Early Detection of Prostate Cancer Guideline

Conference Coverage
Practice Update
Tony Nimeh MD

Friday May 16 1 – 5 p.m.
Orange County Convention Center: Chapin Theater
Moderator: Fritz H. Schroder, M.D.
Pro: H. Ballentine Carter, MD
Pro: Ian M. Thompson, Jr, MD
Con: William J. Catalona, MD
Con: Issac Powell
Summary of the PRO arguments:

1- The guidelines follow the AUA mandate and apply the AUA grades correctly

2- The AUA standards are defined based on current evidence of benefits and harms

3- There is space for shared decision between physician /  expert opinion & patients

4- The recommendations differ by age group

5- The harms of applying testing for PCA are adequately considered

Summary of the CON arguments:

1- The guidelines do not specifically consider higher risk groups

2- Do survival differences justify application to secondary prevention?

3- Make more specific recommendations for men younger than 55 and older than 69

4- Clearly differentiate screening and testing upon request and by shared decision taking

5- The field of early detection develops rapidly, timely revision of the guidelines is necessary.

Pro: Ian M. Thompson, Jr, MD

Dr. Thompson argued that the purpose of the AUA guidelines’s purpose was to provide  evidence-based evaluation of prostate cancer detection to reduce prostate cancer mortality.  The Statements are based on evidence, not values, opinon, or clinical experience.  They are designed to assist in advising an “average” risk man without symptoms about prostate cancer screening.  The process was transparent based on the Institute of Medicine Recommendations for a “trustworthy Guidelline”  and is focused on transparencey, conflict of interest management, multidisciplinary panel, systematic review by methodology team, rating of evidence strength, and external review and plan for updating.  It is an extremely rigorous process. The members of the panel participants included a broad range of expertise and disciplines.  The panel performed a systematic review of 324 prostate cancer diagnosis/screening studies meeting review criteria from 1995 to 2013 and the methodology was substantially different from conclusions reached by selectively citing specific studies or observations to support a point of view.

Review of the guideline statements:

  1. Recommend against PSA-based screening for men <40 yo because of the low prevalence of detectable prostate cancer, lack of evidence of screening benefit and likely similar harms of screening as other ages.
  2. Routine screening not recommended in men between 40-54 yo at average risk because the quality of evidence of benefit is marginal and the quality of evidence of harm is high.
    • For men <55 yo with higher than average risk (e.g. African American men and men with a family history): the decision regarding prostate cancer screening should be individualized based on personal preferences, discussion of the uncertainty of benefit and the harms of screening.
  1. For men aged 55-69 yo, a shared decision making should take place and proceed based on patients’ values/ preferences. The discussion should weigh the benefit of preventing 1 prostate cancer death per 1000 screened over a decade vs the harms of screening and treatment. Of note, this is significantly different from the US Preventative Services Task Force which recommends against screening.
  • Men aged 55 -69 should not be screened in the absence of shared-decision making (e.g. health fairs, health system promotions, etc)
  • To reduce the harms, less frequent screening (e.g. 2 years) likely preserves the majority of benefits and reduces over diagnosis and false positives.
  1. For men > 70: the panel recommended against routine PSA-based screening or in any patient with less than a 10-15 year life expectancy. This is because although some men >70 who are in excellent health may benefit from prostate cancer screening but the absolute reduction in moretaliy while possible is likely small and the potential for harm is high, or at least higher than benefit.

Pro: H. Ballentine Carter, MD

Dr. Carter (PRO) argued that screening for cancer is a form of prevention: the bar is high for proving that lifetime benefit outweigh harms.  The quality of the evidence for screening was moderate and for harm was high.

The panel did not use the PLCO trial to inform the benefit of screening because the PLCO trial was not informative of screening benefits. Negative trial did not compare PSA screening to none.  The controls were opportunistic screening with an average of 2.7 tests over 6 years; the intervention were organized screening with an average of 5 tests over 6 years.

The panel used the European ERSPC trial to provide the evidence for the benefits of screening men age 55 to 69 yo (Schroder et al, N Engl J Med 2012).  In that trial, the benefits were no all equally distributed across populations (7 countries) or across age groups. The benefits accrued with time, but remained modest after a decade of screening, increasing from 0.71 to 1.07 deaths prevented per 1000 men with 2 additional years of follow-up.

The panel had to consider harms of screening such as biopsy complications: In 2 separate studies there was a 4% 30-day hospitalization risk (Nam, J Urol 2010; Loeb, J Urol 2011) which would translate into 4-5 men/hour requiring hospitalization post biopsy in the U.S. with over a 1,000,000 men getting a biopsy per year. Most concerning however, is over diagnosis and over treatment: ~1 in 4 men would not have known they had cancer without screening (Heijnskijk et al, Br J Cancer 2009) .  Also, there is an important risk of over diagnosis and over-treatment which causes significant downsides & side-effects such as impotence and incontinence. This is considered the main downside of screening in most countries, preventing the introduction of screening for PCa in most countries (Schroder FH et al, Eur Urol 2012).

