- Email: [email protected]
Re: Saturation Technique Does Not Improve Cancer Detection as an Initial Prostate Biopsy Strategy
1252
LETTERS TO THE EDITOR
obese men with prostate cancer and serum PSA levels lower than the cutoff value of 4 ng/ml are even more likely to be underdiagnosed, at least when the disease is still localized and curable. Thus, in obese men (with probably enlarged prostates) PSA variables such as ratio and velocity should be used systematically as adjuvant screening tools in early prostate cancer detection. In addition, more extended biopsy techniques should be adopted to improve cancer detection rates. Although further studies are needed to confirm if and when obese men could actually form a separate high risk group for the development of prostate cancer, urologists should probably exercise a higher level of awareness when performing TRUS guided biopsy in obese males. Respectfully, K. Stamatiou, A. Alevizos, A. Mariolis and F. Sofras Department of Urology University of Crete School of Medicine Heraklion and Department of General Practice/Family Medicine Health Center of Vyronas Athens, Greece 1.
Uzzo, R. G., Wei, J. T., Waldbaum, R. S., Perlmutter, A. P., Byrne, J. C. and Vaughan, E. D., Jr.: The influence of prostate size on cancer detection. Urology, 46: 831, 1995 2. Miyake, H., Sakai, I., Harada, K., Hara, I. and Eto, H.: Clinicopathological features of prostate cancer in Japanese men diagnosed on repeat transrectal ultrasound-guided biopsy. Int J Clin Oncol, 10: 30, 2005 3. Porter, M. P. and Stanford, J. L.: Obesity and the risk of prostate cancer. Prostate, 62: 316, 2005 4. Stamatiou, K., Alevizos, A., Perimeni, D., Sofras, F. and Agapitos, E.: Frequency of impalpable prostate adenocarcinoma and precancerous conditions in Greek male population: an autopsy study. Prostate Cancer Prostatic Dis, 9: 45, 2006
Reply by Authors. We agree that prostate size differences between obese and nonobese men may contribute to possible under detection of prostate cancers among obese men. From a clinical standpoint this difference can be overcome by adjusting the biopsy protocol to provide greater sampling (ie obtaining more cores) in men with larger prostates. If this approach were routinely practiced, it would help to minimize the under detection of cancers among obese men related to prostate size difference. A slightly more troubling concern for prostate cancer screening among obese men is the increasing amount of data suggesting that obese men have lower PSA values.1– 4 While in our study obese and nonobese men had similar PSA values, our study suffered from the limitation that all men had prostate cancer. However, the data from population based studies showing that obese men have lower PSA values are becoming difficult to ignore. Lower PSA values among obese men, whether due to lower androgenic activity or hemodilution from larger plasma volume, suggest that perhaps we should define a lower PSA threshold as “abnormal” among obese men. Certainly, given that obese patients are at increased risk for prostate cancer death,5 it would be logical to screen these men more aggressively, including using a lower PSA threshold. Whether screening and early detection truly reduce prostate cancer mortality is a matter of debate. However, if we believe screening does save lives,
then screening should be directed and used most aggressively in those with the highest risk of prostate cancer death, such as obese men. 1.
