Prostate cancer screening: clinical applications and challenges

Transcription

1 Urologic Oncology: Seminars and Original Investigations 22 (2004) Seminar article Prostate cancer screening: clinical applications and challenges Otis W. Brawley, M.D.* Winship Cancer Institute, Emory University School of Medicine and Emory Rollins School of Public Health, 69 Jesse Hill Jr. Drive, Atlanta, GA 30303, USA Abstract Prostate cancer is a serious illness warranting appropriate screening measures. However, current screening tests that include prostate-specific antigen and digital rectal examination must be proven to save lives to be considered truly legitimate and appropriate public health tools. Even though these tests are associated with the diagnosis of disease, important questions remain as to how well these tests identify all disease and whether screening leads to interventions that save lives. Prostate cancer is undoubtedly a killer, yet there appear to be large numbers of detectable prostate cancers that are of little threat to life. Some men with this grade of cancer receive curative treatment, even though their disease does not require treatment. Some studies suggest that more than three of four men with screen-detected localized disease may not need treatment. One of the great challenges of cancer communications is how to convey the hope of prostate cancer screening while adequately acknowledging the boundaries of our knowledge. The current absence of an appropriate informed consent tool points to the necessity to develop an easy to understand informed consent that allows men to evaluate screening decisions with a clear understanding of what is known, what is not known, and what is believed to be true about prostate cancer screening Elsevier Inc. All rights reserved. Keywords: Prostate; Cancer; PSA; DRE; Overdiagnosis; PCPT Introduction Prostate-specific antigen (PSA) is approved by the US Food and Drug Administration for diagnosis and monitoring of prostate cancer [1]. The concept of a diagnostic test is different from that of a screening test. Diagnostic tests are used in patients for whom there is a suspicion of disease, whereas screening tests are used in asymptomatic individuals for whom there is a low suspicion of disease. It is estimated that more than a third of men older than the age of 50 have lower urinary tract symptoms. It is fair to say that the distinction between a diagnostic test and a screening test is blurred in the clinical application of PSA for prostate cancer testing. A good screening test should be convenient to use, inexpensive, and aimed at a disease that is a major problem. In addition, it should identify a disease for which an intervention saves lives. Screening tests should have high specificity, although extremely high sensitivity is not required Supported in part by Grant Number P60MD from the National Center for Minority Health and Health Disparities of the NIH and by a gift from the Georgia Cancer Coalition. * Corresponding author. Tel.: ; fax: address: otis_brawley@emoryhealthcare.org (O.W. Brawley). [2]. Specificity is a measure of the ability of a test to correctly identify persons without disease. Sensitivity is a measure of the ability of a test to correctly identify persons with disease. Sensitivity and specificity are relatively independent of the underlying prevalence (or risk) of the population screened. However, the positive and negative predictive values are highly dependent on the prevalence of the disease in the screened population. The positive predictive value is the proportion of positive identifications in the screening test for patients who actually have the disease; similarly, the negative predictive value is the proportion of negative identifications in the screening test for patients without disease. Screening is most beneficial, efficient, and economical when used to target cancers common to the general population or populations with a high prevalence (or high risk) for the specific disease being screened. PSA and digital rectal examination (DRE) fulfill several of the criteria to be considered a good screening test because they are convenient, relatively inexpensive, and directed at a major clinical problem. However, in many respects, PSA and DRE are mediocre screening tests. Most notably, these screening tests have not been proven to fulfill the most important criterion of a good screening test: to identify aggressive disease at a time when intervention saves lives. In addition, results from a cohort study indicate that these /$ see front matter 2004 Elsevier Inc. All rights reserved. doi: /j.urolonc

2 354 O.W. Brawley / Urologic Oncology: Seminars and Original Investigations 22 (2004) tests are not highly specific or very sensitive. Although the precise sensitivity and specificity of PSA and of DRE or the two combined are unknown, the sensitivity of the two combined in this cohort study was determined to be approximately 46%, with a specificity of roughly 90% at a PSA threshold of 4.0 ng/ml [3]. A successful screening test is best performed on men who are at risk for the disease. In the case of prostate cancer, the median age of an American man dying from the disease is 78. Thus, prostate cancer is essentially a disease affecting older men. Few men are diagnosed in their forties, and less than 20% of prostate cancers are diagnosed among men younger than 65 years of age. Because prostate cancer is a disease that primarily affects older men, some critics point out that the total number of years of life lost to prostate cancer deaths is far less than that for