Prostate Cancer Screening with PSA and MRI Followed by Targeted Biopsy Only.

BACKGROUND: Screening for prostate cancer is burdened by a high rate of overdiagnosis. The most appropriate algorithm for population-based screening is unknown. METHODS: We invited 37,887 men who were 50 to 60 years of age to undergo regular prostate-specific antigen (PSA) screening. Participants with a PSA level of 3 ng per milliliter or higher underwent magnetic resonance imaging (MRI) of the prostate; one third of the participants were randomly assigned to a reference group that underwent systematic biopsy as well as targeted biopsy of suspicious lesions shown on MRI. The remaining participants were assigned to the experimental group and underwent MRI-targeted biopsy only. The primary outcome was clinically insignificant prostate cancer, defined as a Gleason score of 3+3. The secondary outcome was clinically significant prostate cancer, defined as a Gleason score of at least 3+4. Safety was also assessed. RESULTS: Of the men who were invited to undergo screening, 17,980 (47%) participated in the trial. A total of 66 of the 11,986 participants in the experimental group (0.6%) received a diagnosis of clinically insignificant prostate cancer, as compared with 72 of 5994 participants (1.2%) in the reference group, a difference of -0.7 percentage points (95% confidence interval [CI], -1.0 to -0.4; relative risk, 0.46; 95% CI, 0.33 to 0.64; P<0.001). The relative risk of clinically significant prostate cancer in the experimental group as compared with the reference group was 0.81 (95% CI, 0.60 to 1.1). Clinically significant cancer that was detected only by systematic biopsy was diagnosed in 10 participants in the reference group; all cases were of intermediate risk and involved mainly low-volume disease that was managed with active surveillance. Serious adverse events were rare (<0.1%) in the two groups. CONCLUSIONS: The avoidance of systematic biopsy in favor of MRI-directed targeted biopsy for screening and early detection in persons with elevated PSA levels reduced the risk of overdiagnosis by half at the cost of delaying detection of intermediate-risk tumors in a small proportion of patients. (Funded by Karin and Christer Johansson's Foundation and others; GÖTEBORG-2 ISRCTN Registry number, ISRCTN94604465.).

Results from 22 years of Followup in the Göteborg Randomized Population-Based Prostate Cancer Screening Trial.

PURPOSE: Our goal was to analyze results from 22 years of followup in the Göteborg randomized prostate cancer (PC) screening trial. MATERIALS AND METHODS: In December 1994, 20,000 men born 1930-1944 were randomly extracted from the Swedish population register and were randomized (1:1) into either a screening group (SG) or to a control group (CG). Men in the SG were repeatedly invited for biennial prostate specific antigen testing up to an average age of 69 years. Main endpoints were PC incidence and mortality (intention-to-screen principle). RESULTS: After 22 years, 1,528 men in the SG and 1,124 men in the CG had been diagnosed with PC. In total, 112 PC deaths occurred in the SG and 158 in the CG. Compared with the CG, the SG showed a PC incidence rate ratio (RR) of 1.42 (95% CI, 1.31-1.53) and a PC mortality RR of 0.71 (95% CI, 0.55-0.91). The 22-year cumulative PC mortality rate was 1.55% (95% CI, 1.29-1.86) in the SG and 2.13% (95% CI, 1.83-2.49) in the CG. Correction for nonattendance (Cuzick method) yielded a RR of PC mortality of 0.59 (95% CI, 0.43-0.80). Number needed to invite and number needed to diagnose was estimated to 221 and 9, respectively. PC death risk was increased in the following groups: nontesting men, men entering the program after age 60 and men with >10 years of followup after screening termination. CONCLUSIONS: Prostate specific antigen-based screening substantially decreases PC mortality. However, not attending, starting after age 60 and stopping at age 70 seem to be major pitfalls regarding PC death risk.

The Association Between Age, Prostate Cancer Risk, and Higher Gleason Score in a Long-term Screening Program: Results from the Göteborg-1 Prostate Cancer Screening Trial.

