Correspondence

PSA Velocity and Prostate Cancer

N Engl J Med 2004; 351:1800-1802October 21, 2004

Article

To the Editor:

There are some basic methodologic flaws in the work by D'Amico et al. (July 8 issue).1 In their multivariate analyses, the prostate-specific antigen (PSA) velocity was modeled as a binary variable on the basis of a threshold of 2.0 ng per milliliter per year. This threshold was selected on the basis of a univariate analysis of the same data, and hence the P values for all the multivariate analyses are overly optimistic. The multivariate analyses are central to the report, since they are the basis for claims that the PSA velocity provides prognostic information beyond that provided by the standard prognostic variables. Hilsenbeck and Clark2 and Altman et al.3 have previously discussed statistical errors that result from the analysis of data with optimally selected cutoff points determined on the basis of the same set of data. Although the cutoff point of 2.0 ng per milliliter per year was the optimal quartile for the data presented by D'Amico et al., further validation with independent data, with other known prognostic variables taken into account, is necessary before this index can be recommended for clinical use or for risk stratification in clinical trials.

Lori E. Dodd, Ph.D.
Richard Simon, Sc.D.
National Cancer Institute, Rockville, MD 20852
doddl@mail.nih.gov

3 References

1. 1

   D'Amico AV, Chen MH, Roehl KA, Catalona WJ. Preoperative PSA velocity and the risk of death from prostate cancer after radical prostatectomy. N Engl J Med 2004;351:125-135
   Full Text | Web of Science | Medline

2. 2

   Hilsenbeck SG, Clark GM. Practical p-value adjustment for optimally selected cutpoints. Stat Med 1996;14:103-112
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3. 3

   Altman DG, Lausen B, Sauerbrei W, Schumacher M. Dangers of using “optimal“ cutpoints in the evaluation of prognostic factors. J Natl Cancer Inst 1994;86:829-835
   CrossRef | Web of Science | Medline

To the Editor:

The provocative implications of the report by D'Amico et al. raise concerns about the use of a single, nonvalidated prognostic variable to select patients for adjuvant systemic therapy after radical prostatectomy. Some 68 to 75 percent of patients have no evidence of cancer (i.e., undetectable PSA levels), and only 7 percent die of cancer within 15 years after surgical treatment.1,2 The key questions with regard to adjuvant therapy after surgery are what level of risk justifies the potential side effects and how best to quantify the risk. Furthermore, the prognostic value of a PSA level that rises at a rate of more than 2.0 ng per milliliter per year before radical prostatectomy is clouded by biologic and interassay variations that average 30 percent in men without cancer.3 Some men could have an increase of 2.0 ng per milliliter per year by chance alone. Nomograms that incorporate all known risk factors to estimate probabilities of an event over time (e.g., recurrence) perform better than any single risk factor or risk group.4 A rapid rate of rise in the PSA level before surgery may be associated with a more advanced stage of cancer. However, it has not been validated by independent cohort studies as a prognostic factor to be applied in clinical trials (Figure 1Figure 1Probability of Freedom from Recurrence of Prostate Cancer, According to PSA Velocity.).

Fernando J. Bianco, Jr., M.D.
Michael W. Kattan, Ph.D.
Peter T. Scardino, M.D.
Memorial Sloan-Kettering Cancer Center, New York, NY 10021
scardinp@mskcc.org

4 References

1. 1

   Walsh PC. Surgery and the reduction of mortality from prostate cancer. N Engl J Med 2002;347:839-840
   Full Text | Web of Science | Medline

2. 2

   Bianco FJ Jr, Dotan ZA, Kattan MW, Fearn P, Easthan JE, Scardino PT. 15-Year cancer-specific and PSA-progression free rates after radical prostatectomy. J Urol 2004;171:313-314
   Web of Science

3. 3

   Eastham JA, Riedel E, Scardino PT, et al. Variation of serum prostate-specific antigen levels: an evaluation of year-to-year fluctuations. JAMA 2003;289:2695-2700
   CrossRef | Web of Science | Medline

4. 4

   Kattan MW. Nomograms are superior to staging and risk grouping systems for identifying high-risk patients: preoperative application in prostate cancer. Curr Opin Urol 2003;13:111-116
   CrossRef | Web of Science | Medline

