The Journal of Urology
Volume 173, Issue 6 , Pages 2205-2206, June 2005

RE: THE PROSTATE SPECIFIC ANTIGEN ERA IN THE UNITED STATES IS OVER FOR PROSTATE CANCER: WHAT HAPPENED IN THE LAST 20 YEARS?

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Reply by Authors. 

In our 1987 article in The New England Journal of Medicine 91% of the cancers were palpable.1 When we examined the relationship of preoperative PSA to the size of the largest cancer in the peripheral zone (PZ) serum PSA appeared to be proportional to tumor burden at all volumes of cancer. During the ensuing 16 years (1988 to 2004) there was a nearly straight-line decline in this relationship of PSA to the size of the PZ cancer to only 3% in the last 5 years. The big question is what caused this dramatic change in the last 20 years? Part of the answer is that serum PSA never had a great relationship to PZ cancer volume in the first place. This disparity was due in large part to the fact that serum PSA between 2 and 10 ng/ml is determined by benign prostatic hyperplasia in the transition zone, as shown by Roehrborn et al in the control arm of the Pancreas Investigators Vital Outcomes Trial.2 Moreover, our 2002 article based on 875 consecutive radical prostatectomies clearly demonstrated that the spread of preoperative serum PSA values between 1 and 10 (or even 20) ng/ml was so random in its preoperative relationship to the largest cancer in the peripheral zone that PSA is essentially useless for any estimate of PZ cancer size.3

So why do we find so much cancer when we biopsy the prostate at PSA levels between 2 and 20 ng/ml? It is because prostate cancer is ubiquitous, although age dependent. As Sakr et al have shown in men accidentally killed on the streets of Detroit, 8% of those in their twenties have histological evidence of prostate cancer, increasing with each decade of life, until 80% of men in their seventies have prostate cancer.4 Lastly, we as urologists must never forget, and should always tell our patients, that only 226 men per 100,000 who are 65 years or older actually die of prostate cancer—an extraordinarily small risk.

As to the concern over conversion of polyclonal PSA values in the early 1980s to current monoclonal values, all serums from all radical prostatectomies are frozen at −70C in our laboratories. We reran large numbers of the earlier polyclonal PSA serums with a monoclonal-monoclonal assay to ensure our conversion was accurate. The values were close to our “calculated” values. The reviewers are apparently unaware that our laboratory supplies the WHO international PSA calibrator, against which all PSA assays worldwide are standardized.5

As to the p values in table 4 in the article for percent Gleason grade 4/5 as it relates to serum PSA, grade 4/5 was highly significantly related to serum PSA (p <0.001) in the first 5 years (1983 to 1988) but unrelated to serum PSA in the last 5 years (p <0.678). Their respective correlations were 0.274 (1983 to 1988) and 0.031 (1999 to 2003). There simply was not enough grade 4/5 cancer volume in the most recent 5 years to exert any influence on serum PSA, which is in sharp contrast to the 1983 to 1988, 5-year period, where virtually all histological variables in table 4 were related to prostate cancer. There has never been a prostate cancer death caused by well differentiated Gleason grade 1, 2 or 3. It is grade 4/5 cancer that counts.6

I have never seen any convincing data that prostate cancer from the peripheral zone produces more PSA than BPH nodules in the transition zone. It is clearly not true of our 3 mm step section radical prostatectomy data at Stanford, where every radical prostatectomy specimen in the last 20 years has been quantified by a single expert pathologist, John E. McNeal.

Finally, death from prostate cancer may be “elusive” in Austria but the National Cancer Institute in the United States spends millions each year confirming the accuracy of each death certificate. As to the free-to-total PSA ratio, free or “nicked” PSA comes from BPH nodules, not prostate cancer.

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REFERENCES 

  1. Stamey TA , Yang N , Hay AR , McNeal JE , Freiha FS , Redwine E . Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate . N Engl J Med . 1987;317:909
  2. Roehrborn CG , McConnell J , Bonilla J , Rosenblatt S , Hudson PB , Malek GH , et al.   Serum prostate specific antigen is a strong predictor of future prostate growth in men with benign prostatic hyperplasia . J Urol . 2000;163:13
  3. Stamey TA , Johnstone IM , McNeal JE , Lu AY , Yemoto CM . Preoperative serum prostate specific antigen levels between 2 and 22 ng./ml. correlate poorly with post-radical prostatectomy cancer morphology: prostate specific antigen cure rates appear constant between 2 and 9 ng./ml . J Urol . 2002;167:103
  4. Sakr WA , Grignon DJ , Haas GP , Heilbrun LK , Pontes JE , Crissman JD . Age and racial distribution of prostatic intraepithelial neoplasia . Eur Urol . 1996;30:138
  5. Stamey TA . Progress in standardization of immunoassays for prostate-specific antigen . Urol Clin North Am . 1997;24:269
  6. Stamey TA , McNeal JE , Yemoto CM , Sigal BM , Johnstone IM . Biological determinants of cancer progression in men with prostate cancer . JAMA . 1999;281:1395

PII: S0022-5347(05)60291-1

Refers to article:

  • THE PROSTATE SPECIFIC ANTIGEN ERA IN THE UNITED STATES IS OVER FOR PROSTATE CANCER: WHAT HAPPENED IN THE LAST 20 YEARS?

    THOMAS A. STAMEY, MITCHELL CALDWELL, JOHN E. McNEAL, ROSALIE NOLLEY, MARCI HEMENEZ, JOSHUA DOWNS
    The Journal of Urology October 2004 (Vol. 172, Issue 4, Part 1, Pages 1297-1301)

The Journal of Urology
Volume 173, Issue 6 , Pages 2205-2206, June 2005

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