Introduction What is the rationale for screening? 1 5 In any population screened for cancer, four basic groups of patients exist: those diagnosed with cancer who would not have developed cancer symptoms during their lifetime (overdiagnosis); those diagnosed with cancer at an early stage that might otherwise have led to symptoms and/or the need for more aggressive curative treatment; those diagnosed with cancer at a curable stage with aggressive disease that might otherwise have progressed to metastatic disease at the time of diagnosis; and those whose cancer is diagnosed by screening at the same stage as it would have been diagnosed through clinical routines, and that involves cancers that are too late for curative therapy. Ideally, screening should reduce the number of patients in the fourth group (that cannot be cured), and increase those in the second and third group. The window of opportunity for decreasing cancer-mortality by screening for cancer lies with the second and third group. Randomized clinical trials, considered the gold standard for the evaluation of a screening test, have to show how sizeable the window of opportunity is. The difference between the first group and the second is however not always clear at the time of initial diagnosis. Any screening procedure carries a risk of overdiagnosis and overtreatment, which should be balanced against the benefits for those in which the cancers are diagnosed at a curative stage. Whether this balance is justifiable depends on more than mortality differences of randomized study groups only, but also on quality of life issues measured against the cultural background of the population studied. Incidence Does screening influence prostate cancer incidence? 6 http://www.cancer.gov 7 8 9 10 11 Mortality What happens to prostate cancer mortality by screening and detecting indolent tumors? http://www.cancer.gov 12 14 6 15 16 17 Early diagnosis Screen detected tumors are diagnosed more early Screen detected tumors are not only diagnosed more often, but can be expected more early during their natural course. Lead-time is defined as the time period from detection by a screening procedure to the time of diagnosis in absence of screening due to symptoms. If the patient dies during the lead-time period of the tumor, the lead-time is indefinite and therefore equal to overdiagnosis. 18 19 20 21 22 The natural course of screen-detected cancers 1 23 24 Overdiagnosis Overdiagnosis and overtreatment, what does it mean? During recent years, increased interest has risen to the possibility that increased detection of prostate cancer may lead to the diagnosis of cancers that rather should not have been diagnosed, and certainly should not have been treated, as their detection and subsequent treatment is unlikely to benefit patients, or even might harm them. Related to this, the terms ‘overdiagnosis’ and ‘overtreatment’ are being used. So, when is prostate cancer overdiagnosed? By using the clinical definition of overdiagnosis, that is diagnosing tumors that would otherwise remain clinically unrecognized until the individual died from other causes, it is clear that this definition can only be applied in retrospect in the evaluation of studies. There are currently no clinical or biological parameters that can identify such tumors 100% adequately at the time of diagnosis. By studying the natural course of prostate cancer, and comparing autopsy results with findings from screened populations, clinical and histological parameters can be identified that predict indolent tumors best. Those indolent tumors are likely to be only a subset of the tumors that are overdiagnosed in retrospect. Overdiagnosis is predominantly being associated with early detection or screening programs. Overdiagnosis appears to be especially harmful when it results in invasive treatment of the tumors that would unlikely to be harmful. This is called overtreatment. Overdiagnosis occurs when screening detects small tumors that would otherwise remain clinically unrecognized until the individual dies from other causes. Such tumors are predominantly found in the low PSA ranges. Unfortunately, an unknown number of biologically more aggressive cancers may hide between the larger number of detectable tumors with favorable stages. Though some of the aggressive tumors can be diagnosed by adverse histological criteria such as high Gleason score in the biopsy, some of these features might be missed due to the heterogeneity of prostate cancers and their representation in the biopsy sampling. This might justify the amount of overtreatment that has been practiced in various areas of the world. Overtreatment is thus defined as unnecessary invasive treatment with respect to the outcome of the natural course of the tumor in combination with its host. 22 15 25 25 Informed decision making, reduction of unnecessary prostate biopsies The increasing number of diagnostic procedures and subsequently of prostate cancer diagnosis in various areas of the world is partly fed by an increased awareness of prostate cancer and the anxiety raised of suffering from a devastating disease at the end of life. Men should ask themselves if they are at specific risk for having prostate cancer, and if they want to follow the step wise procedure of PSA testing, urologic investigations, prostate biopsies, and