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.

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.

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.

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.

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.

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.

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.

PSA levels and cancer detection rate by centre in the European Randomized Study of Screening for Prostate Cancer.

BACKGROUND: To describe the variation in PSA level by age group and screening round in the ERSPC centres and the variation in cancer detection rates in relation to the underlying prostate cancer incidence. METHODS: Individual data on men invited for the first and second screening rounds according to protocol (excluding early recalls and interval cancers) were obtained from the central database of the ERSPC (cut-off date 31st December 2006). Data were compared between and within centres for the core age group (55-69 at entry). The cancer detection rate (CDR) was compared with the expected background prostate cancer incidence rate in the absence of screening adjusted for the incidence rate in non-attenders and the control arm (IRS). RESULTS: Mean PSA values in the age groups 55-59 years and 65-69 years showed little variation by centre, except for the Dutch centre, where an increase from 1.6 to 1.8 ng/ml and a decline from 2.9 to 2.5ng/ml was observed, respectively. Most tumours were detected at the PSA range 4.0-9.9 ng/ml, with a shift to more cancer detection at 3.0-3.9 ng/ml in the second screening round. There was high variability in the CDR between the centres in both the first (16-46 per 1000) and the second screening rounds (14-50 per 1000). Although the ratio CDR/IRS was less variable, it is somewhat lower in Italy and Switzerland (12 and 14,respectively) and higher in the Netherlands (28), than in most other centres and in Belgium the ratio increased markedly, from 20 to 44 between the first and second rounds. CONCLUSION: There was no clear evidence of a relationship between the underlying incidence and mean PSA levels at screening or the cancer detection rate.

Detection rates of cancer, high grade PIN and atypical lesions suspicious for cancer in the European Randomized Study of Screening for Prostate Cancer.

THE AIM OF THE STUDY: This article presents the incidence of prostate cancer, isolated high grade prostatic intraepithelial neoplasia (PIN) and atypical lesions suspicious for prostate cancer (LSPC) during subsequent screening rounds in the centres of five of the countries participating in the European Randomized Study of Screening for Prostate Cancer (ERSPC). The incidence and predictive value of high grade PIN and LSPC for prostate cancer in subsequent biopsy following these diagnoses were evaluated. PATIENTS AND METHODS: Study group consisted of 56,653 screened men in the ERSPC centres of Finland, Italy, Netherlands, Sweden and Switzerland, who underwent 3-7 screening rounds at 2-4 year interval. Data for prostate cancer were obtained from the ERSPC central database. Data for high grade PIN and LSPC were gathered from each ERSPC centre. Detection rates of subsequent prostate cancer in the first re-biopsy after these diagnoses were determined. RESULTS: The average cancer detection rate was 3.5%, 3.2% and 3.5% for the completed rounds 1, 2 and 3, respectively, in all five centres. Incidence of high grade PIN increased from 1.5% in the first round to 5.0% in the third round, varying among centres in the first round between 0.8% and 7.6%. The cancer detection rate in the first re-biopsy after the diagnosis of high grade PIN was 12.9%. Incidence of LSPC was 2.4%, 2.7%, 2.2% and 2.6% in the first, second, third and fourth round, respectively. The cancer detection rate at the first re-biopsy after the diagnosis of LSPC was in average 33.8%. CONCLUSIONS: Cancer detection rate was stable during the three screening rounds. The wide variation in frequency in particular of high grade PIN among the ERSPC centres suggests a considerable inter-observer variation. The average comparatively low detection rate of isolated high grade PIN in the first screening round may be screening-related, while its consistent increase during three screening rounds could be the consequence of a.o. previous screening and ageing of the population. The observed low risk of prostate cancer after isolated high grade PIN in this screening setting is in line with the current recommendation to abstain from early repeat biopsies after this diagnosis. The association of LSPC with high incidence of prostate cancer in re-biopsies confirms the need for early repeat biopsies and follow-up of these men. The low percentage of LSPC (<3% of biopsies) throughout all rounds is reassuring as it limits the biopsy burden in a screening setting.

Change of tumour characteristics and treatment over time in both arms of the European Randomized study of Screening for Prostate Cancer.

