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EDITORIAL: TOWARDS A BETTER CRYSTAL BALL
0022-5347/98/1605-1739$03.00/0
THE JOURNAL OF UROLOGY
Vol. 160, 1739-1740, November 1998 Printed in U.S.A.
Copyright 0 1998 by AMERICAN UROLOGICAL ASSOCIATION, INC.
EDITORIAL: TOWARDS A. .BETTER CRYSTAL BALL As our understanding of prostate cancer improves patients increasingly test our ability to provide the detailed information they desire on the curability of the disease. In essence they want us t o provide a crystal ball with which to look into the future. In this issue 3 articles suggest opportunities to improve our predictive and prognostic capabilities in prostate cancer detection and management. Until this decade our ability to ascertain accurately clinical stage was woefully inadequate, with over staging occurring in up to 66% of patients undergoing radical prostatectomy for clinically localized disease. With the use of prostate specific antigen (PSA), numerous PSA subtypes and Gleason scoring our predictive capacity has improved increasingly. In patients undergoing radical prostatectomy many centers have shown consistent factors associated with final pathological stage and prognosis, for example preoperative PSA, Gleason score and clinical stage. These predictivelprognostic factors have also led to the current passion for nomograms. The most popular of these tools, the nomograms of Partin et a1 for predicting final pathological stage1 and Kattan et al for predicting 5-year PSA-free recurrence2 after radical prostatectomy are in wide clinical use. These models perform reasonably well, although questions exist regarding the ability of the nomogram of Partin et a1 to predict seminal vesicle invasion and lymph node status. Can and do we need to improve these modeling instruments? Certainly, in patients undergoing radiation therapy accurate prediction of lymph node or seminal vesicle status would be helpful in patient selection and outcomes evaluation. Although pretreatment PSA and Gleason score are reasonable predictors of failure, they remain inadequate to define a population for whom curative therapy is appropriate or node dissection unnecessary. The study by Stone et a1 (page 1722) is a reasonable attempt to allow us to predict the latter. They concluded that the presence of a positive seminal vesicle biopsy or perineural invasion was an indication for pelvic lymph dissection based on a multivariate analysis of more than 200 laparoscopic pelvic lymph node specimens. Although PSA was an independent predictor in univariate analysis, it did not predict well in multivariate analysis. I have concerns about the accuracy of seminal vesicle biopsy but it appears useful in the hands of these investigators. The effort to define patients in absolute need of a pelvic lymph node dissection is important but I believe that prudence dictates pelvic lymph node dissection in other select patients, such as those with a PSA greater than 20, especially when Gleason score is 7 or greater. I am less sanguine about the efforts of Rabbani et a1 (page 1727). They sought to identify those who might benefit ”from technical modifications such as excision of the bladder neck or wide excision of the neurovascular bundles” by examining 242 patients treated with radical prostatectomy with or without neoadjuvant androgen ablation. Only pre-radical prostatectomy PSA was statistically significant in multivariate analysis as a predictor of margin positivity. They defined patients who were at high risk for positive apical margins without neoadjuvant androgen therapy as those with 3 or more positive biopsies of the standard 6 cores, and for whom “more careful dissection at the apex with wide excision of the neurovascular bundles” may be beneficial. It is unclear how helpful the recommendation is because the sites of margins positive at the apex (that is posterolaterally or anteriorly
where they often occur) and so forth were not defined. They also have created yet another nomogram to help predict patients with a greater than 10% chance of cancer at the margins based on PSA, and number and location of positive cores stratified by use or no use of neoadjuvant androgen ablation. Considering the increasing number of reports showing the lack of PSA-free survival benefit from neoadjuvant androgen ablation, it would seem prudent to delete the separate cutoff based on the use of neoadjuvant androgen ablation for neurovascular bundle excision. Thus, a patient in whom resection of the neurovascular bundle would be considered without neoadjuvant therapy should still be considered if neoadjuvant androgen ablation is used. In addition, is a 10% risk significant enough