Sergery, Ultrasound, Adjuvant and Neoadjuvant Therapy

Therapeutic Strategies for Localized Prostate Cancer I:

10TH INTERNATIONAL PROSTATE CANCER UPDATE Therapeutic Strategies for Localized Prostate Cancer I: Surgery, Ultrasound, Adjuvant and Neoadjuvant Therapy Martin I. Resnick, MD,* E. David Crawford, MD,† Martin E. Gleave, MD,‡ John Lynch, MD,§ John P. Mulhall, MD, Karl Pummer, MD,¶ Guy Vallancien, MD# *Case Western Reserve University School of Medicine, Cleveland; †University of Colorado Health Sciences Center, Denver; ‡University of British Columbia, Vancouver; §Georgetown University School of Medicine, Washington, DC;  Loyola University Medical Center, Maywood, Ill; ¶Karl-Franzens University, Graz, Austria; #Institut Montsouris, Paris Over the past decade, because of the introduction and widespread availability of prostate-specific antigen determinations, carcinoma of the prostate that is localized and potentially curable has been diagnosed in an increasing number of men. Advances in surgical management with preservation of the neurovascular bundles, in addition to hormone therapy, have added to the success and improved quality of life of patients undergoing treatment. New forms of treatment (including laparoscopic prostatectomy and high-intensity focused ultrasound) are advances that are continuing to be developed and that may have a significant role in the management of this disease. With further investigation and technologic advancement, it is anticipated that more and more men with localized disease will be identified and cured, with preservation of sexual and urinary function. Key words: Prostatectomy, radical • Prostatic neoplasms • Therapy, adjuvant • Ultrasound I t is well recognized that the increased use of serum prostate-specific antigen (PSA) determinations has resulted in a marked rise in the number of patients identified with localized cancer of the prostate. Most of these patients are asymptomatic and have prostate glands with no palpable nodularity or asymmetry typical of carcinoma of the prostate. The age and health status of many of these patients make them excellent candidates for curative therapy, either radical prostatectomy or radiation therapy. Pathologic examination of excised prostates reveals that many patients, particularly those with Gleason sum tumors of 6 or less and serum PSA determinations of less than 10 ng/mL, have a very high likelihood of having localized disease. In most instances, staging studies, such as bone scan, CT, and pelvic lymphadenectomy, are not required. Many recent innovations in both the surgical and radiotherapeutic management of these patients with localized disease have resulted in a marked reduction in treatment-related morbidity. Supplement REVIEWS IN UROLOGY 23 Therapeutic Strategies I continued Vessel Sealing System Hemostasis is fundamental to urologic cancer surgery, and many methods of achieving hemostasis have been developed. These methods include surgical clips, sutures, and other energy-based ligation methods. A recently developed system called LigaSure (Valleylab) effectively seals vessels 1 to 7 mm in diameter with minimal sticking, charring, or thermal spread.1-3 The system applies a precise amount of bipolar energy and pressure to change the nature of the vessel walls. Collagen and elastin within the vessel walls fuse and reform into a single structure, obliterating the lumen and creating a permanent seal. A feedback-controlled response system delivers the appropriate amount of energy to seal the vessel effectively. The high current allows the collagen in the vessel walls and connective tissue to melt quickly and uniformly so that it can reform into a plastic-like seal. The performance of the LigaSure vessel sealing system was recently evaluated during a number of urologic procedures at the University of Colorado Health Sciences Center (UCHSC). These procedures included radical prostatectomy, radical cystectomy, radical inguinal orchiectomy, and radical nephrectomy. Using LigaSure, surgeons can perform radical retropubic prostatectomy without relying on clips or suture for hemostasis (suture is, of course, required for anastomosis). LigaSure may be used in pelvic lymphadenectomy, performed either laparoscopically or as an open