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					 PROSTATE CANCER:
To Screen or Not To Screen

       January 16, 2001




   Mark A. Grabarczyk, M.D.
    Wake Forest University
    Baptist Medical Center
                                     Case Presentation:

          Mr. G is a 55 y/o WM with no significant PMHx who presents to his PCP
          for a general physical exam after excessive badgering by his son. He was
          last seen by a physician 2 yrs. ago for an URI but otherwise has not had
          any other interaction in more than 5 years. He states that he feels well
          and is without complaints.

          His physician completes a very detailed and comprehensive H&P, with the
          only pertinent finding being a symmetrically enlarged non-tender prostate
          without any discrete nodularity. Mr. G. denies any urinary
          symptomatology.

          Routine labs were drawn and Mr. G. was scheduled for flexible
          sigmoidoscopy. He was called approximately 2 days later because of a lab
          abnormality – PSA 6.4. His PCP referred him to an urologist who
          performed another DRE and an U/S guided prostate biopsy.

          Mr. G. limped home after the biopsy and rested the remainder of the day.
          At 4:00 am the next morning, Mr. G. called is son, an intern in Internal
          Medicine, complaining of severe pain, hematuria, and inability to empty
          his bladder. “Son – I am peeing blood and I have a basketball in my
          stomach!” His son recognizing something was wrong referred him to the
          E.D. to be evaluated. Mr. G. required an indwelling foley catheter for
          approximately 5 days as his prostate hematoma resolved.

          All biopsies were free of prostate cancer and he was diagnosed with
          benign prostatic hypertrophy.



Goals:
 Provide background information demonstrating the complexity of prostate
   cancer.

 Review and critique the available prostate cancer screening techniques

 Discuss the risks and benefits of prostate cancer screening

 Review and critique recommendations of the major prostate screening guidelines

 Discuss the future of prostate cancer screening (new trials and techniques)

 Hopefully provide some insight in to this incredibly controversial topic




                                                2
Introduction:
Prostate cancer is the most common noncutaneous cancer in American men1. After lung cancer
it accounts for more cancer deaths in men than any other cancer site. The American Cancer
society predicts that there were about 180,400 new cases of prostate cancer in this country in the
year 2000 and about 31,900 men died of this disease2. Despite its prevalence, the natural history
of this disease is remarkably heterogeneous. For example, only 3% of men die from prostate
cancer, even though it is detected clinically in one third of men under the age of eighty and in
two-thirds of older men at autopsy3,4. In many patients, the cancer progresses slowly, resulting
in moderately or poorly differentiated tumors that remain localized to the prostate gland.
Although potentially life threatening, such cancers are often curable. In other patients, however,
tumor growth is rapid and can spread beyond the confines of the prostate. In such cases, the
cancer is no longer curable and long-term survival is considerably diminished. Survival in men
with prostate cancer is related to many factors, one of the most important being extension of the
tumor beyond the capsule of the prostate at the time of diagnosis. The ten-year survival among
men with cancer confined to the prostate is 75%, compared with 55% and 15%, respectively,
among those with regional extension and distant metastases5. Thus, a screening program for
prostate cancer ideally should identify those men with more aggressive tumors that have not
spread beyond the prostate gland. Other important aspects should include development of
treatments that improve morbidity and mortality with minimal side effects.

When applying a screening program to the general public, determination of which segment of the
population will benefit from screening and when to start is often very difficult. Prostate cancer is
in general an indolent disease taking years to manifest itself clinically. It is hypothesized that
men diagnosed with prostate cancer in their 40’s and 50’s had onset of the disease in their mid to
late 30’s giving prostate cancer a ten to fifteen year latency period. Determining when and who
to screen has been based on epidemiologic data as well as evolving data regarding suggested risk
factors.

Between 1976 and 1994, prostate cancer rates doubled and mortality increased by 20%6. The
reasons for the increase are not known, but increases in life expectancy, growing disease
prevalence secondary to increased exposure to environmental carcinogens, and increase use of
screening and diagnostic modalities have been suggested as causes.


                                           Table 1
         Annual Prostate Cancer Incidence and Mortality Rates per 100,000 Population

                 Year                       Incidence                 Mortality Rate
                 1994                         144.0                       26.0
                 1992                         190.1                       26.7
                 1990                         132.0                       26.5
                 1985                          88.0                       23.4
                 1976                          73.5                       22.1

         Adapted from Ries et al.6



                                                 3
Although the overall number of cases diagnosed increased in all age groups, the increase is the
most evident in the younger age groups. The percentage of men younger than age 70 years
diagnosed with prostate cancer increased 9% between 1986 and 1993. This most likely related to
the widespread use of screening measures.7 Another recent trend is that men are now more likely
to present with clinically localized disease (53% in 1986 compared with 74% in 1996) and lower
grade tumors. These data suggest that it is not so much the prevalence of prostate cancer that is
increasing but the detection of more cases from a pool of men with latent, unsuspected disease.
With the assumption that these cases are earlier in the disease process representing more organ
confined disease and therefore curable disease.

When investigating the possible risk factors related to the development of prostate cancer, the
epidemiologic data obtained is quite intriguing. Worldwide, the United States is in the top one-
third of countries with respect to age–adjusted prostate cancer death rates per 100,000
population8 (Table 2).