Baillargeon, J., Pollock, B. H., Kristal, A. R., Bradshaw, P., Hernandez, J., Basler, J. et al: The association of body mass index and prostate-specific antigen in a population-based study. Cancer, 103: 1092, 2005 2. Gray, M. A., Delahunt, B., Fowles, J. R., Weinstein, P., Cookes, R. R. and Nacey, J. N.: Demographic and clinical factors as determinants of serum levels of prostate specific antigen and its derivatives. Anticancer Res, 24: 2069, 2004 3. Ku, J. H., Kim, M. E., Lee, N. K., Park, Y. H. and Ahn, J. O.: Influence of age, anthropometry, and hepatic and renal function on serum prostate-specific antigen levels in healthy middle-age men. Urology, 61: 132, 2003 4. Barqawi, A. B., Golden, B. K., O’Donnell, C., Brawer, M. K. and Crawford, E. D.: Observed effect of age and body mass index on total and complexed PSA: analysis from a national screening program. Urology, 65: 708, 2005 5. Calle, E. E., Rodriguez, C., Walker-Thurmond, K. and Thun, M. J.: Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med, 348: 1625, 2003
Re: Saturation Technique Does Not Improve Cancer Detection as an Initial Prostate Biopsy Strategy J. S. Jones, A. Patel, L. Schoenfield, J. C. Rabets, C. D. Zippe and C. Magi-Galluzzi J Urol, 175: 485– 488, 2006 To the Editor. We read with interest the study by Jones et al regarding contemporary prostate biopsy techniques. Although the study addresses an interesting and important topic, we have some methodological concerns that may temper conclusions based on this study. Our first concern relates to the attempt by the authors to answer the question of whether saturation biopsy is equivalent to standard 10-core biopsy by demonstrating that there is no statistical difference in prostate cancer detection rates between these 2 groups. They arrive at a p value of “⬎0.9” using statistical methodology that is not explicitly declared. When arrayed in a simple 2 ⫻ 2 table and analyzed with 3 different statistical methods we arrive at different 2-sided p values for their data, although our p values remain greater than the accepted 5% type I error rate (table 1).1 Our second concern relates to the statistical power and type II () statistical error rate used in the study.2 Assuming an ␣ level of 5%, a baseline detection rate of 52% (standard biopsy group), and the sample sizes and group ratios of the
TABLE 1 No. Prostate Ca Detected Biopsy Technique:
Yes
No
Saturation (24 cores) Standard (10 cores)
62 45
77 42
Pearson’s chi-square p ⫽ 0.297, Pearson-Yates chi-square p ⫽ 0.365, Fisher’s exact test p ⫽ 0.339.
LETTERS TO THE EDITOR TABLE 2 % Minimal Detectable Ca Detection Rate* Improvement
% Statistical Power (1-)
5 10 15 20
8.6 26.4 55.0 82.2
* Using saturation biopsy.
current study, we have calculated the statistical power of the current study to detect various theoretical changes in the biopsy detection rate that could potentially have occurred in the saturation biopsy group (table 2). We believe that a change in prostate specific antigen (PSA) in the range of 10% would be clinically important, yet the current study is only powered to detect a minimal difference of roughly 20%. Our last concern relates to confounding and bias. In this study there are several possible confounders, including age, family history of prostate cancer, Gleason score, serum PSA level and kinetics, digital rectal examination results and the surgeon performing the biopsy. Although the authors present stratification tables for PSA level and Gleason score, they do not present stratified statistical analyses for these comparisons, nor do they adjust for these and other potential confounders in a multivariate model. The lack of difference between the 2 biopsy regimens that they observed may simply reflect imbalance in the baseline covariates between the groups. In conclusion, we are not attempting to advocate saturation biopsy as a routine technique for prostate cancer detection. Rather, we are suggesting that the current study was too underpowered and had too many potential biases to support the claim that saturation biopsy should be abandoned as an initial biopsy strategy. Respectfully, Brant A. Inman and Robert P. Myers Department of Urology Mayo Clinic College of Medicine Rochester, Minnesota 55905 e-mail: [email protected] 1.
2.
Fleiss, J. L., Levin, B. and Paik, M. C.: Statistical Methods for Rates and Proportions, 3rd ed. New York: John Wiley & Sons, pp. 50 – 63, 2003 Altman, D. G. and Bland, J. M.: Absence of evidence is not evidence of absence. BMJ, 311: 485, 1995
Reply by Authors. We appreciate the interest of Inman and Myers in our work. As noted in the article, this is an evaluation of an ongoing database, and implicitly the data were not prospectively powered. During periodic analysis we determined that the value of saturation biopsy for this population clearly was not demonstrated as being superior to our own 10-core cases or to rates predicted by the literature. After 139 patients we concluded that “[it] is feasible that a larger series might reveal a small advantage to saturation biopsy as an initial biopsy strategy, but our findings in this pilot study make that appear unlikely and preclude us from further exploration of the concept.” We agree with the limitations and statistical comments expressed in the letter but are comfortable that these data support that conclusion, and
1253
currently reserve saturation biopsy for patients undergoing repeat biopsy or reevaluation biopsy on an active surveillance protocol.
