Prostate cancer screen: rectal exam not helpful

 A new systematic review and meta-analysis found that digital rectal exam (DRE) did not add any useful information about detecting prostate cancer above and beyond that of PSA (prostate-specific antigen) screening (see prostate ca DRE adds little EurUrolOnc2024 in dropbox, or doi.org/10.1016/j.euo.2023.12.005)

 

Details:

-- a general search was done in August 2023 identifying prospective studies simultaneously investigating the diagnostic performance of DRE and PSA for prostate cancer (PCa) screening

-- eight studies were identified including 85,738 participants, three were randomized controlled trials and five were prospective diagnostic studies, all reporting the positive predictive value (PPV) and cancer detection rate (CDR) of both DRE and PSA for the same cohort of patients

    -- studies were excluded if they did not have original patient data or were not formal studies, if they did not conduct both DRE and PSA on that same cohort, if they enrolled participants with clinically suspected PCa or urinary symptoms. The goal was clearly to involve studies with a community-based population, specifically those composed of randomly selected individuals gathered for screening purposes only

    -- their Table 1 has a lot of the important aspects of the individual 8 studies, noting the differences in numbers of individuals in the different studies (from 241 to 38,350), the age groups, definitions of suspicious or abnormal DRE findings, cutpoints of PSA values leading to biopsies, biopsy techniques, Gleason scores on the biopsies done, and stage of cancers detected

-- primary endpoints: positive predictive value (PPV) and cancer detection rate (CDR) of DRE

-- secondary endpoints: PPV and CDR of both PSA alone and in combination with DRE, specifically to compare the CDR and PPV of different screening strategies

 

Results:

-- PPV for different groupings of screening test done from the pooled group of patients:

    -- DRE: PPV 0.21 (0.13-0.33)

    -- PSA: PPV 0.22 (0.15-0.30)

        -- no statistically significant difference between the groups, p=0.9

    -- DRE plus PSA: PPV 0.19 (0.13-0.26), p=0.5, no significant difference

-- CDR:

    -- DRE: 0.01 (0.01-0.02)

    -- PSA: 0.03 (0.02-0.03)

    -- DRE plus PSA: 0.03 (0.02-0.04)

        -- there was a statistically significant difference for both the comparisons of PSA to DRE as well as for the combination of DRE and PSA to DRE alone (both with p<0.05)

 

-- there was significant heterogeneity in all of the studies for DRE, PSA, and the combination of the two, all with p<0.001, as is clear from their figure 2:

 

 

 

Commentary:

-- DRE has been assessed as a means to detect early prostate cancer, well before the advent of the PSA test. However, even many early studies did not find it was so great:

    -- studies have found that DRE is much less predictive of PCa when done by non-urologists: in a study of 2102 men who were biopsied, 443 had PCa. Suspicious DREs varied between 4% to 28%, with 3 of 6 examiners feeling that DRE was significantly more abnormal than the others. (though urologists have much higher concordance of findings, up to 94%): https://onlinelibrary.wiley.com/doi/10.1002/pros.20759 .

    -- a more recent German study found that of 46K men having DRE done at age 45, as recommended in Germany, 57 had suspicious lesions, but only 3 had prostate cancer (PSA screening had a 4-fold higher detection rate, DRE had a false-positive rate of 2.2, 86% of men with non-suspicious DREs had PSA-detected prostate cancer ( https://www.sciencedirect.com/science/article/abs/pii/S2588931123002031 ) [i was unable to get this article through 2 academic medical center libraries, only this abstract. It seems that some of these numbers are quite high, so would have liked to check it]

    -- studies have also found that DRE testing is often considered unpleasant by men (though I suspect that pelvic exams are not the most pleasant things for women…..), and could possibly be a factor in decreasing some men’s engaging in primary care. For example, 17% of men in one study put off seeing a doctor for at least a year for fear of getting a rectal exam (though this study was assessing the exam adherence for men with symptoms of rectal cancer, which may be different from routine screening of asymptomatic men by rectal exam for PCa): https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3320717/ . I guess this is why men are often considered the weaker sex….