procedure. In this technique, LigaSure is used to divide the lateral tissue and isolate the bladder neck as it funnels into the prostate as well as to control bleeding from the seminal vesicle pedicle and division of the vasa. LigaSure is also of value in dividing the lateral pedicles from the base to the apex of the prostate with preservation of the neurovascular bundles. Another application of LigaSure is in control of the dorsal venous complex, whether an antegrade or retrograde 24 REVIEWS IN UROLOGY Supplement approach is used. At the UCHSC, the dorsal venous complex was controlled in 10 patients with an average blood loss for the entire procedure of 200 to 250 mL. In each case, only the LigaSure device was used to achieve hemostasis of the dorsal venous complex without the use of sutures. Results of Surgical Management Both the grade and stage of disease influence the outcome of radical prostatectomy. Results of several studies indicate that those patients with localized disease (stage T1, T2) have longer disease-specific survival than those with advanced stage disease (stage T3).4-6 Ten-year data in patients with stage T1 or T2 disease reveal 85% freedom from PSA relapse in those patients with either organ-confined disease or focal capsule invasion. Those patients who have capsular penetration with Gleason scores between 2 and 6 with grade 2 tumors have a 54% freedom from PSA relapse, and those with capsular penetration and Gleason scores greater than 7 have a 42% freedom from PSA relapse. Of those patients with seminal vesical involvement, only 43% remain PSA disease-free.4-6 Another question involves the management of patients with margin-positive disease, in particular those with rising PSA levels following radical prostatectomy. Both the role of radiation therapy and when it should be instituted are debated.7-10 Though evidence suggests that many patients achieve a reduction in PSA levels, long-term disease-free survival remains unknown and longer follow-up is needed. Most patients with positive margins, particularly those with focal disease, are observed, and adjunctive therapy is instituted in those who demonstrate a rising PSA level during the follow-up period. The value of radiation therapy in those patients who have positive margins but whose PSA levels remain undetectable after surgery is also unknown. Some researchers have proposed a role for neoadjuvant endocrine therapy in patients undergoing radical prostatectomy. Results of some studies have indicated that such therapy can reduce the rate of positive surgical margins.11,12 Others, however, have found no advantage with this approach.13 Follow-up data show no significant difference in PSA failure rates among patients treated with neoadjuvant therapy and those not treated before radical prostatectomy.11-13 There is much interest in determining the status of disease in those patients with recurrence following radical prostatectomy. Radioimmunodetection and positron emission tomography (PET) can be used to differentiate patients with localized disease from those with distant spread. Those with localized disease appear to do better with radiation therapy, while those with distant spread tend not to do better, yet may benefit from either androgen ablation alone or androgen ablation in combination with radiation therapy. Only carefully controlled studies performed with adequate numbers of patients will help resolve these issues. New Treatment Options for Erectile Dysfunction Radical prostatectomy was originally a non–nerve-sparing procedure that was universally associated with postoperative erectile dysfunction. In 1982, Walsh and Donker14,15 reported on nerve-sparing radical prostatectomy, and follow-up indicated a high rate of potency preservation in patients with disease confined to the prostate who were under 65 years of age. Erectile dysfunction following radical prostatectomy can be neurogenic, arteriogenic, venogenic, or of mixed vascular (arteriovenogenic) origin. Neurogenic impotence, an obvious sequela of cavernous nerve interruption, may also occur transiently following cavernous nerve traction or dissection. Arteriogenic erectile dysfunction is believed to result from transection of the accessory pudendal arteries. Venogenic