- Email: [email protected]
Editorial: Prostate Cancer
0022-5347/96/1551-0226$03.00/0
THEJOLT".
OF
Vol. 155,226-227, January 1996 Printed in U.S.A.
UROLQCY
Copynght 0 1996 by AMERICAN URO~~CICAL ASSOCIATION, INc.
EDITORIAL: PROSTATE CANCER The previous 4 articles in this issue of the Journal describe a potpourri of issues related to prostate cancer. Each study makes an individual contribution with specific importance. Dalkin (page 206) describes management of anastomotic strictures after radical prostatectomy. The incidence of approximately 12% is usually reported, although our experience has suggested a slightly lower incidence. He describes a common sense approach to the problem and separates immature from mature strictures. The former type occurred shortly after catheter removal, and was initially treated by dilation and subsequent urethrotomy if necessary. The latter type seemed to respond best to urethrotomy. Identifying the exact location of the stricture is usually not possible until at least 1 or 2 months after catheter removal, and incising the stricture immediately can be hazardous. Most of us treat strictures in a manner similar to the approach recommended by the author. It is important to note that 2 patients still needed dilation, and one wonders whether they would have been better served with another incision. We currently have no patient on long-term dilations. Also, the author makes bilateral incisions in the stricture and we have had our best results with only 1 incision in the anterior midline. As the author demonstrates, severe stricture should be uncommon and can be treated in almost every case with incision using a cold knife with preservation of continence. The rare patient who presents with a dense stricture and incontinence is best served by complete transurethral resection of the matured scar tissue and subsequent insertion of a sphincter. These cases occur rarely and are completely preventable by proper surgical technique. Flutamide is used increasingly as part of total androgen ablation, and in neoadjuvant treatment before radical prostatectomy. Wysowski and Fourcroy (page 209) review the hepatotoxicity secondary to the drug. They acknowledge the dificulty in determining the incidence of the complication because the total number of prescriptions is unknown. However, they rightfully note that under reporting of the number of cases would offset that error. A total of 20 deaths due to flutamide has been reported to the Food and Drug Administration and 26 more patients required hospitalization. Many of us have seen isolated cases of severe jaundice, which happily have resolved after discontinuing the medication. The authors estimate the incidence of flutamide hepatotoxicity to be less than 1to 10%. The message in this article is important and clear, that is flutamide can occasionally cause severe liver damage or death. Blood enzyme and bilirubin levels should be measured during the first few months of treatment, and patients should be cautioned about the potential for this complication and its early signs. Treatment of presumed localized or locally extensive prostate cancer with hormones before radical prostatectomy has gained enormous popularity. Initially, such treatment seemed to offer an opportunity to render surgically incurable disease (stage T3)curable by surgery. In references cited by Gleave et al (page 213)this hypothesis proved to be flawed. Subsequently, several randomized studies (references 12 to 14 in article) demonstrated a decrease in the incidence of positive margins following 3 months of endocrine therapy in patients with clinical stage T1 or T3 tumors. The purpose of the current study was to determine the duration of adjuvant therapy necessary for maximum efficacy to assess the effect of hormones on pathological stage. The study demonstrated that "more was better than less" because with an ultrasensitive assay prostate specific antigen (PSA)reached a nadir in more patients by 8 months
(84%)than &r 3 months (22%). The positive margin rate was 4% a b r 8 months of therapy. However, only 6 of 50
patients had clinical stage T3 tumors and 15 (30%)had well differentiated disease (Gleason score 2 to 4). The authors compared this finding to literature reports of 30 to 60% positive margins but, unfortunately, the series cited (references 1 to 5 in article) do not represent the true incidence in the modem era, when better staging and selection of patients with a clinical stage similar to that found by Gleave et a1 demonstrated a positive margin rate of approximately 30%.1 The major issue with any neoadjuvant therapy is whether, once a tumor is of sufficient size to be clinically detectable, androgen-insensitive cells have already evolved. If so (and it certainly seems so) preoperative endocrine therapy will only mask the true incidence