BACKGROUND: Studies have suggested associations between greater age, increased risk of prostate cancer (PC), and higher Gleason score. OBJECTIVE: The present study aimed at investigating these associations within the Göteborg-1 randomized, population-based PC screening trial. DESIGN, SETTING, AND PARTICIPANTS: The screening arm of the Göteborg-1 screening trial comprises 10000 randomly selected men (aged 50-64 yr at randomization) from the Göteborg region of Sweden. Between 1995 and 2014, they were biennially invited to prostate-specific antigen (PSA) testing to an upper age limit of 70 yr (range 67-71 yr). PSA ≥3 ng/ml triggered a prostate biopsy (sextant biopsy 1995-2009, thereafter a ten-core biopsy). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The impact of age on Gleason score, given a screen-detected PC, was investigated with multinomial logistic regression analyses adjusted for year of testing and screening round. RESULTS AND LIMITATIONS: Overall, 7625 men had at least one PSA test and 1022 men were diagnosed with PC. For men with screen-detected PC, age was associated with the risk of clinically significant PC above and beyond screening round and year of testing (p < 0.001). For each 1-yr increase in age, the risk of being diagnosed with a Gleason score ≥3 + 4 cancer (vs <7) increased by 11% (95% confidence interval [CI] 4.7-17), whereas the risk of being diagnosed with a Gleason score ≥4 + 3 cancer (vs <7) increased by 8.5% (95% CI -1.6 to 20). CONCLUSIONS: The increased risk of a higher Gleason score in older men should be considered when counseling men regarding early diagnosis and treatment for PC. PATIENT SUMMARY: We found that older age increased both the risk of prostate cancer and the risk of more aggressive prostate cancer.

Prostate Cancer Screening with Magnetic Resonance Imaging: Results from the Second Round of the Göteborg Prostate Cancer Screening 2 Trial.

BACKGROUND: The Göteborg 2 prostate cancer (PC) screening (G2) trial evaluates screening with prostate-specific antigen (PSA) followed by magnetic resonance imaging (MRI) in case of elevated PSA levels. OBJECTIVE: To assess the safety of using a 2-yr interval in men who were previously screened positive with PSA but had negative MRI or positive MRI with a negative biopsy. DESIGN, SETTING, AND PARTICIPANTS: A total of 61 201 men aged 50-60 yr were randomized and 38 366 were invited for screening (years 2015-2020). Men with positive MRI (Prostate Imaging Reporting and Data System [PI-RADS] score ≥3) were scheduled for targeted biopsies. Men with negative MRI or negative biopsies were reinvited after 2 yr. Round 1 and 2 MRI scans (PI-RADS ≥3) of men not diagnosed with PC in round 1 were re-read and classified according to Prostate Cancer Radiological Estimation of Change in Sequential Evaluation (PRECISE) by two radiologists. Interval PCs (detected outside the program before invitation to round 2) were identified by linking to the Regional PC Registry. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Tabulation of overall detection of PC was done. RESULTS AND LIMITATIONS: Between October 2017 and June 2020, 474 men with round 1 elevated PSA and MRI underwent a second screening. Of those, 19% had nonelevated PSA in round 2 and were not examined further. Of the remaining 376 men, 89% had negative MRI. Targeted biopsies yielded 14 PCs: nine grade group (GG) 1 and five GG 2-3. In men with PI-RADS ≥3 and PC diagnosed in round 2, only two (GG 1) progressed according to the PRECISE criteria and the remainder were stable. Ten interval PCs were diagnosed: seven GG 1, one GG 2, and two GG 5. The two GG 5 PCs were PI-RADS 4 and 5 with negative round 1 biopsy. CONCLUSIONS: A 2-yr interval seems to be safe in men with negative MRI, while men with PI-RADS 4 and 5 lesions with negative biopsies should have a closer follow-up. PATIENT SUMMARY: In prostate cancer screening, a 2-yr follow-up seems to be safe if magnetic resonance imaging did not show highly suspicious findings.

Bi- or multiparametric MRI in a sequential screening program for prostate cancer with PSA followed by MRI? Results from the Göteborg prostate cancer screening 2 trial.