impotence is thought to be secondary Therapeutic Strategies I CAI % of patients CVOD 100 90 80 70 60 50 40 30 20 10 0 <4 4-8 8 - 12 > 12 Duration (mo) Figure 1. Chronology of venous leak development after radical prostatectomy. (CAI, cavernosal artery insufficiency ; CVOD, cavernosal venous occlusive disease.) (Based on data from Mulhall JP, Graydon RJ. Int J Impot Res. 1996.16) surgery may be of value in these patients, allowing penile lengthening and stretch that may prevent long-term erectile problems. Others have advocated placement of a penile prosthesis at the time of radical prostatectomy. Finally, nerve mapping at the time of radical prostatectomy and cavernous nerve interposition grafting have shown promising results in highly selected patients. Mulhall and Graydon16 stress that % of patients with erection recovery to corporal smooth muscle collagenization and fibrosis. Mulhall and Graydon16 have demonstrated the hemodynamics of erectile dysfunction following nerve-sparing radical retropubic prostatectomy. In a recent study, the chronology of venous leak development after radical prostatectomy was examined in patients with excellent preoperative erectile function in whom erectile dysfunction developed postoperatively17 (Figure 1). In patients who did not receive any immediate treatment for erectile dysfunction after radical prostatectomy, the postoperative incidence of venous leak was 8% at less than 4 months, 22% at 4 to 8 months, and 50% at 8 to 12 months. In a similar population, another study looked at the correlation between postoperative hemodynamic diagnosis and the ability to regain spontaneous erectile function.18 Again, in men who had excellent erectile function preoperatively in whom erectile dysfunction developed postoperatively, there was a 50% incidence of spontaneous recovery of erectile function at 12 months postoperatively in those with normal vascular evaluation with presumed vascular impotence. Approximately 25% of men experienced resolution of erectile dysfunction when hemodynamic evidence of erectile insufficiency was present (Figure 2). Since its introduction in 1998, sildenafil citrate has been used extensively in patients following radical prostatectomy, but these patients did not respond as well as had been hoped. Data from Pfizer clinical trials suggest that 42% of men responded to this drug following radical prostatectomy; however, this does not translate into 42% of men achieving successful sexual intercourse. Other erectogenic agents are being investigated, but currently there are no available data about their role in those patients who undergo radical prostatectomy. There is general agreement that use of the vacuum device or vasoactive therapy in the early stages after when patients consider undergoing radical prostatectomy, they should first be counseled about all the possible postoperative sexual dysfunctions, including ejaculatory and orgasmic. Intraoperatively, strategies should be used to minimize neural trauma, and patients should be reexamined early after surgery. When erectile dysfunction exists, postoperative pharmacologic therapy should be instituted. Treatment options include oral agents, 50 45 40 35 30 25 20 15 10 5 0 Normal Arteriogenic CVOD Mixed Figure 2. Prediction of erection recovery following prostatectomy. (CVOD, cavernosal venous occlusive disease.) (Based on data from Mulhall JP, Graydon RJ. Int J Impot Res. 1996.16) Supplement REVIEWS IN UROLOGY 25 Therapeutic Strategies I continued transurethral alprostadil, or injection therapy. If these have failed or the patient is not a candidate for these options, then the use of a vacuum erection device may be of benefit. Regular follow-up is essential to ensure that a successful therapeutic approach has been identified. Laparoscopic Prostatectomy Laparoscopic surgery has a growing role in urologic practice. Its use has expanded to a variety of procedures, including adrenalectomy, nephrectomy, nephroureterectomy and, most recently, radical prostatectomy.19 Guillonneau and Vallancien19 have reported their recent experience with laparoscopic radical prostatectomy in 120 consecutive patients presenting with clinically localized disease (T1b-T2b). The procedure is performed with the patient in the