                                               Table 2
                                    Worldwide Age-Adjusted Prostate
                                          Cancer Death Rates
                                        Per 100,000 Population

                          Country                           Mortality Rate

                          Trinidad, Tobago                            32.9
                          Switzerland                                 22.5
                          Norway                                      22.1
                          Sweden                                      21.1
                          Denmark                                     19.5
                          New Zealand                                 19.0
                          Cuba                                        19.0
                          United States                               17.5
                          United Kingdom                              17.1
                          Canada                                      17.0
                          France                                      16.8
                          Hungary                                     15.8
                          Portugal                                    15.3
                          Costa Rica                                  15.0
                          Argentina                                   13.6
                          Spain                                       13.2
                          Italy                                       11.6
                          Mexico                                      10.6
                          Israel                                      9.2
                          Greece                                      8.7
                          Russia Fed.                                 6.9
                          Singapore                                   4.4
                          Japan                                       4.0


                                                       8
                          Adapted from Parker et.al.




                                                       4
Great geographic variations exist in the impact of prostate cancer, as seen in Table 2. The
significance is highlighted by data showing that when individuals from a low incidence/mortality
region move to a high incidence/mortality region, within their own generation, the disease
becomes more common6. For example, when Japanese men relocate to the United States, their
prostate cancer statistics start to resemble those of the local population. Younger age at the time
of relocation and length of time living in the new environment appears to correlate with the
increase.

In contrast, African American men have a 47% higher incidence and a 128% higher mortality
rate than white men living in the same geographic location. In addition, black men have more
advanced disease upon diagnosis (they are 40% more likely to present with metastases), and a
higher mortality rate when compared with white men presenting with identical disease
stages9,10,11. There are many hypotheses attempting to explain this phenomenon. Most revolve
around socioeconomic status and access to healthcare, but at least one retrospective study
showed that even in what is believed to be an equal-access healthcare setting, local failure after
the treatment of prostate cancer with similar stage, grade, and other clinical variables was still
greater in black patients6. Multiple other studies investigating socioeconomic status failed to
show an association between socioeconomic class and prostate cancer epidemiology or between
education level and cancer incidence6,10. Although not understood, African American race is a
significant risk factor for prostate cancer.

The most evident risk factor for prostate cancer is age. Diagnosis is rare before the age of fifty,
but after this age, both the incidence and mortality rate increase almost exponentially. The
Surveillance, Epidemiology, and End Results (SEER) age-adjusted incidence rates are shown in
Table 3. The lifetime probability at birth of being diagnosed with prostate cancer in the United
States has been estimated to be 8%7. Prostate cancer increases faster with age than any other
malignancy, and with an increase in the elderly population because of longer life expectancy,
prostate cancer will continue to be a major health care concern.


                                             Table 3

                                      SEER Age-Adjusted
                                  Incidence Rates per 100,000
                                       Population in 1990

                                  Age                Incidence

                                  50-55                   45.2
                                  60-64                  337.5
                                  > 65                   >1000



Family history also has a strong correlation with the development of prostate cancer. There have
been multiple studies to confirm the association of increased risk of prostate cancer for those



                                                 5
with first-degree male relatives with the disease. Spitz and colleagues12 found a 2.41-fold
increased risk for men with first-degree relatives with prostate cancer. In a study of
Scandinavian twins, Gronberg and coworkers13 found prostate cancer concordance rate of 0.192
and 0.043 for monozygotic versus dizygotic twins suggesting a profound genetic influence on
prostate cancer development. Carter and colleagues14 showed that prostate cancer was diagnosed
in 15% of men who had a father or brother affected by prostate caner compared with 8% of a
control population. Despite all the data, compared with sporadic prostate cancer, hereditary
factors are responsible for a low percentage of cases (approximately 9% of all cases) and most
commonly affect men with early onset disease14. For a comprehensive list of suggested risk
factors see Table 4.


                                        Table 4
                              Prostate Cancer Risk Factors

                        Age                  Family History
                        Race                 Socioeconomic
                      Occupation             Cigarette Smoking
                      Heavy Metals           Sexual Activity
                      Vasectomy              BPH
                      Hormones               High Fat Diet



Prostate Cancer Screening Techniques:
Digital rectal examination and measurement of Serum prostate specific antigen (PSA) are the
most widely used screening tests for prostate cancer. Other potentially useful studies include
transrectal ultrasound and prostate biopsies; although these two are generally reserved for use
after one of the first two screening tests are positive.

The sensitivity and specificity of screening tests for prostate cancer vary widely. This variation
arises in part because it is difficult to recognize false negative results, since biopsies are
generally not performed on men with normal screening results.

The positive predictive value is a better way to assess the performance of prostate cancer
screening because it does not depend on the false negative rate, but even this value is subject to
wide variation. Some of this variation is due to the limited sensitivity of needle biopsy of the
prostate, the usual standard to which other screening methods are measured.

Digital rectal examination (DRE) – Physicians have traditionally used the DRE in early
detection efforts despite a lack of evidence from controlled trials showing that the procedure
reduces disease-specific mortality or net morbidity rates for prostate or rectal cancer19.