OBJECTIVES: The PIRADS Steering Committee has called for "higher quality data before making evidence-based recommendations on MRI without contrast enhancement as an initial diagnostic work up," however, recognizing biparametric (bp) MRI as a reasonable option in a low-risk setting such as screening. With bpMRI, more men can undergo MRI at a lower cost and they can be spared the invasiveness of intravenous access. The aim of this study was to assess cancer detection in bpMRI vs mpMRI in sequential screening for prostate cancer (PCa). METHODS: Within the ongoing Göteborg PCa screening 2 trial, we assessed cancer detection in 551 consecutive participants undergoing prostate MRI. In the same session, readers first assessed bpMRI and then mpMRI. Four targeted biopsies were performed for lesions scored PIRADS 3-5 with bpMRI and/or mpMRI. RESULTS: Cancer was detected in 84/551 cases (15.2%; 95% CI: 12.4-18.4) with mpMRI and in 83/551 cases (15.1%; 95% CI: 12.3-18.2%) with bpMRI. The relative risk (RR) for cancer detection with bpMRI compared to mpMRI was 0.99 (95% one-sided CI: > 94.8); bpMRI was non-inferior to mpMRI (10% non-inferiority margin). bpMRI resulted in fewer false positives, 45/128 (35.2%), compared to mpMRI, 52/136 (38.2%), RR = 0.92; 95% CI: 0.84-0.98. Of 8 lesions scored positive only with mpMRI, 7 were false positives. The PPV for MRI and targeted biopsy was 83/128 (64.8%) for bpMRI and 84/136 (61.8%) for mpMRI, RR = 1.05, 95% CI: 1.01-1.10. CONCLUSIONS: In a PSA-screened population, bpMRI was non-inferior to mpMRI for cancer detection and resulted in fewer false positives. KEY POINTS: • In screening for prostate cancer with PSA followed by MRI, biparametric MRI allows radiologists to detect an almost similar number of prostate cancers and score fewer false positive lesions compared to multiparametric MRI. • In a screening program, high sensitivity should be weighed against cost and risks for healthy men; a large number of men can be saved the exposure of gadolinium contrast medium by adopting biparametric MRI and at the same time allowing for a higher turnover in the MRI room.

Long-term Outcomes for Men in a Prostate Screening Trial with an Initial Benign Prostate Biopsy: A Population-based Cohort.

BACKGROUND: The optimal follow-up regimen for men after a benign prostate biopsy remains unknown. OBJECTIVE: To investigate long-term outcomes for men after an initial benign prostate biopsy. DESIGN, SETTING, AND PARTICIPANTS: All men with a benign biopsy in the first screening round of the Göteborg prostate cancer (PC) screening trial were included. The follow-up period was January 1, 1995-May 15, 2017. INTERVENTION: Prostate-specific antigen (PSA) tests were performed every second year (upper median age limit 69yr). Men with PSA ≥3ng/ml underwent prostate biopsy (sextant biopsy up to 2009). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The 20-yr cumulative PC incidence and PC mortality were calculated using the 1 minus Kaplan-Meier method. RESULTS AND LIMITATIONS: Of 452 men with a benign biopsy and followed for a median of 21.1yr, 169 were diagnosed with PC and five died from PC. The 20-yr cumulative PC incidence and PC mortality were 40.0% and 1.4%, respectively. The corresponding figures were 38.8% and 0.6% for men with initial PSA ≤10ng/ml, and 64.4% and 21.4% for PSA >10ng/ml. The proportion of men untreated at final follow-up was similar in the two PSA groups (22% vs 23%). The use of sextant biopsy for many years of the trial is a limitation. CONCLUSIONS: Men with an initial benign prostate biopsy run a very low risk of dying from PC when participating in a screening program. However, if followed for a long period, many men will be diagnosed and treated for PC. Low-intensity follow-up, as in the Göteborg trial, appears sufficient for men with PSA ≤10ng/ml after a benign biopsy. PATIENT SUMMARY: This study shows that men who participate in a prostate cancer screening trial have a low risk of dying from prostate cancer if the first biopsy does not show cancer.

Long-Term Outcomes after Deferred Radical Prostatectomy in Men Initially Treated with Active Surveillance.

PURPOSE: We sought to determine long-term outcomes after deferred radical prostatectomy. MATERIALS AND METHODS: The study population consisted of all 132 men with screening detected prostate cancer who underwent deferred radical prostatectomy from January 1, 1995 to December 31, 2014 after active surveillance in the Göteborg Randomized, Population-based Prostate Cancer Screening Trial. The last date of followup was May 15, 2017. Followup during active surveillance was performed with prostate specific antigen tests every 3 to 6 months and repeat biopsies every 2 to 4 years. Triggers for radical prostatectomy were disease progression based on prostate specific antigen, grade and/or stage, or patient request. Outcomes included adverse pathology findings at radical prostatectomy, defined as Gleason score greater than 3 + 4, extraprostatic extension, positive margins, seminal vesicle invasion and/or N+, whether the index tumor at radical prostatectomy was identified at biopsy and prostate specific antigen relapse-free survival. Kaplan-Meier analysis was performed. RESULTS: Median time from diagnosis to surgery was 1.9 years (IQR 1.2-4.2) and median postoperative followup was 10.9 years (IQR 7.5-14.5). A total of 52 men (39%) experienced at least 1 unfavorable pathology feature at radical prostatectomy. The 10-year prostate specific antigen relapse-free survival was 79.5%. The index tumor was not identified in the diagnostic biopsy in 38 of the 132 men (29%) or at the last repeat biopsy that preceded radical prostatectomy 22 of 105 (21%). CONCLUSIONS: A large proportion of men had unfavorable pathology findings at deferred radical prostatectomy and the index tumor was frequently not identified. There is a clear need for better risk classification and protocols to determine disease progression during active surveillance.