dorsal supine position with the lower limbs in abduction to provide access to the perineum and in an exaggerated Trendelenburg position. Five trocars are used with standard laparoscopic equipment. The dissection is carried out in the retropubic space with control of the dorsal venous complex and preservation of the neurovascular bundles. A watertight urethrovesical anastomosis is performed with absorbable sutures over a Foley catheter. Patients are usually discharged 2 to 3 days postoperatively. Intraoperative bleeding was 402 ± 293 mL, and only 12 patients (10%) required transfusion. Intraoperative complications, consisting of injury to the epigastric artery, rectal injury, and partial obturator nerve paralysis, developed in 3 patients. Minor complications, including prolonged ileus, urinary tract infection, transient anastomotic leak, and acute retention, occurred in a total of 27 patients. In the last 40 patients, mean operating time was 230 ± 48 minutes. Only 1 of the 40 patients required transfusion. Mean catheter duration was 5.7 ± 3 days, and mean hospital stay was 5.7 ± 3.3 days. Follow-up data in the 40 patients indicate a continence rate of 26 REVIEWS IN UROLOGY Supplement 73.3%. Of 20 patients who were sexually active preoperatively, 9 (45%) reported spontaneous erections postoperatively. The positive margin rate in these patients was similar to that in previous studies. Cost analysis indicated that the standard radical retropubic prostatectomy was more expensive than the laparoscopic approach. The authors’ experience and that of others generally indicate a low perioperative morbidity with a marked reduction in recuperative time. It is estimated that approximately 40 cases are required for the surgeon to be comfortable with the procedure. High-Intensity Focused Ultrasound High-intensity focused ultrasound (HIFU) is generated by a high-power acoustic transducer that produces focused ultrasound waves to generate extremely high temperatures within a very small, precisely defined volume. Because of the temperatures obtained, tissues are destroyed at the target site without damage to any intervening structures. The frequency range for the piezoelectric transducers can vary from 0.5 to 10 MHz. The ideal HIFU system has a variable focus, a stable position during firing, online imaging, short treatment time, and compact probe design. It should be simple to handle and anesthesia required should be minimal. Several devices are currently available for investigational use. Any such system requires monitoring and cooling of the rectal wall to prevent damage. The HIFU technique was introduced in the management of benign prostatic hyperplasia in the 1980s20 and has since been applied to a variety of malignancies.21 Gelet and associates22 reported treating 50 patients (113 treatments) with cancer of the prostate. At the beginning of the clinical trials, the entire gland was not treated at 1 session; rather, half was treated at each of 2 sessions. It is now standard to treat with 1 session. Of Gelet’s 50 patients, 28 had biopsy results that were nega- tive and PSA levels that were 4 ng/mL or less, 3 had no residual cancer but had PSA levels greater than 4 ng/mL, 9 had residual cancer and PSA levels of 4 ng/mL or less, and 10 had residual cancer and PSA levels greater than 4 ng/mL. Morbidity was minimal. Further enhancement of the HIFU software has resulted in the negative biopsy rate of 83.3% with 95% of PSA levels returning to normal.23 In the United States, a clinical protocol has been started involving 3 institutions: Baylor College of Medicine, Georgetown University, and University of California at San Francisco. To date, 10 patients with locally recurrent prostate cancer following externalbeam radiation therapy have been treated with HIFU. All were treated under anesthesia as outpatients, and 8 have had no adverse effects. Two have required secondary procedures to remove obstructing necrotic tissue from the prostatic urethra. In summary, HIFU is capable of obliterating prostatic tissue and cancer via an endorectal approach without significant adverse effects. Further experience is obviously required. Adjuvant Therapy After Radical Prostatectomy Neither adjuvant radiation therapy for local recurrence nor