Editorial Comment

Prostate Cancer in Men 70 Years Old or Older, Indolent or Aggressive: Clinicopathological Analysis and Outcomes

Pathological Characteristics of Prostate Cancer in Elderly Men

The diagnosis of prostate cancer in elderly men is likely to increase over the next several decades, owing to changing demographics and a rising population of men older than 65 years. Given the heterogeneity and well-documented challenges in screening, diagnosing, and managing indolent versus aggressive prostate cancer, the geriatric patient population is particularly vulnerable to prostate cancer treatment nuances. Clinicians must become familiar with geriatric assessment tools to better answer life-expectancy questions prior to counseling patients on treatment options. The preferences and values of patients and their families must always be considered when making screening and treatment decisions. Careful selection of patients following a holistic evaluation will not only minimize overtreatment and undertreatment of prostate cancer, but may also allow for the early identification of unique geriatric vulnerabilities and permit quicker interventions to improve the quality of life of these men during their elderly years.

Melatonin, Sleep, and Prostate Cancer in Elderly Men: Study, Hypothesis Development, and Icelandic Options

9543 Background: To identify clinical factors associated with prostate cancer-specific mortality (PCSM), adjusting for co-morbidity, in elderly men with intermediate-risk prostate cancer treated with brachytherapy alone or in conjunction with external beam radiation therapy (EBRT). Methods: The study cohort comprised 1,978 men of median age 71 (interquartile range [IQR], 66–75) years with intermediate-risk prostate cancer (Gleason score 7 with PSA 20 ng/mL or less and tumor category T2c or less). Fine and Gray's multivariable competing risks regression was used to assess whether presence of cardiovascular disease (CVD), age, treatment, year of brachytherapy, PSA level, or tumor category were associated with the risk of PCSM. Results: After a median follow up of 3.2 (IQR, 1.7 - 5.4) years, 15 men were observed to experience PCSM. The presence of CVD was significantly associated with a decreased risk of PCSM (AHR 0.20, 95% CI 0.04 - 0.99, P = 0.05), whereas an increasing PSA level was significantly associated with an increased risk of PCSM (AHR 1.14, 95% CI 1.02 - 1.27, P = 0.02). In the absence of CVD, cumulative incidence estimates of PCSM were higher (P = 0.03) in men with PSA levels above as compared to the median PSA level (7.3 ng/mL) or less; however, in the setting of CVD there was no difference (P = 0.27) in these estimates stratified by the median PSA level (6.9 ng/mL). Conclusions: Detection of intermediate-risk prostate cancer in elderly men without CVD at lower PSA levels is associated with a lower risk of PCSM; this risk reduction is not observed in men with known CVD. [Table: see text] No significant financial relationships to disclose.

ImportanceIn the United States, the lifetime risk of being diagnosed with prostate cancer is approximately 13%, and the lifetime risk of dying of prostate cancer is 2.5%. The median age of death from prostate cancer is 80 years. Many men with prostate cancer never experience symptoms and, without screening, would never know they have the disease. African American men and men with a family history of prostate cancer have an increased risk of prostate cancer compared with other men.ObjectiveTo update the 2012 US Preventive Services Task Force (USPSTF) recommendation on prostate-specific antigen (PSA)–based screening for prostate cancer.Evidence ReviewThe USPSTF reviewed the evidence on the benefits and harms of PSA-based screening for prostate cancer and subsequent treatment of screen-detected prostate cancer. The USPSTF also commissioned a review of existing decision analysis models and the overdiagnosis rate of PSA-based screening. The reviews also examined the benefits and harms of PSA-based screening in patient subpopulations at higher risk of prostate cancer, including older men, African American men, and men with a family history of prostate cancer.FindingsAdequate evidence from randomized clinical trials shows that PSA-based screening programs in men aged 55 to 69 years may prevent approximately 1.3 deaths from prostate cancer over approximately 13 years per 1000 men screened. Screening programs may also prevent approximately 3 cases of metastatic prostate cancer per 1000 men screened. Potential harms of screening include frequent false-positive results and psychological harms. Harms of prostate cancer treatment include erectile dysfunction, urinary incontinence, and bowel symptoms. About 1 in 5 men who undergo radical prostatectomy develop long-term urinary incontinence, and 2 in 3 men will experience long-term erectile dysfunction. Adequate evidence shows that the harms of screening in men older than 70 years are at least moderate and greater than in younger men because of increased risk of false-positive results, diagnostic harms from biopsies, and harms from treatment. The USPSTF concludes with moderate certainty that the net benefit of PSA-based screening for prostate cancer in men aged 55 to 69 years is small for some men. How each man weighs specific benefits and harms will determine whether the overall net benefit is small. The USPSTF concludes with moderate certainty that the potential benefits of PSA-based screening for prostate cancer in men 70 years and older do not outweigh the expected harms.Conclusions and RecommendationFor men aged 55 to 69 years, the decision to undergo periodic PSA-based screening for prostate cancer should be an individual one and should include discussion of the potential benefits and harms of screening with their clinician. Screening offers a small potential benefit of reducing the chance of death from prostate cancer in some men. However, many men will experience potential harms of screening, including false-positive results that require additional testing and possible prostate biopsy; overdiagnosis and overtreatment; and treatment complications, such as incontinence and erectile dysfunction. In determining whether this service is appropriate in individual cases, patients and clinicians should consider the balance of benefits and harms on the basis of family history, race/ethnicity, comorbid medical conditions, patient values about the benefits and harms of screening and treatment-specific outcomes, and other health needs. Clinicians should not screen men who do not express a preference for screening. (C recommendation) The USPSTF recommends against PSA-based screening for prostate cancer in men 70 years and older. (D recommendation)

