Prostate cancer screening

Benefits of screening with PSA, digital rectal examination unknown as there has been no comprehensive assessment of the trade offs between benefits and risks (2009).

In the US a PSA level of 4.0 ng/mL is the generally excepted threshold at which recommended prostate biopsy occurs.: In Europe, this cut off is 3 ng.

In the Prostate Cancer Prevention Trial prostate cancer was detected in 15.2% of men whose PSA levels remain below 4 ng throughout a seven year trial and then 6.6% of men with a level of 0.5 ng or lower at the end of the trial.

The Physicians Health Study showed a cumulative risk of lethal prostate cancer of only 0.3% through 15 years among men 55 to 59 years of age with the baseline level of PSA below the median of 1 nanograms per milliliter.

The widespread use of PSA testing has led to the overdiagnosis and treatment of the indolent prostate cancer, resulting in significant morbidity, health care costs and questionable survival benefits.

Observational studies have revealed conflicting results in relation to benefits of such screening.

The high rate of overdiagnosis is the main obstacle to the recommendation of population based screening for prostate cancer.

Screening results in substantial overdiagnosis, which is defined as the identification of a case of prostate cancer that would not otherwise have been diagnosed during a patient’s lifetime without such screening.

Studies suggest the 23 to 42% of prostate cancers detected by screening are overdiagnosed.

The cause of overdiagnosis is the high prevalence of small, low-grade prostate cancers in the adult population; approximately 50% of men older than 60 years of age have such tumors.

Subclinical prostate cancer is common in men of greater than 50 years age.

The median age of death due to prostate cancer is 80 years, compared with 72 for lung cancer and 68 for breast cancer: the combination of a high burden of other risks of death and high rates of intervention related complications combines to limit any reduction in all-cause mortality offered by screening.

PSA screening of approximately 19 million men annually, results in more than 1.3 million biopsy procedures and 240,000 diagnoses of prostate cancer.

Screening should not occur among elderly man and those with limited life expectancy because screening does not provide a significant survival benefit within 10 years.

Of  patients who undergo radical prostatectomy is found it patients age greater than 70 years are more likely to have a higher grade in stage of disease and worse survival compared with individuals 70 years or less.

Estimated range of over diagnosis range from 10-36% when defined as detection of clinically insignificant cancers (Loeb S, Postma, R), and 36-50% with the findings the detection of cancers that would have otherwise remained undetected during the patient’s lifetime (Draisma G), and 84% when defined as detection of non-lethal cancer (McGregor M).

In the Prostate Cancer Intervention versus Observation Trial (PIVOT) patient’s were randomized to warchful waiting versus radical prostatectomy with prostate cancer: after a median follow up of over 10 years there is no significant benefit from prostatectomy in patients with the mean age of 67 years.

Autopsy studies of men dying from trauma indicated that pathologic findings of prostate cancer is roughly the decade of life minus 10-30% men aged 40-49, 50% of men in their 60s, and 70% in men in their 80s, and many of these cancers were small and unlikely to be diagnosed (Sakr WA et al).

U.S. Preventative Services Task Force recommends that men aged 75 years or older should not be screened, and younger men should carefully weigh risks and benefits of such screening.

It is felt that little or no benefit of treatment for prostate cancer detected by screening in those aged 75 years or older.

Early detection screening not recommended for men with a life expectancy of less than 10 years.

An adult male has a lifetime risk of diagnosis of 16.4%, and the lifetime risk of dying of only 2.7% (Alterkruse SF et al).

African American adult males have a lifetime risk of diagnosis of 19.6% and the lifetime risk of death of 4.7%.

American Cancer society recommends annual prostate cancer screening with PSA and digital rectal examination should begin at age 50 years.

American Urological Association suggests early detection of and risk assessment for prostate caner to all asymptomatic men at age 40 years with an estimated life expectancy of more than 10 years.

The National Comprehensive Cancer Network recommends a risk-based screening process, including family history, race and age.

To date no study has shown that PSA screening has decreased prostate cancer specific mortality.

The PSA test has low specificity, as the positive predictive value of a PSA level at 3 ng/mL or greater is an indicator of Gleason score of 3+4 or greater is estimated to be 16%.

Most men with an elevated PSA above 4 ng/mL are not found to have cancer of the prostate, and only about 25% of men who undergo a prostate biopsy due to an elevated PSA actually have prostate cancer.

A negative prostate biopsy may give false assurances that prostate cancer is not detected in a patient with an elevated PSA.

Estimated that there are more than 1 million prostate cancer survivors in the US.

Recommended that men at higher risk for developing prostate cancer at earlier ages-African-American and men with a family history of prostate cancer in nonelderly relatives be provided screening at an earlier age.

NCCN (National Comprehensive Cancer Network) recommends baseline risk assessment with PSA and DRE at age 40 years.

Men with a baseline PSA <0.6ng/mL can wait till age 45 for additional prostate cancer screening, and men with a PSA > 0.6 ng/mL should proceed with annual follow-up screening according to the NCCN.

NCCN 2018, recommended PSA screening for all patients age 45-75 years and discourages screening and patients aged greater than 75 years.

NCCN recommends prostate biopsy for patients with a PSA 2.6-4.0 ng/mL and for those with a PSA velocity of 0.5 ng/mL per year when the PSA is less than 2.5 ng/mL.

In a study of 76,693 men randomized to receive annual screening or usual care: after 7-10 years of follow-up, the rate of death from prostate cancer was very low and did not differ significantly between the 2 study groups (Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO)).

PLCO trial associated with a 22% relative increase in the rate of prostate cancer diagnosis at 7 years for the screening group.

PLCO trial indicated that prostate cancer screening did not significantly reduce the death rate from prostate cancer.

