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RE: PROSTATE SPECIFIC ANTIGEN BOUNCE AFTER RADIOACTIVE SEED IMPLANTATION FOLLOWED BY EXTERNAL BEAM RADIATION FOR PROSTATE CANCER
LETTERS TO THE EDITOR receive education about health care and prevention, as well as a report card on the quality of care in the hospital of their choice. Maybe there is only one Johns Hopkins for radical prostatectomy as stated by the author but patients have a right to know if their specialist has a 1% or 50% morbidity and/or mortality rate. When patients have more objective information, the quality of care will increase. Centers of excellence will be real, and not marketing ploys. The American Urological Association should be a proponent for urological report cards to provide patients with invaluable information. These report cards should cover the entire field of urology, and not be confined exclusively to radical prostatectomy. Even better, with national health insurance impartial third party surveys would provide a more accurate and objective report card compared to voluntary self-reporting. Respectfully, Gerald Frankel Center for Bladder and Prostate Disorders Heritage Medical Building 1441 Rosebud Blvd., Suite 261 McKinney, Texas 75069
RE: PROSTATE SPECIFIC ANTIGEN BOUNCE AFTER RADIOACTIVE SEED IMPLANTATION FOLLOWED BY EXTERNAL BEAM RADIATION FOR PROSTATE CANCER F. A. Critz, W. H. Williams, J. B. Benton, A. K. Levinson, C. T. Holladay and D. A. Holladay
2031
assigning significance to such minor fluctuations of PSA. Different assays use different modes of antibody detection and different and varying calibrators, each of which may further contribute to the extent of PSA variability. It is essential to account for the aforementioned factors that may contribute to baseline PSA variability in the absence of any significant or prognostic process or phenomenon. Only then can we assign any significance to the PSA variability described in the study apart from already well described concepts of physiological and assay variability, and can a notion of PSA bounce be identified, described and analyzed. Respecfully, Raj S. Pruthi Section of Urologic Oncology Division of Urology University of North Carolina 427 Burnett-Womack, CB#7235 Chapel Hill, North Carolina 27599 1. Prestigiacomo, A. F. and Stamey, T. A.: Physiological variation of serum prostate specific antigen in the 4.0 to 10.0 ng./ml. range in male volunteers. J Urol, 155: 1977, 1996 2. Prestigiacomo, A. F. and Stamey, T. A.: A comparison of 4 ultrasensitive prostate specific antigen assays for early detection of residual cancer after radical prostatectomy. J Urol, 152: 1515, 1994 3. Roehrborn, C. G., Pickens, G. J. and Carmody, T.: Variability of repeated serum prostate-specific antigen (PSA) measurements within less than 90 days in a well-defined patient population. Urology, 47: 59, 1996
J Urol, 163: 1085–1089, 2000 To the Editor. The authors describe a phenomenon of prostate specific antigen (PSA) bounce in patients who have undergone radiation therapy for prostate cancer. In the study PSA bounce was defined as an elevation of 0.1 ng./ml. above the pre-bounce level followed by a subsequent decrease, and this phenomenon was observed in 35% of their patients. The significant shortcoming of this article is that such minor fluctuations in PSA are not unique to patients undergoing brachytherapy but can be simply explained by the normal, expected and already well described variability of serum PSA determinations. Prestigiacomo and Stamey demonstrated that overall PSA variability is 35% in patients without prostate disease, and is comprised of physiological (24%) and assay (11%) variation.1 The interassay coefficient of variation is even further magnified at low levels of PSA (0.2 ng./ml. or less) when assay variability can exceed 20% (up to 67% on Abbott IMX* at 0.1 ng./ml.).2 In regard to absolute PSA changes, in a study of 295 men without prostate disease (mean PSA 2.7 ng./ml.) Roehrborn et al determined that more than a third of patients had a 1.0 ng./ml. or greater increase in PSA less than 90 days after the initial test.3 For example, a patient with a baseline PSA level of 3.0 ng./ml. may have a subsequent value of 4.0 ng./ml. (an absolute change of 1.0 ng./ml.) with the change not attributable to any disease process but rather due to the aforementioned physiological and assay variability. Certainly, changes in the absolute magnitude of 0.1 ng./ml. (the definition of PSA bounce in the study) represent only a 3% variation in this example and should be attributable to variability alone. With this understanding of PSA variability, minor fluctuations in PSA from 1 blood sample to the next are well within the expected physiological and assay variability. Although PSA bounce as a percentile change was not demonstrated by the authors, the majority of patients had only minor absolute fluctuations in PSA, that is more than 60% of patients had changes of 0.5 ng./ml. or less and more than 80% had changes 1.0 ng./ml. or less. Absolute changes of 0.1 ng./ml. (the definition of PSA bounce) are perhaps too low at any level of serum PSA irrespective of percentile change. To assign significance to such minor fluctuations apart from expected and well described PSA variability is simply to overstate the matter. Perhaps the notion of a PSA bounce is better addressed by applying 2 criteria for assay interpretation. First, a more appropriate definition of PSA bounce accounts for the coefficient of variation of 35%, rather than the arbitrary and excessively low absolute value of 0.1 ng./ml. PSA bounce, or any PSA change deemed significant, should be defined as a percentile change of greater than 35% from baseline, thereby accounting and controlling for the expected physiological and assay variability. Second, identification of and accounting for the many and different assays used are essential before *Abbott Laboratories, Abbott Park, Illinois.
