- Email: [email protected]
Reply to Abraham Morgentaler’s Letter to the Editor re: Masashi Yano, Takashi Imamoto, Hiroyoshi Suzuki et al. The Clinical Potential of Pretreatment Serum Testosterone Level to Improve the Efficiency of Prostate Cancer Screening. Eur Urol 2007;51:375–80
european urology 52 (2007) 286–296
Reply to Abraham Morgentaler’s Letter to the Editor re: Masashi Yano, Takashi Imamoto, Hiroyoshi Suzuki et al. The Clinical Potential of Pretreatment Serum Testosterone Level to Improve the Efficiency of Prostate Cancer Screening. Eur Urol 2007;51:375–80 We appreciate the helpful comments by Professor Abraham Morgentaler and agree with the general suggestions. However, some additional detailed considerations need to be made. First of all, serum testosterone (T) was obtained on a routine basis for men undergoing prostate biopsy. The possibility of selection bias does not need to be considered. Secondly, the stated requirements with respect to the quality of studies have only been met in a few studies until now. Prostate cancer (PCa) is one of the leading malignancies in terms of incidence and cause of cancer death in Western men. In the absence of clinical trial data demonstrating a benefit, the practice of screening for the presence of disease remains controversial. Although prostate biopsy is required for a definitive diagnosis of PCa, this invasive and costly procedure should be avoided in men with a low probability of having PCa. Various strategies have been investigated to improve the sensitivity and specificity of PCa detection in patients with intermediate prostate-specific antigen (PSA) levels. In addition to total PSA, other factors that have been associated with the detection of PCa include age, abnormal digital rectal examination (DRE), hypoechoic lesions on transrectal ultrasound (TRUS), PSA density (PSAD), PSA velocity, transition zone PSAD (PSATZD), the free-to-total PSA ratio (f/T PSA ratio), and age-specific PSA. Recently, several groups have sought to develop models to aid in the prediction of a positive prostate biopsy in men who are being evaluated for PCa. In Japan, screening for PCa is not universal as usually seen in Western countries. Therefore, our study group was unlike any usual set of men undergoing screening for PCa. Indeed, it included more patients with high risk for disease. However, it is generally believed that epidemiologic and biologic differences in PCa exist between Western and Asian men. Thus, the objective of the current study was to investigate clinical and laboratory data predicting the probability of a positive prostate biopsy in a Japanese population. The historical perspective revealed that there is not now—nor has there ever been—a scientific basis for the belief that T causes PCa to grow [1]. Discarding this modern myth will allow exploration of alternative hypotheses regarding the relationship
293
of T and PCa that may be clinically and scientifically rewarding. Some studies in which univariate and multivariate analyses were performed in patients with localized PCa indicate that a lower pretreatment T level is a predictor of extraprostatic disease [2,3]. Their results suggest that one or more factors from PCa cells can generate negative feedback in the hypothalamus-pituitary axis. Inhibin is considered a candidate for such an inhibitory factor. In addition, we previously reported that a higher pretreatment T level appears to be predictive of the marker response to endocrine therapy, showing positive prognostic value and indicating good prognosis in patients at the metastatic stage [4]. However, a higher T level was associated with stage progression of this disease. It was suggested that preexisting low T level may induce growth of fewer androgen-sensitive cells because they are already acclimated to a low androgen environment [5]. According to one hypothesis, PCa cells that develop in the presence of a high level of T may contain a high level of androgen receptor, which would make them very sensitive to androgen ablation. It is obvious that we have much more to learn about the relationship of T and PCa. This study has the limitations of its retrospective nature and small population size. Further study with large clinical trials is needed to construct a prediction model composed of the pretreatment T level and other factors. I would be very pleased if the problem raised by Professor Morgentaler, and also voiced by others based on our report, could be resolved beyond national boundaries, for example, within the framework of the European Association of Urology. Acknowledgments This work was supported by a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology (contract grant numbers: 14207061, 16591582, 16689026, and 17791006), the Japanese Foundation for Prostate Research (2004) and the Japanese Urological Association (2006). References [1] Morgentaler A. Testosterone and prostate cancer: an historical perspective on a modern myth. Eur Urol 2006; 50:935–9. [2] Massengill JC, Sun L, Moul JW, et al. Pretreatment total testosterone level predicts pathological stage in patients with localized prostate cancer treated with radical prostatectomy. J Urol 2003;169:1670–5.