Re: Interstitial Cystitis Versus Detrusor Overactivity: A Comparative, Randomized, Controlled Study of Cystometry Using Saline and 0.3 M Potassium Chloride J. Philip, S. Willmott and P. Irwin J Urol, 175: 566 –571, 2006 To the Editor. The article by Philip et al describing bladder testing for potassium sensitivity in interstitial cystitis (IC) and detrusor overactivity (DO) is well done. Unfortunately, the authors missed a major point concerning the role of potassium in generating symptoms and disease in the lower urinary tract, which is reviewed in a 2003 article in Urology.1 Potassium sensitivity occurs only if there is a dysfunctional epithelium. Asymptomatic people do not have potassium sensitivity because they have a healthy and impermeable epithelium, and no potassium reaches the cell membrane to evoke any type of reaction. If there is a lower urinary dysfunctional epithelium (LUDE), then the potassium diffuses to the cell membrane and beyond into the interstitium, where it can depolarize nerves and muscles, causing urgency, pain and/or incontinence, in any combination. These are critical points that the authors appeared to overlook in the published studies. Traditional urology has artificially created diseases out of symptoms (eg IC) and arbitrary urodynamic findings (eg DO) without any scientific evidence as to what causes urgency, pain or incontinence (DO in this study). The composite of published data on the effect of potassium on the lower urinary tract provides a unifying hypothesis to show that IC, the urethral syndrome, prostatitis, overactive bladder, urethritis and gynecological chronic pelvic pain (CPP) all share one primary pathophysiology, that is lower urinary dysfunctional epithelium.2 Additionally, a potassium leak into the bladder interstitium can cause muscle depolarization and incontinence (DO) and any or all of the aforementioned symptoms. Even in rodent studies bladder muscle is depolarized directly by potassium but only after mucosal injury.3,4 Interstitial cystitis is traditionally diagnosed only when the symptoms are severe and, as such, represents an advanced stage of LUDE disease. It is important to note that IC is not a unique and separate disease process from its early stages, when symptoms are milder and intermittent, and there may be no pain. Although patients with early IC may initially be diagnosed with overactive bladder, urethral syndrome, prostatitis, CPP or recurrent urinary tract infection, the recent data support the fact that the majority have a single problem—LUDE disease. This is a critical point in understanding why the traditional urological diagnostic paradigm just does not work anymore for the disease process we call IC. The accompanying editorial comment by Hanno also misses the same basic point—potassium sensitivity is
LETTERS TO THE EDITOR
obese men with prostate cancer and serum PSA levels lower than the cutoff value of 4 ng/ml are even more likely to be underdiagnosed, at least when the disease is still localized and curable. Thus, in obese men (with probably enlarged prostates) PSA variables such as ratio and velocity should be used systematically as adjuvant screening tools in early prostate cancer detection. In addition, more extended biopsy techniques should be adopted to improve cancer detection rates. Although further studies are needed to confirm if and when obese men could actually form a separate high risk group for the development of prostate cancer, urologists should probably exercise a higher level of awareness when performing TRUS guided biopsy in obese males. Respectfully, K. Stamatiou, A. Alevizos, A. Mariolis and F. Sofras Department of Urology University of Crete School of Medicine Heraklion and Department of General Practice/Family Medicine Health Center of Vyronas Athens, Greece 1.
Uzzo, R. G., Wei, J. T., Waldbaum, R. S., Perlmutter, A. P., Byrne, J. C. and Vaughan, E. D., Jr.: The influence of prostate size on cancer detection. Urology, 46: 831, 1995 2. Miyake, H., Sakai, I., Harada, K., Hara, I. and Eto, H.: Clinicopathological features of prostate cancer in Japanese men diagnosed on repeat transrectal ultrasound-guided biopsy. Int J Clin Oncol, 10: 30, 2005 3. Porter, M. P. and Stanford, J. L.: Obesity and the risk of prostate cancer. Prostate, 62: 316, 2005 4. Stamatiou, K., Alevizos, A., Perimeni, D., Sofras, F. and Agapitos, E.: Frequency of impalpable prostate adenocarcinoma and precancerous conditions in Greek male population: an autopsy study. Prostate Cancer Prostatic Dis, 9: 45, 2006
Reply by Authors. We agree that prostate size differences between obese and nonobese men may contribute to possible under detection of prostate cancers among obese men. From a clinical standpoint this difference can be overcome by adjusting the biopsy protocol to provide greater sampling (ie obtaining more cores) in men with larger prostates. If this approach were routinely practiced, it would help to minimize the under detection of cancers among obese men related to prostate size difference. A slightly more troubling concern for prostate cancer screening among obese men is the increasing amount of data suggesting that obese men have lower PSA values.1– 4 While in our study obese and nonobese men had similar PSA values, our study suffered from the limitation that all men had prostate cancer. However, the data from population based studies showing that obese men have lower PSA values are becoming difficult to ignore. Lower PSA values among obese men, whether due to lower androgenic activity or hemodilution from larger plasma volume, suggest that perhaps we should define a lower PSA threshold as “abnormal” among obese men. Certainly, given that obese patients are at increased risk for prostate cancer death,5 it would be logical to screen these men more aggressively, including using a lower PSA threshold. Whether screening and early detection truly reduce prostate cancer mortality is a matter of debate. However, if we believe screening does save lives,
then screening should be directed and used most aggressively in those with the highest risk of prostate cancer death, such as obese men. 1.
