Who and when should we screen for prostate cancer?

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Who and when should we screen for prostate cancer? Interviews with key opinion leaders

Who and when to screen, and not to screen, for prostate cancer: the proponents’ view

Michael Leapman (Fig.  2 ), Peter Carroll (Fig.  3 ), and Fritz Schröder (Fig.  4 )

M Leapman & P Carroll: Prostate cancer is a highly prevalent disease that exhibits considerable variation in clinical behavior; some men will enjoy long lives with low-grade disease without treatment, while a significant, but smaller number may succumb to a devastating metastatic burden. Therefore, the current challenge faced in the early management of prostate cancer is to identify and treat disease in men likely to obtain benefit while sparing unnecessary detection and, most importantly, treatment in those who will not.

Compelling randomized evidence suggests that PSA screening of asymptomatic men is associated with a significant reduction in death from prostate cancer. The recent 13-year update of the ERSPC trial, a multi-centered study examining prostate cancer mortality among participants aged 50–74 receiving regular PSA screening compared with no routine screening, has demonstrated a relative risk of death from prostate cancer of 0.79 (95 % CI, 0.69–0.91, P = 0.001) in favor of screening men aged 55–69 years. Moreover, when adjusting for non-participation, the reduction in risk increased to 27 % (95 % CI, 0.61–0.88, P < 0.0007) [5]. Naturally, screening can only reduce mortality by effecting treatment of clinically significant disease, as was observed in the ERSPC experience, in which substantially more cancers were diagnosed and subsequently treated [19].

It is true that eliminating PSA screening will obviously decrease the number of ‘insignificant’ prostate cancer cases detected; however, this would come at the imprudent expense of ignoring disease in intermediate and high-risk patients who may stand to benefit substantially. Indeed, the rationale for treatment in appropriate patients is redoubled by randomized evidence suggesting improvement in survival and metastatic progression with timely treatment of threatening cancers [20]. However, an overall improvement in prostate cancer mortality is alone insufficient to justify expansive screening and treatment of all men if such a strategy will expose those harboring non-lethal tumors to a non-trivial risk of adverse quality of life outcomes; one should not screen if overdiagnosis is followed by overtreatment [21].

Ultimately, the landscape of early prostate cancer detection may not truly be cast in a monochromatic decision palette, namely to screen with PSA or not to screen. Rational practices including the screening of healthy men with a long life expectancy starting at age 45, cessation of screening in those with significant co-morbidity and those of advanced age, extending the interval of screening in most men (2–4 years), and discontinuing screening for those with low-risk profiles at certain ages alone would significantly improve the efficiency of early detection. In addition, nuanced strategies for prostate cancer detection and management represent an auspicious frontier. Although not validated in randomized trials of screening techniques, assays incorporating novel PSA isoforms – including the 4-Kallikrein panel [22] and the Prostate Health Index [23] – appear to add much needed specificity for the detection of high-grade (Gleason ≥7) prostate cancer at a diagnostic prostate biopsy, thereby potentially reducing the number of unnecessary biopsies performed. Advanced imaging modalities, including multi-parametric MRI, may also better refine the candidacy and yield of biopsy [24]. Among newly diagnosed patients, tumor-based risk stratification methods [25] and favorable long-term experiences with active surveillance [10] are poised to improve the confidence and quality with which incidental tumors are managed. Such measures, being currently clinically implemented, are highly promising means to cultivate better screening; these methods will highlight prostate cancer requiring attention while disregarding or proposing active surveillance of those that do not.

F Schröder: In my view, the time for population-based screening has not come and may never do so. The main reason for my pessimistic view on this issue is the high probability (of approximately 40 %) of diagnosing cancers which will not progress clinically, cause symptoms, or lead to death (overdiagnosis) [5]. While there are methods available to decrease overdiagnosis, such as the use of risk calculators and multiparametric MRI of the prostate, these have not been sufficiently validated in multicenter use to establish their accuracy in routine clinical practice. As a main contributor and former principal investigator of the ERSPC screening trial, I am delighted to see increasing worldwide acceptance of the recommendation of our group, including in US, European, and Russian guidelines to apply ‘shared decision-making’. We recommend the use of a procedure developed on the basis of ERSPC data, which is freely available on the website of the SIU [26].

