Differences between men with screening-detected versus clinically diagnosed prostate cancers in the USA

Prostate-specific antigen (PSA) testing was introduced in the United States of America (USA) in the late 1980s with Federal Drug Administration (FDA) approval for prostate cancer surveillance [1]. However, the test indications were soon expanded to include prostate cancer screening. By the early 1990s, the American Urologic Association and the American Cancer Society were recommending PSA testing, along with digital rectal examination (DRE), as part of annual prostate cancer screening [2, 3]. The advent of PSA testing led to a dramatic increase in the incidence of prostate cancer in the USA, with the number of new cases rising from 152,811 in 1990 to over 230,000 in 1992 [4, 5]. During the past decade, the number of American men undergoing aggressive treatment with radical prostatectomy and radiation therapy also increased substantially [6, 7].

Urologic screening studies provide the most comprehensive information about the men undergoing PSA screening [8‐10]. Several trials have taken place in both Europe and the USA. In general, study subjects usually were recruited through advertisements and they were screened with combinations of PSA, DRE, and transrectal ultrasound. The average age of these study participants was in the mid-60s, and minority subjects were not well represented. Minimal data were provided on symptoms, comorbidity, or socioeconomic status. Among American men diagnosed with clinically localized prostate cancers, approximately 90% underwent treatment with radical prostatectomy or radiation therapy.

Population-based data on PSA screening are largely unavailable, including information on the proportion of prostate cancers diagnosed by screening, the demographic, socioeconomic, and clinical characteristics of men with screening-detected cancers, and the association of screening detection with treatment decisions. We used data from the United States-based Prostate Cancer Outcomes Study (PCOS) to 1) determine the proportion of screening-detected prostate cancers in a population-based cohort, 2) compare baseline demographic, socioeconomic, and clinical characteristics between men with screening-detected versus clinically diagnosed cancers, and 3) determine whether men with screening-detected clinically-localized prostate cancers were more likely to undergo aggressive treatment (radical prostatectomy or radiation therapy).

The baseline demographic, socioeconomic, and clinical characteristics of the PCOS subjects are shown in Tables 1 and 2. The majority of subjects were non-Hispanic white men, older than sixty-five, and married at the time of diagnosis. Socioeconomic status was relatively high; a majority had more than a high school education, and a substantial proportion of subjects had private insurance. Among the study subjects, 10.7% presented with symptoms consistent with prostate cancer and were considered to be clinically diagnosed cases. Nearly two-thirds of subjects had lower urinary tract symptoms, while 30.9% were completely asymptomatic. Overall, 83.1% of men rated their general health at "good" or "excellent" before their cancer diagnosis.

We compared baseline characteristics of asymptomatic men, those with lower urinary tract symptoms alone, and men with clinically diagnosed cancers in Table 3. We found that the characteristics of men with lower urinary tract symptoms alone were closer to the asymptomatic men than to the clinically diagnosed cancer cases for race/ethnicity, socioeconomic status, health status, and cancer grade and stage. When we combined these two groups into a single category of screening-detected cases, we found significant differences between the screening-detected and clinically diagnosed cases. Men with screening-detected cancers were more likely to be non-Hispanic white, were younger age, and had a higher socioeconomic status. They also reported being healthier and were more likely to have early stage disease.

We then evaluated whether screening status independently predicted receiving aggressive treatment among the 2796 men who were diagnosed with clinically localized cancer. The primary treatment for these men was radical prostatectomy for 1535 (53.4%), while 518 (20.6%) underwent radiation therapy, 671 (26.0%) were treated conservatively; we had no treatment information for 72 subjects (2.5%). The results of the multivariate analysis are shown in Table 4. After adjusting for age, race/ethnicity, marital status, area of the country, education, insurance coverage, annual income, comorbidity, self-reported health status, and tumor characteristics, we found that men with screening-detected cancers were more likely to receive aggressive treatment. The adjusted percentage of men with screening-detected cancers undergoing aggressive treatment was 76% (95% CI 0.74, 0.78) vs. 70% (95% CI 0.64, 0.76), in men with clinically diagnosed cancers, OR = 1.5 (95% CI 1.1, 2.3), P = 0.05. Other factors that were significantly associated with aggressive treatment included geographic area, ethnicity, age, marital status, comorbidity, health status, and tumor characteristics. We found no significant interactions for treatment selection between screening status with age, comorbidity, PSA level, or Gleason score.

