Prostate-specific Antigen–Based Prostate Cancer Screening: Reduction of Prostate Cancer Mortality After Correction for Nonattendance and Contamination in the Rotterdam Section of the European Randomized Study of Screening for Prostate Cancer

BackgroundLarge randomized screening trials provide an estimation of the effect of screening at a population-based level. The effect of screening for individuals, however, is diluted by nonattendance and contamination in the trial arms.ObjectiveTo determine the prostate cancer (PCa) mortality reduction from screening after adjustment for nonattendance and contamination.Design, setting, and participantsA total of 34 833 men in the core age group, 55–69 yr, were randomized to a screening or control arm in the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer (ERSPC). Prostate-specific antigen (PSA) testing was offered to all men in the screening arm at 4-yr intervals. A prostate biopsy was offered to men with an elevated PSA. The primary end point was PCa-specific mortality.Outcome measurements and statistical analysisNonattendance was defined as nonparticipation in the screening arm. Contamination in the control arm was defined as receiving asymptomatic PSA testing or a prostate biopsy in the absence of symptoms. Relative risks (RRs) were calculated with an intention to screen (ITS) analysis and after correction for nonattendance and contamination using a method that preserves the benefits obtained by randomization.Results and limitationsThe ITS analysis resulted in an RR of 0.68 (95% confidence interval [CI], 0.53–0.89) in favor of screening at a median follow-up of 13 yr. Correction for both nonattendance and contamination resulted in an RR of 0.49 (95% CI, 0.27–0.87) in favor of screening.ConclusionsPCa screening as conducted in the Rotterdam section of the ERSPC can reduce the risk of dying from PCa up to 51% for an individual man choosing to be screened repeatedly compared with a man who was not screened. This benefit of screening should be balanced against the harms of overdiagnosis and subsequent overtreatment.Trial registrationISRCTN49127736.     

Young Age on Starting Prostate-specific Antigen Testing Is Associated with a Greater Reduction in Prostate Cancer Mortality: 24-Year Follow-up of the Göteborg Randomized Population-based Prostate Cancer Screening Trial

BackgroundThe risk of death from prostate cancer (PC) depends on age, but the age at which to start prostate-specific antigen (PSA) screening remains uncertain.ObjectiveTo study the relationship between risk reduction for PC mortality and age at first PSA screening.Design, setting, and participantsThe randomized Göteborg-1 trial invited men for biennial PSA screening between the ages of 50 and 70 yr (screening, n = 10 000) or no invitation but exposure to opportunistic PSA testing (control, n = 10 000).InterventionRegular versus opportunistic PSA screening or no PSA.Outcome measurements and statistical analysisWe modeled the nonlinear association between starting age and the absolute risk reduction in PC mortality in three settings: (1) intention-to-screen (randomized arms); (2) historical control (screening group and 1990–1994 registry data); and (3) attendees only (screening attendees and matched controls). We tested whether the effect of screening on PC mortality depends on the age at starting screening by comparing survival models with and without an interaction between trial arm and age (intention-to-screen and attendees only).Results and limitationsYounger age on starting PSA testing was associated with a greater reduction in PC mortality. Starting screening at age 55 yr approximately halved the risk of PC death compared to first PSA at age 60 yr. The test of association between starting age and the effect of screening on PC mortality was slightly greater than the conventional level of statistical significance (p = 0.052) for the entire cohort, and statistically significant among attendees (p = 0.002). This study is limited by the low number of disease-specific deaths for men starting screening before age 55 yr and the difficulty in discriminating between the effect of starting age and screening duration.ConclusionsGiven that prior screening trials included men aged up to 70 yr on starting screening, our results suggest that the effect size reported in prior trials underestimates that of currently recommended programs starting at age 50–55 yr.Patient summaryIn this study from the Göteborg-1 trial, we looked at the effect of prostate-specific antigen (PSA) screening in reducing men’s risk of dying from prostate cancer given the age at which they begin testing. Starting at a younger age reduced the risk of prostate cancer death by a greater amount. We recommend that PSA screening should start no later than at age 55 yr.     

