone are not sufficient as prognostic biomarkers, these results may provide insights into the biological pathways modulating tumour aggressiveness.

Early detection of cancer: ideas for a debate.

Even if the overall number of cancer is increasing, the mortality has started to decrease in the Western World. The role of early detection in this decrease is a matter of debate. To assess its impact on mortality it is important to distinguish between diagnosis of cancer in symptomatic patients, and early detection in asymptomatic individuals who may self-refer or who may be offered ad hoc or systematic screening. The policies for early detection and screening vary greatly between European countries, despite many similarities in their cancer burden, and this partly reflects the uncertainties surrounding asymptomatic testing for cancer. A Task Force of European expert, held in Azzate (VA), Italy, established to address these issues, acknowledged the need for more research in the field of individual risk assessment since general statistics are more and more perceived as inadequate to design personal early detection plans. The group also recognised that combinations of early detection and screening will enforce the effectiveness of new treatments in curbing mortality curves, although policies will vary with different cancers.

Inguinal hernia is a common complication in lower midline incision surgery.

Inguinal hernia is a known complication after radical retropubic prostatectomy (RRP). We have investigated whether other types of lower midline incision surgery in males increase the risk of inguinal hernia. Male patients operated with open prostatectomy for benign prostate hyperplasia (n = 95), pelvic lymph node dissection for staging of prostate cancer (n = 88), or cystectomy for bladder cancer (n = 76) were identified and were sent questionnaires in which they were asked about postoperative inguinal hernia morbidity. Two-hundred and seventy-one men operated with RRP had previously received a similar questionnaire. The answers were compared with those from a control group of 953 men who had not undergone surgery. Annual attributional hernia morbidity and Kaplan-Meier hernia-free survival were calculated. The cumulative incidence of post-operative inguinal hernia and annual attributional hernia morbidity after the respective surgical procedures were clearly higher during the early years post-operation than for nonoperated patients. Inguinal hernia is a common postoperative complication in males after all the lower midline incision surgery investigated.

Cost-effectiveness of prostate cancer screening: a simulation study based on ERSPC data.

BACKGROUND: The results of the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial showed a statistically significant 29% prostate cancer mortality reduction for the men screened in the intervention arm and a 23% negative impact on the life-years gained because of quality of life. However, alternative prostate-specific antigen (PSA) screening strategies for the population may exist, optimizing the effects on mortality reduction, quality of life, overdiagnosis, and costs. METHODS: Based on data of the ERSPC trial, we predicted the numbers of prostate cancers diagnosed, prostate cancer deaths averted, life-years and quality-adjusted life-years (QALY) gained, and cost-effectiveness of 68 screening strategies starting at age 55 years, with a PSA threshold of 3, using microsimulation modeling. The screening strategies varied by age to stop screening and screening interval (one to 14 years or once in a lifetime screens), and therefore number of tests. RESULTS: Screening at short intervals of three years or less was more cost-effective than using longer intervals. Screening at ages 55 to 59 years with two-year intervals had an incremental cost-effectiveness ratio of $73000 per QALY gained and was considered optimal. With this strategy, lifetime prostate cancer mortality reduction was predicted as 13%, and 33% of the screen-detected cancers were overdiagnosed. When better quality of life for the post-treatment period could be achieved, an older age of 65 to 72 years for ending screening was obtained. CONCLUSION: Prostate cancer screening can be cost-effective when it is limited to two or three screens between ages 55 to 59 years. Screening above age 63 years is less cost-effective because of loss of QALYs because of overdiagnosis.

Bone marrow micrometastases in patients with stage I-II localised prostate cancer.

Prostate cancer commonly metastasises to the bones. Detection of bone marrow micrometastases (BMM) may give important information that helps define treatment strategies. This study was undertaken to analyse BMM in early prostate cancer patients and to determine the accuracy of immunohistochemical (IHC) and morphological methods in detecting cancerous cells. Preoperative core bone marrow biopsy (BMB) was performed in 103 patients with T1-2, N0, M0 prostate cancer after neoadjuvant androgen blockade. BMB were examined by IHC using monoclonal antibodies for cytokeratins (CK) (18, 19, PAN) and by cytomorphology of IHC-positive cells. In 103 patients, BMM were detected in 2 cases (2%) and an additional 3 cases (3%) were classified as suspicious. IHC alone revealed positive cells in 19 patients (18%). Cytomorphology disclosed IHC false-positive staining of some apparently normal bone marrow elements such as plasmocytes. The study shows a rather low rate of BMM in early prostate cancer. It also stresses the importance of cytomorphology as an adjunct to IHC as IHC alone may not be sufficient and appropriate for BMM detection.