systemic endocrine therapy after radical prostatectomy has been proved to increase the cure rate in these patients. Many questions remain, including who needs adjuvant therapy, when it should be offered, and what types of therapy are recommended. It is generally recognized that both those patients who fail to achieve undetectable levels of PSA following radical prostatectomy and those in whom a rising PSA level develops during the postoperative period have recurrent disease. It is also recognized that many of these patients experience a very slow rise in PSA level, and recurrence is not synonymous with subsequent disease progression and death. Because many of these patients do well clini- Therapeutic Strategies I cally, both the need for treatment and type of appropriate treatment remain controversial. Questions persist as to the value of adjuvant therapy. While in many of these patients radiation therapy results in a decline in PSA level, with time PSA levels gradually rise again. Similarly, endocrine therapy tends to suppress tumors, but with time many recur. These effects must be weighed against the side effects of the different approaches. It is difficult to evaluate the results of adjuvant radiation therapy. Published series span the availability of PSA, and most do not separate failure from either local or systemic disease. Before the availability of PSA, an abnormal result from digital rectal examination was used as the initial evidence of recurrence. Patient numbers were small, and local failure rates and 5-year disease-free survival rates ranged from 0% to 55% and 47% to 91%, respectively (Table 1). More recent studies are somewhat different. Detectable PSA is used as an indicator of treatment failure. In addition, needle biopsy was performed in some recent studies. It is believed that recurrent disease volumes were low in these initial reports (Table 2). Though many of these patients demonstrate a decline in PSA levels, it remains unclear whether survival is affected (Table 3). A definitive conclusion as to the value of adjuvant radiotherapy cannot be made at this time. Results are likely to be better in patients with disease confined to the prostatic fossa than in those with systemic manifestations. These distinctions can be made with new radioimmunodetection techniques in addition to PET scanning. Neoadjuvant Therapy: Is It Worthwhile? Because the failure rate is higher in patients with positive surgical margins, a major goal is to find treatments that come as close as possible to complete removal of all malignant cells and re- Table 1 Adjuvant Radiation Therapy After Radical Prostatectomy in the Pre-PSA Era Reference Year Number of patients Pilepich28 Bahnson29 Forman30 Jacobson31 Anscher8 Gibbons7 Hanks32 Ray33 1984 1986 1986 1987 1987 1986 1986 1984 18 14 16 26 46 22 21 32 Local failure (%) 0 0 0 0 4 55 10 34 5-year DFS (%) 50 75 91 69 68 73 86 47 PSA, prostate-specific antigen; DFS, disease-free survival. From Mulhall JP, Graydon RJ. Int J Impot Res. 1996.16 duce the likelihood of tumor recurrence. The US intergroup study demonstrated positive surgical margins in more than 50% fewer patients in the group receiving neoadjuvant therapy than in the untreated control group.11 Findings were similar in another randomized multicenter trial in Canada (Table 4).24 Unfortunately, a reduction in the rate of positive surgical margins does not necessarily equate to a reduction in the biochemical and local recurrence rate. Three-year follow-up data on patients in the US intergroup study doc- umented no difference in PSA recurrence between the 2 groups. Similarly, the Canadian study did not demonstrate any significant difference in PSA recurrence rate at 36-month follow-up. Recurrence rates were 30% and 40% in the control and the neoadjuvant arms, respectively.25 Many factors have been hypothesized to account for the lack of an apparent difference in PSA recurrence rates. The sample size of the studies may not have been large enough to demonstrate a difference, the treatment period or the follow-up period may Table 2 Adjuvant Radiation Therapy After Radical Prostatectomy (Series Including PSA) Reference 34 Schild Kaplan35 Zietman36 Eisbruch37 Freeman38 Partin39 Lange40 Cheng41 Carter42 Anscher43 