Reply by Authors. Pruthi raises an excellent point when he suggests that PSA bounce, especially with low PSA elevations such as 0.1 ng./ml., may be due to normal variation of serum PSA determinations. Indeed, we also suggested that some of our PSA bounce measurements may be caused by using different laboratories with different assay techniques. However, we believe that intra-assay or interassay variation has a minor role in the production of PSA bounce. A unique feature of PSA bounce is the nonrandom distribution of this phenomenon. Of all PSA bounce measurements 67% occur between 12 and 24 months of followup and 92% are observed by 36-month followup. Even when PSA increases of 0.1 and 0.2 ng./ml. are studied, there is still a nonrandom distribution similar to the observation of all PSA bounces. To recheck these observations, we calculated the distribution of men by time who had a PSA bounce of only 0.1 ng./ml. In the 43 men in our current database who had a PSA bounce of only 0.1 ng./ml. 65% of the bounces occurred between 12 and 24 months with a peak time to bounce of 18 months. All bounces occurred by 54-month followup. This time distribution is virtually identical to the distribution in our article of all men with a bounce, that is 67% had a PSA bounce between 12 and 24-month followup. The nonrandom distribution of PSA bounce of only 0.1 ng./ml. does not suggest PSA variation. We believe that if most PSA increases of 0.1 ng./ml. were due to normal variability of serum PSA determinations, this event would occur randomly for the 5 years of observation. Pruthi cites the studies of Prestigiacomo and Stamey (reference 1 in letter) and Roehrborn et al (reference 3 in letter) to document normal variability of PSA measurements and support his argument that PSA bounce of low magnitude might be caused by this phenomenon. However, the prostates in both of these studies were described as normal glands and were considerably different from those in our study on PSA bounce. Our cases contained malignant epithelium but, more importantly, malignant and benign epithelium was undergoing destruction from irradiation. Whether the prostates in our study will exhibit normal physiological variation in PSA production is unknown. Furthermore, in contrast to the study of Roehrborn et al we measured PSA every 180 days, and not every 90 days. Pruthi also suggests that PSA bounce might be better defined as a PSA increase of 35% or more over baseline to minimize physiological assay variation. However, PSA increase to 0.3 from 0.2 ng./ml. reflects a 50% PSA increase but the absolute PSA increase is only 0.1 ng./ml. Thus, a percent increase definition for PSA bounce may only complicate the calculation of PSA bounce but not address the issue of physiological assay variability. In conclusion, we agree that interassay and intra-assay variation may explain some of our observations on PSA bounce but not the majority.
RE: PROSTATE SPECIFIC ANTIGEN BOUNCE AFTER RADIOACTIVE SEED IMPLANTATION FOLLOWED BY EXTERNAL BEAM RADIATION FOR PROSTATE CANCER F. A. Critz, W. H. Williams, J. B. Benton, A. K. Levinson, C. T. Holladay and D. A. Holladay
2031
assigning significance to such minor fluctuations of PSA. Different assays use different modes of antibody detection and different and varying calibrators, each of which may further contribute to the extent of PSA variability. It is essential to account for the aforementioned factors that may contribute to baseline PSA variability in the absence of any significant or prognostic process or phenomenon. Only then can we assign any significance to the PSA variability described in the study apart from already well described concepts of physiological and assay variability, and can a notion of PSA bounce be identified, described and analyzed. Respecfully, Raj S. Pruthi Section of Urologic Oncology Division of Urology University of North Carolina 427 Burnett-Womack, CB#7235 Chapel Hill, North Carolina 27599 1. Prestigiacomo, A. F. and Stamey, T. A.: Physiological variation of serum prostate specific antigen in the 4.0 to 10.0 ng./ml. range in male volunteers. J Urol, 155: 1977, 1996 2. Prestigiacomo, A. F. and Stamey, T. A.: A comparison of 4 ultrasensitive prostate specific antigen assays for early detection of residual cancer after radical prostatectomy. J Urol, 152: 1515, 1994 3. Roehrborn, C. G., Pickens, G. J. and Carmody, T.: Variability of repeated serum prostate-specific antigen (PSA) measurements within less than 90 days in a well-defined patient population. Urology, 47: 59, 1996