DRE can detect tumors in the posterior and lateral aspects of the prostate gland. Tumors not
detectable by DRE are those 25-35% of which occur elsewhere in the gland, and stage T1


                                                 6
cancers, which by definition are not palpable. When used alone in men over the age of 50 years,
the DRE has a 1-2% detection rate16,20-22. A clinically abnormal exam increases the odds of a
clinically significant intracapsular prostate tumor by 1.5-2.0 fold and increases the odds of
extracapsular disease 3-9 fold. However, results on DRE that do not indicate cancer do not
appear to significantly reduce the post-test odds of clinically significant prostate cancer. In other
words, the NPV of DRE is low, largely secondary to the low sensitivity of the test. The PPV of
DRE varies widely from 6-33%15,16. The sensitivity is estimated at 18-68% in asymptomatic
men15,17,18. Alone this test is nearly useless as a screening tool. There is some data to suggest
combining DRE with PSA increases the PPV and sensitivity. This will be discussed shortly.

Prostate Specific Antigen (PSA) – PSA is a glycoprotein that is expressed by epithelial cells of
normal and neoplastic prostate tissue. In general, serum PSA levels are low (<3ng/ml), but
levels >4ng/ml are more commonly associated with prostate pathology. Unfortunately, prostate
cancer is just one of many disease processes that elevates PSA. Others include benign prostatic
hyperplasia, prostatitis, trauma, DRE, and possibly prostatic intraepithelial neoplasia (PIN)23.

The PSA concentration increases yearly after the age of 40 years; it increases at a faster rate in
elderly men24. For example, one study showed that PSA increases by approximately 3.2%/yr in
healthy 60 year olds without prostate cancer25. As a result, many advocate different reference
ranges based on age. These age specific reference ranges have been proposed as a means to
increase the sensitivity and specificity of serum PSA in screening for prostate cancer (this will be
discussed further later). Overall, these age-based ranges have not been proven to alter the
clinical course of this disease.

Measurement of serum PSA is the most sensitive noninvasive test available for early detection of
prostate cancer. However, elevations in serum PSA are neither sensitive nor specific for prostate
cancer. As stated earlier there are a number of other prostate pathologies that raise PSA. In
addition, some men with prostate cancer have serum PSA values < 4.0ng/ml. In three studies of
men 50 years and older, 43% of men with prostate cancer had values < 4.0ng/ml, while 25% of
men without prostate cancer had values > 4.0ng/ml26.

A report from the Physicians’ Health Study provided estimates of the sensitivity and specificity
of PSA in a relatively unselected population of over 22,000 men with long-term follow-up. The
sensitivity of a single baseline PSA measurement for any prostate cancer and for aggressive
cancers diagnosed within four years was 73% and 87% respectively. The overall specificity was
91%. It was estimated that the discovery of an elevated serum PSA advanced the detection of
aggressive cancers by 5.4 years26.

Other studies have shown a wide range of sensitivities, specificities, and PPV. In review,
sensitivity ranged from 19-87%, specificity 36-91%, and PPV 8-44%15,18,27. Of note, PPV does
improve as the PSA value increases. For example, PSA values 4.0-10.0ng/ml have a PPV of
21% compared with PSA >10.0ng/ml where PPV varies 42-64%.

Combination DRE and PSA – Evidence from three uncontrolled trials that allow a direct
comparison of the yields of PSA and DRE suggests that combining both tests improves the
overall rate of prostate cancer detection when compared with either test alone23. In these studies,



                                                  7
18-26% of patients had either an abnormal PSA or DRE. Cancer was detected in 3.5-4.0% of the
patients. Although PSA detected more cancers than DRE, each detected cancer not identified by
the other. Also of note, approximately 20% of prostate cancers with aggressive features are
found in men with PSA < 4.0ng/ml. In one study, combining PSA/DRE increased the PPV from
28% to 49%15,17,18.

Transrectal Ultrasound (TRUS) – TRUS is an office-based procedure that requires no sedation
or analgesia and is relatively well tolerated by most men. This test is not recommended as a
primary screening tool for prostate cancer because of its low sensitivity and PPV. In one study,
nearly 40% of cancers would have been missed if biopsies were performed only on those with
suspicious findings on TRUS26.

Prostate Biopsy – Transrectal biopsy is another relatively simple office-based procedure. The
procedure is to obtain tissue from suspicious areas, followed by biopsies from the base, middle,
and apical areas on each side of the prostate (sextant biopsies). This procedure has multiple
limitations as a primary screening tool including cost, complications, and availability to large
numbers.

Prostate biopsy is the gold standard for prostate cancer diagnosis, but it remains an imperfect
test. Currently only 4-25% of biopsies contain cancers, indicating that 75-96% of biopsies are
done needlessly or miss the cancer. In many patients, especially those with elevated PSA, the
initial biopsy may have missed the cancer. This is important in studies of screening, as most are
unable to provide the true false-negative rate, resulting in an underestimate of the true cancer
rate. In men with persistent elevations of PSA, repeat biopsy revealed cancer in 19%, 20%, and
23% of patients28. In untreated men with known adenocarcinoma of the prostate, sextant
biopsies revealed cancer in 80%, indicating a 20% false-negative rate28.

