Ali Khatami

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.

Outcome Following Active Surveillance of Men with Screen-detected Prostate Cancer. Results from the Göteborg Randomised Population-based Prostate Cancer Screening Trial

BACKGROUND Active surveillance (AS) has emerged as a treatment strategy for reducing overtreatment of screen-detected, low-risk prostate cancer (PCa). OBJECTIVE To assess outcomes following AS of men with screen-detected PCa. DESIGN, SETTING, AND PARTICIPANTS Of the 968 men who were diagnosed with screen-detected PCa between 1995 and 2010 in the Göteborg randomised, population-based PCa screening trial, 439 were managed with AS and were included in this study. Median age at diagnosis was 65.4 yr of age, and median follow-up was 6.0 yr from diagnosis. INTERVENTION The study participants were followed at intervals of 3-12 mo and were recommended to switch to deferred active treatment in case of a progression in prostate-specific antigen, grade, or stage. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The end points-overall survival (OS), treatment-free survival, failure-free (no relapse after radical treatment) survival, and cancer-specific survival-were calculated for various risk groups (very low, low, intermediate, and high) with Kaplan-Meier estimates. A Cox proportional hazards model as well as a competing risk analysis were used to assess whether risk group or age at diagnosis was associated with failure after AS. RESULTS AND LIMITATIONS Forty-five per cent of all screen-detected PCa were managed with AS, and very low-risk and low-risk PCa constituted 60% of all screen-detected PCa. Thirty-seven per cent (162 of 439) switched from surveillance to deferred active treatment, and 39 men failed AS. The 10-yr OS, treatment-free survival, and failure-free survival were 81.1%, 45.4%, and 86.4%, respectively (Kaplan-Meier estimates). Men with low-, intermediate-, and high-risk tumours had a hazard ratio for failure of 2.1 (p=0.09), 3.6 (p=0.002), and 4.6 (p=0.15), respectively, compared to very low-risk tumours (Cox regression). Only one PCa death occurred, and one patient developed metastasis (both in the intermediate-risk group). The main limitation of this study is the relatively short follow-up. CONCLUSIONS A large proportion of men with screen-detected PCa can be managed with AS. AS appears safe for men with low-risk PCa.

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

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.

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.

Role of Magnetic Resonance Imaging in Prostate Cancer Screening: A Pilot Study Within the Göteborg Randomised Screening Trial

BACKGROUND Magnetic resonance imaging (MRI) and targeted biopsies (TB) have shown potential to more accurately detect significant prostate cancer compared with prostate-specific antigen (PSA) and systematic biopsies (SB). OBJECTIVE To compare sequential screening (PSA+MRI) with conventional PSA screening. DESIGN, SETTING, AND PARTICIPANTS Of 384 attendees in the 10th screening round of the Göteborg randomised screening trial, 124 men, median age 69.5 yr, had a PSA of ≥ 1.8 ng/ml and underwent a prebiopsy MRI. Men with suspicious lesions on MRI and/or PSA ≥ 3.0ng/ml were referred for biopsy. SB was performed blinded to MRI results and TB was performed in men with tumour-suspicious findings on MRI. Three screening strategies were compared (PSA ≥ 3.0+SB; PSA ≥ 3.0+MRI+TB and PSA ≥ 1.8+MRI+TB). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Cancer detection rates, sensitivity, and specificity were calculated per screening strategy and compared using McNemars test. RESULTS AND LIMITATIONS In total, 28 cases of prostate cancer were detected, of which 20 were diagnosed in biopsy-naïve men. Both PSA ≥ 3.0+MRI and PSA ≥ 1.8+MRI significantly increased specificity compared with PSA ≥ 3.0+SB (0.92 and 0.79 vs 0.52; p<0.002 for both), while sensitivity was significantly higher for PSA ≥ 1.8+MRI compared with PSA ≥ 3.0+MRI (0.73 vs 0.46, p=0.008). The detection rate of significant cancer was higher with PSA ≥ 1.8+MRI compared with PSA ≥ 3.0+SB (5.9% vs 4.0%), while the detection rate of insignificant cancer was lowered by PSA ≥ 3.0+MRI (0.3% vs 1.2%). The primary limitation of this study is the small sample of men. CONCLUSION A screening strategy with a lowered PSA cut-off followed by TB in MRI-positive men seems to increase the detection of significant cancers while improving specificity. If replicated, these results may contribute to a paradigm shift in future screening. PATIENT SUMMARY Major concerns in prostate-specific antigen screening are overdiagnosis and underdiagnosis. We evaluated whether prostate magnetic resonance imaging could improve the balance of benefits to harm in prostate cancer screening screening, and we found a promising potential of using magnetic resonance imaging in addition to prostate-specific antigen.