Prostate cancer is the most common intrinsic cancer in men and the 2nd most common cause of cancer related death in men over fifty years of age. The benefit of early screening for prostate cancer is yet to be proven. Multiple organizations currently offer recommendations regarding prostate cancer screening. Prostate Specific Antigen (PSA) testing was introduced into widespread use in the late 80’s and its role in screening is debatable. We surveyed by mail every primary care physician in West Virginia who has a state license. Results from 438 respondents indicated that the American Cancer Society (ACS) guidelines were most commonly used and that PSA testing does seem to be a good screening test. We present the results and discuss the different points of view regarding prostate cancer screening.

Predicting Prostate Cancer in Elderly Men

We thank Drs. Lehrer and Rheinstein for their interest in our study1 and their comments regarding the important topic of prostate cancer screening in healthy older men. They reported estimates of 5-year relative survival among men in the United States with prostate cancer as they age, comparing age ranges of 75 to 79 years, 80 to 84 years, and ≥85 years. Relative survival is defined as the overall survival of patients with prostate cancer divided by the overall survival of a similar cancer-free population.2 It is appropriate to consider a prognosis statistic and compare it with the life expectancy of the patients. However, problems inherent to defining a sufficiently similar cancer-free population (necessary for estimating relative survival) pose challenges to the interpretation of this analysis. The comparison of multiple age groups, including one at the extreme of life expectancy, may introduce additional bias. Nevertheless, the trend reported by the authors is consistent with the results of our study, namely that men with prostate cancer fare worse than those without prostate cancer, and that the older men are when diagnosed with prostate cancer, the worse the prognosis.1 Lehrer and Rheinstein raised concerns that the relative survival rates for men in these older age ranges are not substantially different from the survival probabilities in the United States among all men of those ages. They argued that the comparable percentages across groups are evidence that healthy older men would not benefit from screening. Critically, however, their relative survival estimates did not account for the varying disease stage or aggressiveness of prostate cancer. Our study demonstrated that the absolute incidence of specifically high-risk prostate cancer increased with age among all men in Norway.1 By measuring relative survival using all prostate cancer, Lehrer and Rheinstein have diluted the mortality risk by including men with low-risk prostate cancer. Men with low-risk disease most likely were diagnosed because their physicians thought they were healthy enough to warrant the workup required to diagnose prostate cancer (ie, they were healthier than the normal population).3 The comparable values for SEER*Stat relative survival and life expectancy for the general population suggest that, overall, healthier-than-average older men with above-average life expectancies might lose their survival advantage if they are diagnosed with prostate cancer. The results of our study using Norwegian data indicated that it is men aged 70 to 79 years who have the greatest absolute incidence of being diagnosed with high-risk prostate cancer.1 High-risk disease comprises localized prostate cancers that are curable with definitive treatment but highly prone to becoming metastatic or fatal.4 With a life expectancy of >10 years, a healthy man aged 70 to 79 years could live long enough to develop metastatic disease or die of his cancer. Current National Comprehensive Cancer Network guidelines actually recommend radical therapy for men with high-risk disease whose expected survival is >5 years.5 We do not advocate for the universal screening of older men. Rather, the results of our study1 suggest that older men are among those with the highest incidence of potentially lethal disease. Conversations regarding the pros and cons of screening may be worthwhile for those older men who are healthy enough to benefit from the treatment of high-risk disease. No specific funding was disclosed. Tyler M. Seibert was supported by grant K08EB026503 from the National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health for work performed as part of the current study. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Dr. Seibert also has received grant funding from Varian Medical Systems, past honoraria for providing medical education materials from WebMD Inc, and honoraria from HealthLytix Inc for work performed outside of the current study. Minh-Phuong Huynh-Le reports no conflicts of interest.