The Risks and Benefits of Prostate Cancer Screening
When reviewing the risks and benefits of screening for prostate cancer, it is important to
understand the inherent problems with availability of hard evidence. Currently, there are no
randomized controlled trials to support either screening or treatment of early-detected prostate
cancer. Because of this lack of evidence, the major organizations making screening
recommendations do not agree on the best approach. This alone makes the decision very
difficult for both the physician and the patient.

The benefits of early screening theoretically include the idea that detecting prostate cancer early
will increase the number of organ-confined cases and allow for curative therapy. The goal is to
find those men who are asymptomatic with latent prostate cancer. Retrospective trials support
such a hypothesis, but have major flaws in study design. It is not that the evidence refutes
screening, but the lack of evidence supporting screening efforts.

The risks of screening become clear quickly. Reviewing the efficacy of available screening
methods demonstrates the futility with screening. All professional organizations involved in
making recommendations about screening for prostate cancer agree on the major health
implications of prostate cancer especially as the population ages.


                                                 8
The major risk is the false positive test leading to a large number of unneeded biopsies,
subjecting these men to the risks of the procedure. Prostate biopsy is, in general, a low risk
procedure, but with the number of men who would receive biopsies based on a falsely positive
PSA/DRE make the risks real (i.e. Mr. G.). Complications of biopsy include rectal bleeding,
hematuria, infection, local hematoma, and pain, which in general are self-limiting but can occur
in up to 40% of procedures19. Prostate biopsies also lack sensitivity, specificity and PPV, and
many men need multiple biopsies secondary to persistently abnormal PSA/DRE testing.

For those men who are diagnosed with prostate cancer, the decision on whether or not to undergo
aggressive treatment is very difficult. There are only projected models that support the early
treatment of prostate cancer. There really are no trials to evaluate treatment in this population.
Subgroup analyses in several retrospective/prospective observational trials do not show a
difference in mortality/morbidity with early therapy. Currently, there are no completed RCTs to
address this issue.

The risks of radical prostatectomy, external beam radiation therapy, and brachytherapy are
substantial. Radical prostatectomy carries a 0.5-2% perioperative mortality rate. External beam
radiation and brachytherapy peri-operative mortality is 0.1-1%19,29. All aggressive treatments for
prostate cancer carry substantial risks of incontinence and impotency. Most studies support an
impotency rate of 50-85%19,23. Newer techniques including nerve-sparing procedures boast a
markedly reduced incidence of impotence and incontinence. These studies show impotency and
incontinency rates at 0-43% and 2-19% respectively23.

(In efforts to put all these numbers into tangible, better-understood terminology, I have
attempted to calculate NNT and NNH for screening with both DRE and PSA. NNT = 7-11
and NNH = 2-5. These calculations are based on numbers assuming early treatment proves
to be beneficial.)

When making the decision whether to screen for prostate cancer, it is important to provide
adequate information to patients regarding the risks and benefits of further work-up and
treatment of prostate cancer.

Review of the Major Organizations Guidelines Regarding Prostate
Cancer Screening (all information is adapted from the professional organizations
guidelines and the summaries of the National Guideline Clearinghouse)

American Urological Association
Title: Prostate specific antigen (PSA): best practice policy.
Source: Oncology 14(2):267-268, 2000
Release date: December 21, 1999
Funding Source: American Urological Association, Inc.

Major Recommendation:



                                                 9
The Use of PSA for Early Detection of Prostate Cancer
   Candidates for early detection testing
    Asymptomatic men age 50 or over with an anticipated life expectancy of ten or more
      years
    Asymptomatic men age 40-50 years old with a family history of prostate cancer or
      African-American men with an anticipated life expectancy of ten or more years

   Decisions regarding early detection of prostate cancer should be individualized and benefits
   and consequences should be discussed with the patient before PSA testing occurs.

   Tests for early detection: PSA and DRE
    PSA testing detects more tumors than does DRE, and it detects them earlier. However,
      the most sensitive method of early detection of prostate cancer is the combination of PSA
      and DRE. Both tests should be employed in a program of early prostate cancer detection.
    Transrectal ultrasonography is not useful for early detection and adds little to the
      combination of PSA and DRE.

   Tests Results
      1. A Urologist should be consulted for prostate biopsy when any of the following finds
          are present:
               PSA is 4.0ng/ml or more
               A significant PSA rise from one test to the next (an increase of greater than
                   0.75ng/ml in one year = PSA Velocity)
               DRE is abnormal
      2. A variety of factors can affect PSA and should be considered in the interpretation of
          results.
      3. Performance of PSA: Although methods exist to improve cancer detection rates (test
          sensitivity) or to decrease the number of unnecessary biopsies (test specificity), each
          method involves a tradeoff and should be discussed with the patient.