many other diseases [4]. This argument has been used to support testing for other very significant diseases for which screening has been shown effective such as colon cancer. The effects of PSA and DRE The effects of prostate cancer screening have been studied and documented. The question Does prostate cancer screening ultimately save lives? remains a legitimate and unanswered question. Studies clearly demonstrate that prostate cancer screening identifies disease and raises incidence rates. For example, when incidence rates in the United States and the United Kingdom are compared demographically, results shows that much of the rise of incidence in the United States is the result of the effects of increased screening, as opposed to the United Kingdom, a country with significantly less screening than the United States. Interestingly, the mortality rates in these two countries are very simila,r and both countries had significant declines in mortality throughout the 1990s [5]. The United States is a country of diverse medical practices that are sometimes reflected in disparate incidence rates of disease. For instance, disparate incidences with almost identical mortality curves have been found in the United States. Throughout the 1990s, the prostate canner incidence rate in the Seattle metropolitan area was considerably higher than in the state of Connecticut. Lu-Yao and colleagues [6] found that in comparison to men in Connecticut, men in the Seattle metropolitan area underwent more intensive screening for prostate cancer. As a result of aggressive screening, more men in the Seattle metropolitan area received intensive treatment with radical prostatectomy and external beam radiotherapy, compared to men in Connecticut. In addition, prostate cancer specific mortality was essentially identical over a decade of follow-up. Similar disparities have been reported in other countries. Bartsch and colleagues [4] compared two different areas of Austria: one area where aggressive PSA screening (without DRE) was followed by well-controlled highquality treatment compared with a second area where very little screening was performed. They found a marked decline in mortality in the area with intensive screening and treatment. These population studies (both the negative and the positive) must be interpreted cautiously [7]. For example, Labrie and colleagues [8] published results of a screening trial that was initially interpreted as showing that screening saves lives. When the published data were reanalyzed by intent to screen, prostate cancer screening was correlated with a 16% increased risk of death (RR 1.16) [9]. This suggests that the Quebec study suffered from substantial selection biases [10]. A well-controlled randomized prospective study is the only definitive method to demonstrate that screening saves lives. To date no well-designed study has been completed. The US National Cancer Institute and a European collaborative are currently conducting such trials for prostate cancer. These two clinical trials will hopefully provide answers within the next several years [9,11]. Observations from the placebo arm of the recently completed Prostate Cancer Prevention Trial (PCPT) demonstrate the myriad of problems that trouble prostate cancer screening. In this study, men with a median age of 62 years, normal DRE and a serum PSA 3 ng/ml were randomized to daily finasteride [4-azaandrost-1-ene-17-carboxamide,N- (1,1-dimethylethyl)-3-oxo-,(5a,17b)] or placebo [12]. During the 7 years on placebo, 571 (12.2%) of 4692 men completing the trial were diagnosed with a prostate cancer after detection of abnormal PSA or DRE. About half the men were diagnosed because of an abnormal serum PSA and roughly half because of an abnormal DRE. Of those men completing 7 years with a normal serum PSA and DRE who consented to prostate biopsy, 576 (12.2%) of 4692 men were found to have prostate cancer. The PCPT may provide the best estimate of the sensitivity and specificity of the PSA, DRE, and the combination. These data have not yet been published. The results of the PCPT suggest that large numbers of screened men are diagnosed with cancers that do not require treatment. This is commonly referred to as overdiagnosis [13,14]. Overdiagnosis also is illustrated by the differing incidences and similar mortality rates demonstrated in the population comparisons of the United States and United Kingdom and in the population comparisons of metropolitan Seattle and Connecticut. The National Cancer Institute Probability of Developing or Dying of Cancer Software (DEVCAN) provides a statistical estimate of cancer risk [15]. Using the Surveillance, Epidemiology, and Ends Results Program (SEER) data, it is estimated that 3.58% of American males who do not develop prostate cancer by age 60 will ultimately die of the disease (95% CI, 3.51 to 3.65). Men in European countries that are not aggressively screened or treated for localized prostate cancer have very similar risks of death [5]. If the results of PCPT s placebo arm