Eighteen-year follow-up of the Göteborg Randomized Population-based Prostate Cancer Screening Trial: effect of sociodemographic variables on participation, prostate cancer incidence and mortality.

OBJECTIVE: This study examined whether previously reported results, indicating that prostate-specific antigen (PSA) screening can reduce prostate cancer (PC) mortality regardless of sociodemographic inequality, could be corroborated in an 18 year follow-up. MATERIALS AND METHODS: In 1994, 20,000 men aged 50-64 years were randomized from the Göteborg population register to PSA screening or control (1:1) (study ID: ISRCTN54449243). Men in the screening group (n = 9950) were invited for biennial PSA testing up to the median age of 69 years. Prostate biopsy was recommended for men with PSA ≥2.5 ng/ml. Last follow-up was on 31 December 2012. RESULTS: In the screening group, 77% (7647/9950) attended at least once. After 18 years, 1396 men in the screening group and 962 controls had been diagnosed with PC [hazard ratio 1.51, 95% confidence interval (CI) 1.39-1.64]. Cumulative PC mortality was 0.98% (95% CI 0.78-1.22%) in the screening group versus 1.50% (95% CI 1.26-1.79%) in controls, an absolute reduction of 0.52% (95% CI 0.17-0.87%). The rate ratio (RR) for PC death was 0.65 (95% CI 0.49-0.87). To prevent one death from PC, the number needed to invite was 231 and the number needed to diagnose was 10. Systematic PSA screening demonstrated greater benefit in PC mortality for men who started screening at age 55-59 years (RR 0.47, 95% CI 0.29-0.78) and men with low education (RR 0.49, 95% CI 0.31-0.78). CONCLUSIONS: These data corroborate previous findings that systematic PSA screening reduces PC mortality and suggest that systematic screening may reduce sociodemographic inequality in PC mortality.

Long-term Results of Active Surveillance in the Göteborg Randomized, Population-based Prostate Cancer Screening Trial.

BACKGROUND: Active surveillance (AS) has become a well-accepted and widely used treatment strategy. OBJECTIVE: To assess the long-term safety of AS for men with screen-detected prostate cancer (PCa). DESIGN, SETTING, AND PARTICIPANTS: All men with screen-detected PCa who had very low-, low-, or intermediate-risk PCa and were managed with AS (January 1, 1995 to December 31, 2014) in the Göteborg screening trial. INTERVENTION: Prostate-specific antigen tests every 3-12 mo, rebiopsies in cases of clinical progression, and every 2-3 yr in men with stable disease. Triggers for intervention were disease progression (prostate-specific antigen, grade, and/or stage) or patient initiative. OUTCOMES MEASUREMENTS AND STATISTICAL ANALYSIS: Treatment-free, failure-free, PCa-specific, and overall survival. The Kaplan-Meier method and Cox proportional hazards models were used. RESULTS AND LIMITATIONS: Four-hundred and seventy-four men were managed with AS (median age at diagnosis 66.0 yr, median follow-up 8.0 yr). Two-hundred and two men discontinued AS and initiated treatment. The 10-yr and 15-yr treatment-free survival was 47% and 34%, respectively. The hazard ratio for the treatment for low- and intermediate-risk PCa, compared with very low risk, was 1.4 (95% confidence interval [CI] 1.01-1.94) and 1.6 (95% CI 1.13-2.25). Fifty-four men failed AS. The 10-yr and 15-year failure-free survival was 87% and 72%, respectively. These estimates were 94% and 88% for the very low-risk group, 85% and 77% for the low-risk group, and 73% and 40% for the intermediate-risk group. The hazard ratio for failure for low- and intermediate-risk PCa, compared with very low-risk, was 2.2 (95% CI 1.05-4.47) and 4.8 (95% CI 2.44-9.33). Six men died from PCa and none had very low-risk PCa. The 10-yr and 15-yr PCa-specific survival was 99.5% and 96%, respectively. These estimates were 100% for the very low-risk group, 100% and 94% for the low-risk group, and 98% and 90% for the intermediate-risk group. No predefined protocol was used. CONCLUSIONS: AS is safe for men with very low-risk PCa, but for men with low- and intermediate-risk PCa, AS carries a risk of missing the possibility of being able to cure the cancer. It is questionable whether men who are not in the lowest tumor risk group and who have a long remaining life expectancy are suitable candidates for this strategy. PATIENT SUMMARY: Long-term results from this study indicate that some men will miss their chance of cure with active surveillance and it is questionable whether active surveillance is a suitable strategy for men who are not in the lowest tumor risk group and who have a very long remaining life expectancy.

