Johan Stranne

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.

Urinary Incontinence and Erectile Dysfunction After Robotic Versus Open Radical Prostatectomy: A Prospective, Controlled, Nonrandomised Trial

BACKGROUND Robot-assisted laparoscopic radical prostatectomy (RALP) has become widely used without high-grade evidence of superiority regarding long-term clinical outcomes compared with open retropubic radical prostatectomy (RRP), the gold standard. OBJECTIVE To compare patient-reported urinary incontinence and erectile dysfunction 12 mo after RALP or RRP. DESIGN, SETTING, AND PARTICIPANTS This was a prospective, controlled, nonrandomised trial of patients undergoing prostatectomy in 14 centres using RALP or RRP. Clinical-record forms and validated patient questionnaires at baseline and 12 mo after surgery were collected. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES Odds ratios (ORs) were calculated with logistic regression and adjusted for possible confounders. The primary end point was urinary incontinence (change of pad less than once in 24h vs one time or more per 24h) at 12 mo. Secondary end points were erectile dysfunction at 12 mo and positive surgical margins. RESULTS AND LIMITATIONS At 12 mo after RALP, 366 men (21.3%) were incontinent, as were 144 (20.2%) after RRP. The unadjusted OR was 1.08 (95% confidence interval [CI], 0.87–1.34). Erectile dysfunction was observed in 1200 men (70.4%) 12 mo after RALP and 531 (74.7%) after RRP. The unadjusted OR was 0.81 (95% CI, 0.66–0.98). CONCLUSIONS In a Swedish setting, RALP for prostate cancer was modestly beneficial in preserving erectile function compared with RRP, without a statistically significant difference regarding urinary incontinence or surgical margins. PATIENT SUMMARY We compared patient-reported urinary incontinence after prostatectomy with two types of surgical technique. There was no statistically significant improvement in the rate of urinary leakage, but there was a small improvement regarding erectile function after robot-assisted operation.

INGUINAL HERNIA AFTER RADICAL RETROPUBIC PROSTATECTOMY FOR PROSTATE CANCER: A STUDY OF INCIDENCE AND RISK FACTORS IN COMPARISON TO NO OPERATION AND LYMPHADENECTOMY

PURPOSE The incidence, mechanisms and risk factors of inguinal hernia after radical retropubic prostatectomy are sparsely elucidated in the literature. We determined the rate of inguinal hernia after radical retropubic prostatectomy and compared it to the incidence in patients with prostate cancer who did not undergo operation or underwent only pelvic lymph node dissection. MATERIALS AND METHODS We followed 375, 184 and 65 men who underwent radical retropubic prostatectomy plus pelvic lymph node dissection, pelvic lymph node dissection only and no surgery with respect to inguinal hernia for a mean of 39, 47 and 45 months, respectively. The prostatectomy group was also evaluated in regard to the potential risk factors of previous hernia surgery and post-prostatectomy anastomotic stricture. RESULTS The incidence of hernia was 13.6%, 7.6% and 3.1% in the prostatectomy, lymph node dissection and unoperated group, respectively. The difference was statistically significant in the prostatectomy and unoperated groups according to the Mantel-Cox log rank test and Cox proportional hazards rate. Previous hernial surgery and post-prostatectomy anastomotic stricture were more common in patients with an inguinal hernia after prostatectomy. CONCLUSIONS The incidence of inguinal hernia is clearly increased in men who have undergone radical retropubic prostatectomy plus pelvic lymph node dissection compared with those who undergo no surgery for prostate cancer. Inguinal hernia appears to develop more often in men with prostate cancer who undergo radical retropubic prostatectomy and pelvic lymph node dissection than in those who undergo pelvic lymph node dissection only. While surgical factors trigger hernial development, previous hernial surgery and post-prostatectomy anastomotic stricture may be important risk factors. In fact, the latter may largely explain the difference in the incidence of inguinal hernia in our lymph node dissection and prostatectomy groups. Prophylactic surgical procedures must be evaluated to address this problem.

LAPPRO: A prospective multicentre comparative study of robot-assisted laparoscopic and retropubic radical prostatectomy for prostate cancer

Abstract Objective. This study describes the study design and procedures for a prospective, non-randomized trial comparing open retropubic and robot-assisted laparoscopic radical prostatectomy regarding functional and oncological outcomes. Material and methods. The aim was to achieve a detailed prospective registration of symptoms experienced by patients using validated questionnaires in addition to documentation of surgical details, clinical examinations, medical facts and resource use. Four patient questionnaires and six case-report forms were especially designed to collect data before, during and after surgery with a follow-up time of 2 years. The primary endpoint is urinary leakage 1 year after surgery. Secondary endpoints include erectile dysfunction, oncological outcome, quality of life and cost-effectiveness at 3, 12 and 24 months after surgery. Results. The study started in September 2008 with accrual continuing to October 2011. Twelve urological departments in Sweden well established in performing radical prostatectomy are participating. Personal contact with the participating departments and patients was established to ascertain a high response rate. To reach 80% statistical power to detect a difference of 5 absolute per cent in incidence of urinary leakage, 700 men in the retropubic group and 1400 in the robotic group are needed. Conclusions. The Swedish healthcare context is well suited to performing multicentre long-term prospective clinical trials. The similar care protocols and congruent specialist training are particularly favourable. The LAPPRO trial aims to compare the two surgical techniques in aspects of short- and long-term functional and oncological outcome, cost effectiveness and quality of life, supplying new knowledge to support future decisions in treatment strategies for prostate cancer.

