Evolving recommendations in prostate cancer screening

BY : SUMMAR MOHAMED ELMORSHIDY,M.B.BCH,MSC ASSISTANT LECTURER OF CLINICAL ONCOLOGY CLINICAL ONCOLOGY DEPARTMENT ASSIUT UNIVERSITY

Introduction :The aim of screening

Detects disease in early asymptomatic stage

Give early intervention and management

Reduce the risk of the disease that has already occurred .(secondry prevention )

Guidelines on the practice of screening

The disease :severeHigh prevelance in preclinical stageThe natural history of the disease known

Long period between first sign and metastatic disease The treatment possible treatment safe and effective

The test :Acceptable sensitivity and specificity Simple and cheap Safe and acceptable

Types of screening

Population or mass screening is defined as the examination of asymptomatic men (at risk)

It usually takes place as part of a trial or study and is initiated by the screener.

In contrast, early detection or opportunistic screening comprises individual case findings, which are initiated by the person being screened (patient) and/or his physician.

The primary endpoint of both types of screening : 1.Reduction in mortality from PCa 2.The quality of life is important as expressed by quality-of-life adjusted gain in life

years.

Burden of disease

Natural history

Poorly understood Most data relate to pre-PSA era Competing co-morbidity more likely to cause death (minimum 10-y life

expectancy) Patients with high grade and stage disease more likely to die of prostate

cancer Which tumours cause problems: will the patient die of or withthe disease? Which of the tumours known to be present at autopsy will be detected by

screening?

Tumour markers: PSA

ROC curvePSA : The most useful tumour marker available in clinical practice for diagnosis, staging and monitoring of disease response to radiotherapy surgery and hormonal treatments .

PSA( drawbacks)

Organ specific not disease specific Elevated PSA : the levels can also be raised in other medical conditionsBPHInfection InfarctionInstrumentation, massage, DRESports, sexual activity Another problem is that all men have slightly different PSA levels according to age.

Age Specific PSA, Reference Range

Age, yr Reference Range, ng/ml

40-49 0.0-

2.550-59 0.0-3.5

60-69 0.0-4.5

0.0-6.570-79

Charecteristics of Screening Tests

Test

DRE

TRUS

PSA> 4

ng/ml

Sensitivity%

Specificity%

PositivePredictive Value

%45-58

71-91

67-89

96-9789-94

59-97

24-5815-43

33-47

The historical approach to prostate cancer screening

It was based in part on the historically poor outcomes of treatment of metastatic prostate cancer and the realization that PSA-detected tumors were often cured with radiation or surgery.

All patients over a certain age (often age 50) were recommended to undergo annual screening.

If a PSA was found to be greater than 4.0 ng/mL, a biopsy was recommended. If biopsy found cancer, treatment with radiation or surgery was generally recommended.

This approach led to a remarkable spike in prostate cancer detection, treatment, and the conduct of the PLCO and ERSPC studies.

Early Approach to Prostate Cancer Screening and Treatment

Evidence based Results of 2 Big Randomized trials in 1990 of prostate cancerscreening

PLCO cancer screening trial¹ Prostate, Lung, Colorectal and Ovarian screening

Recruited 76,693 men.

Histology and Gleason grade did not differ significantly between the two groups. The majority of cases were stage 2.

After 13 years of follow-up, there was no evidence of a mortality benefit for organized annual PSA screening in the PLCO trial compared with opportunistic screening used in normal care.

ERSPC trialEuropean Randomised Study of Screening for Prostate Cancer : Recruited 182,000 men It examined the role of PSA screening in a largely unscreened

population from eight countries with different screening and treatment strategies.

After 13 years of follow-up, a significant 21% reduction (rate ratio 0.79; 95% CI, 0.69–0.91) in death from prostate cancer

This reduction in the risk of death is found in a predefined subgroup of men age 55–69.

c One trial suggests screening is ineffective, and one

suggests a regimented screening program does reduce risk of prostate cancer death !!!!!

conflicting results

So,,,,,,,,controversies starts here

And after Twenty years of experience with this initial approach to screening began to change with several sets of observations.

FIRST : It was recognized that many tumors detected via PSA screening were small and low-grade; the possible extent

of overdetection .

Concurrent with this observation, the first reports of the outcomes of Active surveillance for low-risk prostate cancer detected through PSA testing began to appear With the maturation of these series, it became clear that low-grade (Gleason 3 + 3) and low-volume intermediate-grade (Gleason 3 + 4) prostate cancers will achieve high prostate cancer–specific survival at periods up to 15 years.