Mortality results from the Göteborg randomised population-based prostate-cancer screening trial.

BACKGROUND: Prostate cancer is one of the leading causes of death from malignant disease among men in the developed world. One strategy to decrease the risk of death from this disease is screening with prostate-specific antigen (PSA); however, the extent of benefit and harm with such screening is under continuous debate. METHODS: In December, 1994, 20,000 men born between 1930 and 1944, randomly sampled from the population register, were randomised by computer in a 1:1 ratio to either a screening group invited for PSA testing every 2 years (n=10,000) or to a control group not invited (n=10,000). Men in the screening group were invited up to the upper age limit (median 69, range 67-71 years) and only men with raised PSA concentrations were offered additional tests such as digital rectal examination and prostate biopsies. The primary endpoint was prostate-cancer specific mortality, analysed according to the intention-to-screen principle. The study is ongoing, with men who have not reached the upper age limit invited for PSA testing. This is the first planned report on cumulative prostate-cancer incidence and mortality calculated up to Dec 31, 2008. This study is registered as an International Standard Randomised Controlled Trial ISRCTN54449243. FINDINGS: In each group, 48 men were excluded from the analysis because of death or emigration before the randomisation date, or prevalent prostate cancer. In men randomised to screening, 7578 (76%) of 9952 attended at least once. During a median follow-up of 14 years, 1138 men in the screening group and 718 in the control group were diagnosed with prostate cancer, resulting in a cumulative prostate-cancer incidence of 12.7% in the screening group and 8.2% in the control group (hazard ratio 1.64; 95% CI 1.50-1.80; p<0.0001). The absolute cumulative risk reduction of death from prostate cancer at 14 years was 0.40% (95% CI 0.17-0.64), from 0.90% in the control group to 0.50% in the screening group. The rate ratio for death from prostate cancer was 0.56 (95% CI 0.39-0.82; p=0.002) in the screening compared with the control group. The rate ratio of death from prostate cancer for attendees compared with the control group was 0.44 (95% CI 0.28-0.68; p=0.0002). Overall, 293 (95% CI 177-799) men needed to be invited for screening and 12 to be diagnosed to prevent one prostate cancer death. INTERPRETATION: This study shows that prostate cancer mortality was reduced almost by half over 14 years. However, the risk of over-diagnosis is substantial and the number needed to treat is at least as high as in breast-cancer screening programmes. The benefit of prostate-cancer screening compares favourably to other cancer screening programs. FUNDING: The Swedish Cancer Society, the Swedish Research Council, and the National Cancer Institute.

Is delayed radical prostatectomy in men with low-risk screen-detected prostate cancer associated with a higher risk of unfavorable outcomes?

BACKGROUND: Strategies of active surveillance (AS) of low-risk screen-detected prostate cancer have emerged, because the balance between survival outcomes and quality of life issues when radically treating these malignancies is disputable. Delay before radical treatment caused by active surveillance may be associated with an impaired chance of curability. METHODS: Men diagnosed with low-risk (T1c/T2; prostate-specific antigen [PSA] = <10.0; PSA density, <0.2 ng/mL; Gleason score, 3 + 3=6; 1-2 positive biopsies) prostate cancer in the Swedish section of the European Randomized Study of Screening for Prostate Cancer who received radical prostatectomy (RP) were studied. One group received immediate RP, whereas another group received delayed RP after an initial period of expectant management. These groups were compared regarding histopathological and biochemical outcomes, correcting for baseline differences. RESULTS: Mean follow-up after diagnosis was 5.7 years (standard deviation [SD], 3.2). The immediate RP group (n = 158) received RP a mean of 0.5 (SD, 0.2) years after diagnosis; the delayed RP group (n = 69) received RP after 2.6 (SD, 2.0) years (P < .001). After adjustment for small baseline dissimilarities, no differences in RP frequencies of Gleason score >6 (odds ratio [OR], 1.54; P = .221), capsular penetration (OR, 2.45; P = .091), positive margins (OR, 1.34; P = .445), RP tumor volume (difference, 0.099; P = .155), or biochemical progression rates (P = .185, P = .689) were found between groups, although all data were in favor of immediate RP. CONCLUSIONS: With limited patient numbers available for analysis, differences in intermediate outcomes between immediate RP and delayed RP were nonsignificant. The delayed RP group may be subject to a selection bias. Prospective evaluation of active surveillance protocols is essential.

