Carl-Gustaf Pihl

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.

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.

Guidelines on processing and reporting of prostate biopsies: the 2013 update of the pathology committee of the European Randomized Study of Screening for Prostate Cancer (ERSPC)

The histopathological examination of a prostate biopsy is the basis of prostate cancer diagnostics. Prostate cancer grade and extent of cancer in the diagnostic biopsy are important determinants of patient management. Quality of the prostate biopsy and its processing may influence the outcome of the histopathological evaluation. Further, an unambiguous and concise pathology reporting is essential for an appropriate clinical decision process. Since our initial report in 2003, there have been several practice changes, including the increased uptake of follow-up biopsies of patients who are under active surveillance, increasingly taken under guidance of MRI, or who underwent a prostate-sparing therapy. Therefore, we investigated the literature on the current pathology practices and recommendations with regard to prostate biopsy processing and reporting, both at initial diagnosis and in the context of follow-up biopsies in order to update our guidelines on the optimal processing and reporting of prostate biopsies.

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.

Outcome of Laterally Directed Sextant Biopsies of the Prostate in Screened Males Aged 50–66 Years

Objective: Prostate cancer has its most frequent location in the posterior–lateral part of the gland. The aim of this study was to evaluate the cancer detection rate of six systemic prostate biopsies with mid lobar biopsies taken far laterally in the prostate. Patients and Methods: A total of 692 patients (aged 50–66 years) enrolled in a screening study underwent prostate biopsies because of an elevated serum prostate–specific antigen (PSA; ≧3ng/ml) level. The outcome of the biopsies was related to findings at digital rectal examination (DRE) and transrectal ultrasound (TRUS) and to the location within the prostate. Results: Prostate cancer was detected in 164 patients. DRE and TRUS were suspicious of malignancy in 66 cases (40%) and 84 cases (51%), respectively. The two biopsies taken far laterally midlobar in the prostate detected as many as 83% of the cancers and when combined with two apical biopsies, 96% of all cancers were detected. Conclusion: At PSA screening in this age–group, only 57% of the prostate cancers detectable by sextant biopsies were palpable or visible at TRUS. Most of the cancers (96%) were detectable by only four systematic, carefully directed biopsies. In men with normal DRE, the two lateral midlobar biopsies should be taken first during the biopsy procedure.

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.

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.

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 ≤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.

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 ≥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.

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.