for complete sacrifice of a neurovascular bundle or is a more careful dissection with tailoring and sacrificing a portion of the neurovascular bundle, especially if the apical biopsy is negative, more prudent? Furthermore, the authors do not provide us with enough information on how many neurovascular bundles were sacrificed in patients with organ confined disease. I believe that strict attention to the well defined principles of anatomical radical prostatectomy with careful dissection of the apex, incorporates at both layers of Denonvilliers’ fascia with the specimen, wide excision of the bladder neck, careful preoperative planning for the neurovascular bundles based on the location and number of positive biopsies, and ultrasonographic findings will reduce positive margins. Furthermore, planning an operation with possible compromised technique based on the use of neoadjuvant androgen ablation is not justified. Finally, the significant risk of prostate cancer that exists among black men and unfortunate death rate in this population given all urologists great concern. Even in equal access health care environments there appears to be a difference in progression-free survival, stage for stage, in black compared to white men.3 Efforts t o elucidate the reasons for such a higher propensity and poorer outcome in this population have shed little light to date. Moul et a1 have reported that in a n equal access health care system, across all stages and grades black men presenting to screening clinics had higher PSA and associated tumor volumes.* This study questioned the level of public awareness among black American men regarding the value of prostate cancer detection and emphasized needs to improve it. Clearly, appropriate guidelines and metrics for early detection of prostate cancer in black Americans must be devised to improve our ability to detect cancer earlier in this at risk population. In this issue Smith et a1 (page 1734) evaluated the differences in prostate cancer detection rates between black and white Americans with PSA between 2.6 and 4 ng./ml., and benign digital rectal examination. They reported a 2-fold higher detection rate in black men. Although only 391 of 981 men with the entry criteria underwent biopsy, the overall cancer detection rate was an impressive 27%. However, the detection rate in black men was 45% compared to 26% in white men. Of the black men 77% underwent radical prostatectomy, 40% of whom had locally advanced disease (pT3) compared to 18% of white men. Of the black Americans 30% also had a Gleason score of 7 or greater compared to only 10% of white Americans. The grade and stage of these cancers clearly reflected clinically significant disease. The fact that large percentages of black Americans had pathologically advanced disease is of concern and speaks to our need to de-
1739
1740
TOWARDS A BETTER CRYSTAL BALL
velop more effective early detection methods for this population. These results, although requiring further study and confirmation,provide a foundation for considering lowering absolute levels of PSA in men who have the highest mortality in the world h m this disease. Concerns about over detection should be ameliorated by the use of percent free PSA. The authors have defined in a prior study a cutoff of 27% free PSA, which maintains a high sensitivity while avoiding 18%of biop sies. Although our ability to prognosticate and predict still remains imprecise, admirable strides are being made. Further studies along the lines of Stone and Smith et a1 can only make for a better crystal ball.
Brian J. Miles Department of Urology Baylor College of Medicine Houston, Texas
REFERENCES
1. Partin, A. W., Kattan, M. W., Subong, E. N. P., Walsh, P. C., Wojno, K. J., Oesterling, J. E., Scardino, P. T. and Pearson, J. D.: Combination of prostate specific antigen, clinical stage, and Gleason score predict pathological stage of localized prostate cancer: A multi-institutional update. J.A.M.A., 277: 1445, 1997. 2. Kattan, M. W., Eastham, J. A., Stapleton, A. M. F., Wheeles, T. M. and Scardino, P. T.: A pre-operative nomogram for disease recurrence following radical prostatectomy for prostate cancer. J. Natl. Cancer Inst., 90: 766, 1998. 3. Moul, J. W., Douglas, T. H., McCarthy, W. F. and McLeod, D.: Black race is an adverse prognostic factor for prostate cancer recurrence following radical prostatectomy in an equal access health care setting. J. Urol., 155 1667, 1996. 4. Mod, J. W., Sesterhan, I. A,, Connelly, R. R., Douglas, T., Srivastava, S., Mostofi, F. K. and McLeod, D. G.: Prostate specific antigen values at the time of prostate cancer diagnosis in African American men. J.A.M.A., 274 1277, 1995.