       Sensitivity
           PSA testing in patients with normal serum PSA levels has a sensitivity of 67.5-
               80%.
           Methods to improve sensitivity:
                   o Adjust the “normal” PSA level to a lower value for younger men (age-
                     adjusted PSA)
                   o Follow Serum PSA values in an individual over time (PSA velocity)

       Specificity
          The specificity of PSA testing is 60-70% when the PSA level is > 4.0ng/ml.
          Methods to improve specificity:
                  o Age adjustment (using higher “normal” PSA levels for older men)
                  o Free-to-total PSA ratios (the optimal cut-off point for free/total PSA below
                    which a prostate biopsy would be recommended is unknown)
                  o Adjusting the normal Value of the size of the prostate (PSA Density =
                    PSA/Gland Volume)


                                               10
Potential Benefits:
        Improve prostate cancer detection while minimizing unnecessary biopsies
        Reduce the morbidity and mortality associated with prostate cancer

Potential Harms:
        Trade-off associated with improving PSA sensitivity: Both age-adjusted PSA
          and PSA velocity will increase the number of cancers detected, but both will
          also increase the number of men undergoing biopsy.
        Trade-off associated with improving PSA specificity: All three methods to improve
          PSA specificity (age-adjusted PSA, free-to-total PSA, PSA density) will
          reduce the number of biopsies in men who do not have prostate cancer but will
          increase the risk that some prostate cancers will be missed.
        Complications of confirmatory testing: Prostate biopsy, by means of a
          transrectal, ultrasound guide, are rarely complicated by rectal bleeding,
          hematuria, or prostatic infection. After biopsy, blood in the stool or urine
          usually disappears in a few days. Blood in the semen can be seen up to
          several weeks after biopsy.

Qualifying Statements:
Because of the biologic variability of prostate cancer and the lack of a completed RCT that
proves the benefit of early detection, the use of PSA for early detection of prostate cancer
remains controversial. Two large RCTs are underway to evaluate whether early detection and
treatment of prostate cancer reduces the mortality rate. Until these RCTs are completed, it will
not be known whether the value of early detection of prostate cancer is sufficient to outweigh the
cost and morbidity associated with disease treatment.

American College of Physicians-American Society of Internal
Medicine (ACP-ASIM)

Title: Screening for prostate cancer
Sources: Ann Intern Med 1997 Mar 1; 126(5): 394-406
          Ann Intern Med 1997 Mar 15; 126(6): 480-4
          Ann Intern Med 1997 Mar 15; 126(6): 468-79
Release Date: February 10, 1996
Funding: Government Grants

Major Recommendations:
Recommendation 1: Rather than screening all men for prostate cancer as a matter of routine,
physicians should describe the potential benefits and known complications of screening,
diagnosis, and treatment; listen to the patient concerns; and then individualize the decision to
screen. Factors to consider include the following:
     The principal reason for caution is that the balance of benefit and harm from early
       treatment is unknown. The risks of treatment are known, but the benefits are not known



                                               11
       because RCTs evaluating the effect of early treatment on morbidity and mortality have
       not been done.
      Indirect evidence based on decision models suggests that if screening and treatment prove
       beneficial, men who are 50-69 years of age will benefit the most. Men older that 69 will
       gain little from screening.
      It is important to note that because additional information is obtained from DRE, DRE is
       valuable for evaluating other conditions than prostate cancer.
      In issuing a general recommendation against the routine use of PSA/DRE, the College
       acknowledges that it may be reasonable for a physician to recommend that an individual
       patient be screened for prostate cancer. The area of greatest controversy is screening for
       prostate cancer in men between the ages of 50-69. For men in this age group, the
       physician and patient’s interpretation of the risk-benefit equation should particularly
       guide by the patient’s preference and the physician. Physicians should be prepared to
       discuss this issue with their patients, to provide counseling on an individual basis, and to
       document these discussions. Potential benefits have to be weighed against the potential
       morbidity and mortality related to treatment by radical prostatectomy or radiation
       therapy.
      African-American men and men with a family history of prostate cancer should be made
       aware of their higher lifetime risk. However, available evidence does not suggest that
       they should be cared for differently from men at average risk.

Recommendation 2: The college strongly recommends that physicians help enroll eligible men
in ongoing clinical trials.

Counseling Patients
All men who are considering DRE/PSA should understand the potential risks and benefits of
screening and participate with their physicians in deciding whether to be tested. Before any
testing occurs, patients should be fully informed about the following:
       Prostate cancer is an important health problem.
       The benefits of one-time or repeated screening and aggressive treatment of prostate
          cancer have not yet been proven.
       DRE/PSA can have false-positive and false-negative results.
       The probability that further invasive evaluation will be required as a result of testing is
          relatively high.
       Aggressive therapy is necessary to realize any benefit from the discovery of a tumor.
       A small but finite risk of early death and a significant risk of chronic illness,
          particularly with regard to sexual and urinary function, are associated with treatments.
       Early detection may save lives.
       Early detection and treatment may avert future cancer-related illness.
       The College recommends that informed consent be obtained prior to screening for
          prostate cancer.

Potential Benefits:
The potential benefit of screening for prostate cancer is that early detection may save lives and
avert future cancer-related illness for some men.



                                                12
The decision model suggests that, under a set of assumptions that favors screening (in particular,
that men with organ-confined disease would be cured), men 50-69 years of age who have one
time (prevalence) screening for prostate cancer would appear to gain, on average, several weeks
of life expectancy. For men who subsequently receive a diagnosis of cancer, aggressive
treatment with radical prostatectomy or radiation therapy potentially adds 3 more years of life for
men in their 50’s, 1.5 years for men in their 60’s, and 0.4 years for men in their 70’s. Data
models for men younger than age 50 are currently insufficient.