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european urology 52 (2007) 286–296
[3] Imamoto T, Suzuki H, Fukasawa S, et al. Pretreatment serum testosterone level as a predictive factor of pathological stage in localized prostate cancer patients treated with radical prostatectomy. Eur Urol 2005;47: 308–12. [4] Imamoto T, Suzuki H, Akakura K, et al. Pretreatment serum level of testosterone as a prognostic factor in Japanese men with hormonally treated stage D2 prostate cancer. Endocr J 2001;48:573–8. [5] Jorgensen T, Kanagasingam Y, Kaalhus O, et al. Prognostic factors in patients with metastatic (stage D2) prostate cancer: experience from the Scandinavian prostatic cancer group study-2. J Urol 1997;158:164–70.
Takashi Imamoto* Department of Urology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan *Tel. +81 43 226 2134; Fax: +81 43 226 2136 E-mail address: [email protected] March 16, 2007 Published online ahead of print on March 26, 2007 doi:10.1016/j.eururo.2007.03.046
DOIs of original articles: 10.1016/j.eururo.2006.08.047, 10.1016/j.eururo.2007.03.045
Re: Aure´lien Descazeaud, Marc Zerbib, Thierry Flam et al. Can pT0 Stage of Prostate Cancer be Predicted before Radical Prostatectomy? Eur Urol 2006;50:1248–53 We read with interest the paper entitled ‘‘Can pT0 Stage of Prostate Cancer be Predicted before Radical Prostatectomy?’’ published by Descazeaud et al in a recent issue of European Urology [1]. In their experience, the rate of pT0 tumours after radical prostatectomy (RP) is 0.5%. The combination of clinical stage, preoperative prostate-specific antigen (PSA), number of positive biopsy cores, Gleason score, and prostate weight could help to predict pT0 stage after RP. We agree with the authors on the fact that prostate cancer cannot be found in a very small number of radical prostatectomy specimens after a positive biopsy [1–11]. However, we believe that a protocol should be applied to search for residual prostate cancer on pT0 radical prostatectomy after positive biopsy. In our experience an extensive search for residual cancer reduces the number of pT0 radical prostatectomy specimens after a positive biopsy from 0.6% to 0.15% [9]. When searching for residual prostate cancer on pT0 radical prostatectomy after positive biopsy, we undertake the following successive steps (the procedure is usually stopped at the step where cancer is found): 1. The diagnostic needle biopsies are reviewed to exclude the possibility of a false-positive biopsy diagnosis and to assess the approximate location of the biopsy with tumour, such as apex, midzone, and base, both left and right.
2. The slides of the surgical specimens are reviewed for residual cancer that is initially overlooked or missed. 3. If the prostate is not totally embedded, the remaining prostate tissue is processed in toto. If the prostate is completely sampled, then this step is skipped. This type of information is usually contained in the pathology form where all the steps of the processing procedure are recorded. The information is further confirmed by searching the specimen’s container for residual pieces. 4. Additional deeper sections (ie, 3–5 sections) of the prostatectomy area (paraffin block) corresponding to the location of the core with cancer are recut. Further sections are also obtained from all the other paraffin blocks. 5. Additional deeper sections (ie, 3–5 sections) of the area corresponding to the location of the positive core as well as of all the remaining blocks are recut after block-flipping. 6. Immunostains for p63 (or 34bE12) and a-methylacyl-coenzyme A racemase (AMACR) are performed to evaluate suspicious foci. 7. Immunostain for cytokeratin CAM 5.2, for p63 and for PSA are performed to identify the so-called ‘‘minimal residual cancer,’’ especially in patients receiving neoadjuvant hormonal therapy. 8. The description of the macroscopic appearance of external and cut surfaces of the surgical specimen are reviewed and the contour of the tissue sections on the slides are inspected for hints or clues that might indicate that part of the tissue is missing either due to the surgical procedure or technical reasons. 9. DNA specimen analysis is performed on formalinfixed tissue to confirm the identity of the biopsies and prostatectomies, whenever necessary.