Variability in diagnostic opinion among pathologists for single small atypical foci in prostate biopsies.

Pathologists are increasingly exposed to prostate biopsies with small atypical foci, requiring differentiation between adenocarcinoma, atypical small acinar proliferation suspicious for malignancy, and a benign diagnosis. We studied the level of agreement for such atypical foci among experts in urologic pathology and all-round reference pathologists of the European Randomized Screening study of Prostate Cancer (ERSPC). For this purpose, we retrieved 20 prostate biopsies with small (most <1 mm) atypical foci. Hematoxylin and eosin-stained slides, including 10 immunostained slides were digitalized for virtual microscopy. The lesional area was not marked. Five experts and 7 ERSPC pathologists examined the cases. Multirater kappa statistics was applied to determine agreement and significant differences between experts and ERSPC pathologists. The kappa value of experts (0.39; confidence interval, 0.29-0.49) was significantly higher than that of ERSPC pathologists (0.21; confidence interval, 0.14-0.27). Full (100%) agreement was reached by the 5 experts for 7 of 20 biopsies. Experts and ERSPC pathologists rendered diagnoses ranging from benign to adenocarcinoma on the same biopsy in 5 and 9 biopsies, respectively. Most of these lesions comprised between 2 and 5 atypical glands. The experts diagnosed adenocarcinoma (49%) more often than the ERSPC pathologists (32%) (P<0.001). As agreement was particularly poor for foci comprising <6 glands, we would encourage pathologists to obtain intercollegial consultation of a specialized pathologist for these lesions before a carcinoma diagnosis, whereas clinicians may consider to perform staging biopsies before engaging on deferred or definite therapy.

Is tumor vascularity in prostate core biopsies a predictor of PSA recurrence after radical prostatectomy?

The purposes of this study were to evaluate if tumour vascularity by Chalkley counting (TVC) in prostate core biopsies can be a predictor of PSA recurrence after radical prostatectomy in prostate cancer and to estimate the concordance between the TVC in core biopsies and the subsequently examined prostatectomy specimen. All patients, with Gleason score < or =7 in core biopsy, clinical stage T1 or T2 who had a radical prostatectomy during 1990-1997 at Sahlgrenska University Hospital, were selected as a primary group. Patients with neoadjuvant hormonal therapy were excluded. The patients were divided into two groups, one with PSA recurrence and one group without PSA recurrence. 25 patients had PSA recurrence during the follow up period and 25 patients from non-recurrence group were randomly selected. TVC was assessed from the prostate tissue by immunostaining against CD34. TVC was statistically significant predictor of PSA relapse. The PSA-free survival rate was only 17% in patients within the highest TVC quartile compared to 67% in patients within the lowest TVC quartile.

Interobserver reproducibility of modified Gleason score in radical prostatectomy specimens.

The Gleason score (GS) of prostate cancer is calculated by adding primary and secondary Gleason grades with patterns occupying less than 5% of the tumour often not included despite their probable prognostic significance. A modified Gleason score (mGS) comprising primary and tertiary patterns of higher grade has been proposed, but its interobserver variability has yet to be elucidated. Slides from 69 consecutive prostatectomy specimens were circulated among four genitourinary pathologists. GS and mGS were assessed, and results were compared in pairs. Mean weighted kappa for GS and mGS were 0.56 (range 0.52-0.66) and 0.58 (range 0.49-0.74), respectively. The difference between GS and mGS was 0, 1 and 2 score units in 66%, 26% and 8%, respectively, mean 0.41 score units (range 0.24-0.51). The increment was greater for transition-zone tumours than for peripheral-zone tumours (0.63 and 0.35 score units, respectively, P=0.002). An odd mGS (5, 7 or 9) was more often given than an odd GS (77% and 62%, respectively, P<0.001). Disagreement between observers greater than 1 score unit was more common with mGS than GS (18% and 4%, respectively, P<0.001). In conclusion, overall mean weighted kappa for interobserver reproducibility of mGS is at least as high as that of GS. However, there is a clustering of mGS in odd scores, and severe disagreement is more commonly observed than with GS. Training of mGS assessment would possibly improve agreement. Tertiary Gleason patterns need to be better defined.

Interobserver reproducibility of percent Gleason grade 4/5 in prostate biopsies.