In a cohort of 993 men with such tumors, of whom 13% had Gleason 3 + 4 tumors, combined cause-specific survival at 10 years was 98.1% and at 15 years was 94.3%

Drawbacks :

By studying the biopsy outcomes of the European Randomized Study of Prostate Cancer Screening and, it also has become apparent that using a single biomarker (i.e., PSA) to determine a man’s risk of prostate cancer was naive; other measures of risk had a profound impact on prostate cancer risk

  Also phase III randomized clinical trials have demonstrated very little (if any) benefit of treatment of

low-grade tumors ,,,,, but mortality benefit for high-grade tumors, the clinical community recognized that screening should seek to identify the man with high-

grade cancer in whom a biopsy may have net potential benefit from detection (and, presumably, treatment).

On the other hand, if biopsy would preferentially detect a low-grade cancer, the benefit-risk ratio would more likely argue against a biopsy. The first tool developed for this was the PCPTRC (www.prostate-cancer-risk-calculator.com)

Potential impact of over-diagnosis

A man is healthy and without symptoms

He has a PSA test that leads to the diagnosis of an early prostate cancer, that may not cause any problems in his lifetime

He knows he has a prostate cancer but will now be most likely advised to embark on an active surveillance programme (close monitoring for signs of progression, NOT definitive treatment)

He may choose to have definitive treatment with surgery or radiotherapy but this will affect his urinary and sexual function (and possibly bowel function), when arguably treatment was not needed

Other relevant findings High rate of false positives in ERSPC trial

3 out of 4 men (75%)with an elevated PSA were not found to have cancer

Significant increases in distress at the time of biopsy compared with levels of distress associated with the PSA test have been found (analysis of data from the UK ProtecT trial; 195 men who had received a negative biopsy) ⁴

TO sum up

KEY Question 1

What is the direct evidence that screening for prostate cancer with prostate-specific antigen (PSA), as a single-threshold test or as a function of multiple tests over time, decreases morbidity and/or mortality?

Results of randomized trials

No difference in prostate cancer specific

mortality

Key question 2 :

What are the harms of PSA-based screening for prostate cancer?

The Finnish center of the ERSPC trial reported that after three rounds of PSA testing (using a cut-off point of 4.0 ng/mL and testing every 4 years), 12.5% of participants received at least one false-positive result.

A false positive was defined as a positive result and consequent workup with no histopathologic diagnosis of cancer within 1 year of the screening test

In the entire ERPSC trial, 75.9% of men that underwent a biopsy because of an elevated PSA value had a false-positive result.

The PLCO trial also published findings related to false-positive tests. After four PSA tests, men had a 12.9% cumulative risk of receiving at least one false-positive result (defined as a PSA level of ≥4.0 ng/mL and no prostate cancer diagnosis after 3 years), and a 5.5% risk of having at least one biopsy as a direct consequence of a false-positive screening test.

Physical harms of screening documented in the PLCO trial included rare bleeding or pain from digital rectal examination (0.3 events per 10,000 men screened), bruising or fainting due to venipuncture (26.2 events per 10,000 men screened),

and complications of diagnostic procedures (e.g., biopsy), such as infection, bleeding, and urinary difficulty (68 events per 10,000 evaluations).

AUA recommendations

recommends against PSA screening in men under age 40 years.

does not recommend routine screening in men between ages 40 to 54 years at average risk

For ages 55 to 69 years the decision to undergo PSA screening involves weighing the benefits of preventing prostate cancer mortality in 1 man for every 1,000 men screened over a decade against the known potential harms associated with screening and treatment.

strongly recommends shared decision-making for men age 55 to 69 years that are considering PSA screening, and proceeding based on a man's values and preferences

To reduce the harms of screening, a routine screening interval of two years or more may be preferred over annual screening in those men who have participated in shared decision-making and decided on screening.

Does not recommend routine PSA screening in men age 70+ years or any man with less than a 10 to 15 year life expectancy

does not recommend routine screening in men between ages 40 to 54 years at average risk of prostate cancer.

recommends screening with limited confidence in the target group age 55 to 69 years

This age range represents the group with the highest quality evidence of benefit.

There is potential for harm, and for this reason recommends shared decision making prior to screening decisions.

The AUA used as evidence six trials-Stockholm, Norrkoping, Quebec, ERSPC, Goteborg and PLCO trials

So,,,, WHAT IS THE WAY FORWARD

Finding a better test for prostate cancer or at least the risk of prostate cancer sor example Imaging methods e.g. multi-parametric MRI

Learning about the genetics of prostate cancer Which genes predispose a man to developing prostate cancer? Are there specific characteristics that help to distinguish between indolent and aggressive cancers?

A number of organisations have provided stances on the use of PSA testing for prostate cancer. For example: United Kingdom (PCRMP) US Preventative Services Task Force American Urological Association American Cancer Society Cancer Council Australia / Australian Health Ministers Advisory Council Urological Society of Australia and New Zealand

A new model model included a combination of six plasma protein biomarkers (PSA, free PSA, intact PSA, hK2, MSMB, MIC1), genetic polymorphisms (232 SNPs) associated with prostate cancer susceptibility, and clinical variables (age, family, history, previous prostate biopsy, and prostate examination) with the endpoint of Gleason score 7+ cancers.