Recently, several prospective randomized prostate cancer screening studies have been reported. We report the results of a questionnaire administered to primary care physicians (PCPs) to determine their attitudes on prostate cancer screening and compared these results to those obtained when the same questionnaire was administered to a different large cohort of PCPs in 2006 prior to the reporting of these randomized studies. A 24-item questionnaire designed to assess prostate cancer knowledge and screening attitudes was administered to PCPs within central Florida and those PCPs attending a state conference. Completed surveys were returned and analyzed. All reported p values were two-sided, and those p values less than 0.05 were considered to be statistically significant. Seven hundred and eighty PCPs received the study questionnaire, and 168 (22 %) PCPs returned the completed questionnaire. Sixty-eight percent of responders stated that they recommend prostate cancer screening to >75 % of their patients over the age of 50 years, up from 47 % in 2006 (p < 0.001). Seventy-four percent of responders felt screening was effective. The overall mean score of the knowledge survey was 66 %, which was similar to the cohort from 2006. Knowledge scores were not associated with screening attitudes and behaviors. On multivariate analysis, practice setting and percentage of Medicaid patients in the practice were associated with attitude scores. Our current findings imply that despite the recent landmark studies published on prostate cancer screening, PCPs' screening attitudes have changed minimally over the past 5 years.

At present, increased early detection of prostate cancer appears to be the most feasible way to reduce cancer-related mortality. As a result significant efforts have been made to identify more men with curable cancer. This article reviews the role of serum prostate-specific antigen in an early detection or screening strategy and describes efforts to enhance the specificity of prostate-specific antigen testing.

The heated national controversy about prostate-specific antigen (PSA)–based prostate cancer screening raises important questions about guidelines and patient-centered care. It also suggests opportunities for pathologists and laboratory medicine. Most readers will be familiar with the following background: Since the introduction of the PSA test in the 1970s, it has become one of the most popular preventive care tests in the country. Yet the evidence for reduced mortality attributable to PSA screening is, at best, weak. Two recently published, large, randomized studies reported conflicting results. The European Randomized Study of Screening for Prostate Cancer found a modest reduction in mortality with screening; the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial did not. In addition to the uncertainty regarding benefits, there has also been increasing appreciation of harms attributable to prostate cancer screening. Biopsies and prostatectomies are not benign procedures. Large numbers of patients are required to undergo these procedures with their associated risks of infection, impotence, and incontinence for every one patient whose life may be extended through early detection of a cancer. Accordingly, guideline development organizations, notably including the American Cancer Society and the American Urologic Association, have issued expert opinions recommending that prostate cancer screening should only be entertained in men who might reasonably stand to benefit and who are in a position to make a fully informed choice that incorporates their personal risk/benefit profile with their personal values. These appear on the surface to be very reasonable recommendations, but, in fact, they reflect an almost impossible aspiration in today’s health care environment. A recent study assessed whether primary care physicians could properly interpret basic statistics (mortality and survival time) of hypothetical cancer screening tests to advise their patients. Most could not. How do the American Cancer Society and the American Urologic Association think that patients will make fully informed choices if even their doctors misunderstand the implications of screening test results? Clinical laboratories, like most entities in US health care, are designed primarily for ‘‘cookbook’’ medicine, not personalized medicine. Laboratories and pathologists are paid based on volume, not outcomes, and certainly not based on time spent educating physicians and patients. Physicians and patients are expected to integrate complex, probabilistic data into sound decisions yet, like all humans, are innately, cognitively ill-equipped to do so. Even if physicians and patients could process such data, highquality effectiveness data based on real-world clinical experience isn’t even available for most laboratory tests. The path forward will depend on leadership from pathology. If pathology does not create solutions, other specialty organizations may step up to fill the gaps, to the detriment of the professional status of pathologists. First, we need comprehensive systems of diagnosticinformation support for doctors and patients. Laboratories and pathologists need to move beyond our historic role of simply providing test results and develop ways to communicate results in clinical and probabilistic context. This might include models of risk and benefit that combine available patient-specific data, such as age and history (and, in the future, genomics), together with the results of clinical effectiveness studies to estimate risk and benefit for individual patients. This, in turn, will require a major commitment to measuring clinical effectiveness. Most tests on our laboratories’ menus were initially popularized based on preliminary, clinical correlations, and relatively few have attained high-level clinical evidence to guide their use. Randomized, controlled studies for all diagnostic tests and scenarios may be an impractical goal, but other methods including registry-based studies and health services research can often shine a great deal of light on quantitative, clinical impact. Building such systems will likely require a number of years. Something we can do more quickly is to discontinue Accepted for publication May 25, 2012. Published as an Early Online Release July 16, 2012. From the Department of Pathology and ARUP Laboratories, University of Utah, Salt Lake City. The author has no relevant financial interest in the products or companies described in this article. doi: 10.5858/arpa.2012-0241-ED Reprints: Brian R. Jackson, MD, MS, Department of Pathology and ARUP Laboratories, University of Utah, Salt Lake City, 500 Chipeta Way, Salt Lake City, UT 84108 (e-mail: brian.jackson@aruplab.com).