Characteristics of Prostate Cancer Found at Fifth Screening in the European Randomized Study of Screening for Prostate Cancer Rotterdam: Can We Selectively Detect High-grade Prostate Cancer with Upfront Multivariable Risk Stratification and Magnetic Resonance Imaging?

Background

The harm of screening (unnecessary biopsies and overdiagnosis) generally outweighs the benefit of reducing prostate cancer (PCa) mortality in men aged ≥70 yr. Patient selection for biopsy using risk stratification and magnetic resonance imaging (MRI) may improve this benefit-to-harm ratio.

PSA-based Screening for Prostate Cancer: How Does It Compare with Other Cancer Screening Tests?

CONTEXT: Despite the substantive societal impact of prostate cancer, the medical community is currently divided on the balance between benefit and harm of screening for prostate cancer using prostate-specific antigen (PSA). OBJECTIVE: To examine whether PSA-based screening for prostate cancer meets current guidelines on efficacy and effectiveness for screening, and how it compares with other currently implemented cancer-screening methods. EVIDENCE ACQUISITION: A literature search was conducted for reviews and individual studies that have examined the performance of screening for colorectal, cervical, breast, and prostate cancer. Each screening method was assessed using the United Kingdom National Screening Committee guidelines. Data on screening test performance (sensitivity, specificity, etc) were extracted from these articles for comparison. EVIDENCE SYNTHESIS: In common with other cancers for which screening is conducted, prostate cancer represents a significant morbidity and mortality burden. The PSA test can be considered "simple" and "safe" within appropriate boundaries. The sensitivity/specificity profile of PSA is not optimal but has clinical validity: Cases missed at screening detected as interval cases do not have a poor outcome. Early prostate cancer intervention can be beneficial for long-term outcomes, although the benefits need to be weighed against the adverse effects of intervention. Early evidence from screening studies also suggests positive stage and grade shifts, although Level 1 mortality data are still awaited. Robust cost-effectiveness data are still lacking, although current evidence suggests that PSA screening may lie within acceptable limits. CONCLUSION: Until better markers become available, PSA can be regarded as an appropriate screening tool for prostate cancer at a population level.     

Prostate Cancer Mortality Reduction by Prostate-Specific Antigen–Based Screening Adjusted for Nonattendance and Contamination in the European Randomised Study of Screening for Prostate Cancer (ERSPC)

Background

Prostate-specific antigen (PSA) based screening for prostate cancer (PCa) has been shown to reduce prostate specific mortality by 20% in an intention to screen (ITS) analysis in a randomised trial (European Randomised Study of Screening for Prostate Cancer [ERSPC]). This effect may be diluted by nonattendance in men randomised to the screening arm and contamination in men randomised to the control arm.

Objective

To assess the magnitude of the PCa-specific mortality reduction after adjustment for nonattendance and contamination.

Design, setting, and participants

We analysed the occurrence of PCa deaths during an average follow-up of 9 yr in 162 243 men 55–69 yr of age randomised in seven participating centres of the ERSPC. Centres were also grouped according to the type of randomisation (ie, before or after informed written consent).

Intervention

Nonattendance was defined as nonattending the initial screening round in ERSPC. The estimate of contamination was based on PSA use in controls in ERSPC Rotterdam.

Measurements

Relative risks (RRs) with 95% confidence intervals (CIs) were compared between an ITS analysis and analyses adjusting for nonattendance and contamination using a statistical method developed for this purpose.

Results and limitations

In the ITS analysis, the RR of PCa death in men allocated to the intervention arm relative to the control arm was 0.80 (95% CI, 0.68–0.96). Adjustment for nonattendance resulted in a RR of 0.73 (95% CI, 0.58–0.93), and additional adjustment for contamination using two different estimates led to estimated reductions of 0.69 (95% CI, 0.51–0.92) to 0.71 (95% CI, 0.55–0.93), respectively. Contamination data were obtained through extrapolation of single-centre data. No heterogeneity was found between the groups of centres.