Baillargeon, J., Pollock, B. H., Kristal, A. R., Bradshaw, P., Hernandez, J., Basler, J. et al: The association of body mass index and prostate-specific antigen in a population-based study. Cancer, 103: 1092, 2005 2. Gray, M. A., Delahunt, B., Fowles, J. R., Weinstein, P., Cookes, R. R. and Nacey, J. N.: Demographic and clinical factors as determinants of serum levels of prostate specific antigen and its derivatives. Anticancer Res, 24: 2069, 2004 3. Ku, J. H., Kim, M. E., Lee, N. K., Park, Y. H. and Ahn, J. O.: Influence of age, anthropometry, and hepatic and renal function on serum prostate-specific antigen levels in healthy middle-age men. Urology, 61: 132, 2003 4. Barqawi, A. B., Golden, B. K., O’Donnell, C., Brawer, M. K. and Crawford, E. D.: Observed effect of age and body mass index on total and complexed PSA: analysis from a national screening program. Urology, 65: 708, 2005 5. Calle, E. E., Rodriguez, C., Walker-Thurmond, K. and Thun, M. J.: Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med, 348: 1625, 2003
Re: Saturation Technique Does Not Improve Cancer Detection as an Initial Prostate Biopsy Strategy J. S. Jones, A. Patel, L. Schoenfield, J. C. Rabets, C. D. Zippe and C. Magi-Galluzzi J Urol, 175: 485– 488, 2006 To the Editor. We read with interest the study by Jones et al regarding contemporary prostate biopsy techniques. Although the study addresses an interesting and important topic, we have some methodological concerns that may temper conclusions based on this study. Our first concern relates to the attempt by the authors to answer the question of whether saturation biopsy is equivalent to standard 10-core biopsy by demonstrating that there is no statistical difference in prostate cancer detection rates between these 2 groups. They arrive at a p value of “⬎0.9” using statistical methodology that is not explicitly declared. When arrayed in a simple 2 ⫻ 2 table and analyzed with 3 different statistical methods we arrive at different 2-sided p values for their data, although our p values remain greater than the accepted 5% type I error rate (table 1).1 Our second concern relates to the statistical power and type II () statistical error rate used in the study.2 Assuming an ␣ level of 5%, a baseline detection rate of 52% (standard biopsy group), and the sample sizes and group ratios of the
TABLE 1 No. Prostate Ca Detected Biopsy Technique:
Yes
No
Saturation (24 cores) Standard (10 cores)
62 45
77 42
Pearson’s chi-square p ⫽ 0.297, Pearson-Yates chi-square p ⫽ 0.365, Fisher’s exact test p ⫽ 0.339.
LETTERS TO THE EDITOR TABLE 2 % Minimal Detectable Ca Detection Rate* Improvement
% Statistical Power (1-)
5 10 15 20
8.6 26.4 55.0 82.2
* Using saturation biopsy.