Subgroups most likely to benefit:
Black men and men with a family history of prostate cancer should be made aware of their
higher lifetime risk.

Men of average health who are 50-69 years of age: Using the best available evidence, the
analysis of risks and benefits of screening using the decision model suggests that, under a set of
assumptions that favor screening and treatment, one-time testing with DRE/PSA may eventually
be proven to have a clinically important net benefit in terms of life expectancy and a reasonable
cost.

Potential Harms:
In exchange for those potential but unproven benefits, prospective candidates for screening face
a 15-40% chance of requiring a biopsy. Minor, self-limiting complications have been reported in
as many as 40% of men who have had biopsies.

The risks of radical treatment of prostate cancer are well established. Men who undergo
aggressive treatment face a greater than 50% chance of permanent sexual dysfunction, a 20-30%
likelihood of some degree of incontinence, and a 0.5-1.0% chance of perioperative death.
Radiotherapy generally possesses lower associated risks for the adverse events but confers risks
for other chronic sequelae, including a 10% chance of bowel dysfunction.

Subgroups most likely to be harmed:
Men older than age 70: Because the decision model demonstrated only an increase of a few days
for men 69 year of age, even with generous assumptions. If these assumptions are less favorable,
screening could result in a net harm.

Qualifying Statements:
Men who have first-degree relatives with prostate cancer and black men have a higher lifetime
risk for developing prostate cancer. Some authorities recommend earlier and more aggressive
testing in this population. However, no direct or indirect evidence from large studies qualifies
these recommendations.

American Cancer Society (ACS)

Title: ACS prostate cancer screening guideline: update 1997.
Source: CA Cancer J Clin 1997 Sep-Oct;47(5): 261-4.
Release Date: 1997
Funding: American Cancer Society


                                                13
Major Recommendations:
The American Cancer Society recommends that both DRE/PSA should be offered annually,
beginning at 50 years of age, to men with life expectancy of at least ten years, and to younger
men who are at high risk. Information should be given to patient regarding the potential risks
and benefits of intervention.
    Men who choose to undergo screening should begin at age 50 years. However, black
       men and those with a family history of first-degree relatives with prostate cancer may be
       at a younger age (e.g. 45 years). More data on the precise age to start prostate cancer
       screening are needed for men at high risk.
    Screening for prostate cancer in asymptomatic men can detect tumors at a more favorable
       stage (confined to the prostate). Mortality from prostate cancer has decreased, but it has
       not been established that this is secondary to screening efforts.
    Health care professionals skilled in recognizing subtle prostate abnormalities, including
       those of symmetry and consistency, as well as the more classic finding of marked
       induration or nodules, should perform DRE of the prostate.

Potential benefits:
Prostate cancer screening may result in the diagnosis of earlier-stage disease in younger men,
which may decrease prostate cancer mortality rates.
Subgroups most likely to benefit:
African-American men experience the highest prostate cancer incidence rates in the world, and
associated mortality rates are twice those of white men.

Potential Harms:
Some cancers detected by prostate cancer screening may be latent or indolent and thus may be
unlikely to produce clinical symptoms or affect survival. Because there are no methods to
distinguish between slow-growing cancers and more clinically significant early-stage cancers,
men whose screening results are positive are faced with the difficult decision of whether to
submit to curative therapy and the associated risks.

Qualifying statements:
No direct evidence exists to date to show that prostate cancer screening decreases prostate cancer
mortality rates.

United States Preventive Services Task Force (USPSTF)

Title: Screening for prostate cancer
Source: Guide to clinical preventive services. 2nd ed. Baltimore (MD): Williams & Wilkins;
1996. 119-34.
Release Date: 1996
Funding: United States Government
Major recommendations:
Routine screening for prostate cancer with DRE, PSA, or TRUS is not recommended (“D”
recommendation). Patients who request screening should be given objective information about
the potential benefits and risks of early detection and treatment. If screening is to be performed,
the best-evaluated approach is to screen with DRE/PSA and to limit screening to men with a life


                                                14
expectancy of ten years. There is currently insufficient evidence to determine the need and
optimal interval for repeating screening or whether PSA thresholds must be adjusted for density,
velocity, or age.
                                      Strength of Recommendations
      A. There is good evidence to support the recommendation that the condition be specifically
         considered in a periodic health examination.
      B. There is fair evidence to support the recommendation that the condition be specifically
         considered in a periodic health examination.
      C. There is insufficient evidence to recommend for or against the inclusion of the condition in a
         periodic health examination, but recommendations may be made on other grounds.
      D. There is fair evidence to support the recommendation that the condition be excluded from
         consideration in a periodic health examination.
      E. There is good evidence to support the recommendation that the condition be excluded from
         consideration in a periodic health examination.