Dr. Carter argued that there is a modest benefit to PSA based screening over a decade for men age 55-69 yo that may be greater over a longer time.  The current approach to screening and treatment in the US leaves reasonable doubt if the benefits outweigh the substantial risks; “more information on the balance of benefits and adverse effects is needed before general recommendations can be made”. Targeted screening of those most likely to benefit from treatment would reduce harms.

Dr. Carter argued that the harms of PCa screening are not over-estimated such as treatment related hospitalization (1 in 30), erectile dysfunction (1 in 30), incontinence (1 in 50), treatment related rectal anal procedures (1 in 50), and diagnostic and/or treatment-related death (1 in 300).

Dr. Carter argued that beyond the age of 70, there is no evidence of screening benefit in ERSPC (Schroder FH et al, N Engl J Med 2012) and that treatment benefit comparing watchful waiting to surgery showed no significant absolute risk reduction beyond the age of 65 (Bill-Axelson A et al, N Engl J Med 2011; 2014)

Dr. Carter argued that the AUA Guideline is not a recommendation against PSA based screening outside the age range of 55-69, it is rather a recommendation against routine screening of average risk, asymptomatic men outside the age range of 55-69 yo, it is a call for abandoning a “one size fits all” approach replaced by targeting those most likely to benefit from screening.

CON: William J. Catalona, MD

Dr. Catalona (CON) argued that prostate cancer is a devastating & deadly disease affecting real patients that may be prevented by early detection and treatment.   The guidelines are based on incomplete and flawed data and inaccurate estimates of the beneftis and harms of PSA testing. They are untenable for providing optimal care to men younger than 55 or older than 70.

The Guideline Panel’s mandate was to produce evidence-based recommendations but it did not go beyond the available yet poor quality level-1 evidence from randomized clinical trials for the benefits of PSA screening.  The panel placed too much weight on the poor-quality clinical trials.  The panel considered only level-1 evidene for benefits, yet for harms it used non-level-1 evidence and cited older studies that clearly overestimate harms.

Overestimating harm: Dr. Catalona argued that because mortality benefits in clinical trials takes time to become apparent, in the short term, trial results underestimate the absolute benefits of screening over a man’s lifetime.  The early trial data also exaggerates overidagnosis because many of the excess cases detected in the screening arm of a trial (which is a proxy for overdiagnosis) are true early detected life-treatening cancers that get counted as overdiagnosed cases.

The AUA linked the risks of PSA testing with the risks of treatment wrongly assuming that every prostate cancer paritnet receives treatment. This assumption does not take into account active surveillance: an increasingly popular treatment option and becoming standard of care.

The AUA Guidelines say that we must tell patients that “You would have to screen 1000 men to prevent 1 PCa death”; however, statistical modeling studies estimate that the additional number of cancers needed to be detected to prevent 1 PCa death is only 5 (Heijnskijk, NEJM 2013; Gulati Ann Int Med 2013).   The panel ignored the important fact that PSA testing reduces metastases, which substantially shifts balance towards benefits and away from harm.

Other professional organizations (EAU NCCN, ASCO, ACS, ACP, Melbourne) reviewed the same body of evidence yet created more liberal screening guidelines.  In many guidelines, PSA testing is recommended for men in their 40s and early 50s.

Higher risk men: A baseline PSA >1.0 in men in 40’s is a strong risk factor for life-threatening PCa; therefore, one cannot identify most high-risk men without measuring a baseline PSA in early mid-life.

The AUA guideline panel stated that they “do not recommend” screening average risk men younger than 55 yo or older than 70 but at most, they should have said “there are insufficient data to recommend for or against” screening these men.

Most other guidelines recommend screening for men with >10 year life expectancy (Ref: ASCO, EAU, ACS, NCCN, Melbourne): in the U.S., life expectancy at age 70 is 15 years and older men have a far greater risk for aggressive disease which may benefit from early detection of an aggressive tumor.

In the Goteborg trial, 9 years after screening was stopped at upper age limit of 69, the incidence of high-risk and fatal prostate cancer increased in the screening arm until it equaled that of the unscreened arm.  Furthermore, the NCI surveillance modeling network has projected that if screening were phased out in 2012, the number of cases of distant stage disease would return to the pre-PSA screening era levels by the year 2025. The AUA Guideline State that the preferred screening interval may be 2 years or more, but the PSA can go from 2.4 to 24 in 2 years and longer screening intervals may detec aggressive cancers too late; thus doing more harm than good.

The AUA guideliens suggested increasing the PSA biopsy threshold to >10 for men over 70 based on the PIVOT data however, because high-grade cancers produce less PSA on a per-cell basis, higher PSA thresholds may not provide timely detection of aggressive cancers.

Conclusions:

Dr. Schroder concluded by mentioning the following points:

  • The AUA mandate for production of guidelines are adequate
  • The inclusion of decision taking with low level and lacking evidence addresses clinical needs
  • Constructive views presented as PRO and CON can be applied in pending guideline revisions
  • The AUA recommendations to revise guidelines every 12-18 months seems wise and should be applied.