Post-Radical Prostatectomy Inguinal Hernia: A Simple Surgical Intervention can Substantially Reduce the Incidence—Results From a Prospective Randomized Trial

PURPOSE After radical retropubic prostatectomy a postoperative inguinal hernia develops in 15% to 20% of patients. We investigated whether a simple prophylactic procedure during radical retropubic prostatectomy would reduce this incidence. MATERIALS AND METHODS A total of 294 consecutive patients scheduled for radical retropubic prostatectomy at our clinic were prospectively included in the study. Patients with a present inguinal hernia or a previous inguinal hernia surgery were not included in the analysis. The subjects were randomized for side of prophylactic intervention (left or right). At radical retropubic prostatectomy a nonresorbable figure-of-8 suture was placed lateral to the internal ring of the inguinal canal and the spermatic cord on either side according to outcome of the randomization. Patients were followed at regular followup visits at the clinic. At the end of the study all patients were invited for a final interview and examination by an independent examiner who was unaware of the side of intervention. RESULTS Of the patients 86% (254) showed up for the final examination. The cumulative inguinal hernia incidence was 3.5% on the intervention side and 9.1% on the control side (log rank Mantel-Cox p = 0.011). There were no serious adverse events, and no increase in postoperative discomfort in the groin and testicular region on the intervention side. The procedure added 5 to 10 minutes to the duration of surgery. CONCLUSIONS The prophylactic procedure was simple and safe to perform, and it decreased the risk of postoperative inguinal hernia formation by 62%. We believe it should be considered for patients undergoing radical retropubic prostatectomy.

Ki-67 in screen-detected, low-grade, low-stage prostate cancer, relation to prostate-specific antigen doubling time, Gleason score and prostate-specific antigen relapse after radical prostatectomy

Objective. To evaluate the correlation of Ki-67 as a proliferation marker to prostate-specific antigen doubling time (PSADT), Gleason score and its possible role as a predictor of PSA relapse after radical prostatectomy in early prostate cancer (PC). Material and methods. Out of 660 patients detected with PC in the Swedish branch of the European Randomized Study of Prostate Cancer, 270 were managed with active surveillance. During follow-up (mean 63 months), 70 men were treated with radical retropubic prostatectomy (RRP). In 50 of these patients the preoperative PSADT was calculated and archive prostatectomy specimens were stained for Ki-67. The quantification of positive staining cells was performed by counting five to 15 randomly selected microscopic fields using an eyepiece graticule at 400×magnification and at least 1000 tumour cells were counted for each patient. One pathologist, blinded to the PSADT values, performed the pathological assessment. The correlation between Ki-67, PSADT and Gleason grade was explored. Cox proportional hazard model was used to evaluate the prognostic power for Ki-67 and other markers on the risk of PSA relapse after RRP. Results. Ki-67 was not correlated with PSADT (p=0.45) but was correlated with Gleason grade (p<0.0001). In the Cox proportional hazard model Ki-67 (p=0.03) [hazard ratio (HR) 2.49, 95% confidence interval (CI) 1.07–5.80] and total PSA (p=0.0068) (HR 1.86, 95% 1.19–2.92) were associated significantly with the risk of disease progression. Conclusion. In men with screen-detected, clinically low-grade, low-stage prostate cancer, Ki-67 may be a valuable prognostic marker of PSA relapse after radical prostatectomy.

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.

Surgical treatment of localized prostate cancer.

Radical retropubic prostatectomy (RRP) is the reference method for treatment of localised, organ confined prostate cancer. Since the introduction of nerve-sparing procedure for RRP in the 1980s, the operation has become widespread and is today one of the most common surgical procedures in Urology. In this overview the indications, operative procedure and side effects of RRP are briefly discussed.

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.