Reply to Abraham Morgentaler’s Letter to the Editor re: Masashi Yano, Takashi Imamoto, Hiroyoshi Suzuki et al. The Clinical Potential of Pretreatment Serum Testosterone Level to Improve the Efficiency of Prostate Cancer Screening. Eur Urol 2007;51:375–80 We appreciate the helpful comments by Professor Abraham Morgentaler and agree with the general suggestions. However, some additional detailed considerations need to be made. First of all, serum testosterone (T) was obtained on a routine basis for men undergoing prostate biopsy. The possibility of selection bias does not need to be considered. Secondly, the stated requirements with respect to the quality of studies have only been met in a few studies until now. Prostate cancer (PCa) is one of the leading malignancies in terms of incidence and cause of cancer death in Western men. In the absence of clinical trial data demonstrating a benefit, the practice of screening for the presence of disease remains controversial. Although prostate biopsy is required for a definitive diagnosis of PCa, this invasive and costly procedure should be avoided in men with a low probability of having PCa. Various strategies have been investigated to improve the sensitivity and specificity of PCa detection in patients with intermediate prostate-specific antigen (PSA) levels. In addition to total PSA, other factors that have been associated with the detection of PCa include age, abnormal digital rectal examination (DRE), hypoechoic lesions on transrectal ultrasound (TRUS), PSA density (PSAD), PSA velocity, transition zone PSAD (PSATZD), the free-to-total PSA ratio (f/T PSA ratio), and age-specific PSA. Recently, several groups have sought to develop models to aid in the prediction of a positive prostate biopsy in men who are being evaluated for PCa. In Japan, screening for PCa is not universal as usually seen in Western countries. Therefore, our study group was unlike any usual set of men undergoing screening for PCa. Indeed, it included more patients with high risk for disease. However, it is generally believed that epidemiologic and biologic differences in PCa exist between Western and Asian men. Thus, the objective of the current study was to investigate clinical and laboratory data predicting the probability of a positive prostate biopsy in a Japanese population. The historical perspective revealed that there is not now—nor has there ever been—a scientific basis for the belief that T causes PCa to grow [1]. Discarding this modern myth will allow exploration of alternative hypotheses regarding the relationship
293
of T and PCa that may be clinically and scientifically rewarding. Some studies in which univariate and multivariate analyses were performed in patients with localized PCa indicate that a lower pretreatment T level is a predictor of extraprostatic disease [2,3]. Their results suggest that one or more factors from PCa cells can generate negative feedback in the hypothalamus-pituitary axis. Inhibin is considered a candidate for such an inhibitory factor. In addition, we previously reported that a higher pretreatment T level appears to be predictive of the marker response to endocrine therapy, showing positive prognostic value and indicating good prognosis in patients at the metastatic stage [4]. However, a higher T level was associated with stage progression of this disease. It was suggested that preexisting low T level may induce growth of fewer androgen-sensitive cells because they are already acclimated to a low androgen environment [5]. According to one hypothesis, PCa cells that develop in the presence of a high level of T may contain a high level of androgen receptor, which would make them very sensitive to androgen ablation. It is obvious that we have much more to learn about the relationship of T and PCa. This study has the limitations of its retrospective nature and small population size. Further study with large clinical trials is needed to construct a prediction model composed of the pretreatment T level and other factors. I would be very pleased if the problem raised by Professor Morgentaler, and also voiced by others based on our report, could be resolved beyond national boundaries, for example, within the framework of the European Association of Urology. Acknowledgments This work was supported by a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology (contract grant numbers: 14207061, 16591582, 16689026, and 17791006), the Japanese Foundation for Prostate Research (2004) and the Japanese Urological Association (2006). References [1] Morgentaler A. Testosterone and prostate cancer: an historical perspective on a modern myth. Eur Urol 2006; 50:935–9. [2] Massengill JC, Sun L, Moul JW, et al. Pretreatment total testosterone level predicts pathological stage in patients with localized prostate cancer treated with radical prostatectomy. J Urol 2003;169:1670–5.