Conclusions

PSA screening reduces the risk of dying of PCa by up to 31% in men actually screened. This benefit should be weighed against a degree of overdiagnosis and overtreatment inherent in PCa screening.     

Does Biliopancreatic Diversion Carry Increased Risk for Colorectal Cancer? A Cohort Study

Background Because of the rearrangement of the gastrointestinal tract, biliopancreatic diversion (BPD) could lead to an increased risk of colorectal cancer caused by possible carcinogenetic action of the unabsorbed food and bile acid on colonic mucosa. Methods The incidence of colorectal cancer in 1,898 obese subjects submitted to BPD from May 76 to July 2002 with a minimum follow-up of 5 years was retrospectively evaluated. Results Among 28,811 person-years, seven cases of colorectal cancer were detected, for an overall incidence of 29.4 per 100,000, which is not different from that observed in the general Italian population, and lower than that reported for obese and type 2 diabetes patients. Logistic regression model suggests that occurrence of colorectal cancer is positively related to the time elapsed from BPD. Conclusion This study indicates that BPD does not carry any increased risk for colorectal cancer. The complete postoperative restoration of insulin sensibility could exert a valuable protective action.     

Suicide Risk in Men with Prostate-Specific Antigen–Detected Early Prostate Cancer: A Nationwide Population-Based Cohort Study from PCBaSe Sweden

Background

The risk of suicide is increased among cancer patients including men with prostate cancer (PCa). However, whether this increased risk applies to men diagnosed subsequent to prostate-specific antigen (PSA) testing is not known.

Objective

To assess the risk of suicide among men diagnosed with PCa subsequent to PSA testing.

Design, setting, and participants

The Prostate Cancer Base Sweden (PCBaSe Sweden) database, the Swedish Cause of Death Register, and the Swedish census database were used. The PCBaSe Sweden is a merged database that includes data from the Swedish National Prostate Cancer Register (NPCR) for cases diagnosed between January 1, 1997, and December 31, 2006. The number of suicides registered for cases in the PCBaSe cohort was compared with the expected number of suicides in an age-matched general male Swedish population.

Measurements

Standardised mortality ratios (SMRs) with 95% confidence intervals (CIs) were calculated for different categories of cases.

Results and limitations

There were 128 suicides among the 77 439 PCa cases in the NPCR compared with an expected number of 85 (SMR: 1.5; 95% CI, 1.3–1.8). The risk of suicide was not increased for the 22 405 men with PSA-detected T1c tumours (SMR: 1.0; 95% CI, 0.6–1.5), whereas the 22 929 men with locally advanced nonmetastatic tumours (SMR: 2.2; 95% CI, 1.6–2.9) and the 8350 men with distant metastases (SMR: 2.1; 95% CI, 1.2–3.6) had statistically significant increased SMRs for suicide. Potential effects of comorbid medical and psychiatric conditions could not be investigated.

Conclusions

No increased risk of committing suicide was observed among men with PCa diagnosed subsequent to PSA testing, whereas the risk was twice as high among men with locally advanced or metastatic disease, compared with an age-matched male population.     

Could Differences in Treatment Between Trial Arms Explain the Reduction in Prostate Cancer Mortality in the European Randomized Study of Screening for Prostate Cancer?