PURPOSE: Percent Gleason grade 4/5 (GG4/5) has been proposed as a predictor of prognosis in prostate cancer and it has been shown to add prognostic information to that given by Gleason score (GS). We recently noted that the interobserver reproducibility of percent GG4/5 in total prostatectomy specimens is at least as good as that of the GS. However, to our knowledge the reproducibility of percent GG4/5 in needle biopsies has not yet been investigated. MATERIALS AND METHODS: A consecutive series of needle biopsies from 69 men with prostate cancer was reviewed. Biopsies were taken according to a standardized octant protocol. All 279 slides containing cancer were circulated among 4 genitourinary pathologists, who assessed GS and percent GG4/5. Results were compared pairwise and weighted kappa was calculated. RESULTS: The 4 observers had a mean weighted kappa for GS and percent GG4/5 of 0.48 to 0.55 (overall mean 0.51) and 0.52 to 0.68 (overall mean 0.60), respectively. There was less disagreement in percent GG4/5 when a single biopsy was positive for cancer than when 6 or more biopsies were positive. The number of positive biopsies showed a stronger correlation with a discrepancy in percent GG4/5 than cancer length. Disagreement was worse when cribriform or fusion patterns were present. CONCLUSIONS: Interobserver reproducibility of percent GG4/5 on prostate biopsies is at least as good as that of GS. Hence, concern about interobserver variability should not deter pathologists from using percent GG4/5. Grading appears to be most difficult when cancer is present in multiple biopsies or it contains cribriform or fusion patterns.

Free-to-total prostate-specific antigen ratio as a predictor of non-organ-confined prostate cancer (stage pT3).

OBJECTIVE: To evaluate whether the free-to-total prostate-specific antigen (F/T-PSA) ratio can be used to differentiate between stage pT2 and pT3 prostate cancer. MATERIAL AND METHODS: A total of 176 consecutive patients from the Göteborg Screening Study (median T-PSA 4.2 ng/ml) who underwent radical prostatectomy (without neoadjuvant hormonal therapy) were included in the study. The pT stage was correlated with classical risk factors such as T-PSA and Gleason sum and the impact of the F/T-PSA ratio was evaluated. RESULTS: A total of 42/176 patients (23.9%) had stage pT3 prostate cancer. Patients with an F/T-PSA ratio in the lowest quartile (<10.7%) had extracapsular tumor growth in 46.5% of cases, compared to 16.7% for those with an F/T-PSA ratio >10.7% (p=0.0002). Patients with high-risk features (T-PSA >10 ng/ml or Gleason sum > or =7) had a high risk (54-60%) for stage pT3 prostate cancer. In low-risk patients, the subgroup with an F/T-PSA ratio <10.7% had a risk of 37.0%, compared to only 13.3% for those with a ratio of >10.7% (p=0.0092). CONCLUSIONS: In patients with low-risk early-stage prostate cancer, the F/T-PSA ratio provides statistically significant, independent and clinically relevant preoperative information about the risk of extracapsular tumor growth.

Does initial surveillance in early prostate cancer reduce the chance of cure by radical prostatectomy?--A case control study.

OBJECTIVE: To evaluate whether initial surveillance followed by prostatectomy impairs pathological stage compared to immediate surgery in men with prostate cancer detected as a result of early screening. MATERIAL AND METHODS: A total of 26 patients with prostate cancer [T1c-T2, Gleason score <7, prostate-specific antigen (PSA) 3-13 ng/ml] who were managed by means of initial surveillance (mean 23.4 months, range 8-55 months) followed by radical retropubic prostatectomy (RRP) were evaluated. For each of these cases two matched control cases were selected from patients who were operated on without prior surveillance. The two groups were matched for PSA, age, T stage and Gleason score at biopsy. Evaluation of prostatectomy specimens included measurement of tumour volume, pT stage and Gleason score. RESULTS: Tumour volume did not differ significantly between cases and controls: 1.35 vs 1.05 cm (3), respectively. The frequency of extracapsular growth, Gleason score and time to progression after RRP within a mean follow-up period of 2 years were also similar between the two groups. CONCLUSION: In selected patients with very early prostate cancer it seems that close surveillance followed by prostatectomy when signs of progression appear is a low-risk option. However, before this strategy can be generally recommended longer follow-up periods should be used and a randomized study should be performed.

Prostate specific antigen based biennial screening is sufficient to detect almost all prostate cancers while still curable.