It is proposed that, through restriction to individuals delineated as high risk, polygenic risk scores (PRSs) might enable more efficient targeting of existing cancer screening programmes and enable extension into new age ranges and disease types. To address this proposition, we present an overview of the performance of PRS tools (ie, models and sets of single nucleotide polymorphisms) alongside harms and benefits of PRS-stratified cancer screening for eight example cancers (breast, prostate, colorectal, pancreas, ovary, kidney, lung, and testicular cancer). For this modelling analysis, we used age-stratified cancer incidences for the UK population from the National Cancer Registration Dataset (2016-18) and published estimates of the area under the receiver operating characteristic curve for current, future, and optimised PRS for each of the eight cancer types. For each of five PRS-defined high-risk quantiles (ie, the top 50%, 20%, 10%, 5%, and 1%) and according to each of the three PRS tools (ie, current, future, and optimised) for the eight cancers, we calculated the relative proportion of cancers arising, the odds ratios of a cancer arising compared with the UK population average, and the lifetime cancer risk. We examined maximal attainable rates of cancer detection by age stratum from combining PRS-based stratification with cancer screening tools and modelled the maximal impact on cancer-specific survival of hypothetical new UK programmes of PRS-stratified screening. The PRS-defined high-risk quintile (20%) of the population was estimated to capture 37% of breast cancer cases, 46% of prostate cancer cases, 34% of colorectal cancer cases, 29% of pancreatic cancer cases, 26% of ovarian cancer cases, 22% of renal cancer cases, 26% of lung cancer cases, and 47% of testicular cancer cases. Extending UK screening programmes to a PRS-defined high-risk quintile including people aged 40-49 years for breast cancer, 50-59 years for colorectal cancer, and 60-69 years for prostate cancer has the potential to avert, respectively, a maximum of 102, 188, and 158 deaths annually. Unstratified screening of the full population aged 48-49 years for breast cancer, 58-59 years for colorectal cancer, and 68-69 years for prostate cancer would use equivalent resources and avert, respectively, an estimated maximum of 80, 155, and 95 deaths annually. These maximal modelled numbers will be substantially attenuated by incomplete population uptake of PRS profiling and cancer screening, interval cancers, non-European ancestry, and other factors. Under favourable assumptions, our modelling suggests modest potential efficiency gain in cancer case detection and deaths averted for hypothetical new PRS-stratified screening programmes for breast, prostate, and colorectal cancer. Restriction of screening to high-risk quantiles means many or most incident cancers will arise in those assigned as being low-risk. To quantify real-world clinical impact, costs, and harms, UK-specific cluster-randomised trials are required. The Wellcome Trust.

Prostate specific antigen screening for prostate cancer: Knowledge of, attitudes towards, and utilization among primary care physicians

Chemotherapy for prostate cancer: small steps or leaps and bounds? No huzzahs just yet!