We found that the majority of cancers (89.3%) in a population-based PCOS cohort were detected by screening. Compared to men with clinically diagnosed prostate cancer, men with screening-detected cancers were younger, more likely to be married, less likely to be a member of a minority group, and in better health. The cancers detected by screening were more likely to be clinically localized and less likely to be poorly differentiated. Among men with clinically localized prostate cancers, those with screening-detected cancers were significantly more likely to undergo aggressive treatment, even after adjusting for demographics, comorbidity, and tumor characteristics

Our finding that a high proportion of prostate cancers diagnosed in 1994 and 1995 were detected by screening is consistent with the temporal correlation between the increased use of PSA testing and the increased incidence of prostate cancer in the USA beginning during the early 1990s [4, 5]. Although prostate cancer incidence rates decreased for several years in the mid 1990s, more recent data show that incidence rates are again increasing [5, 19, 20] and survey results from the Centers for Disease Control's Behavioural Risk Factor Surveillance System (BRFSS) show that a high proportion of American men continue to undergo PSA testing [20]. These data suggest that our findings are still relevant for prostate cancers being diagnosed in the USA. We also found that men with screening detected cancers were more likely to have early stage cancers, again mirroring the epidemiologic data showing an increased incidence of early stage cancers and a decreased incidence of advanced stage cancers [4, 5]. The majority of screening-detected tumors were moderately to poorly differentiated; however, a significantly higher proportion of clinically diagnosed cancers were poorly differentiated.

Previous data, including an analysis of the PCOS cohort, have shown African Americans to be twice as likely as non-Hispanic whites to present with advanced stage cancers [4, 5, 21]. In the current analysis, we found a greater prevalence of ethnic/racial minorities in the clinically diagnosed versus screening-detected cancers. This disparity may reflect ethnic/racial differences in accessing preventive health care services, particularly arising from socioeconomic barriers. This in turn could contribute to disparities in cancer stage at diagnosis [22‐24]. However, African Americans also have been reported to demonstrate more skeptical attitudes towards screening [25] and the stage disparity could be due to racial differences in tumor aggressiveness [26].

Men with screening-detected clinically localized cancers were more likely to undergo aggressive treatment with radical prostatectomy or radiation therapy than men with clinically diagnosed cancers. The odds ratio for receiving aggressive treatment was statistically significant at 1.5, but the adjusted absolute difference between screening-detected and clinically diagnosed cases was only 6 percentage points. This modest association between screening status and treatment selection suggests that clinical practice may be only partly consistent with the American College of Physicians' view that "aggressive treatment is necessary to realize any benefit from the discovery of a tumor [27]." Our findings may reflect the scientific uncertainty about whether and how to treat screening-detected prostate cancers [28].

Our study has some potential limitations. We classified men presenting with symptoms of advanced cancer as being clinically diagnosed. We do not know that these symptoms actually prompted diagnostic PSA testing. However, the tumor registry medical record abstractors are trained to identify the events leading to a cancer diagnosis; they would attempt to record only symptoms consistent with cancer. Classifying PSA as a screening test is also difficult given the high prevalence of lower urinary tract symptoms in older men [15]. Few members of our study cohort were truly asymptomatic because nearly two-thirds reported lower urinary tract symptoms. However, our classifications for clinical diagnosis and screening detection were internally valid because men diagnosed with symptoms of advanced cancer were significantly more likely to present with advanced stage and more aggressive cancers than the combined group of men who were either asymptomatic or had only lower urinary tract symptoms. Additionally, when we compared demographic and socioeconomic characteristics across groups, we generally found that the men with lower urinary tract symptoms alone most closely resembled the asymptomatic men.

Selection bias may have occurred because 44% of the sampled patients did not complete the 6-month survey. Responders were younger than non-responders, more likely to be non-Hispanic white, had higher socioeconomic status, had earlier stage disease, and were more likely to receive radical prostatectomy. Results may be less generalizable to older men, those with lower socioeconomic status, or members of racial/ethnic groups other than non-Hispanic white. However, these were also the groups who were less likely to have screening-detected cancers. We do not believe that including these non-responders would have altered our findings on the differences between screening-detected and clinically diagnosed cancers. However, based on their demographics, socioeconomic status, and advanced disease stage, the non-responders were not likely to have a high proportion of screening-detected cancers and thus we may have overestimated the proportion of screening-detected cancers. Another potential limitation arose from asking subjects to recall their baseline symptoms 6 months after diagnosis. Recall errors could lead us to misclassify screening status. However, Legler and colleagues prospectively studied a subset of PCOS subjects and found high concordance for symptom recall at 6-months after diagnosis compared with reports at the time of diagnosis [29]. Finally, we may have had incomplete symptom data, particularly for questions appearing only in the medical record abstract. The abstracts would report a symptom if it appeared in the medical records; the absence of a symptom could be due to either the patient being asymptomatic or the physician's failure to ask about or record the symptom. We performed a sensitivity analysis by using only subject reported symptoms from the survey, then only symptoms reported on the medical record abstract, and then ultimately using a combination of both sources. The results for all analyses were essentially the same.

The great majority of prostate cancers diagnosed in our study cohort were detected by screening. Appropriately, younger and healthier men were more likely to be diagnosed by screening. Minority status and lower socioeconomic status appeared to be screening barriers. Screening detected earlier stage and less histologically aggressive prostate cancers. After adjusting for baseline demographic, socioeconomic, clinical, and tumor factors, men with a screening-detected clinically localized cancer were slightly more likely to receive aggressive treatment, either radical prostatectomy or radiation therapy, than men with clinically diagnosed cancers.