 

-- this is not to say that PSA is a great test:

    -- it is unclear what the appropriate PSA cutpoint should be for pursuing a further assessment (eg multiple biopsies): in the US we typically use 4.0 ng/mL, though many studies (especially in other countries) use the 3.0 ng/mL value, the latter being more sensitive, leading to more PCa’s picked up, but 3.0 is much less specific, with many more men undergoing negative biopsies

        -- the Prostate Cancer Prevention Trial in 2003 found that 6.6% of men with PSA <0.5 ng/mL had prostate cancer on biopsy (this was in the placebo group in a study of finasteride to prevent cancer, where many men in that placebo group volunteered to have prostate biopsies…), which increased progressively until the 3.1-4.0 ng/mL range where there were 27% with PCa. And, of those with cancer but PSA <0.5 ng/mL, 15% had a Gleason grade of 7-10 (ie were considered to have high-grade cancers): https://gmodestmedblogs.blogspot.com/2013/10/low-psa-but-prostate-cancer.html

        -- and there are several studies suggesting that most men with prostate cancer do not die from it (high false positive rate). Per the American Cancer Society, prostate cancer is the most common cancer in men (other than skin cancer), with an estimated 299,010 men expected to be diagnosed with prostate cancer in 2024. However, only 35,250 prostate cancer deaths are projected (1 in 8 men are diagnosed, but 1 in 44 men die from it): https://www.cancer.org/cancer/types/prostate-cancer/about/key-statistics.html . So, prostate cancer has a huge prevalence in the US, but a smaller number of men seem to die from it, though still lots of men do die.  so being able to pick up PCa’s early is important but there is the cost that many may get unnecessarily pretty toxic interventions (surgery, radiation, meds). If only there were a better marker of what would become bad, clinically-significant PCa…..

 

-- this current study found that:

    -- the cancer detection rate was significantly higher by PSA than DRE (though the PPV was similar)

    -- the combination of DRE and PSA screening yielded no benefit over just doing PSA screening alone

 

-- the international guidelines are mixed on the role of DRE screening in the detection of prostate cancer

    -- the 2023 AUA/SUO guidelines (American Urological Association along with the Society of Urologic Oncology) take a middle-of-the-road position, stating that “clinicians may use digital rectal exam (DRE) alongside PSA to establish risk of clinically significant prostate cancer”, a conditional recommendation; evidence level, grade C: https://www.auanet.org/guidelines-and-quality/guidelines/early-detection-of-prostate-cancer-guidelines

    -- an amalgam of European societies including the European Association of Urology, in 2023 “informed men requesting an early diagnosis should be given a PSA test and undergo a DRE”: https://d56bochluxqnz.cloudfront.net/documents/full-guideline/EAU-EANM-ESTRO-ESUR-ISUP-SIOG-Guidelines-on-Prostate-Cancer-2023_2023-06-13-141145.pdf

        -- however, of note, this current systematic review/meta-analysis was published by the European Association of Urology, though in December 2023 after these guidelines were published

 

Limitations:

-- as a meta-analysis, they are combining different studies with different patients of different ages, different PSA levels, different cancer stages, some difference in definitions of abnormal DREs and PSA levels, different numbers of prostate biopsies done and different techniques for performing biopsies. This could undercut their conclusions and generalizability of their results

-- there were also differences in the groups of men in the studies; prevalence of abnormal  screening tests in different studies (and therefore the generalizability of results to a community-based group of average PCa risk), and even the percent of men with abnormal findings who actually had a biopsy (eg, in one study, only 29 of 82 patients who had positive screens for actually had biopsies done.  ??selection bias).

-- and, a major limitation in the PCa screening done, inherent in the screens themselves as noted above, is the unknown numbers of deaths or serious morbidities related to the detected cancers: how many of these cancers were really clinically significant?

-- also, as found in this study, DRE did not add anything to PSA for large cohorts of patient. it would have been useful to know how many individual men with abnormal DREs actually had PSAs above the cutpoint of 4.0 and would have therefore proceeded to have a PCa workup? If there were many such individuals, then DREs might still have a real role in screening. If PSAs were elevated in essentially all with abnormal DREs, then there would be no added utility for individuals to get DREs at all (though DREs do have other clinical functions, such as diagnosing prostatitis)

 

So, what is one to do??

-- unfortunately, we do not have great, specific tests for early detection of prostate cancer that has a really high likelihood of progressing to a clinical disease that adversely affects both mortality and significant disability/morbidity

-- it does seem from many individual studies (and this systematic review/meta-analysis) that DRE is not very helpful, and perhaps should not be part of the usual screening testing

-- PSA screening does undoubtedly pick up many clinically-important cancers, though also lots of cancers that would not lead to major morbidity/mortality, and surgery/radiation therapy/chemotherapy themselves may well lead to significant morbidity/mortality

-- per the authors of this current study, perhaps doing PSA evaluations and adding MRIs (and their associated result stratification into PI-RADS scores) to the screening process when indicated might help: it seems that MRIs are better at picking up a higher proportion of the clinically significant PCa’s (see the article for their support of replacing the dyad of PSA-DRE with PSA-MRI)

 

-- lots of questions, but the convergence of studies, many included in this systematic review/meta-analysis, point strongly to simplify PCa screening to just ordering PSAs, when screening is appropriate after the usual informed consent process

 

geoff

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