3 O.W. Brawley / Urologic Oncology: Seminars and Original Investigations 22 (2004) were widely applied to the US population older than age 60, less than 4% would die of prostate cancer yet more than 24% of men would have detectable disease. Clinically significant disease, meaning disease of risk to the patient s life, is a distinct subset of clinically diagnosable disease. Although more than 24% of men completing the placebo arm of the PCPT were diagnosed with prostate cancer, if one uses an intent-to-treat analysis, the percentage of the 9000 men enrolled on the placebo arm diagnosed prostate cancer is greater than 12%. The intent-to-treat analysis suggests that overdiagnosis occurred in two of three men diagnosed with prostate cancer. If one looks only at men completing the trial, overdiagnosis occurs in seven of every eight men. Overdiagnosis of prostate cancer is a cause for great concern because treatment of screen-detected cancers can cause morbidity, such as impotence and urinary incontinence, and carries a small risk of death. Also troubling was the finding that a large proportion of men with high-grade disease exists whereas less than 4% of men are expected to die from their disease. Consider that 6% of all men completing the trial on the placebo arm have Gleason 7 or greater disease; this finding puts the prognostic significance of Gleason grading to question. Recognizing that half of all prostate cancers were missed during 7 years of annual screening and found at the end of study biopsy, the usefulness of the PSA and DRE for prostate cancer screening is open to question in terms of their ability to detect disease. Age-adjusted PSA cut-offs and changes in PSA over time have been suggested to improve the sensitivity and specificity of PSA screening. Further analysis of PCPT data may establish a better cut-off value. However, in the near future, those who believe in early detection of prostate cancer might forego PSA screening and simply choose to get a prostate biopsy. Although it is possible that PSA and DRE screening will be found to save lives, it may also be that the overdiagnosis and resultant overtreatment has such a negative effect on overall quality of life as to outweigh the benefit, hence the need to find ways of predicting those tumors that require therapy and the need to find treatments with fewer sideaffects. Recommendations of expert organizations Prostate cancer screening is common in the United States despite the recommendations of most expert organizations that advise against its use, or state the lack of sufficient evidence to advocate its use. Most recently, the US Preventive Services Task Force examined the evidence in support of prostate cancer screening and found there was insufficient evidence to recommend its use [16]. Other expert organizations have assessed the evidence and issued public statements that do not endorse screening [9]. These include the American College of Physicians, American Society of Internal Medicine, American Academy of Family Physicians, Canadian Task Force on the Periodic Health Examination, Canadian Urology Association, International Union against Cancer, Medical Research Council of the United Kingdom, and the Medical Research Council of Australia. The American Cancer Society and the American Urologic Association recommend that screening be offered to normal-risk men, older than 50 years of age, and that they be allowed to make a choice after being informed of potential risks and benefits of screening and treatment [17]. Each of these organizations has provided a statement recognizing that while prostate cancer screening has associated harms, screening might still save lives. Although some of these organizations are more optimistic than others that screening will save lives, all professional organizations advise against mass screening also known as opportunistic screening because of the widely accepted public health principle that a screening procedure should not be implemented without proof of net benefit. Ethics and informed consent The racial disparity in prostate cancer is well documented. American men who identify themselves as black have a 2.42 times increased death rate, compared to men who identify themselves as white (73 per 100,000 compared to 30.2 per 100,000 age adjusted to the 2000 standard) [18]. Increasing recognition of the overall disparity in health between blacks and whites has led to increased attention to the disparity in prostate cancer. This disparity has often been used to justify screening, even if not yet proven to save lives. The mantra has been, We have to do something! Recent studies demonstrate that increased public awareness has led to earlier detection and a shift toward lower stage of prostate cancer at diagnosis. The increased rate of pathological organ confined disease is translating into improved disease-free survival rates. These early data suggest that the survival gap in black and white American men is narrowing and may become statistically insignificant [19]. In addition, black and white prostate cancer patients appear to have similar rates of PSA progression after undergoing radical prostatectomy [20]. Although these findings appear positive, they fail to definitively prove that screening for prostate cancer saves lives. Screening bias, especially the form of length bias known as overdiagnosis, could still lead to an appearance of benefit when there is none. For example, the apparent increase in survival rates of black men may be the result of increased screening efforts that are leading to increased diagnoses of indolent prostate cancers; these are black men who did not need treatment for a disease that would never have threatened their health. In the United States, individual and mass screening for