Impact of competing mortality on the cancer-related mortality in localized prostate cancer.

OBJECTIVES: To evaluate the impact of competing mortality and extended observation time on the cancer-related mortality in localized prostate cancer (PC). METHODS: A comparison was made between two theoretical populations of prostate cancer patients. Both populations had a slowly increasing mortality due to PC, corresponding to a 10-year cause-specific mortality of 15%. One population (A) experienced a high competing mortality reaching 50% after 10 years, corresponding to series on deferred treatment. The other population (B) experienced a low competing mortality, 10% after 10 years, corresponding to series on radical prostatectomy. The impact of these different competing mortality rates on the absolute number of patients succumbing to PC and the effect of extended follow-up to 15 years was assessed. RESULTS: The ultimate risk of death from PC after 10 years was 8% in group A and 12.3% in group B. When the observation time was extended to 15 years, group A had a 16.5% risk of cancer death and group B had a 35.3% risk. The PC mortality increased twofold between 10 and 15 years in group A (8% versus 16.5%) and threefold in group B (12.3% versus 35.3%). CONCLUSIONS: Low cause-specific mortality rates at 10 years of follow-up in series on deferred treatment comprising older patients with high competing mortality cannot be extrapolated to younger patients with a low competing mortality. Long expected survival is associated with a considerable cancer-related mortality at 15 years (35%) despite favorable outcome at 10 years.

Stone formation in the prostatic urethra after cryotherapy for prostate cancer.

We report on 3 cases of stone formation in the prostatic urethra after cryosurgical ablation of the prostate. This complication occurred late in the course, many months after the normal postoperative healing process apparently was finished and patients enjoyed normal voiding. Transrectal ultrasound proved to be useful in making the diagnosis. Treatment included lithotripsy and cold resection of residual dead tissue.

Clinical value of human glandular kallikrein 2 and free and total prostate-specific antigen in serum from a population of men with prostate-specific antigen levels 3.0 ng/mL or greater.

OBJECTIVES: To investigate the clinical value of human glandular kallikrein 2 (hK2) compared with free (f) and total (t) prostate-specific antigen (PSA) in the early detection of prostate cancer (PCa). METHODS: In PCa screening conducted in 1995 to 1996 in Göteborg, Sweden, 5853 of 9811 randomly selected men (aged 50 to 66 years; median 61) accepted PSA testing; those with tPSA levels of 3. 0 ng/mL or greater were offered digital rectal examination, transrectal ultrasound, and sextant biopsies. Serum from 604 of 611 biopsied men (18% with positive digital rectal examinations, tPSA range 3.0 to 220 ng/mL, 144 men with PCa) was analyzed for hK2 (research assay) and tPSA and fPSA (Prostatus). Sera were stored at -20 degrees C for a maximum of 2 weeks for tPSA and fPSA and 3 years for hK2. RESULTS: hK2 levels and hK2 x tPSA/fPSA values were significantly elevated in men with PCa. Receiver operating characteristic data revealed that the area under the curve for hK2 x tPSA/fPSA was significantly greater than that for tPSA and greater, but not significantly greater, than that for percent fPSA. Also, the cancer-detecting sensitivity was significantly improved (P <0.05) using hK2 x tPSA/fPSA compared with tPSA and percent fPSA at specificity levels of 75% to 90%. At 75% specificity, a sensitivity of 74% was obtained compared with 64% or 54% using percent fPSA or tPSA; at 90% specificity, the corresponding sensitivity level was 55%, 41%, and 36%, respectively. CONCLUSIONS: Discrimination of men with and without PCa in a randomly selected population was improved by measuring hK2 in addition to tPSA and fPSA.

Transrectal ultrasound with separate measurement of the transition zone volume predicts the short-term outcome after transurethral resection of the prostate.

