Prostate Cancer Screening

> Epidemiology

Prostate cancer (PC) is a major public health problem worldwide, being the second most common cancer and the fifth leading cause of cancer death in men. It is the most common cancer in men, in more than half of the countries (105 out of 185) and the leading cause of cancer death in men in 46 countries. The highest rates are observed in the Caribbean.

Mortality from CP has decreased in many countries due to screening, early detection, and advances in treatment in developed countries but is increasing in several countries (e.g., Central and South America, Central and Eastern European countries). East, many Asian countries) possibly due to changes in risk factors, a more Westernized lifestyle and limited access to treatment.

Localized CP is asymptomatic . By the time symptoms occur, the disease is usually too advanced to cure.

In fact, one of the most common presentations before the advent of screening was paralysis, related to spinal cord metastases. Therefore, the concept of screening is particularly attractive for PC because it provides the opportunity to identify the disease at a curable stage.

Research into a test that could detect PCa earlier led to the development of the prostate-specific antigen (PSA) blood test, first isolated and defined in the 1970s. Several screening studies conducted in the late 1980s and early The 1990s showed that PSA testing could identify more PC confined to an organ, clinically localized stage compared to evaluations of tumors palpable by digital rectal examination, which laid the foundation for widespread adoption of PSA testing, which resulting in a rapid increase in the incidence of CP.

There is level 1 evidence for PSA screening from large-scale randomized controlled trial studies, which compared regular PSA testing of men aged 50-70 years, every 2-4 years without screening. The European Randomized Study of Screening for Prostate Cancer (ERSPC) reports a reduction in mortality from PC of 20% in 16 years of follow-up in favor of detection. In this follow-up, the number needed to invite screening to prevent 1 CP death is 570, and the number needed to diagnose is 18.

The corresponding estimates from the Swedish Goteborg-1 trial, with 18 years of follow-up, are a reduction in CP mortality of 35%. To prevent 1 PC death at age 18 years, the number needed to invite screening was 231, and the number needed for diagnosis was 10.

In contrast, at 17 years of follow-up in the US Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Tria there was no significant difference in PCa mortality between the screening arm compared to the usual care arm. However, this has been attributed to a high degree of contamination of PSA testing in the usual care group, with more than 50% of patients randomized to no screening but nevertheless undergoing PSA testing.

Statistical models have been used to reconcile differences in implementation and settings and have reported that both trials provide evidence consistent with screening reducing CP mortality, estimated at 25%–31% in ERSPC and 27%–32% in PLCO, respectively. Similarly, there is well-documented evidence from large prospective observational studies regarding the prognostic utility of measuring a man’s baseline PSA level in midlife to determine subsequent risk of life-threatening PCa in the future.

Peak age-specific PC mortality rates in the US have been reduced by 50% due to PSA testing and improvements in treatment, but recently this trend has flattened due to recommendations against screening with PSA in previous years, primarily from the 2012 US Preventive Services Task Force. Studies now document a recent increase in PCa metastases.

PSA testing can have several beneficial effects. Most men have a “normal” PSA value , below the cutoff for further evaluation, and up to 97% of men report some comfort with testing. Screening can reduce a man’s risk of developing metastatic PC and dying from the disease.

For every CP death prevented, life is lengthened by an average of 8 years.

However, screening can also induce many unwanted effects, including the anxiety of false-positive PSA tests and the complications of further investigation with prostate biopsy, including hospitalization for infectious complications or proctorrhagia.

The greatest harm of the PSA test is overdiagnosis , that is, the diagnosis of indolent, slow-growing CP, which would otherwise go undiagnosed during a man’s lifetime. Indolent disease is defined in terms of the grade of the cancer. Gleason score 6, also called grade group 1, is a low-grade cancer that does not require immediate treatment .

High-grade disease , for which therapeutic action should be considered, is defined as a Gleason score ≥7 (grade group 2). Overdiagnosis turns healthy men into patients, which can affect psychological well-being and quality of life. More importantly, over the past 2 decades, in the US the majority of men at low risk for CP underwent treatment with surgery and radiation. Such overtreatment has no (or almost no) benefit, in terms of mortality reduction but leads to significant and persistent side effects, most notably, urinary and erectile dysfunction.