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.

Short-term Results after Robot-assisted Laparoscopic Radical Prostatectomy Compared to Open Radical Prostatectomy

BACKGROUND Robot-assisted laparoscopic radical prostatectomy has become a widespread technique despite a lack of randomised trials showing its superiority over open radical prostatectomy. OBJECTIVE To compare in-hospital characteristics and patient-reported outcomes at 3 mo between robot-assisted laparoscopic and open retropubic radical prostatectomy. DESIGN, SETTING, AND PARTICIPANTS A prospective, controlled trial was performed of all men who underwent radical prostatectomy at 14 participating centres. Validated patient questionnaires were collected at baseline and after 3 mo by independent health-care researchers. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The difference in outcome between the two treatment groups were analysed using logistic regression analysis, with adjustment for identified confounders. RESULTS AND LIMITATIONS Questionnaires were received from 2506 (95%) patients. The robot-assisted surgery group had less perioperative bleeding (185 vs 683 ml, p<0.001) and shorter hospital stay (3.3 vs 4.1 d, p<0.001) than the open surgery group. Operating time was shorter with the open technique (103 vs 175 min, p<0.001) compared with the robot-assisted technique. Reoperation during initial hospital stay was more frequent after open surgery after adjusting for tumour characteristics and lymph node dissection (1.6% vs 0.7%, odds ratio [OR] 0.31, 95% confidence interval [CI 95%] 0.11-0.90). Men who underwent open surgery were more likely to seek healthcare (for one or more of 22 specified disorders identified prestudy) compared to men in the robot-assisted surgery group (p=0.03). It was more common to seek healthcare for cardiovascular reasons in the open surgery group than in the robot-assisted surgery group, after adjusting for nontumour and tumour-specific confounders, (7.9% vs 5.8%, OR 0.63, CI 95% 0.42-0.94). The readmittance rate was not statistically different between the groups. A limitation of the study is the lack of a standardised tool for the assessment of the adverse events. CONCLUSIONS This large prospective study confirms previous findings that robot-assisted laparoscopic radical prostatectomy is a safe procedure with some short-term advantages compared to open surgery. Whether these advantages also include long-term morbidity and are related to acceptable costs remain to be studied. PATIENT SUMMARY We compare patient-reported outcomes between two commonly used surgical techniques. Our results show that the choice of surgical technique may influence short-term outcomes.

Radical retropubic prostatectomy: A review of outcomes and side-effects

Abstract Background. Radical prostatectomy (RP) is worldwide probably the most common procedure to treat localized prostate cancer (PC). Due to a more widespread use of Prostate-Specific Antigen (PSA) testing, patients operated today are often younger and have organ confined disease justifying a more preservative surgery. At the same time, surgical technique has improved resulting in lower risk of permanent side-effects. This paper aims to give an overview of results from modern surgery regarding cancer control and side-effects. A brief overview of the history is given. Material and Methods. A literature research identified recently published papers focusing on outcome and side-effects after RP. Results. One large randomized study (SPCG-4) compared RP and watchful waiting (WW). The study showed that RP was superior to WW in preventing local progression (RR = 0.36), distant metastasis (RR = 0.65) and death from PC (RR = 0.65). Observational studies also show a better outcome for men treated with RP compared to WW. Peri-operative mortality after RP is low in most material around 0.1%. The risk of stricture of the vesico-urethral anastomosis has decreased with improved technique from historically 10–20% to a low incidence of around 2–9% today. Also the risk of incontinence has declined with improved technique. However, while the rates of severe incontinence is usually very low, as many as 30% still report light incontinence after long-term follow-up. Erectile dysfunction (ED) is still a frequent side-effect after RP. This risk is dependent on age, pre-operative sexual function, surgical technique and other risk factors for ED such as smoking, diabetes, etc. In selected subgroups the risk of ED is low. Inguinal hernia is a more recently described complication after open retropubic RP with a postoperative incidence of 15–20% within three years of surgery. Conclusion. RP is an effective method to achieve cancer control in selected patients. With modern technique it is a safe procedure with a low risk of permanent side-effects except for ED.

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.

Age at surgery, educational level and long-term urinary incontinence after radical prostatectomy

Study Type – Harm (case series)