of positive margins. Even if all tumor cells in the prostate can potentially be killed by endocrine therapy, only patients with stage PO disease could expect to be cured ultimately. This expectation follows the simple logic that if any viable cells are found in the center of the prostate, there is no reason to assume that viable cells would not also be found in the periphery if they were there before the endocrine therapy. Most importantly, no long-term survival advantage has yet been demonstrated by preoperative endocrine therapy in a randomized trial. In this study followup was only 3 months. The fact that the markers of proliferation (proliferation cell nuclear antigen and Ki67) were not positive in the specimens does not lend any further support to the presence of androgen nonresponsive cells at that point. When survival data from the randomized studies are reported, it will be important to begin to mark time zero at 3 to 6 months after discontinuing hormones rather than from the date of surgery in patients receiving hormones preoperatively. The authors state that by 3 months the endocrine effect has resolved, since testosterone levels return to normal. It is more important to determine when the individual testosterone returns to the pretreatment level and in our experience this may take more than 3 months. Therefore, patients on preoperative endocrine therapy have perhaps a 6-month lead time before one would expect the tumors to become evident, and PSA recurrence may be delayed with no ultimate impact on survival. In the final analysis, even if one expects that the incidence of positive margins is decreased after endocrine therapy, there is no evidence to suggest that long-term survival will be improved and in my view logic would not support that it should. As noted by Wysowski and Fourcroy, endocrine therapy is not without risks. Furthermore, it is certainly not without costs in terms of medication, office visits, added laboratory tests, time away from work and the other known side effects of antiandrogen therapy. It is clearly experimental in the truest sense of the term and clearly not supportable as routine practice before radical prostatectomy. Obesity, universally condemned as a curse of modem America, poses an advantage once prostate cancer occurs according to the article by Daniell (page 220) after an analysis of 235 men with nonstage T 1 prostate cancer diagnosed between 1990 and 1992. The data suggest that obese men were more inclined to have lower stage disease and that tumor specific mortality was lower in obese men as well as in nonsmokers. Daniell suggests that this finding may be related to increased endogenous estrogen and decreased endogenous testosterone associated with obesity. The data were carefully analyzed but suffer from many uncertainties. Hormone levels were not routinely measured. Other studies (references 10, 11 and 15 in article) contradict
226
PROSTATE CANCER
227
the findings, while other data (references 6 to 9 in article) tors contributing to prostate cancer. Therefore, this populaseem to be in agreement. I have observed that when epide- tion could be a select group. Finally, Daniel1 defines anyone miological data such as these are in disagreement over a 10%overweight as obese. One must wonder what percentage specific issue, resolution is virtually impossible without in- of the general population in that area (or in any area) would sertion of basic science or cancer control science. qualify as nonobese according to this criterion. This article presents an interesting analysis of various Without knowing the actual hormonal levels, it is difficult to ascribe these changes to increased estrogen. We really do factors in people with prostate cancer. However, it certainly not know whether the tumors were detected early in obese would not deter most of us from recommending that most men, although this is unlikely. We have no PSA data to follow patients with prostate cancer lose weight and eat more the progress of the patients. Differences in survival would be healthful diets as a means of potentially prolonging life. colored by an increased death rate from other causes (cardioJean B. &Kernion vascular) in obese prostate cancer patients before the prosDepartment of Urology tate cancer would become evident. On the other hand, perUCLA School of Medicine haps markedly obese men have more physical or mental Los Angeles, California complaints, or higher risks of other illnesses that would bring them to the doctor sooner than healthy, relatively young 1. Catalona, W. J. and Smith,D. S.: 5-Year tumor recurrence rates men. This study was from a farm community and studies are after anatomical radical retropubic prostatectomy for prostate cancer. J. Urol., part 2, 152 1837, 1994. ongoing that suggest that farm men may be exposed to fac-
THEJOLT".
OF
Vol. 155,226-227, January 1996 Printed in U.S.A.
UROLQCY
Copynght 0 1996 by AMERICAN URO~~CICAL ASSOCIATION, INc.
EDITORIAL: PROSTATE CANCER The previous 4 articles in this issue of the Journal describe a potpourri of issues related to prostate cancer. Each study makes an individual contribution with specific importance. Dalkin (page 206) describes management of anastomotic strictures after radical prostatectomy. The incidence of approximately 12% is usually reported, although our experience has suggested a slightly lower incidence. He describes a common sense approach to the problem and separates immature from mature strictures. The former type occurred shortly after catheter removal, and was initially treated by dilation and subsequent urethrotomy if necessary. The latter type seemed to respond best to urethrotomy. Identifying the exact location of the stricture is usually not possible until at least 1 or 2 months after catheter removal, and incising the stricture immediately can be hazardous. Most of us treat strictures in a manner similar to the approach recommended by the author. It is important to note that 2 patients still needed dilation, and one wonders whether they would have been better served with another incision. We currently have no patient on long-term dilations. Also, the author makes bilateral incisions in the stricture and we have had our best results with only 1 incision in the anterior midline. As the author demonstrates, severe stricture should be uncommon and can be treated in almost every case with incision using a cold knife with preservation of continence. The rare patient who presents with a dense stricture and incontinence is best served by complete transurethral resection of the matured scar tissue and subsequent insertion of a sphincter. These cases occur rarely and are completely preventable by proper surgical technique. Flutamide is used increasingly as part of total androgen ablation, and in neoadjuvant treatment before radical prostatectomy. Wysowski and Fourcroy (page 209) review the hepatotoxicity secondary to the drug. They acknowledge the dificulty in determining the incidence of the complication because the total number of prescriptions is unknown. However, they rightfully note that under reporting of the number of cases would offset that error. A total of 20 deaths due to flutamide has been reported to the Food and Drug Administration and 26 more patients required hospitalization. Many of us have seen isolated cases of severe jaundice, which happily have resolved after discontinuing the medication. The authors estimate the incidence of flutamide hepatotoxicity to be less than 1to 10%. The message in this article is important and clear, that is flutamide can occasionally cause severe liver damage or death. Blood enzyme and bilirubin levels should be measured during the first few months of treatment, and patients should be cautioned about the potential for this complication and its early signs. Treatment of presumed localized or locally extensive prostate cancer with hormones before radical prostatectomy has gained enormous popularity. Initially, such treatment seemed to offer an opportunity to render surgically incurable disease (stage T3)curable by surgery. In references cited by Gleave et al (page 213)this hypothesis proved to be flawed. Subsequently, several randomized studies (references 12 to 14 in article) demonstrated a decrease in the incidence of positive margins following 3 months of endocrine therapy in patients with clinical stage T1 or T3 tumors. The purpose of the current study was to determine the duration of adjuvant therapy necessary for maximum efficacy to assess the effect of hormones on pathological stage. The study demonstrated that "more was better than less" because with an ultrasensitive assay prostate specific antigen (PSA)reached a nadir in more patients by 8 months
(84%)than &r 3 months (22%). The positive margin rate was 4% a b r 8 months of therapy. However, only 6 of 50
patients had clinical stage T3 tumors and 15 (30%)had well differentiated disease (Gleason score 2 to 4). The authors compared this finding to literature reports of 30 to 60% positive margins but, unfortunately, the series cited (references 1 to 5 in article) do not represent the true incidence in the modem era, when better staging and selection of patients with a clinical stage similar to that found by Gleave et a1 demonstrated a positive margin rate of approximately 30%.1 The major issue with any neoadjuvant therapy is whether, once a tumor is of sufficient size to be clinically detectable, androgen-insensitive cells have already evolved. If so (and it certainly seems so) preoperative endocrine therapy will only mask the true incidence of positive margins. Even if all tumor cells in the prostate can potentially be killed by endocrine therapy, only patients with stage PO disease could expect to be cured ultimately. This expectation follows the simple logic that if any viable cells are found in the center of the prostate, there is no reason to assume that viable cells would not also be found in the periphery if they were there before the endocrine therapy. Most importantly, no long-term survival advantage has yet been demonstrated by preoperative endocrine therapy in a randomized trial. In this study followup was only 3 months. The fact that the markers of proliferation (proliferation cell nuclear antigen and Ki67) were not positive in the specimens does not lend any further support to the presence of androgen nonresponsive cells at that point. When survival data from the randomized studies are reported, it will be important to begin to mark time zero at 3 to 6 months after discontinuing hormones rather than from the date of surgery in patients receiving hormones preoperatively. The authors state that by 3 months the endocrine effect has resolved, since testosterone levels return to normal. It is more important to determine when the individual testosterone returns to the pretreatment level and in our experience this may take more than 3 months. Therefore, patients on preoperative endocrine therapy have perhaps a 6-month lead time before one would expect the tumors to become evident, and PSA recurrence may be delayed with no ultimate impact on survival. In the final analysis, even if one expects that the incidence of positive margins is decreased after endocrine therapy, there is no evidence to suggest that long-term survival will be improved and in my view logic would not support that it should. As noted by Wysowski and Fourcroy, endocrine therapy is not without risks. Furthermore, it is certainly not without costs in terms of medication, office visits, added laboratory tests, time away from work and the other known side effects of antiandrogen therapy. It is clearly experimental in the truest sense of the term and clearly not supportable as routine practice before radical prostatectomy. Obesity, universally condemned as a curse of modem America, poses an advantage once prostate cancer occurs according to the article by Daniell (page 220) after an analysis of 235 men with nonstage T 1 prostate cancer diagnosed between 1990 and 1992. The data suggest that obese men were more inclined to have lower stage disease and that tumor specific mortality was lower in obese men as well as in nonsmokers. Daniell suggests that this finding may be related to increased endogenous estrogen and decreased endogenous testosterone associated with obesity. The data were carefully analyzed but suffer from many uncertainties. Hormone levels were not routinely measured. Other studies (references 10, 11 and 15 in article) contradict
226
PROSTATE CANCER
227
the findings, while other data (references 6 to 9 in article) tors contributing to prostate cancer. Therefore, this populaseem to be in agreement. I have observed that when epide- tion could be a select group. Finally, Daniel1 defines anyone miological data such as these are in disagreement over a 10%overweight as obese. One must wonder what percentage specific issue, resolution is virtually impossible without in- of the general population in that area (or in any area) would sertion of basic science or cancer control science. qualify as nonobese according to this criterion. This article presents an interesting analysis of various Without knowing the actual hormonal levels, it is difficult to ascribe these changes to increased estrogen. We really do factors in people with prostate cancer. However, it certainly not know whether the tumors were detected early in obese would not deter most of us from recommending that most men, although this is unlikely. We have no PSA data to follow patients with prostate cancer lose weight and eat more the progress of the patients. Differences in survival would be healthful diets as a means of potentially prolonging life. colored by an increased death rate from other causes (cardioJean B. &Kernion vascular) in obese prostate cancer patients before the prosDepartment of Urology tate cancer would become evident. On the other hand, perUCLA School of Medicine haps markedly obese men have more physical or mental Los Angeles, California complaints, or higher risks of other illnesses that would bring them to the doctor sooner than healthy, relatively young 1. Catalona, W. J. and Smith,D. S.: 5-Year tumor recurrence rates men. This study was from a farm community and studies are after anatomical radical retropubic prostatectomy for prostate cancer. J. Urol., part 2, 152 1837, 1994. ongoing that suggest that farm men may be exposed to fac-