A Vickers and S Carlsson [to M Leapman and P Carroll]: Could you please clarify what you think current policy should be and whether all men should be screened?

M Leapman & P Carroll: On the basis of randomized screening trials, PSA screening should be offered to healthy individuals without known risk factors for prostate cancer beginning at age 45 [5, 27]. No stark policy, however, will account for the complexities involved with screening and early diagnosis of prostate cancer. As a result, screening of asymptomatic men should be approached in the setting of a shared decision between a patient and physician cognizant of the individual’s age, health status, personal preferences, and risk factors including family history, race, prior PSA, and biopsy status. As noted above, the efficiency of screening can be improved and contemporary screening guidelines are incorporating refinements as suggested [28].

A Vickers and S Carlsson: You say that “ discontinuing screening for those with low baseline risk profiles [would]significantly improve the efficiency of [PSA] screening ”. Could you give a specific example of the profile of a man for whom screening should be discontinued?

M Leapman & P Carroll: Obviously, those in poor health or of advanced age do not benefit from early detection efforts. The optimal frequency of PSA testing has not been explicitly compared in a randomized fashion, but screening at 2–4 year intervals appears appropriate in low-risk patients based on PSA levels. Baseline PSA status may offer a valuable insight into a patient’s further risk for harboring or developing significant prostate cancer. Persuasive evidence from a Swedish population-based cohort examining PSA levels at age 60 suggests that men with levels <1 ng/mL possess a low (near zero) risk of prostate cancer death in extended follow-up [14, 17]. It would be reasonable to forego further screening of a 60-year-old without other known risk factors with baseline PSA <1 in the absence of cause.

in the state of Michigan, where nearly half of all patients diagnosed with low-risk disease are initially managed with active surveillance [30]

F Schröder: Weighing pros and cons of a medical procedure will always remain the responsibility of the person at risk. We, as doctors and urologists, have to help by addressing the questions arising after reading the first section of the decision aid, which is only one page.

Who and when to screen, and not to screen, for prostate cancer: the skeptics’ view

Peter C Albertsen (Fig.  5 ) and Dragan Ilic (Fig.  6)

should PSA be avoided entirely in asymptomatic men, or should screening be restricted to certain subgroups and, if so, whom?

P Albertsen: Few cancers generate as much controversy as prostate cancer concerning screening, diagnosis, and treatment. From 1977 to 2005, the lifetime risk of prostate cancer diagnosis in the US increased from 7.3 % to 17 % [31, 32]. During this same period, the lifetime risk of dying from prostate cancer fell from 3.0 % to 2.4 %.

My views on prostate cancer screening and treatment have been shaped by my training in urology at Johns Hopkins and epidemiology and public health at the University of Wisconsin, as well as by my patients. One patient in particular had a powerful influence. He was referred for treatment of a localized prostate cancer and underwent successful surgery. His postoperative PSA was undetectable and all surgical margins were negative. I told him he was cured only to have him return 2 years later with widespread metastases. I treated him successfully with anti-androgen therapy for an additional 16 years. According to the Halsted model of cancer progression he should have been cured by surgery [33]. I had the original specimen re-cut to document negative margins and concluded that we had a poor understanding of the natural history of this disease and the efficacy of treatment.

To address this problem, I developed a Markov model of prostate cancer progression. With the assistance of Jack Wennberg’s research group, the model was published in JAMA [34]. At the time, it was severely criticized by the urologic community, but when reviewed today the model bears a remarkable resemblance to data recently published by the SPCG-4 [35]. The sensitivity analysis indicated that data concerning the natural history of this disease was most critical to estimating the relative value of intervention. This is why I gathered data on the natural history of this disease from patients enrolled in the Connecticut tumor registry and published them in JAMA in 1998 and 2005 [36, 37].