BackgroundDifferential treatment between trial arms has been suggested to bias prostate cancer (PC) mortality in the European Randomized Study of Screening for Prostate Cancer (ERSPC).ObjectiveTo quantify the contribution of treatment differences to the observed PC mortality reduction between the screening arm (SA) and the control arm (CA).Design, setting, and participantsA total of 14 136 men with PC (SA: 7310; CA: 6826) in the core age group (55–69 yr) at 16 yr of follow-up.Outcome measurements and statistical analysisThe outcomes measurements were observed and estimated numbers of PC deaths by treatment allocation in the SA and CA, respectively. Primary treatment allocation was modeled using multinomial logistic regression adjusting for center, age, year, prostate-specific antigen, grade group, and tumor-node-metastasis stage. For each treatment, logistic regression models were fitted for risk of PC death, separately for the SA and CA, and using the same covariates as for the treatment allocation model. Treatment probabilities were multiplied by estimated PC death risks for each treatment based on one arm, and then summed and compared with the observed number of deaths.Results and limitationsThe difference between the observed and estimated treatment distributions (hormonal therapy, radical prostatectomy, radiotherapy, and active surveillance/watchful waiting) in the two arms ranged from −3.3% to 3.3%. These figures, which represent the part of the treatment differences between arms that cannot be explained by clinicopathological differences, are small compared with the observed differences between arms that ranged between 7.2% and 10.1%. The difference between the observed and estimated numbers of PC deaths among men with PC was 0.05% (95% confidence interval [CI] −0.1%, 0.2%) when applying the CA model to the SA, had the two groups received identical primary treatment, given their clinical characteristics. When instead applying the SA model to the CA, the difference was, as expected, very similar—0.01% (95% CI −0.3%, 0.2%). Consistency of the results of the models demonstrates the robustness of the modeling approach. As the observed difference between trial arms was 4.2%, our findings suggest that differential treatment explains only a trivial proportion of the main findings of ERSPC. A limitation of the study is that only data on primary treatment were available.ConclusionsUse of prostate-specific antigen remains the predominant explanation for the reduction in PC mortality seen in the ERSPC trial and is not attributable to differential treatment between trial arms.Patient summaryThis study shows that prostate cancer deaths in the European screening trial (European Randomized Study of Screening for Prostate Cancer) were prevented because men were diagnosed and treated earlier through prostate-specific antigen screening, and not because of different, or better, treatment in the screening arm compared with the control arm.     

Multicenter European External Validation of a Prostate Health Index–based Nomogram for Predicting Prostate Cancer at Extended Biopsy

Background

External validation of a prediction tool is mandatory to assess the tool's accuracy and generalizability within different patient cohorts.

Objective

To externally validate a previously developed Prostate Health Index (PHI)–based nomogram for predicting the presence of prostate cancer (PCa) at biopsy.

Design, setting, and participants

The study population consisted of 883 patients who were scheduled for a prostate biopsy at one of five European tertiary care centers. Total prostate-specific antigen (tPSA), free prostate-specific antigen (fPSA), and [−2]pro–prostate-specific antigen (p2PSA) levels were determined. The fPSA-to-tPSA ratio (%fPSA), p2PSA, and PHI ([p2PSA / fPSA] × √tPSA) were calculated.

Intervention

Extended initial and repeat prostate biopsy.

Outcome measurements and statistical analysis

Logistic regression models were fitted to test the predictors of PCa and to determine their predictive accuracy. A calibration plot was used to evaluate the extent of overestimation or underestimation between nomogram predictions and observed PCa rate. Decision curve analysis (DCA) provided an estimate of the net benefit obtained by using the PHI-based nomogram.

Results and limitations

Of 833 patients, 365 (41.3%) were diagnosed with PCa at extended prostate biopsy. In accuracy analyses, PHI was the most informative predictor of PCa (0.68), outperforming tPSA (0.51) and %fPSA (0.64). The predictive accuracy of the previously developed nomogram was 75.2% (95% confidence interval, 71.4–78.1). Calibration of the nomogram was good in patients at a low to intermediate predicted probability of PCa, while calibration was suboptimal, with a tendency to overestimate the presence of PCa, in high-risk patients. Finally, DCA demonstrated that the use of the PHI-based nomogram resulted in the highest net benefit. The main limitation of the study is the fact that only Caucasian patients were included.

Conclusions

At external validation, the previously developed PHI-based nomogram confirmed its ability to determine the presence of PCa at biopsy. These findings provide further evidence supporting the potential role of the nomogram in the biopsy decision pathway for European men with suspected PCa.

Patient summary

In the current study, we externally validated a Prostate Health Index–based nomogram to predict the presence of prostate cancer (PCa) at biopsy. This tool may help clinicians determine the need for a prostate biopsy in European patients with suspected PCa.