In recent years, there has been a big change in therapeutic trends. More than half of men with low-risk disease are now recommended so-called active surveillance as the first management option, that is, careful monitoring with repeated tests and examinations and a switch to curative treatment in case of signs of progression of the illness.

Avoiding overtreatment of indolent cancer is crucial because active treatment with surgery, radiation, or focal ablative therapies can have a significant impact on quality of life. Many years after treatment with radical prostatectomy or radiotherapy for favorable-risk PCa, significant deterioration still persists, in a substantial proportion of men in one or many functional domains: sexual, urinary (incontinence), and bowel.

Modeling the lifetime effects of annual PSA testing between ages 55 and 69 vs. without detection, Heijnsdijk et al. estimated a 23% loss of life years gained with screening, mainly due to deterioration in quality of life due to long-term side effects of treatment.

The guidelines agree on recommending shared decision-making before starting screening, and that the age range for screening should be between 45 and 70 years. There is little variation in the age of onset (45-55) and in the criteria for an upper age limit. The proposal to perform the screening described in the clinical care guidelines in a later discussion is based on the recommendations of the Memorial Sloan Kettering Cancer Center, but they are similar to those of other groups.

In a subsequent discussion, the authors propose 7 steps for primary care physicians, based on the following principles:

1) Primary care is pressed for time and the doctors who provide care there cannot be expected to have in-depth knowledge of the subspecialty. Therefore, the goal is to make the decision making shared and the subsequent detection algorithm relatively simple. 

2) Ensuring that PSA screening, rather than harm, is primarily a matter of making sure it does as little harm as possible. The recommendations reflect a “harm reduction” approach . 

3) , since there is great variability within urology regarding adherence to practice guidelines, the authors engage primary care physicians to verify that the urologists to whom they refer patients are participating in the best practical way ( described in points 5, 6 and 7).

   1. Obtain consent for prostate cancer screening, preferably using the “Simple Scheme”

PC screening is a preference-sensitive decision with important consequences. As such, it is essential to obtain informed consent from patients after shared decision making. Although this generally only needs to be done once, informed consent is required to enter into a screening regimen, not for each and every PSA test, but there are valid concerns regarding the time required given the limitations on a very busy primary care practice.

Some guidelines recommend practices that are difficult to implement, such as one in which patients are informed of 16 separate PSA-related facts and asked 12 questions about their preferences. The authors developed what is known as the “Simple Schema” for primary care physicians, which requires no knowledge beyond what would be expected of any primary care physician, is brief, and focuses on harm reduction.

The critical step is to warn patients about the risk of PSA testing identifying low-risk disease and the need to avoid aggressive treatment in these cases. It is essential to place emphasis from the beginning on active surveillance as an optimal management strategy for low-risk disease.

A common question among primary care physicians is whether they should more strongly endorse PSA testing for men at higher risk, such as African Americans or those with a family history or genetic disposition.

In summary , there is no reason to think that the benefit-harm ratio of PSA testing varies enough for higher-risk groups to mandate screening. Furthermore, attempts to tailor PSA screening based on genomic risk, known as “polygenic risk scoring,” have not shown clinical utility for population screening.

    2. The PSA test is only for healthy men aged 45 to 70.

It is widely known that the introduction of PSA testing has led to widespread overdiagnosis. What is less recognized is that overdiagnosis is highly age-dependent. In fact, almost half of the overdiagnoses associated with the introduction of PSA testing occurred in men >70 years of age. Critically, PSA testing is of doubtful value in men <70 years: the risk ratio for mortality from PC in >70 years reported by the ERSPC is 1.18, i.e. probably no benefit and at most about a 20% reduction in the risk of death from CP. Therefore, stopping screening at age 70 will have a large effect on overdiagnosis with little or no effect on mortality.

Note that stopping screening means that PSA testing has generally been discouraged in asymptomatic men >70 years of age with PSA levels in the normal range (<3 ng/ml). The follow-up of men >70 years old with PSA levels >3 ng/ml depends on clinical criteria, taking into account age and general health, which would be “PSA surveillance.”

Also note that it is reasonable to abandon screening before age 70 in men with significant comorbidities or to continue screening 1 year after age 70 in men with exceptional health. Taking into account that the indicated age for the start of screening is 45 years, but not earlier, it is possible to identify a subgroup of men who are at significant risk of morbidity or mortality from CJP within 10 years.