PURPOSE: We evaluated whether biennial screening with prostate specific antigen (PSA) only is sufficient to detect prostate cancer while still curable. MATERIALS AND METHODS: In Göteborg, Sweden 9,972 men 50 to 65 years old were randomized to PSA screening. During 1995 and 1996 these men were invited for a first PSA screening and invited during 1997 and 1998 for a second screening. The screening procedure included PSA measurement in all men and in those with a PSA of 3 ng./ml. or greater also it included digital rectal examination, transrectal ultrasound and sextant biopsies. RESULTS: In the first screening 5,854 men participated and 145 cancers were detected. In the second screening 5,267 men participated and 111 cancers were detected. Only 9 interval cancers were diagnosed. In the second screening 102 cancers (92%) were associated with PSA less than 10 ng./ml. Of 465 men with increased PSA and who underwent biopsy with a benign outcome in the first screening 50 had cancer at the second screening. Of 241 men in whom PSA increased between screenings 1 and 2 cancer was detected in 46. None of the 2,950 men with an initial PSA of less than 1 ng./ml. had a PSA of greater than 3 ng./ml. or interval cancer. CONCLUSIONS: In men with a PSA of less than 2 ng./ml. it seems safe to offer repeat screening after 2 years with PSA only. Men with a PSA of 2 to 3 ng./ml. or a value of greater than 3 ng./ml. with negative biopsy may be better served by a shorter screening interval. Thus, different screening intervals are implied depending on baseline PSA.

Follow-up of men with elevated prostate-specific antigen and one set of benign biopsies at prostate cancer screening.

OBJECTIVE: To study the follow-up of men with elevated prostate-specific antigen (PSA) (>3 ng/ml) after one benign set of sextant biopsies. From the Göteborg branch of the European Randomised Study of Screening for Prostate Cancer (ERSPC). METHOD: 456 men with one set of benign sextant biopsies were followed every second year for 4 years with PSA determinations. In cases of elevated PSA, transrectal ultrasound (TRUS) guided sextant biopsies were suggested. Digital rectal examination (DRE), prostate volume, PSA, PSA density (PSAD) and the ratio between free and total PSA (PSA F/T) were recorded. RESULTS: Complete data were available for 322 men. 3 groups were identified. In 84/322 (26%) men cancer was found ("cancer" group). 182/322 (56%) had benign biopsies ("benign" group) and 56/322 (17%) had normalised PSA ("normalised PSA" group). Median prostate volumes were 36, 46, and 33 cc respectively in the three groups. DRE and/or TRUS were abnormal in only 30% of the men in all groups. Cancer was not found in any prostate >70 cc volume. In prostates of <20 cc either cancer was found or PSA was normalised. The "normalised PSA" group had initial PSA, PSAD and PSA F/T similar to cancer, normalising during follow-up. CONCLUSIONS: Patients with one negative sextant biopsy still have a high likelihood of cancer, especially men with persistently elevated PSA and small prostates (<20 cc) while the majority of men with large prostates (>70 cc) have PSA elevation due to benign prostate hyperplasia (BPH) and not to cancer.

Interobserver reproducibility of percent Gleason grade 4/5 in total prostatectomy specimens.

PURPOSE: Recently the percent Gleason grade 4/5 was proposed as a predictor of the outcome of prostate cancer and it has been shown that it adds prognostic information to that given by Gleason score. To our knowledge the interobserver variability of percent Gleason grade 4/5 has not yet been investigated. We assessed the percent Gleason grade 4/5, including the identification of high grade patterns and estimation of the percent tumor area, which is potentially more difficult than conventional Gleason grading. MATERIALS AND METHODS: A consecutive series of 69 total prostatectomy specimens was reviewed. A single slide per specimen was circulated among 4 genitourinary pathologists, who assessed Gleason score and the percent Gleason grade 4/5. Results were compared pairwise and a weighted kappa was calculated for Gleason score and the percent Gleason grade 4/5. RESULTS: The 4 observers had a mean weighted kappa for Gleason score and the percent Gleason grade 4/5 of 0.52 to 0.66 (overall mean 0.56) and 0.58 to 0.72 (overall mean 0.66), respectively. The best agreement for percent Gleason grade 4/5 was in 2 pathologists at the same department (weighted kappa 0.86). Transition zone tumors had a lower weighted kappa for Gleason score but a higher weighted kappa for percent Gleason grade 4/5 than peripheral zone tumors. In cases of the greatest disagreement in the percent Gleason grade 4/5 crush artifact, cribriform cancer and high grade PIN within the tumor were significantly more common. An intraobserver reproducibility of weighted kappa 0.91 was achieved for Gleason score and the percent Gleason grade 4/5. CONCLUSIONS: Interobserver reproducibility of the percent Gleason grade 4/5 is substantial and at least as good as that of the Gleason score. Hence, concern about interobserver variability should not deter pathologists from using the percent Gleason grade 4/5 as a prognostic marker for prostate cancer.