Year Number of patients 1992 1993 1993 1994 1993 1993 1990 1993 1989 1989 11 39 84 34 95 50 71 131 42 16 Local failure (%) 0 0 0 0 2 3 3 5 5 13 Follow-up (y) 1 2.2 1.8 4.8 4.4 4.5 4.2 4.4 5 3 PSA, prostate-specific antigen. Supplement REVIEWS IN UROLOGY 27 Therapeutic Strategies I continued Table 3 Local Recurrence Rates at 5, 10, and 15 Years After Either Radical Prostatectomy Plus Adjuvant Therapy or Radical Prostatectomy Alone RP + adj. RT Reference Year Number of patients 5y Gibbons7 Anscher8 Jacobson31 1986 1987 1987 22 46 26 5% 4% 0% 10 y 4% RP alone 15 y 4% Number of patients 5y 10 y 15 y 23 113 24 30% 25% 17% 51% 68% RP + adj. RT, radical prostatectomy plus adjuvant therapy; RP alone, radical prostatectomy alone. Table 4 Randomized Studies of Short-term Neoadjuvant Hormone Therapy Investigator Labrie, 199544 Soloway, 199511 Goldenberg, 199624 Witjes, 199745 Hugosson, 199612 Sample size Clinical stage Type of NHT Change in serum PSA Change in TRUS volume Positive margin rate 161* 303 213 354 111 T2/T3 T2b T1/T2 T2/T3 T1-T3a 3 mo L + F 3 mo L + F 3 mo CPA 3 mo G + F 3 mo T + C NA 14.3 to < 0.5 in 70 13 to 1.1 µg/L 20 to 0.8 µg/L NA NA 44 to 35 cc 43 to 33 cc 38 to 27 cc NA 8% vs 34%† 18% vs 48%† 28% vs 65%† 27% vs 46%† 23% vs 41%† NHT, neoadjuvant hormone therapy; PSA, prostate-specific antigen; TRUS, transrectal ultrasonography; L + F, leuprolide acetate plus flutamide; NA, not applicable; CPA, 300 mg cyproterone actetate daily; G + F, goserelin plus flutamide; T + C, triptorelin plus cyproterone acetate 50 mg bid. *30 patients refused randomization and were included in the NHT arm. † Statistically significant difference in primary end point. have been too short, and the patients selected may not have been those most likely to benefit from this treatment. Half of the enrolled patients had lowrisk tumors. A benefit of neoadjuvant therapy may become apparent with longer follow-up or analysis of data on a subgroup of patients (for instance, those with tumors of higher grade or stage). Duration of treatment for more than 3 months may be required. A prospective phase II trial was initiated to determine the duration required for PSA to reach its nadir and to characterize the pathologic effects of 8 months of androgen-withdrawal therapy.26,27 Gleave and associates26,27 reported serum PSA level decreases averaging 80% to 90% during the first month of therapy and a further 50% decrease 28 REVIEWS IN UROLOGY Supplement between the third and eighth months. Microscopic extension through the prostatic capsule with negative margins was seen in 13% of the patients studied. The positive margin rate was seen in 5% of the patients studied, a rate lower than what was previously reported after 3 months of neoadjuvant hormone therapy. After a mean of 48 months of follow-up, biochemical recurrence was seen in only 10% of patients, most within the first 2 years after surgery. This rate of recurrence for 8 months of endocrine therapy compares favorably with recurrence rates in previously reported cooperative studies. Gleave and coworkers note that differences in PSA recurrence rates are most pronounced when only patients with high-risk features are considered. Further studies are required to determine the potential benefit of longerterm therapy. In a study initiated by the Canadian Urologic Oncology Group, 547 men with clinically confined prostate cancer were randomized to either 3 or 8 months of leuprolide acetate and flutamide before radical prostatectomy.25 Positive margin rates were 17% and 5%, and organ-confined rates were 71% and 91%, in the 3- and 8-month groups, respectively. This phase III study documents an ongoing biochemical and pathologic regression of prostate cancer during this time, suggesting that optimum duration of neoadjuvant hormone therapy is longer than 3 months. The answer to whether longer therapy will alter PSA recurrence rates must await further follow-up. ■ Therapeutic Strategies I References 1. Kennedy JS, Stranahan PL, Taylor KD, Chandler JG. High-burst-strength, feedback-controlled bipolar vessel sealing. Surg Endosc. 1998;12:867-878. 2. Kennedy J, Taylor K, Chandler J. High-burststrength, servoregulated, bipolar vessel sealing. Paper presented at: Joint Euro-Asian Congress of Endoscopic Surgery; June 1997; Bologna, Italy. 