Type of Evidence:
      Intervention                                                     Level of Evidence
        Routine DRE                                                    II-2
        Routine PSA                                                    I, II-2, III
        Routine TRUS                                                   II-2, III

                                             Level of Evidence
 I:    Evidence obtained from at least one randomized controlled trial
 II-1: Evidence obtained from well-designed controlled trials without randomization
 II-2: Evidence obtained from well-designed cohort or case-control analytic studies, preferably from more
       than one center or research group.
 II-3: Evidence obtained from multiple time series with or without the intervention. Dramatic results in
       uncontrolled experiments could also be regarded as this type evidence.
 III: Opinions of respected authorities, based on clinical experience, descriptive studies and case reports;
        or reports of expert committees.


Potential Benefits:
Decreased complications associated with screening and resultant treatment of prostate cancer.

Potential Harms:
Widespread screening will subject many men to anxiety from abnormal test results and the
discomfort of prostate biopsies; aggressive treatment for screen-detected cancers will expose
thousands of men to the risks of incontinence, impotence, death, and other sequelae without clear
benefit.

Qualifying Statements:
Recommendations appearing in this report are intended as guidelines, providing clinicians with
information on proven effectiveness of preventive services published in clinical research.
Recommendations for or against performing these maneuvers should not be interpreted as
standards of care but rather as statements regarding the quality of the supporting scientific
evidence.




                                                        15
Canadian Task Force on Preventive Health Care

Title: Screening for prostate cancer
Source: Canadian Task Force on the Periodic Health Examination. Ottawa (Canada): Health
Canada; 1994. p. 812-23.
Release Date: June 1994 (Reviewed 1999)
Funding: Health Canada
Major Recommendations:
     Poor evidence exists to include or exclude DRE in the periodic health examination (PHE)
       for men > 50 years of age (C, II-2, II-3). Insufficient evidence exists to have physicians
       who presently do the procedure change their behavior.
     Fair evidence exists to exclude PSA testing from the PHE for men > 50 years of age (D,
       II-3).
     Fair evidence exists to exclude TRUS from the PHE for men > 50 years of age (D, II-3).

Potential Benefits:
No studies have been done that show screening to be beneficial. Some evidence exists that for
early prostate cancer, no therapy has beneficial effects. No RCTs have been done to evaluate
aggressive treatment of prostate cancers, although two are underway in the United States and
Europe.

Potential Harms:
The PPV for prostate cancer screening with PSA is 8-33%. Some evidence shows that 67-92%
of men with an elevated PSA will have an unnecessary biopsy. One must also take into account
the risks related to aggressive treatment – death, incontinence, impotency, strictures, and bowel
injury.


American College of Preventive Medicine

Title: Screening for prostate cancer in American men
Source: Am J Prev Med 1998 Jul; 15(1): 81-4
Release date: 1998
Funding: American College of Preventive Medicine
Major Recommendations:
The American College of Preventive Medicine recommends against routine population screening
with DRE/PSA. Men age 50 or older with a life expectancy greater than 10 years should be
given information about the potential benefits and harms of screening for prostate cancer, as well
as, the limits of current evidence and should be allowed to make their own choice, in
consultation with their physician.

Potential Benefits:
Decreased morbidity and mortality due to prostate cancer

Potential Harms:
Both screening and treatment can be harmful


                                               16
          A positive DRE and/or PSA requiring repeat testing can lead to more invasive diagnostic
           tests, such as needle biopsy, which carries a small risk of infection, sepsis, or bleeding.
          Radical prostatectomy and radiation therapy can produce serious complications affecting
           quality of life such as incontinence, erectile dysfunction, strictures, bowel dysfunction,
           and death.
          Little is known about the psychological burden involved in prostate cancer screening and
           the decision-making regarding treatment.

Qualifying Statements:
   There is no direct evidence whether or not early detection and treatment of prostate
       cancer reduces mortality because RCTs to address this question have not been completed.
   The effectiveness of treatment of prostate cancer is also uncertain. Well-designed RCTs
       of surgery, radiation, and other treatment modalities have not been completed.

What Is The Future Of Prostate Cancer Screening?
There have been numerous attempts to improve the efficacy of prostate cancer screening and
many more are still under investigation. Here is a little insight in to what is currently available
and what is on its way.

Age-Adjusted PSA
By adjusting the “normal” range for PSA values, the sensitivity, specificity, and PPV can be
improved24. The ultimate value of this approach is to lessen the number of unnecessary biopsies
in older patients and perhaps increase the detection rate in younger men.

              Age-Adjustment: White Males                     Age-Adjustment: Black Males
           40-49 years-old       0-2.5ng/ml               40-49 years-old        0-2.0ng/ml
           50-59 years-old       0-3.5ng/ml               50-59 years-old        0-4.0ng/ml
           60-69 years-old       0-4.5ng/ml               60-69 years-old        0-4.5ng/ml
           70-79 years old       0-6.5ng/ml               70-79 years old        0-5.5ng/ml



One study comparing the use of age-adjusted PSA with the standard of > 4.0ng/ml demonstrated
an increase in the PPV, but at a cost of reducing the number of cancers detected (4.1% vs. 5.3%
of all cancers detected). The author determined that using a standard serum PSA cutoff of
4.0ng/ml would have saved 182 more life-years compared with using age-adjusted PSA24.
Another study of 6600 men 50 years of age or older, those with PSA > 4.0ng/ml or abnormal
DRE underwent biopsy, their results were as noted24:
     A decrease in PSA cutoff to 3.5ng/ml in men 50-59 years of age with normal DRE would
         result in 45% increase in the number of biopsies and a projected 15% increase in the
         number cancers detected.
     An increase in the PSA cutoff to 4.5ng/ml in men 60-69 years of age would result in 15%
         fewer biopsies, but 8% of organ-confined tumors would be missed.
     An increase in the PSA cutoff to 6.5ng/ml in men 70 years of age or older resulted in
         44% fewer biopsies but missed 47% of organ-confined cancers.