OBJECTIVE: To evaluate a change in tumour characteristics and applied treatments over time in the control arm of all centres of the European Randomized study of Screening for Prostate Cancer (ERSPC) and to compare this with similar data of the screening arm. METHODS: Between 1993 and 2003, 182,160 men, aged 50-74 years, were randomised to the screening arm (N=82,816) and the control arm (N=99,184). Men in the screening arm were offered Prostate Specific Antigen (PSA) testing every 4 years whilst men in the control arm received usual care. Tumour characteristics and treatment were evaluated in all men diagnosed with prostate cancer up to December 2006 or the third screening round. Data on the control arm were divided into 3 periods: 1994-1998, 1999-2002 and 2003-2006. RESULTS: Tumour characteristics were more favourable over time in both the control and the screening arm, with especially increasing proportions of T1C tumours with 29% in 1994-1998 versus 50% in 2003-2006 and 48% at the initial screening round versus 75% at the third screening round, respectively. Tumour characteristics observed in the last period of the control arm were comparable to tumour characteristics in the initial screening round. In the control arm, treatment changed over time with surgery as the most common treatment in the entire observed period, but almost doubling of expectant management and the combination of hormone therapy and radiotherapy over time. In the initial screening round, surgery was the most common treatment (42%), changing over time to expectant management as the most frequently applied treatment in the third screening round (33%). CONCLUSION: Tumour characteristics in the control arm became more favourable over time and show similarity with prostate cancer cases detected at the initial screening round. The most prominent change in treatment over time was an increase of application of expectant management in both arms of the ERSPC. These observations reflect an increasing rate of opportunistic testing over time in men randomised to the control arm.

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.

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.

Population-based screening for prostate cancer by measuring free and total serum prostate-specific antigen in Sweden.

OBJECTIVE: To report the initial results from Sweden of a large population-based randomized study of screening using prostate-specific antigen (PSA) to detect prostate cancer, as the efficacy of such screening to decrease prostate cancer mortality has not yet been proven. METHODS: From the population registry men aged 50-66 years were randomized to screening (9973) and to future controls (9973). Men randomized to screening were invited to have their serum measured for free PSA (fPSA) and total PSA (tPSA) in serum using the Prostatus f/tPSA assay (Perkin-Elmer, Turku, Finland). Men with a tPSA of < 3.0 ng/mL were not further investigated, while those with a tPSA of > or = 3.0 ng/mL were investigated with a digital rectal examination (DRE), transrectal ultrasonography (TRUS) and sextant biopsies. RESULTS: Of those invited, 60% accepted PSA testing and 11.3% had a tPSA of > or = 3.0 ng/mL. Altogether 145 cancers were detected (positive predictive value, PPV, 24%); none were stage M1, two were stage N+ and 10 stage T3-4. Most (59%) cancers were impalpable and 39% were both impalpable and invisible on TRUS. At biopsy, 7% were Gleason score 2-4, 71% 5-6, 19% 7 and 2% Gleason score 8-10. A threshold tPSA of > or = 4.0 ng/mL would have detected 109 cancers in 366 biopsied men (PPV 30%) while cancer detection would have been 14% higher with a PPV of 36% using a threshold tPSA of > or = 3.0 ng/mL combined with a f/tPSA threshold of < or = 18%. CONCLUSIONS: PSA screening detects early-stage low-grade prostate cancer. Both the sensitivity and specificity can be increased by incorporating f/tPSA with a tPSA threshold of < 4 ng/mL.

Three-month neoadjuvant hormonal therapy before radical prostatectomy: a 7-year follow-up of a randomized controlled trial.

OBJECTIVE: To describe the outcome, assessed as the level of prostate specific antigen (PSA), of a mature (more than half the events recorded) prospective randomized study with a median follow-up of 82 months of neoadjuvant hormonal therapy before radical prostatectomy, as this has been suggested to decrease the rate of positive surgical margins (i.e. provide greater potential to completely excise the tumour). PATIENTS AND METHODS: From December 1991 to March 1994, 126 patients with clinically localized prostate cancer were randomized between direct radical prostatectomy or a 3-month course of a gonadotrophin-releasing hormone analogue before surgery. The patients were followed by PSA determinations and a value of > 0.5 ng/mL used to define progression. RESULTS: The incidence of positive surgical margins decreased from 45.5% to 23.6% (P = 0.016) with hormone treatment. Despite this there was no difference in PSA progression-free survival at the last follow-up; it was 51.5% for those undergoing radical prostatectomy only and 49.8% for those who received hormonal pretreatment (P = 0.588). CONCLUSIONS: Three months of neoadjuvant hormonal therapy before radical prostatectomy offers no benefit to the patient and cannot be recommended for routine clinical use.