3. Kennedy JS, Buysse SP, Lawes KR, Ryan TP. Recent innovations in bipolar electrosurgery. Minimally Invasive Therapy and Allied Technologies. 1999;8:95-99. 4. Epstein JI, Carmichael MJ, Pizov G, Walsh PC. Influence of capsular penetration on progression following radical prostatectomy: a study of 196 cases with long-term followup. J Urol. 1993;150: 135-141. 5. Stein A, deKernion JB, Smith RB, et al. Prostate specific antigen levels after radical prostatectomy in patients with organ confined and locally extensive prostate cancer. J Urol. 1992;147:942-946. 6. Walsh PC, Partin AW, Epstein JI. Cancer control and quality of life following anatomical radical retropubic prostatectomy: results at 10 years. J Urol. 1994;152:1831-1836. 7. Gibbons RP, Cole BS, Richardson RG, et al. Adjuvant radiotherapy following radical prostatectomy: results and complications. J Urol. 1986;135: 65-68. 8. Anscher MS, Prosnitz LR. Postoperative radiotherapy for patients with carcinoma of the prostate undergoing radical prostatectomy with positive surgical margins, seminal vesicle involvement and/or penetration through the capsule. J Urol. 1987;138:1407-1412. 9. Paulson DF, Moul JW, Robertson JE, Walther PJ. Postoperative radiotherapy of the prostate for patients undergoing radical prostastectomy with positive margins, seminal vesicle involvement and/or penetration through the capsule. J Urol. 1990;143:1178-1182. 10. Haab F, Meulemans A, Boccon-Gibod L, et al. Effect of radiation therapy after radical prostatectomy on serum prostate-specific antigen measured by an ultrasensitive assay. Urology. 1995;45:10221027. 11. Soloway MS, Sharif IR, Wajsman Z, et al. Randomized prospective study comparing radical prostatectomy alone versus radical prostatectomy preceded by androgen blockade in clinical stage B2 (T2bNxM0) prostate cancer. The Lupron Depot Neoadjuvant Prostate Cancer Study Group. J Urol. 1995(2 pt 1);154:424-428. 12. Hugosson J, Abrahamsson PA, Ahlgren G, et al. The risk of malignancy in the surgical margin at radical prostatectomy reduced almost three-fold in patients given neo-adjuvant hormone therapy. Eur Urol. 1996;29:413-419. 13. Dalkin BL, Ahmann FR, Nagle R, Johnson CS. Randomized study of neoadjuvant testicular androgen ablation therapy before radical prostatectomy in men with clinically localized prostate cancer. J Urol. 1996;155:1357-1360. 14. Walsh PC. Radical prostatectomy, preservation of sexual function, cancer control. The controversy. Urol Clin North Am. 1987;14:663-673. 15. Walsh PC, Donker PJ. Impotence following radical prostatectomy: insight into etiology and pre- vention. J Urol. 1982;128:492-497. 16. Mulhall JP, Graydon RJ. The hemodynamics of erectile dysfunction following nerve-sparing radical retropubic prostatectomy. Int J Impot Res. 1996;8:91-94. 17. Slovick R, Hotaling J, Mulhall JP. An analysis of the chronology of venous leak development after radical prostatectomy [abstract]. J Urol. 1999;161: 273. Abstract 1055. 18. Slovic R, Hotaling J, Valenzuela R, et al. Hemodynamic diagnosis in the patient with post-radical prostatectomy impotence correlates with recovery of erectile function [abstract]. J Urol. 1999;161:179. Abstract 690. 19. Guillonneau B, Vallancien G. Laparoscopic radical prostatectomy: the Montsouris technique. J Urol. 2000;163:418-422. 20. Bihrle R, Foster RS, Sanghvi NT, et al. High intensity focused ultrasound for the treatment of benign prostatic hyperplasia: early United States clinical experience. J Urol. 1994;151:1271-1275. 21. Gelet A, Chapelon JY. Effects of high intensity focused ultrasound on malignant cells and tissues. In: Marbert M, ed. Applications of Newer Forms of Therapeutic Energy in Urology. Oxford, England: Medical Media Ltd; 1995:107-114. 22. Gelet A, Chapelon JY, Bouvier R, et al. Local control of prostate cancer by transrectal high intensity focused ultrasound therapy: preliminary results. J Urol. 1999;161:156-162. 23. Thuroff S, Chaussy C. High intensity focused ultrasound in localized prostate cancer. In: Chaussy C, Eisenberger F, Jocham D, Wilbert D, eds. High Energy Shock Waves in Medicine. Munich: Thieme Publishers. 