THE JOURNAL OF UROLOGY
Vol. 160, 1739-1740, November 1998 Printed in U.S.A.
Copyright 0 1998 by AMERICAN UROLOGICAL ASSOCIATION, INC.
EDITORIAL: TOWARDS A. .BETTER CRYSTAL BALL As our understanding of prostate cancer improves patients increasingly test our ability to provide the detailed information they desire on the curability of the disease. In essence they want us t o provide a crystal ball with which to look into the future. In this issue 3 articles suggest opportunities to improve our predictive and prognostic capabilities in prostate cancer detection and management. Until this decade our ability to ascertain accurately clinical stage was woefully inadequate, with over staging occurring in up to 66% of patients undergoing radical prostatectomy for clinically localized disease. With the use of prostate specific antigen (PSA), numerous PSA subtypes and Gleason scoring our predictive capacity has improved increasingly. In patients undergoing radical prostatectomy many centers have shown consistent factors associated with final pathological stage and prognosis, for example preoperative PSA, Gleason score and clinical stage. These predictivelprognostic factors have also led to the current passion for nomograms. The most popular of these tools, the nomograms of Partin et a1 for predicting final pathological stage1 and Kattan et al for predicting 5-year PSA-free recurrence2 after radical prostatectomy are in wide clinical use. These models perform reasonably well, although questions exist regarding the ability of the nomogram of Partin et a1 to predict seminal vesicle invasion and lymph node status. Can and do we need to improve these modeling instruments? Certainly, in patients undergoing radiation therapy accurate prediction of lymph node or seminal vesicle status would be helpful in patient selection and outcomes evaluation. Although pretreatment PSA and Gleason score are reasonable predictors of failure, they remain inadequate to define a population for whom curative therapy is appropriate or node dissection unnecessary. The study by Stone et a1 (page 1722) is a reasonable attempt to allow us to predict the latter. They concluded that the presence of a positive seminal vesicle biopsy or perineural invasion was an indication for pelvic lymph dissection based on a multivariate analysis of more than 200 laparoscopic pelvic lymph node specimens. Although PSA was an independent predictor in univariate analysis, it did not predict well in multivariate analysis. I have concerns about the accuracy of seminal vesicle biopsy but it appears useful in the hands of these investigators. The effort to define patients in absolute need of a pelvic lymph node dissection is important but I believe that prudence dictates pelvic lymph node dissection in other select patients, such as those with a PSA greater than 20, especially when Gleason score is 7 or greater. I am less sanguine about the efforts of Rabbani et a1 (page 1727). They sought to identify those who might benefit ”from technical modifications such as excision of the bladder neck or wide excision of the neurovascular bundles” by examining 242 patients treated with radical prostatectomy with or without neoadjuvant androgen ablation. Only pre-radical prostatectomy PSA was statistically significant in multivariate analysis as a predictor of margin positivity. They defined patients who were at high risk for positive apical margins without neoadjuvant androgen therapy as those with 3 or more positive biopsies of the standard 6 cores, and for whom “more careful dissection at the apex with wide excision of the neurovascular bundles” may be beneficial. It is unclear how helpful the recommendation is because the sites of margins positive at the apex (that is posterolaterally or anteriorly
where they often occur) and so forth were not defined. They also have created yet another nomogram to help predict patients with a greater than 10% chance of cancer at the margins based on PSA, and number and location of positive cores stratified by use or no use of neoadjuvant androgen ablation. Considering the increasing number of reports showing the lack of PSA-free survival benefit from neoadjuvant androgen ablation, it would seem prudent to delete the separate cutoff based on the use of neoadjuvant androgen ablation for neurovascular bundle excision. Thus, a patient in whom resection of the neurovascular bundle would be considered without neoadjuvant therapy should still be considered if neoadjuvant androgen ablation is used. In addition, is a 10% risk significant enough for complete sacrifice of a neurovascular bundle or is a more