My training in epidemiology taught me to view healthcare delivery from a public health perspective. Screening programs were best assessed by addressing four key questions: (1) Is prostate cancer a suitable disease for screening? (2) Is treatment for prostate cancer effective? (3) Is PSA an effective screening test for this disease? (4) Does screening result in any harm?

Only recently have we begun to appreciate that a large number of men harbor indolent disease, as clearly demonstrated by data from the Finasteride Chemoprevention trial [39]. Many pathologists now question whether Gleason 3 + 3 tumors are sufficiently aggressive to cause morbidity [40]. Indeed, recent data from the ERSPC trials suggest that half of all screen-detected cancers are indolent [5].

The efficacy of treatment also poses problems. Most urologists and radiation therapists assume that surgery and radiation are curative. However, what do the data say? The SPCG-4 suggests that some men are cured by surgery, but many men are not [35]. Further, men with high-grade disease often die from prostate cancer despite surgery and that surgery is primarily palliative for men aged over 65. With regards to radiation, even less information concerning its efficacy is available to date.

How well does PSA perform as a screening tool? Unfortunately, many lethal tumors produce low amounts of PSA and are missed by screening studies. Additionally, prostate enlargement, prostatitis, and surgical manipulation can lead to a significant number of false positive values. Finally, screening can result in considerable morbidity as documented by the USPSTF report [1].

I have been an advocate of active surveillance for men with low-grade disease [9]. Data from the ProTECT trial should provide important new data concerning efficacy when published in the spring of 2016 [41]. Ideally, screening should only identify men destined to suffer from clinically significant disease and patients should only be offered treatments that yield substantial benefit.

D Ilic: Prostate cancer is a leading cancer affecting men worldwide [42]. Despite its high prevalence, the current evidence suggests that screening asymptomatic men for prostate cancer is not warranted [1, 43]. The most recent Cochrane systematic review identified five randomized controlled trials examining the effectiveness of screening [43]. A meta-analysis of data from those five trials determined no significant difference in prostate cancer mortality between men randomised to screening in comparison to those who were not (risk ratio (RR) = 1.00; 95 % CI, 0.86–1.17) [43].

Only two of the five randomized controlled trials included in the 2013 systematic review were determined to methodologically present a low-risk of bias [43]. The point of interest lies in the differing results and conclusions offered by two studies: the ERSPC and the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial [27, 44].

In 2014, the ERSPC published 13-year follow-up data, reporting a 21 % reduction in the risk of prostate cancer mortality through screening (RR = 0.79; 95 % CI, 0.69–0.91) [5]. A sub-group analysis of prostate cancer mortality by age at randomization identified a significant decrease in prostate cancer mortality in the 65–69 year age group (RR = 0.69; 95 % CI, 0.55–0.87). No statistically significant difference in prostate cancer mortality was observed between screening and control groups in men aged <54, 55–59, and 60–64 years [5]. The results also suggest that screening is not beneficial in men aged over 70 years (RR = 1.17; 95 % CI, 0.82–1.66). The ERSPC study authors concluded that, “…the time for population-based screening has not yet arrived…” [5].

P Albertsen: Based upon what we know in 2015, PSA testing does benefit some men. For this reason I strongly support the recommendations of the AUA. These guidelines were based extensively on the data provided by the ERSPC. However, we need to do better. I am aware of your work with Hans Lilja, suggesting that a PSA value at age 50 is predictive of the long-term probability of developing clinically significant prostate cancer [18]. I believe we can refine the group of men who should be tested. We also need to incorporate the natural increase in PSA that comes with prostate enlargement that occurs when a man ages through his 50s and 60s. A graphic chart that tracks PSA levels or, possibly, percent free-PSA or the new prostate health index test against age and prostate volume, similar to a pediatric growth chart, might be helpful. Men consistently falling outside the 90th percentile, for example, might undergo MRI testing before considering a prostate biopsy. All of these refinements should be aimed at lowering the incidence of low-volume, low-grade cancer. In my mind, we have yet to define a best practice screening and treatment algorithm. While the AUA recommendations are a start, we have not agreed upon the test(s) needed, the frequency of their application, the value of imaging versus biopsies, nor on which treatments work best for which patients.