potential treatment. Balanced information regarding this procedure and its consequences should be offered to every man considering prostate testing. Validated information (that is: well understandable text that delivers the information that is required) has been made available in several countries around the world, and it has been shown that such information reduces the number of men who initially wanted to be screened. Based on population data it is possible to provide risk assessments for every step of the screening procedure. Such assessments produce an individual risk calculation based on relevant risk parameters. This might support patients and doctors in their decision to follow or refrain from further steps, dependent on their interpretation of the risk calculated. At the time of cancer diagnosis, it may provide information on the risk of the presence of an indolent tumor, as discussed above. Current risk calculators have incorporated family history, age, micturition complaints, PSA, DRE, TRUS results, and histologic features of the prostate biopsies into their assessment. With an increasing number of relevant parameters, the level of predictive accuracy is enhanced. It is likely that new parameters might be added once tested in population-based biorepositories. Candidate parameters therefore obviously are serum and urine markers for the early diagnostic steps, and histologic markers at the time that biopsies have been taken. 26 27 28 Screening efficiency A small number of studies already have provided evidence that supports strategies to reduce the number of screens in the general population. Such strategies will inevitably lead to the reduction of overdiagnosis of prostate cancer. 29 30 In men who were enrolled onto a cardiovascular study in Sweden, 21,277 men aged <50 years old were assessed over a period of more than 20 years starting between 1974 and 1986. Two decades later, 498 (2.3%) were eventually diagnosed with prostate cancer (outside a structured screening procedure). In retrospect, the level of serum kallikreins (hK2, total PSA, and free PSA) at baseline and thereafter were strongly associated with emerging prostate cancer. This supports the idea of risk stratification for screening on prostate cancer in an early age, that is during the fourth decade of life. Men at low risk may refrain from frequent serum testing for long periods of time based on their individual risk assessment that incorporates the information obtained from currently available and newly validated parameters. Overtreatment Side effects of treatment are substantial Treatment for prostate cancer may involve surgery, external beam radiation therapy, brachytherapy, high intensity focused ultrasound (HIFU), watchful waiting, active surveillance, chemotherapy, cryosurgery, hormonal therapy, or combinations. The most frequently applied treatments for organ confined prostate cancer are radical prostatectomy, external beam radiotherapy and brachytherapy. 31 33 32 32 34 35 37 It is obvious that invasive treatment may influence the quality of life of men with prostate cancer and their families substantially. But so does a potential threat of prostate cancer that is not actively treated or not even diagnosed yet. It is unlikely that quality of life studies will be able to indicate the best balance between these points of view for management decisions on an individual patient level. Active surveillance as alternative to invasive treatment 38 Risk stratification for indolent disease 39 40 41 Conclusions It is still too early to say whether population-based prostate cancer screening is a useful tool with regard to cancer mortality. We must wait until the results of ongoing prostate cancer screening trials are available. Until then, opportunistic screening should not be encouraged and those men who do want a PSA test should participate in carefully designed, balanced information program. Even if PSA screening is found to reduce prostate-cancer-specific mortality, levels of overdiagnosis may remain unacceptable for population-based screening. To reduce overdiagnosis in a screening setting, markers are needed that reduce the risk on a positive prostate biopsy, increasing the specificity of this procedure. Men from the age of forty, as well as their advising doctors, need instruments to reduce their doubts and anxiety of the potential presence of a prostate cancer. This, together with balanced information about the benefits and risks of the individual outcome of screening procedures, might induce a more selective and step-wise screening action. Risk assessment, incorporating the main determinants known for the presence of prostate cancer from the age of 50, such as age, family history, and micturition complaints, should form the base of an individual screening approach. Objective values of serum markers might enhance the accuracy of such of risk predictors. 42 Until alternative screening tools are found, PSA will continue to be used, and overdiagnosis will remain an unavoidable drawback of prostate cancer screening. The current challenge is to ensure that in the still growing numbers of men diagnosed with prostate cancer world-wide, overdiagnosis does not result in overtreatment. To this end, research efforts presently focus on clarifying which cancers can be managed through active surveillance.