The yield is relatively low, that is, very few young men have an elevated PSA, and some specialists have therefore made the reasonable suggestion that screening begin at 50, on the basis that this is the lowest age included in the randomized ERSPC trial.

On the other hand, because younger men have a longer life expectancy, they will lose a greater number of quality-adjusted years of life to cancer-related death and are at low risk for overdiagnosis. It has also been shown that, because PSA is a much stronger predictor of CP-specific mortality than race or family history, the age at the start of screening should be the same for virtually all men.

   3. Remind the frequency of screening based on PSA level and discontinue screening in men >60 years of age unless PSA is above the median (1 ng/ml).

PSA is not only diagnostic of current PC risk but also highly predictive of future risk. On the other hand, because CP is generally slow, screening intervals can increasingly be extended, safely, for men with low PSA. There is clear data that men with a low PSA are very unlikely to develop aggressive CP within 8 to 10 years. This finding has led to the “traffic light” algorithm as follows:

• PSA <1 ng/ml: green light. Repeat the PSA at an interval of 8 to 10 years.
• PSA 1 to 2.99 ng/ml: amber light: Repeat PSA every 2 to 4 years.
• PSA 3 ng/ml: red light. Consider further studies.

90% of PC deaths at age 85 occur in men with PSA above the median of 1 ng/ml at age 60. It has also been shown that men with low PSA who continue testing are at some risk of overdiagnosis but receive no mortality benefit compared to stopping screening. Therefore, men with PSA <1 ng/ml at age 60 should discontinue screening.

    4. For men with elevated PSA (≥3 ng/ml), repeat the PSA.

Many men will experience a temporary rise in PSA related to a benign disease . For example, in a landmark JAMA article, 44% of men with PSA >4 and 40% of those with PSA >2.5 returned to normal PSA within a year. A typical recommendation is that the PSA should be repeated 4-6 weeks after an abnormal PSA.

    5. Use secondary tests, such as markers or images before the biopsy, or refer to the urologist who does it

Only a small proportion of men with a moderately elevated PSA will have the type of high-grade CP that is important to identify. Typically, for every 100 men with PSA >3 ng/ml, nearly 70%, 20%, and 10%, respectively, will have benign disease, low-grade (indolent) PC, and high-grade cancer.

There are now a wide variety of secondary tests available to determine which men with an elevated PSA should undergo a prostate biopsy. These secondary tests, which include biomarkers as well as multiparametric MRI, have been shown to reduce both unnecessary biopsies and overdiagnosis of indolent disease.

Some of these tests can be implemented in the primary care setting. For example, BioReference Laboratories offers a combination test for PSA, meaning when a PSA test is selected, the blood sample is automatically checked for the 4Kscore if the PSA is elevated. However, in most cases, secondary tests, particularly MRI, are ordered by the urologist. As such, it is incumbent upon the primary care physician to be associated with a urologist who takes a conservative approach to biopsy, incorporating secondary testing and only performing biopsy in men at high risk for high-grade PC.

    6. Refer only to urologists who recommend active surveillance for almost all patients with low-grade cancer .

The greatest harm of the PSA test is overtreatment, with consequent urinary, sexual and intestinal dysfunction. Guidelines suggest that treatment should be restricted to men with high-grade disease.

Men with Gleason score 6 (grade 1 group) should be managed conservatively, with an approach known as active surveillance, which involves PSA monitoring, periodic repeat biopsies, and late intervention for men who progress to grade 1 disease. ≥2. However, rates of active surveillance vary greatly between different practices: in 1 study, the proportion of low-risk men under active surveillance ranged from 25% to 80%.

As a result, the urologist chosen by the primary care physician must take not only a conservative approach to biopsy but also a conservative approach to treatment. The primary care physician needs to ensure that the urologist considers active surveillance before the biopsy and recommends active surveillance for all, or almost all, men with Gleason score 6 (grade group 1).

7. Refer preferably to urologists from the main academic centers.

The volume-outcome relationship is one of the most replicated findings in anti-cancer drugs. In summary, both the chance of cure and the chance of side effects are strongly correlated by provider volume. In 1 study, the risk of PC recurrence was almost half as great for surgeons with 250 radical prostatectomies vs. those who only had experience of 10 previous cases. As such, primary care physicians should recommend that patients requiring treatment for their CP, patients with disease group grade 2 or higher, should be treated at a high-volume center.