294
european urology 52 (2007) 286–296
[3] Imamoto T, Suzuki H, Fukasawa S, et al. Pretreatment serum testosterone level as a predictive factor of pathological stage in localized prostate cancer patients treated with radical prostatectomy. Eur Urol 2005;47: 308–12. [4] Imamoto T, Suzuki H, Akakura K, et al. Pretreatment serum level of testosterone as a prognostic factor in Japanese men with hormonally treated stage D2 prostate cancer. Endocr J 2001;48:573–8. [5] Jorgensen T, Kanagasingam Y, Kaalhus O, et al. Prognostic factors in patients with metastatic (stage D2) prostate cancer: experience from the Scandinavian prostatic cancer group study-2. J Urol 1997;158:164–70.
Takashi Imamoto* Department of Urology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan *Tel. +81 43 226 2134; Fax: +81 43 226 2136 E-mail address: [email protected] March 16, 2007 Published online ahead of print on March 26, 2007 doi:10.1016/j.eururo.2007.03.046
DOIs of original articles: 10.1016/j.eururo.2006.08.047, 10.1016/j.eururo.2007.03.045
Re: Aure´lien Descazeaud, Marc Zerbib, Thierry Flam et al. Can pT0 Stage of Prostate Cancer be Predicted before Radical Prostatectomy? Eur Urol 2006;50:1248–53 We read with interest the paper entitled ‘‘Can pT0 Stage of Prostate Cancer be Predicted before Radical Prostatectomy?’’ published by Descazeaud et al in a recent issue of European Urology [1]. In their experience, the rate of pT0 tumours after radical prostatectomy (RP) is 0.5%. The combination of clinical stage, preoperative prostate-specific antigen (PSA), number of positive biopsy cores, Gleason score, and prostate weight could help to predict pT0 stage after RP. We agree with the authors on the fact that prostate cancer cannot be found in a very small number of radical prostatectomy specimens after a positive biopsy [1–11]. However, we believe that a protocol should be applied to search for residual prostate cancer on pT0 radical prostatectomy after positive biopsy. In our experience an extensive search for residual cancer reduces the number of pT0 radical prostatectomy specimens after a positive biopsy from 0.6% to 0.15% [9]. When searching for residual prostate cancer on pT0 radical prostatectomy after positive biopsy, we undertake the following successive steps (the procedure is usually stopped at the step where cancer is found): 1. The diagnostic needle biopsies are reviewed to exclude the possibility of a false-positive biopsy diagnosis and to assess the approximate location of the biopsy with tumour, such as apex, midzone, and base, both left and right.
2. The slides of the surgical specimens are reviewed for residual cancer that is initially overlooked or missed. 3. If the prostate is not totally embedded, the remaining prostate tissue is processed in toto. If the prostate is completely sampled, then this step is skipped. This type of information is usually contained in the pathology form where all the steps of the processing procedure are recorded. The information is further confirmed by searching the specimen’s container for residual pieces. 4. Additional deeper sections (ie, 3–5 sections) of the prostatectomy area (paraffin block) corresponding to the location of the core with cancer are recut. Further sections are also obtained from all the other paraffin blocks. 5. Additional deeper sections (ie, 3–5 sections) of the area corresponding to the location of the positive core as well as of all the remaining blocks are recut after block-flipping. 6. Immunostains for p63 (or 34bE12) and a-methylacyl-coenzyme A racemase (AMACR) are performed to evaluate suspicious foci. 7. Immunostain for cytokeratin CAM 5.2, for p63 and for PSA are performed to identify the so-called ‘‘minimal residual cancer,’’ especially in patients receiving neoadjuvant hormonal therapy. 8. The description of the macroscopic appearance of external and cut surfaces of the surgical specimen are reviewed and the contour of the tissue sections on the slides are inspected for hints or clues that might indicate that part of the tissue is missing either due to the surgical procedure or technical reasons. 9. DNA specimen analysis is performed on formalinfixed tissue to confirm the identity of the biopsies and prostatectomies, whenever necessary.