Author/Editor Response

In response to the thoughtful comments of Dr. Bianco and colleagues and Drs. Dodd and Simon, we report in Table 2 of our article that several factors in addition to the PSA velocity (namely, the PSA level, the Gleason score on biopsy, and the clinical tumor stage) contributed significantly to the risk of cancer-specific death. An explanation for the nearly significant association between the preoperative PSA velocity and the time to recurrence shown in the figure provided by Dr. Bianco and colleagues may be that the median follow-up in their cohort was shorter than that in ours (3.4 years vs. 5.1 years). In addition, comparing 7-year estimates of mortality within a cohort followed for a median of 3.4 years is problematic, in that true mortality at 7 years will be underestimated, and comparisons at that time point are limited because of limited data. Finally, the way PSA velocity was calculated needs clarification. In our study, the PSA velocity was calculated on the basis of measurements obtained at least six months apart, and all PSA samples were analyzed in a single laboratory with equivalent assays. Calculating the PSA velocity on the basis of values that are spaced less than six months apart or on the basis of PSA levels obtained with the use of a variety of methods or assays can lead to an erroneous value for the PSA velocity.

Despite these potential limitations, the association of a PSA velocity of more than 2.0 ng per milliliter per year with a shorter time to recurrence in an independent data set is noteworthy. The risk of recurrence is the basis for inclusion in clinical trials of treatment for localized prostate cancer. Our study supports reported associations between an elevated PSA velocity and advanced stage and grade at prostatectomy1 and a rapid PSA doubling time,2 as well as between a PSA velocity of more than 2.0 ng per milliliter per year and a shorter time to recurrence. A PSA velocity of more than 2.0 ng per milliliter per year, in conjunction with other predictive factors,3 may help stratify patients with surgically managed disease into categories according to the risk of recurrence, for inclusion in clinical trials.

Anthony V. D'Amico, M.D., Ph.D.
Brigham and Women's Hospital, Boston, MA 02115
adamico@lroc.harvard.edu

Ming-Hui Chen, Ph.D.
University of Connecticut, Storrs, CT 06262-0003

William J. Catalona, M.D.
Northwestern Feinberg School of Medicine, Chicago, IL 60611-3111

3 References

1. 1

   Carter HB, Pearson JD, Metter EJ, et al. Longitudinal evaluation of prostate-specific antigen levels in men with and without prostate disease. JAMA 1992;267:2215-2220
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2. 2

   Egawa S, Arai Y, Tobisu K, et al. Use of pretreatment prostate-specific antigen doubling time to predict outcome after radical prostatectomy. Prostate Cancer Prostatic Dis 2000;3:269-274
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3. 3

   D'Amico AV, Moul J, Carroll PR, Sun L, Lubeck D, Chen MH. Cancer-specific mortality following surgery or radiation for patients with clinically localized prostate cancer managed during the PSA era. J Clin Oncol 2003;21:2163-2172
   CrossRef | Web of Science | Medline

Citing Articles (6)

Citing Articles

1. 1

   James A. Eastham, Christopher P. Evans, Anthony Zietman. (2010) What is the optimal management of high risk, clinically localized prostate cancer?. Urologic Oncology: Seminars and Original Investigations 28:5, 557-567
   CrossRef

2. 2

   Jean-Pierre Droz, Lodovico Balducci, Michel Bolla, Mark Emberton, John M. Fitzpatrick, Steven Joniau, Michael W. Kattan, Silvio Monfardini, Judd W. Moul, Arash Naeim, Hendrik van Poppel, Fred Saad, Cora N. Sternberg. (2010) Background for the proposal of SIOG guidelines for the management of prostate cancer in senior adults. Critical Reviews in Oncology/Hematology 73:1, 68-91
   CrossRef

3. 3

   John M. Fitzpatrick, Eugeniu Banu, Stephane Oudard. (2009) Prostate-specific antigen kinetics in localized and advanced prostate cancer. BJU International 103:5, 578-587
   CrossRef

4. 4

   Ofer Yossepowitch, James A. Eastham. (2008) Role of radical prostatectomy in the treatment of high-risk prostate cancer. Current Prostate Reports 6:3, 107-114
   CrossRef

5. 5

   Ofer Yossepowitch, James A. Eastham. (2008) Radical prostatectomy for high-risk prostate cancer. World Journal of Urology 26:3, 219-224
   CrossRef

6. 6

   Ofer Yossepowitch, James A. Eastham. (2008) Role of radical prostatectomy in the treatment of high-risk prostate cancer. Current Urology Reports 9:3, 203-210
   CrossRef