Reconciling the effects of screening in the ERSPC and PLCO trials
Some 20 years after PSA screening began in the U.S., two large randomized trials published apparently conflicting results: The European Randomized Study of Screening for Prostate Cancer (ERSPC) found that screening reduced prostate cancer mortality, but the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) found no reduction. Interpreting the results is complicated by differences in their implementation. Compared to the ERSPC, the PLCO involved a shorter interval between screens, a higher PSA threshold for biopsy referral, less frequent biopsy, and more frequent screening in the control group. In collaboration with investigators from both trials, we investigated differences between trials using two approaches. First, we estimated aggregate effects of screening on incidence in each arm of each trial in terms of a mean lead time. Then we analyzed whether the association between the risk of prostate cancer death and the mean lead time differed between trials. Finding no evidence of a different association, we concluded that the trials provide compatible evidence that screening reduces prostate cancer mortality (Tsodikov et al., 2017). Second, we applied screening efficacy estimated using ERSPC data to simulated trials with systematically varied settings for known differences in trial implementation, including screening intervals, PSA thresholds, biopsy receipt, and control arm contamination. We concluded that trial results are sensitive to implementation, and differences in biopsy frequency and control arm contamination were major contributors to the apparent differences in published results for the two trials (de Koning et al., 2018).
Modeling prostate cancer natural history in black men
National guidelines for prostate cancer screening do not provide explicit recommendations for black men, whose risk of dying of the disease is approximately twice that in the general population. Since empirical studies comparing screening strategies in a black population are not feasible, we used modeling to investigate whether black men should be screened differently than the general population. We developed race-specific versions of our natural models and calibrated them to population incidence trends among black men and the general population. Our results show that black men have considerably higher risk of disease onset and progression to metastasis. These results support initiating screening earlier in black men and potentially screening them more frequently (Tsodikov et al., 2017).
Projecting expected effects of discontinued vs age-restricted screening
Concerns about overdiagnosis and overtreatment of prostate cancer associated with PSA screening and limited absolute benefit reported from screening trials motivated major revisions to U.S. guidelines. Most notably the U.S. Preventive Services Task Force recommended against routine PSA screening in 2012, while other guidelines panels (e.g., the American Cancer Society, the American Urological Association, and American College of Physicians) recommended shared decision-making for healthy men with at least 10-year life expectancy, typically up to age 70 or 75 years. These inconsistent guidelines have created uncertainty among health care providers with millions of men who are candidates for screening. Two models projected the expected impacts of completely discontinued PSA screening vs a continuation of historical PSA screening restricted to men under 70 years of age. The models projected that completely discontinued PSA screening may result in many avoidable prostate cancer deaths. In contrast, age-restricted PSA screening would eliminate 64%-66% of overdiagnoses relative to a continuation of historical PSA screening and prevent 61%-64% of avoidable prostate cancer deaths relative to completely discontinued PSA screening. The results support finding ways to continue screening that reduce harms while preserving as much of the benefit of screening as possible (Gulati et al., 2014).
Healthy men and their primary care physicians must choose between conflicting clinical guidelines.
Explaining observed declines in prostate cancer mortality
Prostate cancer death rates have declined by nearly one-half since the early 1990s. Many assume that PSA screening, which became popular in the early 1990s, is responsible for this drop in prostate cancer deaths. However, treatment for prostate cancer has also been changing. In the 1980s, radical prostatectomy increased in prominence, while, during the 1990s, hormonal therapies, previously reserved for advanced disease, were added to treatment regimens for localized tumors. Three models were used to quantify the fraction of the mortality decline attributable to changes in initial treatment. The models projected that changes in treatment explained 22% to 33% of the mortality decline by 2005. By isolating and quantifying the effects on mortality of treatment changes, we were able to more clearly quantify the likely role of PSA screening in the population setting (Etzioni et al., 2012).
Examining effects of control arm contamination in the PLCO cancer screening trial
The prostate section of the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial found a non-significant increase in prostate cancer mortality in the intervention arm compared to the control arm. However, 45% of participants reported receiving at least one prior PSA test before entering the trial, control arm participants continued to receive PSA tests at a higher frequency than the general population, and prostate cancer mortality was lower than expected in both arms. Three models were applied to study the effects of pre-trial and control arm screening on the published mortality rate ratio. The models found that under a clinically significant mortality reduction associated with PSA screening similar to that observed in the ERSPC trial, pre-trial and control arm screening substantially reduced the power of the PLCO to detect a mortality difference between arms and lead to a nontrivial chance of finding excess mortality in the intervention arm (Gulati et al., 2012).
Characterizing prostate cancer natural history
Informed decisions about PSA screening for prostate cancer and about treatment following detection by screening require information about disease natural history, including the chances that the cancer has been overdiagnosed or that the cancer would lead to death if untreated. We leveraged three models to summarize key events in the development and progression of prostate cancer and to project risks of clinical progression and disease-specific deaths for PSA-detected cancers in the absence of treatment. The models projected that the lifetime risk of developing a preclinical prostate tumor is 20%-33% (range across models), that 38%-50% of these tumors would be diagnosed in the absence of screening and that 12%-25% would lead to death in the absence of treatment. Risks of overdiagnosis, metastasis, and prostate cancer death depended on age, Gleason grade, and PSA at diagnosis (Gulati et al., 2011).
Reconciling differing estimates of lead time and overdiagnosis due to PSA screening
Lead time and overdiagnosis are unobservable quantities that are key to evaluating the trade-offs between the potential benefits and harms of PSA screening. Previous studies, including two studies by CISNET prostate investigators (Tsodikov et al., 2006; Etzioni et al., 2002), published mean lead time estimates that ranged from 3 to 7 years and overdiagnosis estimates that ranged from 25% to 84% of all screen-detected cases. These prior estimates were highly disparate because they were developed under differing systems of practice of PSA use (e.g., PSA cutoffs and biopsy practices), different populations, as well as different assumptions and definitions of lead time and overdiagnosis. CISNET investigators recognized this opportunity to bring order to this disparate literature by developing estimates using U.S. practice patterns and a consistent set of definitions. By standardizing in this manner, three CISNET modeling groups were able to reduce the range of mean lead times to 5-7 years and overdiagnosis frequencies to 23%42% (Draisma et al., 2009). The two major randomized trials of prostate cancer screening (PLCO and ERSPC) use considerably different screening protocols, including PSA thresholds for biopsy and biopsy practices, and produced apparently conflicting results about the benefit of PSA screening. This CISNET prostate working group is working with investigators from both trials to reconcile differences in their circumstances of implementation and to assist in translating estimates of both benefit and harm to inform public health guidelines for the use of PSA screening.
The Iceberg Effect
Quantifying the role of prostate-specific antigen (PSA) screening in U.S. prostate cancer mortality
The value of PSA screening remains uncertain. Even before randomized clinical trials on the potential benefits of PSA screening on prostate cancer mortality began, the test was rapidly adopted in several countries including the United States. However, while there is a general consensus that PSA screening explains much of the decline in the incidence of distant prostate cancers, there is still considerable debate about its role in the observed mortality decline. Two models were used to determine the plausible contribution of PSA screening in the decline of U.S. mortality. The researchers used common estimates of PSA screening rates and assumed that, by shifting the disease from a distant to a localized/regionalized clinical stage, screening does result in a corresponding improvement in disease-specific survival and mortality. The researchers concluded that PSA screening may account for much but not all of the observed reduction in prostate cancer mortality. Other factors, such as changing treatment practices, also may have played a role in improving prostate cancer outcomes (Etzioni, et al., 2008).