In the PCLO trial there were 50 deaths in the prostate screening group and 44 deaths in the control group.

Stratified data from the PLCO study showed that PSA and young and healthy men reduce the risk of prostate cancer specific mortality (Crawford ED et al).

The USPSTS review of randomized trials found that the screening of 1000 US men 55 to 69 years of age may prevent deaths from prostate cancer in 1.3 men in 13 years after initial screening.

European Randomized Study for Reducing Prostate Cancer (ERSPC) randomized 162,387 men into a screening group or a control group and found that PSA screening reduced prostate cancer specific mortality, but at a significant cost of over diagnosis and overtreatment: the absolute difference between screening and control group was 0.71 prostate cancer deaths per 1000 men.

ERSPC study suggested that to prevent one prostate cancer death 1410 men would need to be screened during a nine-year period, and that 48 patients with prostate cancer would need to be treated to prevent one death from prostate cancer.

ERSPC study reported a 20% to 25% reduction in the risk of prostate cancer mortality at 16 years, despite the median age at first screening being relatively old and the treatment somewhat inadequate by contemporary standards.

In the above study at 16 year follow-up: 570 men need to undergo PSA screening and 18 cancers need to be treatedto prevent one prostate cancer death.

ERSPC found 17.8% of 61,604 men received false positive results.

ERSPC trial had  no effect on overall survival.

Göteberg trial of 20,000 men born between 1930-1944 and found with 14 years of follow-up 12.7% of screened group was diagnosed with prostate cancer while 8.2% of control group, with a 40% reduction in prostate cancer mortality: estimated that 12 men needed to be diagnosed and treated to prevent one death (Hogosson J et al).

An 11 year follow-up of the European Randomized Study of Screening for Prostate Cancer demonstrated screening significantly reduced death from prostate cancer (Schroder FH et al).

Observation patient data estimates that nearly 100 low-risk patients have to undergo treatment to save one life.

The Prostate Cancer Prevention Trial (PCPT) screened patients for prostate cancer and found that a 28% cohort of men mainly in their 60s can be diagnosed with prostate cancer and SEER data suggest that the lifetime risk for a 60-year-old American man to die from prostate cancer is 3%: therefore this study provides strong evidence that overdiagnosis is a problem with prostate cancer screening (Thompson IM et al).

In the above study the PSA cut off point of 4.0 ng per milliliter has a sensitivity of 21% and a specificity of 94% for detecting prostate cancer.

In the PCPT study sensitivity was higher for detection of poorly differentiated cancers at 51%, with the specificity of 89%.

In the PCCT trial the positive predictive value (PPV) for PSA level between 4 and 10 ng/ml is approximately 25%: meaning that 3 of every 4 PSA levels between 4-10 ng/ml are false positives.

The positive predictive value (PPV) for a PSA above 10 ng/ml is 42-64%.

Approximately 75% of prostate cancer detected with a PSA between 4 and 10 ng/ml are localized to the prostate, while less than half with PSA of 10 ng/ml are organ confined.

PCCT trial of more than 18,000 men 55 and older with a PSA ≤ 3 ng/ml randomized to finasteride or placebo: 14% of men screened for 7 years were diagnosed with prostate cancer , and 28% of men largely in their 60s can be diagnosed with prostate cancer.

The PCCT demonstrated that prostate cancer can be diagnosed in any patient that PSA can be measured and that no level is free of the diagnosis.

Estimated that in the last 20 years PSA screening has caused more than 1 million American men to be diagnosed with PC and receive treatment that was not necessary to save their lives (Welch HG , Albertsen PC).

Presently, it is suggested to stop PSA the question screening at age 75.

Men, aged 40-49 years, with a baseline Prostate-Specific Antigen below 1.0 ng/mL have a very low long-term risk of prostate cancer.

Population-based PSA screening of men for PC reduces prostate cancer mortality at the expense of over diagnosis and over treatment and is not recommended.
Early PSA testing can be offered to men  greater than 50 years, men greater than 45 years with a family history of prostate cancer, African-Americans 45 years or older and BRCA1/2 carriers of 40 years or older.
Proscreen Trial- a randomized trial of 61,193 men aged 53-63 years with a PSA of 3 ng/mL or higher,  underwent testing for high-grade prostate cancer with a 4-Kallikrein panel risk score, and a subsequent MRI of the prostate followed by targeted biopsy in patients with a kallikrein Panel score of 7.5% or higher.
Findings in this study were one additional high-grade cancer per 196 men, and one low grade cancer per 909 men were detected among those randomized to screening.
On the CAP randomized clinical trial of PSA screening with a single testing, compared with standard practice without routine screening , reduced prostate cancer deaths at a medium follow up of 15 years: the absolute reduction in the death was small, the risk of death from prostate cancer was .69% vs .78% in the control group.
The use of MRI directed targeted biopsy for screening in early detection in patients with elevated PSA levels reduces the risk of over diagnosis by half the cost of delaying detection of intermediate risk tumors in a small proportion of patients (GOTEBORG-2 trial investigators).
Screening for prostate cancer with PSA and MRI with subsequent combined biopsies for prostate cancer has a high probability to be more cost-effective compared with PSA screening using standard biopsy.
The harms associated with PSA screening is the performance of unnecessary, biopsies and risks associated with those procedures.
The cumulative percentage of false positive PSA results is between 10 and 15% with approximately 5% risk of falls positive screen with a subsequent negative biopsy.
The major with biopsy of the prostate is infection, which occurs in 5 to 7% of patients, and can result in hospitalization in 1 to 3%.
The complications to prostate biopsy include hematuria, less than 1%, rectal bleeding, urinary obstruction or retention, transient erectile dysfunction and substantial discomfort.

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