4.0=3.1
How can this be?
22% is a significant difference that can be explained scientifically. The basis for this difference can be attributed to the two PSA calibration materials in a straight-forward way.
In 1994, Hybritech® established the PSA cutoff at 4.0 ng/mL, which was adopted as the threshold for recommending a prostate biopsy. The concentration of PSA in the Hybritech calibration material was determined using the widely accepted Lowry total protein method. In 1995, using other protein quantitation methods, Stamey and his associates determined the molecular weight of PSA to be 28,430 Daltons, ~20% lower than that previously reported by Hybritech scientists. When the World Health Organization (WHO) set out to establish global PSA standardization in 1999, it adopted the molecular weight of PSA assigned by Stamey.
A 22% difference exists between the Hybritech calibrated Access® PSA assay and the WHO 96/670 calibrated assay. This moves the traditional cutoff of 4.0 ng/mL down to 3.1 ng/mL.
Clinical Impact:
Beckman Coulter evaluated the impact of WHO calibration through analysis of a 6630 subject prospective clinical study. That study provided the basis for the approval of Hybritech PSA in conjunction with DRE for detection of prostate cancer and identified 4.0 ng/mL as a value at which to consider a biopsy. Using the 4.0 ng/mL cutoff, 208 subjects were identified with cancer. If the WHO calibration was used with a 4.0 ng/mL cutoff, 38 (18%) of the 208 previously identified cancers would not have been detected. Using a 3.1 ng/mL cutoff, all 208 subjects would be identified.
The Prostate Cancer Prevention Trial demonstrated a significant amount of cancer in the PSA range of 3-5 ng/mL. As highlighted in the figure, a substantial percentage (up to 30%) of men with cancer in this PSA range have aggressive cancer. Therefore, it is important that physicians understand the impact of the assay calibration to their interpretation of PSA values in this critical range.
The classic Hybritech PSA calibration has also served as the basis for other PSA-based risk stratification tools such as PSA velocity measurements for cancer detection and aggressiveness. Because a number of PSA interpretive criteria have been established using the Hybritech assay, we provide the corresponding clinical decision points for WHO calibration. These parameters must also be lowered when using the WHO calibration. PSA velocity (change over time) has been shown to be an important risk indicator in men with PSA values less than 4.0 ng/mL. PSA velocity may help identify men with cancer who have not yet reached an established cutoff threshold, yet would benefit from more aggressive management.
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; 267:2215–20.
2 Carter HB, Ferrucci L, Kettermann A, et al. Detection of life-threating prostate cancer with prostate-specific antigen velocity during a window of curabliity. J Natl Cancer Inst. 2006;98:1521–7.
3 Punglia RS, D’Amico AV, Catalona WJ, et al. Effect of verification bias on screening for prostate cancer by measurement of prostate-specific antigen. N Eng J Med. 2003;349:335–342.
4 Catalona WJ, Smith BS, Ornstein DK. Prostate cancer detection in men with serum PSA concentrations of 2.6 to 4.0 ng/mL and benign prostatic examination: Enhancement of specificity with free PSA measurements. JAMA 1997;277:1452–1455.
5 Babaian RJ, Johnston DA, Naccarato W, et al. The incidence of prostate cancer in a screening population with a serum prostate specific antigen between 2.5 and 4.0 ng/mL: Relationship to biopsy strategy. J Urol 2001;165:757–760
6 Catalona WJ, Richie JP, Ahmann FR, Hudson MA, Scardino PT, Flanigan RC, deKernion JB, Ratliff TL, Kavoussi LR, Dalkin BL, Waters WB, MacFarlane MT, Southwick PC. Comparison of digital rectal examination and serum prostate specific antigen in the early detection of prostate cancer: Results of a multicenter clinical trial of 6,630 men. J Urol 1994; 151: 1283-1290.
7 Armitage TG, Cooper EH, Newling DW, Robinson MR, Appleyard, I. The value of the measurement of serum prostate specific antigen in patients with benign prostatic hyperplasia and untreated prostate cancer. Br J Urol 1988 Dec;62(6):584–9.
8 D’Amico AV, Whittington R, Malkowicz SB, Schultz D, Blank K, Broderick GA, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA, 280:969,1998.
Your role in PSA standardization:
Physicians rely on the clinical laboratory for critical patient information. Interpretive criteria such as expected values and recommended cutoffs are the guideposts for integrating laboratory information into appropriate patient management.
If your laboratory chooses to move to Access® WHO calibration for PSA, you must communicate the new cutoff for cancer detection of 3.1 ng/mL as well as the change to other risk stratification values such as PSA velocity.
With the information provided in this communication, the laboratory can make appropriate decisions about their PSA interpretive criteria and help physicians answer questions about their patients’ PSA test results.
Every PSA Result Represents a Man & His Future:
A man sees his physician and receives a PSA test. As he waits for his result, a concern lingers in the back of his mind, “Do I have cancer?” Hopefully his PSA result leads to reassurance and relief.
For another man, a PSA result might bring different news and lead to follow-up including a biopsy. If his cancer is found early, he is likely to benefit from advances in treatment.
As screening for prostate cancer has become a routine component of healthcare for most men over 50, this experience is reenacted in millions of men’s lives every year.
Every man is impacted by his PSA result or by the trend of his PSA results. Every PSA result matters. Beckman Coulter wants you to understand the 22%difference between classic Hybritech® calibration and the WHO calibration.
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Technical Bulletin
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