careful dissection with tailoring and sacrificing a portion of the neurovascular bundle, especially if the apical biopsy is negative, more prudent? Furthermore, the authors do not provide us with enough information on how many neurovascular bundles were sacrificed in patients with organ confined disease. I believe that strict attention to the well defined principles of anatomical radical prostatectomy with careful dissection of the apex, incorporates at both layers of Denonvilliers’ fascia with the specimen, wide excision of the bladder neck, careful preoperative planning for the neurovascular bundles based on the location and number of positive biopsies, and ultrasonographic findings will reduce positive margins. Furthermore, planning an operation with possible compromised technique based on the use of neoadjuvant androgen ablation is not justified. Finally, the significant risk of prostate cancer that exists among black men and unfortunate death rate in this population given all urologists great concern. Even in equal access health care environments there appears to be a difference in progression-free survival, stage for stage, in black compared to white men.3 Efforts t o elucidate the reasons for such a higher propensity and poorer outcome in this population have shed little light to date. Moul et a1 have reported that in a n equal access health care system, across all stages and grades black men presenting to screening clinics had higher PSA and associated tumor volumes.* This study questioned the level of public awareness among black American men regarding the value of prostate cancer detection and emphasized needs to improve it. Clearly, appropriate guidelines and metrics for early detection of prostate cancer in black Americans must be devised to improve our ability to detect cancer earlier in this at risk population. In this issue Smith et a1 (page 1734) evaluated the differences in prostate cancer detection rates between black and white Americans with PSA between 2.6 and 4 ng./ml., and benign digital rectal examination. They reported a 2-fold higher detection rate in black men. Although only 391 of 981 men with the entry criteria underwent biopsy, the overall cancer detection rate was an impressive 27%. However, the detection rate in black men was 45% compared to 26% in white men. Of the black men 77% underwent radical prostatectomy, 40% of whom had locally advanced disease (pT3) compared to 18% of white men. Of the black Americans 30% also had a Gleason score of 7 or greater compared to only 10% of white Americans. The grade and stage of these cancers clearly reflected clinically significant disease. The fact that large percentages of black Americans had pathologically advanced disease is of concern and speaks to our need to de-
1739
1740
TOWARDS A BETTER CRYSTAL BALL
velop more effective early detection methods for this population. These results, although requiring further study and confirmation,provide a foundation for considering lowering absolute levels of PSA in men who have the highest mortality in the world h m this disease. Concerns about over detection should be ameliorated by the use of percent free PSA. The authors have defined in a prior study a cutoff of 27% free PSA, which maintains a high sensitivity while avoiding 18%of biop sies. Although our ability to prognosticate and predict still remains imprecise, admirable strides are being made. Further studies along the lines of Stone and Smith et a1 can only make for a better crystal ball.
Brian J. Miles Department of Urology Baylor College of Medicine Houston, Texas
REFERENCES
1. Partin, A. W., Kattan, M. W., Subong, E. N. P., Walsh, P. C., Wojno, K. J., Oesterling, J. E., Scardino, P. T. and Pearson, J. D.: Combination of prostate specific antigen, clinical stage, and Gleason score predict pathological stage of localized prostate cancer: A multi-institutional update. J.A.M.A., 277: 1445, 1997. 2. Kattan, M. W., Eastham, J. A., Stapleton, A. M. F., Wheeles, T. M. and Scardino, P. T.: A pre-operative nomogram for disease recurrence following radical prostatectomy for prostate cancer. J. Natl. Cancer Inst., 90: 766, 1998. 3. Moul, J. W., Douglas, T. H., McCarthy, W. F. and McLeod, D.: Black race is an adverse prognostic factor for prostate cancer recurrence following radical prostatectomy in an equal access health care setting. J. Urol., 155 1667, 1996. 4. Mod, J. W., Sesterhan, I. A,, Connelly, R. R., Douglas, T., Srivastava, S., Mostofi, F. K. and McLeod, D. G.: Prostate specific antigen values at the time of prostate cancer diagnosis in African American men. J.A.M.A., 274 1277, 1995.