4 356 O.W. Brawley / Urologic Oncology: Seminars and Original Investigations 22 (2004) prostate cancer is widely advocated. Screening is highlighted in the mass media and encouraged by celebrities on a paid or voluntary basis. This widespread advocacy is in contradiction with the majority of expert medical organizations in the United States that have published statements that either recommend against screening or state the lack of sufficient evidence to justify recommending its use [16]. Not surprisingly, many patients become confused when they hear messages encouraging screening and then learn that the value of screening is still open to question. This presents a challenge. The fact that large numbers of black men are suspicious of American medicine is well documented. The fact that black men fear they will be taken advantage of or experimented upon, stems from the fact that in many cases, the American medical establishment disrespected blacks, used blacks, and indeed abused blacks [21]. Some blacks correctly fear that the well meaning may not fully understand what they advocate. For black men aware that most medical organizations do not recommend screening and even speak of the harms associated with screening, the unbalanced pro-screening messages confirm their suspicions of foul play. This suspicion and its confirmation may even cause some Black men to avoid seeking required non-urologic treatment [22]. When offered by healthcare providers, the provision of mass prostate cancer screening can become an ethical dilemma. Consider the facts that the number of abnormal screens and the number of cancers can be estimated with good precision. The proportion that will be treated by the various modalities is also predictable [23]. This means that by offering screening to one thousand men older than the age of 50, one can provide a reasonable estimate of the profit, but no one can estimate the number of lives saved, because no one knows if any lives will be saved. Summary One of the great challenges of cancer communications is how to convey the hope of prostate cancer screening while adequately respecting and disclosing the boundaries of our knowledge. Unfortunately, many advocates of prostate cancer screening are either not aware of or not willing to accept these limitations. Given the current state of knowledge, it is reasonable to accept screening; it is also reasonable to avoid it. For these reasons, a tremendous need exists to develop an easy to understand informed consent tool that allows a man to understand what is known, what is not known, and what is believed about prostate cancer screening. Prostate cancer screening is prone to lead-time bias, length bias, and overdiagnosis. Although PSA and DRE screening clearly detect many asymptomatic cancers, screening also misses many cancers. Many diagnosed cancers are of no threat to a patient. The ability of these screening tests to reliably identify tumors that could be lethal, but are still curable, is limited. In addition, the morbidity and uncertain efficacy of treatments for localized disease presents a significant limitation to screening efficacy. A significant goal of our research agenda should be to distinguish the cancers that are a threat to a patient from those cancers that are of no threat. References [1] US Preventive Services Task Force. Screening for prostate cancer: recommendation and rationale. Ann Intern Med 2002;137: [2] Kramer BS, Brawley OW. Cancer screening. Hematol Oncol Clin North Am 2000;14: [3] Gann PH, Hennekens CH, Stampfer MJ. A prospective evaluation of plasma prostate-specific antigen for detection of prostatic cancer. JAMA 1995;273: [4] Bartsch G, Horninger W, Klocker H, et al. Prostate cancer mortality after introduction of prostate-specific antigen mass screening in the Federal State of Tyrol, Austria. Urology 2001;58: [5] Shibata A, Ma J, Whittemore AS. Prostate cancer incidence and mortality in the United States and the United Kingdom. J Natl Cancer Inst 1998;90: [6] Lu-Yao G, Albertsen PC, Stanford JL, Stukel TA, Walker-Corkery ES, Barry MJ. Natural experiment examining impact of aggressive screening and treatment on prostate cancer mortality in two fixed cohorts from Seattle area and Connecticut. BMJ 2002;325:740. [7] Oliver SE, May MT, Gunnell D. International trends in prostatecancer mortality in the PSA ERA. Int J Cancer 2001;92: [8] Labrie F, Candas B, Dupont A, et al. Screening decreases prostate cancer death: first analysis of the 1988 Quebec prospective randomized controlled trial. Prostate 1999;38: [9] Boyle P. Screening for prostate cancer: have you had your cholesterol measured? BJU Int 2003;92: [10] Alexander FE, Prescott RJ. 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Washington, DC: National Cancer Institute, [16] Harris R, Lohr KN. Screening for prostate cancer: an update of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 2002;137: [17] Smith RA, Cokkinides V, Eyre HJ. American Cancer Society guidelines for the early detection of cancer, CA Cancer J Clin 2003;53: [18] Reddy S, Shapiro M, Morton R Jr, Brawley OW. Prostate cancer in black and white Americans. Cancer Metastasis Rev 2003;22:83 6. [19] Bianco FJ Jr, Wood DP Jr, Gringo DJ, Sakr WA, Pontes JE, Powell IJ. Prostate cancer stage shift has eliminated the gap in disease-free

5 O.W. Brawley / Urologic Oncology: Seminars and Original Investigations 22 (2004) survival in black and white American men after radical prostatectomy. J Urol 2002;168: [20] Banerjee M, Powell IJ, George J, Biswas D, Bianco F, Severson RK. Prostate specific antigen progression after radical prostatectomy in African-American men versus white men. Cancer 2002; 94: [21] Brawley OW. The study of untreated syphilis in the negro male. Int J Radiat Oncol Biol Phys 1998;40:5 8. [22] Brawley OW. Prostate cancer and black men. Semin Urol Oncol 1998;16: [23] Bubolz T, Wasson JH, Lu-Yao G, Barry MJ. l: Treatments for prostate cancer in older men: Urology 2001;58: