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Editorial: Prostate Cancer–Many Treatments But Not Enough Answers
0022-5347/95/1542-04~$03.00/0
Vol. 154,454-455, August 1995 Printed in U S A ,
THE JOURNAL OF UROLOGY Copyright 0 1995 by AMERICANU R O ~ I C A ASS~CIATION, L hc.
EDITORIAL: PROSTATE CANCER-MANY TREATMENTS BUT NOT ENOUGH ANSWERS During the last decade, urologists have witnessed impres- patients treated by radical prostatectomy. It must also be sive increases in the incidence of prostate cancer, the num- emphasized that a clear surgical margin does not exclude the bers of patients with localized disease and the variety of possibility of local recurrence. In a previous study examining treatment alternatives available to patients. Treatment de- neoadjuvant therapy before radical prostatectomy for stage C cisions are difficult due to the wide variety of treatment disease, clear surgical margins were achieved in 62%of the options and the fact that the benefit of 1 treatment over patients but disease recured locally in 25%.3Recently, we another has not been determined with certainty in well de- examined the patterns of recurrence in 114 men with detecb signed, prospective trials. Currently, patients and their phy- able serum PSA values and negative bone scans after radical sicians must consider treatment with surgery, various forms prostatectomy.4 Of the patients with documented local recurof radiation, cryoablation, androgen deprivation, watchful rence 34% were reported to have negative surgical margins, waiting or a combination of these methods. Treatment op- including 20% with organ-confined disease, using step tions are increasing in number and variety as even newer sectioning pathological techniques a t radical prostatectomy. approaches are being incorporated into clinical trials. In this Given that the long-term impact of neoadjuvant therapy is issue of the Journal the results of several treatment regi- not known, urological surgeons should not let neoadjuvant therapy substitute for good surgical technique. Thorough mens are presented. Neoadjuvant androgen deprivation before definitive treat- knowledge of prostatic and pelvic anatomy, proper patient ment, whether surgery or radiation, has attracted consider- selection, selective use of nerve sparing surgery and excellent able interest in this country and abroad.' The goals of such exposure facilitated by good vascular control will minimize therapy would be to induce tumor downstaging, and decrease the incidence of positive surgical margins. The hypothesis that neoadjuvant androgen deprivation the likelihood of positive surgical margins and the risk of prostate cancer recurrence. These goals are of value and will have a favorable impact on prostate cancer recurrence clinical trials examining neoadjuvant therapy deserve sup- rates is worthy of randomized clinical trials as reported in port. Obtaining a clear surgical margin in patients with this issue. The impact of neoadjuvant therapy on long-term extracapsular extension confers a clear advantage, since un- recurrence rates is not known presently as both groups of detectable levels of prostate specific antigen (PSA) a t 5 years investigators admit. I look forward to reanalysis of both of will be achieved in approximately 46%of such patients com- these trials when they have matured, and clinical and PSA pared to 7% of those with extracapsular extension and a recurrence rates can be determined with confidence. positive surgical margin.2 Two studies led by distinguished Transrectal ultrasound guided transperineal percutaneous and experienced surgeons comparing neoadjuvant androgen cryoablation of the prostate is perceived by many as a n efdeprivation followedby radical prostatectomy to radical pros- fective, easy to perform procedure with low morbidity. Objectatectomy alone for the management of stages T2 and T3 tive reporting of early and long-term results may or may not prostatic cancer are reported in this issue of the Journal. support this concept. Wieder et al (page 435) report their Impressive changes in serum PSA, and prostate and cancer preliminary results with 83 patients who underwent a single volume in those receiving neoadjuvant therapy were reported procedure. They are experienced cryosurgeons. Of the 83 in both studies. Neoadjuvant therapy was well tolerated, and patients treated followup biopsies were performed at 3 blood loss and operating times were not influenced by this months in 61. The treatment group was a favorable one since therapy. Soloway et a1 (page 424) treated patients with stage 78%of those treated and available for followup biopsies had T2b prostatic cancer with a luteinizing hormone-releasing low stage disease (stages T1 to T2). Of the biopsies 13% hormone agonist and an antiandrogen for 3 months preoper- revealed residual prostatic cancer. Patients with stages A atively. Patients given neoadjuvant therapy had a signifi- through C disease were less likely to have positive biopsies cantly lower rate of capsular penetration, positive surgical (15.8%,3.5% and 0%,respectively) compared t o those with margins (18%versus 48%) and tumor involvement of the stage D disease (57.1%).Although the number of patients urethral margins (6% versus 17%).Van Poppel et a1 (page with undetectable serum PSA values was not stated, 57.4% 429) treated patients with 6 weeks of estramustine phos- had serum PSA values less than 0.5 ng./ml. The procedures phate preoperatively. Patients with stage T2b cancer given were generally well tolerated and only 6.3% of the patients neoadjuvant therapy were less likely to have positive surgi- required secondary procedures to treat complications. cal margins posterolaterally (19.4%versus 45.9%),apically Based on this preliminary review, Wieder et a1 suggest (13.9%versus 27%)and at the base (8.3%versus 10.8%).In that cryoablation of the prostate is as effective as radical addition, upstaging to stage pT3 cancer was less common in prostatectomy and nearly as effective as radical prostatecthose who received neoadjuvant estramustine phosphate tomy followed by adjunctive radiation in eliminating prostate (16.7%versus 34.4%).Alternatively, patients with stage T3 cancer in patients with localized disease. However, much cancer given neoadjuvant therapy were more likely to have additional information needs to be obtained before cryoablapositive surgical margins. Clinical overstaging in this group tion can be accepted as a technique comparable to radical was common, since 56% of the controls believed to have prostatectomy. Many technical issues must be resolved. The clinical stage T3 cancer had stage pT2 disease after radical efficacy of the procedure may be enhanced by double freezing prostatectomy. a t single locations and more lateral placement of the cry* The resulta of these 2 trials and others to date suggest that probes. The use of thermocouples has been recommended by neoadjuvant therapy is well tolerated, does not induce sig- some to determine better the area of therapeutic freezing. nificant tumor downstaging and decreases the likelihood of The urethral warming device has not been standardized. positive surgical margins. Of concern in these 2 series, and in Although the authors reported low rates of urinary retention those reported previously, is the seemingly high incidence of requiring secondary procedures, our own experience and that positive surgical margins in the control groups. These rates of others5 suggest that the incidence of this comp11cationmay seem at variance with other previously reported series of be higher as we try to achieve more complete cryoablation 454
PROSTATE CANCER-MANY
TREATMENTS, BUT NOT ENOUGH ANSWERS
and define the optimal design of the urethral warming device. Cryosurgery instruments may not be comparable as we11.6 Finally, the costs of the procedure as well as the impact on quality of life must be documented prospectively. At our institution, a cost or quality of life advantage of cryotherapy over radical prostatectomy has not been documented as yet for those with localized disease. In fact, cryosurgery may be more costly if it is associated with either significant complication or retreatment rates. Oefelein et a1 (page 442) report that operative blood loss, not the type of blood transfused, was significantly related to decreased recurrence-free survival after radical prostatectomy. The article is strengthened by use of careful followup, univariate and multivariate statistical analyses, and controlling for time of treatment, biochemical failure and adjuvant radiotherapy. In the multivariate analysis, significant associations with recurrence-free prostate cancer survival were demonstrated for pathological tumor stage, tumor Gleason score, operative blood loss and total units of blood transfused. The authors conclude that the operative events necessitating transfusion are more significant than the immunological effects of transfusion. However, the patients in this study underwent surgery between 1980 and 1990. Although this period allows one to examine long-term disease status, the patient population may not reflect the one currently undergoing surgery or contemporary surgical techniques. In the current study 49% of the patients had stage pT3 or pT4 disease and the mean blood loss (determined by net change in serum hemoglobin) was 2,266 ml. PSA based screening, the more effective use of preoperative staging methods and improvement in surgical techniques have resulted in better patient selection and decreased morbidity, including blood loss. In fact, the mean amount of blood transfused was approximately 650 ml. according to the study reported by Soloway et al. Nevertheless, this study highlights the need for surgeons to pay close attention to careful patient selection and meticulous surgical technique to maximize patient outcomes. Fowler et a1 (page 448) assessed the impact of deferred flutamide therapy in patients with localized and metastatic prostate cancer treated initially with diethylstilbestrol, orchiectomy or a luteinizing hormone-releasing hormone agonist. In 92% of the patients flutamide was administered when the serum PSA level was noted to be increasing. A significant decrease in PSA level (more than 50%)was noted in 80% of patients with localized disease and 54% of those with metastatic cancer during flutamide treatment. Deferred ilutamide treatment benefited only patients with localized disease and a PSA response. Previous studies cited in this report have shown a benefit to the use of initial, combined androgen blockade but no benefit to deferred flutamide in patients with metastatic disease. This benefit may be most apparent in patients with minimal metastatic tumor. The authors defer antiandrogen therapy in patients with metastatic disease based on the cost of the therapy and what they cite as a marginal improvement in overall survival. However, the progression-free survival benefit to combined androgen blockade, if confirmed by ongoing trials, should not be considered insignificant. The cost-effectiveness of this interven-
455
tion compares favorably with other common health care expenditures, especially when used for management of those with minimal disease.’ Fowler et a1 correctly note that patients with localized cancer may enjoy a long disease-free interval when treated with androgen deprivation. The indications for androgen deprivation in those with low stage cancer, or who are older or have significant co-morbid diseases has not been determined. In addition, the preferred form of androgen deprivation (monotherapy versus combined therapy, intermittent or continuous therapy) is the subject of ongoing investigations. Prostate cancer has become a high profile disease based on its increased incidence, the wide application of screening tests, the uncertainty over treatment, and the costs associated with detection and treatment. The costs of treating the disease will increase as we detect more cancers and deliver multiple treatments concurrently or in sequence. Urologists should treat patients sensibly, compassionately and expertly based on the best information available. It is important that we prospectively evaluate the impact of treatment impartially and honestly using the best instruments available. In addition, we should be ready to modify our approach to prostate cancer detection or treatment if convincing evidence suggests that we should do so. Peter R. Carroll Department of Urology The University of California at Sun Francisco1 Mt. Zion Cancer Center University of California School of Medicine San Francisco, California REFERENCES
1. Pilepich, M.V., Krall, J.M., Al-Sharraf, M., John, M.J.,Doggett, R. L. S., Sause, W. T., Lawton, C. A.,Abrams, R. A., Rotman, M.,Rubin, P.,Shipley, W. U., Grignon, D., Caplan, R. and Cox, J. D.: Androgen deprivation with radiation therapy compared with radiation therapy alone for locally advanced prostatic carcinoma: a randomized comparative trial of the Radiation Therapy Oncology Group. Urology, 45: 616,1995. 2. Smith, R. C., Brendler, C. B. and Partin, A. W.: Extended follow-upof the influence of wide excision of the neurovascular bundeb) on prognosis in men with clinically localized prostate cancer. J. Urol., part 2, 153.39% abstract 654,1995. 3. Cher, M.L., Shinohara, K,Breslin, S., Vapnek, J. and Carroll, P. R.: High failure rate with long-term follow-up of neoadjuvant androgen deprivation followed by radical prostatectomy for stage C prostatic cancer. Brit. J. Urol., in press. 4. Shinohara, K., F’resti, J. C., Jr., Ingerman, A., Narayan, P. and Carroll, P.: Local recurrence after radical prostatectomy:characteristics in size, location and P S k J. Urol., part 2, 161: 256A,abstract 115,1994. 5. Shinohara, K. and Carroll, P. R.: Improved results of cryosurgical ablation of the D I - o s ~ ~J.~ .Urol... Dart 2. 153: 3856 abstract 627,1995. 6. Ka~lan.S.A. Greenberg, R. and Baust, J. G.: A comparative tksessment -of cryosu&cal devices: application to prostatic disease. Urology, 45: 692,1995. 7. Hillner, B. E.,McLeod, D. G., Crawford, E. D. and Bennett, C. L.: Estimating the cost effectiveness of total androgen blockade with flutamide in M1 prostate cancer. Urology, 45: 633,1995.
Vol. 154,454-455, August 1995 Printed in U S A ,
THE JOURNAL OF UROLOGY Copyright 0 1995 by AMERICANU R O ~ I C A ASS~CIATION, L hc.
EDITORIAL: PROSTATE CANCER-MANY TREATMENTS BUT NOT ENOUGH ANSWERS During the last decade, urologists have witnessed impres- patients treated by radical prostatectomy. It must also be sive increases in the incidence of prostate cancer, the num- emphasized that a clear surgical margin does not exclude the bers of patients with localized disease and the variety of possibility of local recurrence. In a previous study examining treatment alternatives available to patients. Treatment de- neoadjuvant therapy before radical prostatectomy for stage C cisions are difficult due to the wide variety of treatment disease, clear surgical margins were achieved in 62%of the options and the fact that the benefit of 1 treatment over patients but disease recured locally in 25%.3Recently, we another has not been determined with certainty in well de- examined the patterns of recurrence in 114 men with detecb signed, prospective trials. Currently, patients and their phy- able serum PSA values and negative bone scans after radical sicians must consider treatment with surgery, various forms prostatectomy.4 Of the patients with documented local recurof radiation, cryoablation, androgen deprivation, watchful rence 34% were reported to have negative surgical margins, waiting or a combination of these methods. Treatment op- including 20% with organ-confined disease, using step tions are increasing in number and variety as even newer sectioning pathological techniques a t radical prostatectomy. approaches are being incorporated into clinical trials. In this Given that the long-term impact of neoadjuvant therapy is issue of the Journal the results of several treatment regi- not known, urological surgeons should not let neoadjuvant therapy substitute for good surgical technique. Thorough mens are presented. Neoadjuvant androgen deprivation before definitive treat- knowledge of prostatic and pelvic anatomy, proper patient ment, whether surgery or radiation, has attracted consider- selection, selective use of nerve sparing surgery and excellent able interest in this country and abroad.' The goals of such exposure facilitated by good vascular control will minimize therapy would be to induce tumor downstaging, and decrease the incidence of positive surgical margins. The hypothesis that neoadjuvant androgen deprivation the likelihood of positive surgical margins and the risk of prostate cancer recurrence. These goals are of value and will have a favorable impact on prostate cancer recurrence clinical trials examining neoadjuvant therapy deserve sup- rates is worthy of randomized clinical trials as reported in port. Obtaining a clear surgical margin in patients with this issue. The impact of neoadjuvant therapy on long-term extracapsular extension confers a clear advantage, since un- recurrence rates is not known presently as both groups of detectable levels of prostate specific antigen (PSA) a t 5 years investigators admit. I look forward to reanalysis of both of will be achieved in approximately 46%of such patients com- these trials when they have matured, and clinical and PSA pared to 7% of those with extracapsular extension and a recurrence rates can be determined with confidence. positive surgical margin.2 Two studies led by distinguished Transrectal ultrasound guided transperineal percutaneous and experienced surgeons comparing neoadjuvant androgen cryoablation of the prostate is perceived by many as a n efdeprivation followedby radical prostatectomy to radical pros- fective, easy to perform procedure with low morbidity. Objectatectomy alone for the management of stages T2 and T3 tive reporting of early and long-term results may or may not prostatic cancer are reported in this issue of the Journal. support this concept. Wieder et al (page 435) report their Impressive changes in serum PSA, and prostate and cancer preliminary results with 83 patients who underwent a single volume in those receiving neoadjuvant therapy were reported procedure. They are experienced cryosurgeons. Of the 83 in both studies. Neoadjuvant therapy was well tolerated, and patients treated followup biopsies were performed at 3 blood loss and operating times were not influenced by this months in 61. The treatment group was a favorable one since therapy. Soloway et a1 (page 424) treated patients with stage 78%of those treated and available for followup biopsies had T2b prostatic cancer with a luteinizing hormone-releasing low stage disease (stages T1 to T2). Of the biopsies 13% hormone agonist and an antiandrogen for 3 months preoper- revealed residual prostatic cancer. Patients with stages A atively. Patients given neoadjuvant therapy had a signifi- through C disease were less likely to have positive biopsies cantly lower rate of capsular penetration, positive surgical (15.8%,3.5% and 0%,respectively) compared t o those with margins (18%versus 48%) and tumor involvement of the stage D disease (57.1%).Although the number of patients urethral margins (6% versus 17%).Van Poppel et a1 (page with undetectable serum PSA values was not stated, 57.4% 429) treated patients with 6 weeks of estramustine phos- had serum PSA values less than 0.5 ng./ml. The procedures phate preoperatively. Patients with stage T2b cancer given were generally well tolerated and only 6.3% of the patients neoadjuvant therapy were less likely to have positive surgi- required secondary procedures to treat complications. cal margins posterolaterally (19.4%versus 45.9%),apically Based on this preliminary review, Wieder et a1 suggest (13.9%versus 27%)and at the base (8.3%versus 10.8%).In that cryoablation of the prostate is as effective as radical addition, upstaging to stage pT3 cancer was less common in prostatectomy and nearly as effective as radical prostatecthose who received neoadjuvant estramustine phosphate tomy followed by adjunctive radiation in eliminating prostate (16.7%versus 34.4%).Alternatively, patients with stage T3 cancer in patients with localized disease. However, much cancer given neoadjuvant therapy were more likely to have additional information needs to be obtained before cryoablapositive surgical margins. Clinical overstaging in this group tion can be accepted as a technique comparable to radical was common, since 56% of the controls believed to have prostatectomy. Many technical issues must be resolved. The clinical stage T3 cancer had stage pT2 disease after radical efficacy of the procedure may be enhanced by double freezing prostatectomy. a t single locations and more lateral placement of the cry* The resulta of these 2 trials and others to date suggest that probes. The use of thermocouples has been recommended by neoadjuvant therapy is well tolerated, does not induce sig- some to determine better the area of therapeutic freezing. nificant tumor downstaging and decreases the likelihood of The urethral warming device has not been standardized. positive surgical margins. Of concern in these 2 series, and in Although the authors reported low rates of urinary retention those reported previously, is the seemingly high incidence of requiring secondary procedures, our own experience and that positive surgical margins in the control groups. These rates of others5 suggest that the incidence of this comp11cationmay seem at variance with other previously reported series of be higher as we try to achieve more complete cryoablation 454
PROSTATE CANCER-MANY
TREATMENTS, BUT NOT ENOUGH ANSWERS
and define the optimal design of the urethral warming device. Cryosurgery instruments may not be comparable as we11.6 Finally, the costs of the procedure as well as the impact on quality of life must be documented prospectively. At our institution, a cost or quality of life advantage of cryotherapy over radical prostatectomy has not been documented as yet for those with localized disease. In fact, cryosurgery may be more costly if it is associated with either significant complication or retreatment rates. Oefelein et a1 (page 442) report that operative blood loss, not the type of blood transfused, was significantly related to decreased recurrence-free survival after radical prostatectomy. The article is strengthened by use of careful followup, univariate and multivariate statistical analyses, and controlling for time of treatment, biochemical failure and adjuvant radiotherapy. In the multivariate analysis, significant associations with recurrence-free prostate cancer survival were demonstrated for pathological tumor stage, tumor Gleason score, operative blood loss and total units of blood transfused. The authors conclude that the operative events necessitating transfusion are more significant than the immunological effects of transfusion. However, the patients in this study underwent surgery between 1980 and 1990. Although this period allows one to examine long-term disease status, the patient population may not reflect the one currently undergoing surgery or contemporary surgical techniques. In the current study 49% of the patients had stage pT3 or pT4 disease and the mean blood loss (determined by net change in serum hemoglobin) was 2,266 ml. PSA based screening, the more effective use of preoperative staging methods and improvement in surgical techniques have resulted in better patient selection and decreased morbidity, including blood loss. In fact, the mean amount of blood transfused was approximately 650 ml. according to the study reported by Soloway et al. Nevertheless, this study highlights the need for surgeons to pay close attention to careful patient selection and meticulous surgical technique to maximize patient outcomes. Fowler et a1 (page 448) assessed the impact of deferred flutamide therapy in patients with localized and metastatic prostate cancer treated initially with diethylstilbestrol, orchiectomy or a luteinizing hormone-releasing hormone agonist. In 92% of the patients flutamide was administered when the serum PSA level was noted to be increasing. A significant decrease in PSA level (more than 50%)was noted in 80% of patients with localized disease and 54% of those with metastatic cancer during flutamide treatment. Deferred ilutamide treatment benefited only patients with localized disease and a PSA response. Previous studies cited in this report have shown a benefit to the use of initial, combined androgen blockade but no benefit to deferred flutamide in patients with metastatic disease. This benefit may be most apparent in patients with minimal metastatic tumor. The authors defer antiandrogen therapy in patients with metastatic disease based on the cost of the therapy and what they cite as a marginal improvement in overall survival. However, the progression-free survival benefit to combined androgen blockade, if confirmed by ongoing trials, should not be considered insignificant. The cost-effectiveness of this interven-
455
tion compares favorably with other common health care expenditures, especially when used for management of those with minimal disease.’ Fowler et a1 correctly note that patients with localized cancer may enjoy a long disease-free interval when treated with androgen deprivation. The indications for androgen deprivation in those with low stage cancer, or who are older or have significant co-morbid diseases has not been determined. In addition, the preferred form of androgen deprivation (monotherapy versus combined therapy, intermittent or continuous therapy) is the subject of ongoing investigations. Prostate cancer has become a high profile disease based on its increased incidence, the wide application of screening tests, the uncertainty over treatment, and the costs associated with detection and treatment. The costs of treating the disease will increase as we detect more cancers and deliver multiple treatments concurrently or in sequence. Urologists should treat patients sensibly, compassionately and expertly based on the best information available. It is important that we prospectively evaluate the impact of treatment impartially and honestly using the best instruments available. In addition, we should be ready to modify our approach to prostate cancer detection or treatment if convincing evidence suggests that we should do so. Peter R. Carroll Department of Urology The University of California at Sun Francisco1 Mt. Zion Cancer Center University of California School of Medicine San Francisco, California REFERENCES
1. Pilepich, M.V., Krall, J.M., Al-Sharraf, M., John, M.J.,Doggett, R. L. S., Sause, W. T., Lawton, C. A.,Abrams, R. A., Rotman, M.,Rubin, P.,Shipley, W. U., Grignon, D., Caplan, R. and Cox, J. D.: Androgen deprivation with radiation therapy compared with radiation therapy alone for locally advanced prostatic carcinoma: a randomized comparative trial of the Radiation Therapy Oncology Group. Urology, 45: 616,1995. 2. Smith, R. C., Brendler, C. B. and Partin, A. W.: Extended follow-upof the influence of wide excision of the neurovascular bundeb) on prognosis in men with clinically localized prostate cancer. J. Urol., part 2, 153.39% abstract 654,1995. 3. Cher, M.L., Shinohara, K,Breslin, S., Vapnek, J. and Carroll, P. R.: High failure rate with long-term follow-up of neoadjuvant androgen deprivation followed by radical prostatectomy for stage C prostatic cancer. Brit. J. Urol., in press. 4. Shinohara, K., F’resti, J. C., Jr., Ingerman, A., Narayan, P. and Carroll, P.: Local recurrence after radical prostatectomy:characteristics in size, location and P S k J. Urol., part 2, 161: 256A,abstract 115,1994. 5. Shinohara, K. and Carroll, P. R.: Improved results of cryosurgical ablation of the D I - o s ~ ~J.~ .Urol... Dart 2. 153: 3856 abstract 627,1995. 6. Ka~lan.S.A. Greenberg, R. and Baust, J. G.: A comparative tksessment -of cryosu&cal devices: application to prostatic disease. Urology, 45: 692,1995. 7. Hillner, B. E.,McLeod, D. G., Crawford, E. D. and Bennett, C. L.: Estimating the cost effectiveness of total androgen blockade with flutamide in M1 prostate cancer. Urology, 45: 633,1995.