J Urol, 163: 1085–1089, 2000 To the Editor. The authors describe a phenomenon of prostate specific antigen (PSA) bounce in patients who have undergone radiation therapy for prostate cancer. In the study PSA bounce was defined as an elevation of 0.1 ng./ml. above the pre-bounce level followed by a subsequent decrease, and this phenomenon was observed in 35% of their patients. The significant shortcoming of this article is that such minor fluctuations in PSA are not unique to patients undergoing brachytherapy but can be simply explained by the normal, expected and already well described variability of serum PSA determinations. Prestigiacomo and Stamey demonstrated that overall PSA variability is 35% in patients without prostate disease, and is comprised of physiological (24%) and assay (11%) variation.1 The interassay coefficient of variation is even further magnified at low levels of PSA (0.2 ng./ml. or less) when assay variability can exceed 20% (up to 67% on Abbott IMX* at 0.1 ng./ml.).2 In regard to absolute PSA changes, in a study of 295 men without prostate disease (mean PSA 2.7 ng./ml.) Roehrborn et al determined that more than a third of patients had a 1.0 ng./ml. or greater increase in PSA less than 90 days after the initial test.3 For example, a patient with a baseline PSA level of 3.0 ng./ml. may have a subsequent value of 4.0 ng./ml. (an absolute change of 1.0 ng./ml.) with the change not attributable to any disease process but rather due to the aforementioned physiological and assay variability. Certainly, changes in the absolute magnitude of 0.1 ng./ml. (the definition of PSA bounce in the study) represent only a 3% variation in this example and should be attributable to variability alone. With this understanding of PSA variability, minor fluctuations in PSA from 1 blood sample to the next are well within the expected physiological and assay variability. Although PSA bounce as a percentile change was not demonstrated by the authors, the majority of patients had only minor absolute fluctuations in PSA, that is more than 60% of patients had changes of 0.5 ng./ml. or less and more than 80% had changes 1.0 ng./ml. or less. Absolute changes of 0.1 ng./ml. (the definition of PSA bounce) are perhaps too low at any level of serum PSA irrespective of percentile change. To assign significance to such minor fluctuations apart from expected and well described PSA variability is simply to overstate the matter. Perhaps the notion of a PSA bounce is better addressed by applying 2 criteria for assay interpretation. First, a more appropriate definition of PSA bounce accounts for the coefficient of variation of 35%, rather than the arbitrary and excessively low absolute value of 0.1 ng./ml. PSA bounce, or any PSA change deemed significant, should be defined as a percentile change of greater than 35% from baseline, thereby accounting and controlling for the expected physiological and assay variability. Second, identification of and accounting for the many and different assays used are essential before *Abbott Laboratories, Abbott Park, Illinois.
Reply by Authors. Pruthi raises an excellent point when he suggests that PSA bounce, especially with low PSA elevations such as 0.1 ng./ml., may be due to normal variation of serum PSA determinations. Indeed, we also suggested that some of our PSA bounce measurements may be caused by using different laboratories with different assay techniques. However, we believe that intra-assay or interassay variation has a minor role in the production of PSA bounce. A unique feature of PSA bounce is the nonrandom distribution of this phenomenon. Of all PSA bounce measurements 67% occur between 12 and 24 months of followup and 92% are observed by 36-month followup. Even when PSA increases of 0.1 and 0.2 ng./ml. are studied, there is still a nonrandom distribution similar to the observation of all PSA bounces. To recheck these observations, we calculated the distribution of men by time who had a PSA bounce of only 0.1 ng./ml. In the 43 men in our current database who had a PSA bounce of only 0.1 ng./ml. 65% of the bounces occurred between 12 and 24 months with a peak time to bounce of 18 months. All bounces occurred by 54-month followup. This time distribution is virtually identical to the distribution in our article of all men with a bounce, that is 67% had a PSA bounce between 12 and 24-month followup. The nonrandom distribution of PSA bounce of only 0.1 ng./ml. does not suggest PSA variation. We believe that if most PSA increases of 0.1 ng./ml. were due to normal variability of serum PSA determinations, this event would occur randomly for the 5 years of observation. Pruthi cites the studies of Prestigiacomo and Stamey (reference 1 in letter) and Roehrborn et al (reference 3 in letter) to document normal variability of PSA measurements and support his argument that PSA bounce of low magnitude might be caused by this phenomenon. However, the prostates in both of these studies were described as normal glands and were considerably different from those in our study on PSA bounce. Our cases contained malignant epithelium but, more importantly, malignant and benign epithelium was undergoing destruction from irradiation. Whether the prostates in our study will exhibit normal physiological variation in PSA production is unknown. Furthermore, in contrast to the study of Roehrborn et al we measured PSA every 180 days, and not every 90 days. Pruthi also suggests that PSA bounce might be better defined as a PSA increase of 35% or more over baseline to minimize physiological assay variation. However, PSA increase to 0.3 from 0.2 ng./ml. reflects a 50% PSA increase but the absolute PSA increase is only 0.1 ng./ml. Thus, a percent increase definition for PSA bounce may only complicate the calculation of PSA bounce but not address the issue of physiological assay variability. In conclusion, we agree that interassay and intra-assay variation may explain some of our observations on PSA bounce but not the majority.