                                                   17
Although controversial, it appears that age-adjusted reference ranges will improve case findings
in men younger than 60 years of age; these patients represent the group that stands to gain the
most from screening for prostate cancer.

Serum Free and Bound PSA
Serum PSA exists in multiple forms; it is predominately bound to protease inhibitors, although
one form remains free in the serum. For reasons that are not well understood, the percentage of
free PSA is lower in the serum of individuals with prostate cancer compared to those with
normal prostates or BPH24. A lower free PSA may also be associated with more aggressive
cancers.
The optimal cutoff for Free:Bound PSA to differentiate prostate cancer from other benign
prostate pathologies is unclear. Currently three studies support increased sensitivity, specificity,
and PPV with cutoffs 15-41%30.

PSA Velocity
PSA velocity refers to the rate of change of serum PSA over time. Patients with elevated PSA
levels at baseline that continue to rise over time are more likely to harbor prostate cancer than
those with consistently stable elevations. A serum PSA change greater than 0.75ng/ml per year
is suggestive of prostate cancer. In one study, using PSA velocity cutoff of 0.75ng/ml per year
distinguished patients with prostate cancer from those with either BPH or no prostate disease
with a specificity of 90% and 100%, respectively24.

PSA Density
The PSA density refers to a numerical ratio calculated by dividing the serum PSA by the volume
of the prostate gland as determined by TRUS. An elevated PSA density (>0.15) may be more
suggestive of the presence of prostate cancer than an elevated serum PSA alone, since prostate
cancer elaborates more PSA per gram of tissue than normal prostate tissue or benign prostatic
hyperplasia.
A study of 61 men with prostatic disease clinically confined to the prostate (41 with cancer, 20
with BPH) had PSA densities calculated. The mean PSA densities for prostate cancer and BPH
were 0.581 and 0.044, respectively24.
A second study confirmed a high PPV for PSA density. Among men with a persistently elevated
PSA despite a normal biopsy, a PSA density > 0.15 predicted that a subsequent biopsy had a
greater than 80% likelihood of showing cancer24.
Although PSA density is promising, there is significant intrapatient variation (up to 15%) on
repeat testing making it difficult to interpret.

Radiology
Some preliminary studies show promise for CT/MRI studies as a non-invasive work-up of
positive DRE/PSA testing30,31.



Conclusions:
There are two main philosophical views concerning early detection. One view holds that the
major goal is to search aggressively for asymptomatic cancer and having found it, remove it.
While the effectiveness of therapy may not be established, and its associated adverse affects may


                                                18
be recognized, the main mission is to detect cancer early. This view emphasizes the importance
of using existing tests or developing new tests that can improve early detection and reduce the
number of false positive tests, as well as, expanding research to demonstrate mortality/morbidity
benefit of early detection. The second view uses evidence-based medicine as the sole foundation
for its recommendations. This appears to be the most logical method, but there is essentially no
true evidence for or against screening for prostate cancer in terms of mortality benefit. There is
significant evidence with respect to treatment morbidity, suggesting that currently screening
exposes patients to known harm without proven benefit. One must attempt to combine these two
viewpoints, which generally entails helping patients who are at higher risk, cancer "phobic", or
willing to accept screening and treatment side-effects make an educated decision of whether to
undergo screening. The ACP-ASIM and AUA appear to have the most reasonable approach to
prostate cancer screening. Although they disagree on the issue of general population screening,
they both recognize there are significant pros/cons regarding screening and that patients should
be involved in the decision. There is currently multimedia information available to health care
providers and their patients to help educate them when deciding whether to proceed with prostate
cancer screening.


Summary:

   Prostate cancer is a very heterogeneous disease
   Currently, there is no method to determine which cancers will be more aggressive and
    therefore appropriate for early detection and treatment
   African-American men and those men with first-degree relatives with a history of prostate
    cancer are at a significantly increased risk for developing the disease. Currently available
    data does not support treating these men any differently.
   Even the expects cannot agree on a screening strategy
   The currently available tests lack sensitivity, specificity, and PPV – even the gold standard to
    which all other screening tests are compared
   There are no concrete data for or against prostate cancer screening
   The most reasonable approach involves educating patients about the pros/cons of screening
    and treatment, level of supporting evidence, and risks factors for developing cancer. After
    discussion with their health care professional, patients can make an informed decision
    whether to proceed with prostate cancer screening.
   To date, attempts to improve the efficacy of prostate cancer screening have been
    unsuccessful.
   We can only hope that the trials that are presently underway will provide the information
    needed to solve this controversial issue.




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