OBJECTIVES: To determine whether the volume of prostatic adenomas as assessed by transrectal ultrasound (TRUS) influenced the outcome after transurethral resection of the prostate (TURP). METHODS: TRUS with total prostate and transition zone (TZ) volume determinations was performed preoperatively in 298 consecutive patients undergoing TURP for benign prostatic hyperplasia without prior urodynamic evaluation. Postoperatively, the outcome of surgery was stated as excellent (no or minor remaining symptoms), improved (but with some remaining symptoms), or failure (the same or aggravated symptoms) according to a patient-administered questionnaire. Six possible risk factors were evaluated: TZ volume 20 cc or less, neurologic disorders, previous TURP/transurethral incision of the prostate (TUIP), diabetes, indwelling catheter, and age older than 80 years. RESULTS: Thirty patients (10.1%) had treatment failure, 45 (15.1%) improvement, and 223 (74.8%) had excellent outcome. After subdivision into preoperative TZ volume of 20 cc or less and greater than 20 cc, it was found that the outcomes of 20.9% (n = 19) were failures if the TZ volume was 20 cc or less but only 5.3% (n = 11) if the TZ volume was greater than 20 cc. Additional independent risk factors for failure were neurologic disorders and previous TURP/TUIP. When all patients with risk factors were excluded (TZ volume 20 cc or less, neurologic disorders, previous transurethral surgery, and diabetes), the risk of failure was 3.3%. CONCLUSIONS: Patients with a preoperative TZ volume greater than 20 cc and no history of neurologic disorders, previous TURP/TUIP, or diabetes had a very high chance of favorable outcome after TURP, even though no pressure/flow evaluation had been performed preoperatively.

Reference range of prostate-specific antigen after transurethral resection of the prostate.

OBJECTIVES: The aim of the present study was to investigate how transurethral resection of the prostate (TURP) affected the serum levels of prostate-specific antigen (PSA) and to establish reference ranges of PSA in patients who have undergone TURP. METHODS: PSA was determined preoperatively and 3 months postoperatively in 190 patients who underwent TURP because of benign prostatic hyperplasia (BPH). RESULTS: Mean PSA levels were reduced by 70%, from 6.0 to 1.9 ng/mL. Prostate volume was reduced by 58% from 63.3 to 26.5 cc, which is close to the reported normal volume in men without BPH. Ninety percent of the patients had a postoperative PSA value of less than 4 ng/mL and 98% less than 10 ng/mL. CONCLUSIONS: After a complete TURP with a benign histopathologic specimen, PSA should be expected to be within the normal reference range, that is, less than 4 ng/mL.

Surveillance is not a viable and appropriate treatment option in the management of localized prostate cancer.

Results of conservatively treated localized prostate cancer are rather homogenous in different series if identical statistical methods are used- about 50% cancer-specific survival after 15 years, a rate much higher than that for men who undergo radical treatment. As the high mortality is accompanied by high costs, morbidity surveillance does not seem to be the optimal treatment in the average patient diagnosed with localized prostate cancer today.

Natural course of localized prostate cancer. a personal view with a review of published papers.

The course of untreated localized prostate cancer after 10 years of follow-up is at large unknown. As curative treatment is usually only offered patients with a life expectancy exceeding 10 Years, the expected course of the disease if left untreated is of the utmost interest. This paper aims to describe the outcome for patients who survive for more than 10 years when treated without curative intent. The results indicate that cancer specific mortality in patients with localized prostate cancer increases steadily over time and is approximately 50% after 15 years. This is a much higher figure than in reported series on radical prostatectomy. Even if many deaths occur at an old age, prostate cancer death is shown to be associated with a significant morbidity, need for palliative treatment, hospital care and cost. Preventing prostate cancer death is therefore not only a matter of saving year of life but also to prevent suffering caused by the disease. Modern diagnostic tools, such as prostate specific antigen, seem to detect clinically significant cancers in the vast majority of patients. Over diagnosis seems to be uncommon if diagnostic procedures are restricted to patients with a long life expectancy. Localized prostate cancer is a slow-growing but progressive neoplastic disease. When diagnosed in a man with a longer life expectancy it should be handled as such.