current study, we have calculated the statistical power of the current study to detect various theoretical changes in the biopsy detection rate that could potentially have occurred in the saturation biopsy group (table 2). We believe that a change in prostate specific antigen (PSA) in the range of 10% would be clinically important, yet the current study is only powered to detect a minimal difference of roughly 20%. Our last concern relates to confounding and bias. In this study there are several possible confounders, including age, family history of prostate cancer, Gleason score, serum PSA level and kinetics, digital rectal examination results and the surgeon performing the biopsy. Although the authors present stratification tables for PSA level and Gleason score, they do not present stratified statistical analyses for these comparisons, nor do they adjust for these and other potential confounders in a multivariate model. The lack of difference between the 2 biopsy regimens that they observed may simply reflect imbalance in the baseline covariates between the groups. In conclusion, we are not attempting to advocate saturation biopsy as a routine technique for prostate cancer detection. Rather, we are suggesting that the current study was too underpowered and had too many potential biases to support the claim that saturation biopsy should be abandoned as an initial biopsy strategy. Respectfully, Brant A. Inman and Robert P. Myers Department of Urology Mayo Clinic College of Medicine Rochester, Minnesota 55905 e-mail: [email protected] 1.
2.
Fleiss, J. L., Levin, B. and Paik, M. C.: Statistical Methods for Rates and Proportions, 3rd ed. New York: John Wiley & Sons, pp. 50 – 63, 2003 Altman, D. G. and Bland, J. M.: Absence of evidence is not evidence of absence. BMJ, 311: 485, 1995
Reply by Authors. We appreciate the interest of Inman and Myers in our work. As noted in the article, this is an evaluation of an ongoing database, and implicitly the data were not prospectively powered. During periodic analysis we determined that the value of saturation biopsy for this population clearly was not demonstrated as being superior to our own 10-core cases or to rates predicted by the literature. After 139 patients we concluded that “[it] is feasible that a larger series might reveal a small advantage to saturation biopsy as an initial biopsy strategy, but our findings in this pilot study make that appear unlikely and preclude us from further exploration of the concept.” We agree with the limitations and statistical comments expressed in the letter but are comfortable that these data support that conclusion, and
1253
currently reserve saturation biopsy for patients undergoing repeat biopsy or reevaluation biopsy on an active surveillance protocol.
Re: Interstitial Cystitis Versus Detrusor Overactivity: A Comparative, Randomized, Controlled Study of Cystometry Using Saline and 0.3 M Potassium Chloride J. Philip, S. Willmott and P. Irwin J Urol, 175: 566 –571, 2006 To the Editor. The article by Philip et al describing bladder testing for potassium sensitivity in interstitial cystitis (IC) and detrusor overactivity (DO) is well done. Unfortunately, the authors missed a major point concerning the role of potassium in generating symptoms and disease in the lower urinary tract, which is reviewed in a 2003 article in Urology.1 Potassium sensitivity occurs only if there is a dysfunctional epithelium. Asymptomatic people do not have potassium sensitivity because they have a healthy and impermeable epithelium, and no potassium reaches the cell membrane to evoke any type of reaction. If there is a lower urinary dysfunctional epithelium (LUDE), then the potassium diffuses to the cell membrane and beyond into the interstitium, where it can depolarize nerves and muscles, causing urgency, pain and/or incontinence, in any combination. These are critical points that the authors appeared to overlook in the published studies. Traditional urology has artificially created diseases out of symptoms (eg IC) and arbitrary urodynamic findings (eg DO) without any scientific evidence as to what causes urgency, pain or incontinence (DO in this study). The composite of published data on the effect of potassium on the lower urinary tract provides a unifying hypothesis to show that IC, the urethral syndrome, prostatitis, overactive bladder, urethritis and gynecological chronic pelvic pain (CPP) all share one primary pathophysiology, that is lower urinary dysfunctional epithelium.2 Additionally, a potassium leak into the bladder interstitium can cause muscle depolarization and incontinence (DO) and any or all of the aforementioned symptoms. Even in rodent studies bladder muscle is depolarized directly by potassium but only after mucosal injury.3,4 Interstitial cystitis is traditionally diagnosed only when the symptoms are severe and, as such, represents an advanced stage of LUDE disease. It is important to note that IC is not a unique and separate disease process from its early stages, when symptoms are milder and intermittent, and there may be no pain. Although patients with early IC may initially be diagnosed with overactive bladder, urethral syndrome, prostatitis, CPP or recurrent urinary tract infection, the recent data support the fact that the majority have a single problem—LUDE disease. This is a critical point in understanding why the traditional urological diagnostic paradigm just does not work anymore for the disease process we call IC. The accompanying editorial comment by Hanno also misses the same basic point—potassium sensitivity is