24. Goldenberg SL, Klotz LH, Srigley J, et al. Randomized, prospective, controlled study comparing radical prostatectomy alone and neoadjuvant androgen withdrawal in the treatment of localized prostate cancer. Canadian Urologic Oncology Group. J Urol. 1996;156:873-877. 25. Klotz LH, Goldenberg SL, Jewett M, et al. CUOG randomized trial of neoadjuvant androgen ablation before radical prostatectomy: 36-month posttreatment PSA results. Canadian Urologic Oncology Group. Urology. 1999;53:757-763. 26. Gleave ME, Goldenberg SL, Jones EC, et al. Biochemical and pathological effects of 8 months of neoadjuvant androgen withdrawn therapy before radical prostatectomy in patients with clinically confined prostate cancer. J Urol. 1996;155:213219. 27. Gleave MI, Goldenberg SL, Jones E, et al. Longterm neoadjuvant hormone therapy prior to radical prostatectomy: analysis of outcome by preoperative risk factors. Mol Urol. 1998;2:171-177. 28. Pilepich MV, Walz BJ, Baglan RJ. Postoperative irradiation in carcinoma of the prostate. Int J Radiat Oncol Biol Phys. 1984;10:1869-1873. 29. Bahnson RR, Garnett JE, Grayhack JT. Adjuvant radiation therapy in stages C and D1 prostatic adenocarcinoma: preliminary results. Urology. 1986;27:403-406. 30. Forman JD, Wharam MD, Lee DJ, et al. Definitive radiotherapy following prostatectomy: results and complications. Int J Radiat Oncol Biol Phys. 1986;12:185-189. 31. Jacobson GM, Smith JA Jr, Stewart JR. Postoper- 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. ative radiation therapy for pathologic stage C prostate cancer. Int J Radiat Oncol Biol Phys. 1987;13:1021-1024. Hanks GE, Dawson AK. The role of external beam radiation therapy after prostatectomy for prostate cancer. Cancer. 1986;58:2406-2410. Ray GR, Bagshaw MA, Freiha F. External beam radiation salvage for residual or recurrent local tumor following radical prostatectomy. J Urol. 1984;132:926-930. Schild SE, Buskirk SJ, Robinow JS, et al. The results of radiotherapy for isolated elevation of serum PSA levels following radical prostatectomy. Int J Radiat Oncol Biol Phys. 1992;23:141-145. Kaplan ID, Cox RS, Bagshaw MA. Prostate specific antigen after external beam radiotherapy for prostatic cancer: followup. J Urol. 1993;149:519522. Zietman AL, Coen JJ, Shipley WU, Althausen AF. Adjuvant irradiation after radical prostatectomy for adenocarcinoma of prostate: analysis of freedom from PSA failure. Urology. 1993;42:292-299. Eisbruch A, Perez CA, Roessler EH, Lockett MA. Adjuvant irradiation after prostatectomy for carcinoma of the prostate with positive surgical margins. Cancer. 1994;73:384-388. Freeman JA, Lieskovsky G, Cook DW, et al. Radical retropubic prostatectomy and postoperative adjuvant radiation for pathological stage C (PcN0) prostate cancer from 1976 to 1989: intermediate findings. J Urol. 1993;149:1029-1034. Partin AW, Pound CR, Clemens JQ, et al. Serum PSA after anatomic radical prostatectomy. The Johns Hopkins experience after 10 years. Urol Clin North Am. 1993;20:713-725. Lange PH, Lightner DJ, Medini E, et al. The effect of radiation therapy after radical prostatectomy in patients with elevated prostate specific antigen levels. J Urol. 1990;144:927-933. Cheng WS, Frydenberg M, Bergstralh EJ, et al. Radical prostatectomy for pathologic stage C prostate cancer: influence of pathologic variables and adjuvant treatment on disease outcome. Urology. 1993;42:283-291. Carter GE, Lieskovsky G, Skinner DG, Petrovich Z. Results of local and/or systemic adjuvant therapy in the management of pathologic stage C or D1 prostate cancer following radical prostatectomy. J Urol. 1989;142:1266-1271. Anscher MS, Prosnitz LR. Radiotherapy vs. hormonal therapy for the management of locally recurrent prostate cancer following radical prostatectomy. Int J Radiat Oncol Biol Phys. 1989;17: 953-958. Labrie F, Cusan L, Gomez JL, et al. Downstaging by combination therapy with flutamide and an LHRH agonist before radical prostatectomy. Cancer Surv. 1995;23:149-156. Witjes WP, Schulman CC, Debruyne FM. Preliminary results of a prospective randomized study comparing radical prostatectomy versus radical prostatectomy associated with neoadjuvant hormonal combination therapy in T2-3 N0 M0 prostatic carcinoma. The European Study Group on Neoadjuvant Treatment of Prostate Cancer. Urology. 1997;49(3A suppl):65-69. Supplement REVIEWS IN UROLOGY 29