Robotic Assisted Laparoscopic Salvage Prostatectomy for Radiation Resistant Prostate Cancer

Robotic Assisted Laparoscopic Salvage Prostatectomy for Radiation Resistant Prostate Cancer Jonathan A. Eandi,* Brian A. Link, Rebecca A. Nelson, David Y. Josephson, Clayton Lau, Mark H. Kawachi and Timothy G. Wilson From the Department of Urology (JAE, DYJ, CL, MHK, TGW), and Department of Information Sciences, Division of Biostatistics (RAN), City of Hope, Duarte, California, and Department of Urology, Mercy Health System, Oklahoma City, Oklahoma (BAL) Purpose: We report on outcomes of robotic assisted laparoscopic radical prostatectomy as salvage local therapy for radiation resistant prostate cancer. Materials and Methods: We retrospectively reviewed the charts of all patients who underwent robotic assisted laparoscopic radical prostatectomy for biopsy proven prostate cancer after primary radiation treatment. Patient characteristics, intraoperative and perioperative data, and oncological and functional outcomes were assessed. Results: A total of 18 patients were identified with a median followup of 18 months (range 4.5 to 40). Primary treatment was brachytherapy in 8 patients and external beam radiation in 8, while 2 underwent proton beam therapy. Median age at salvage robotic assisted laparoscopic radical prostatectomy was 67 years (range 53 to 76). Median preoperative prostate specific antigen was 6.8 ng/ml (range 1 to 28.9) and median time to surgery after primary treatment with radiation was 79 months (range 7 to 146). Median operative parameters for estimated blood loss, surgery length and hospital stay were 150 ml, 2.6 hours and 2 days, respectively. No patient required conversion to open surgery or a blood transfusion, or experienced a rectal injury. Perioperative complications occurred in 7 patients (39%) of which the most common was urine leak identified by postoperative cystogram. Five patients (28%) had a positive surgical margin. Although some patients had limited followup, 6 (33%) were continent and 67% were free of biochemical progression. Conclusions: Robotic assisted laparoscopic radical prostatectomy can be performed safely as salvage local therapy after failed radiation therapy. Outcomes are comparable to those of large series of open salvage prostatectomy. Key Words: prostate, prostatic neoplasms, robotics, prostatectomy, salvage therapy Abbreviations and Acronyms ADT androgen deprivation therapy BCR biochemical recurrence PLND pelvic lymph node dissection PSA prostate specific antigen RALP robotic assisted laparoscopic radical prostatectomy RP radical prostatectomy RT radiation therapy SRALP salvage robotic assisted laparoscopic radical prostatectomy Submitted for publication April 13, 2009. Study received institutional review board approval. * Correspondence and requests for reprints: Department of Urology, City of Hope, 1500 East Duarte Rd., Duarte, California 91010 (telephone: 626-256-4673 ext. 67100; FAX: 626-301-8285; e-mail: jaeandi@gmail.com). Financial interest and/or other relationship with Pfizer and Intuitive. Financial interest and/or other relationship with Intuitive Surgical. RADIATION therapy is an accepted treatment for localized prostate cancer. 1 However, the development of BCR after RT for localized prostate cancer occurs in up to 50% of patients. 2,3 Of the many options for treatment of radiation resistant prostate cancer only salvage RP has consistently demonstrated a benefit for long-term disease-free survival. 4 8 Recently it has been shown that 92% of men with post-rt BCR will receive systemic ADT while only 2% will undergo potentially curative salvage RP. 9 Historically open salvage RP has been fraught with a high complication rate and poor functional outcomes. Most notable was the high incidence of intraoperative rectal injury, prolonged postoperative urinary extrava- 0022-5347/10/1831-0133/0 Vol. 183, 133-137, January 2010 THE JOURNAL OF UROLOGY Printed in U.S.A. Copyright 2010 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2009.08.134 www.jurology.com 133

134 ROBOTIC SALVAGE PROSTATECTOMY sation, development of bladder neck contracture and urinary incontinence. 6,10,11 More recent studies have shown an improvement in morbidity from this procedure. 4 8,11 With the rapidly expanding application of robotics in urological surgery, RALP has become a common surgical treatment modality for localized prostate cancer. Advantages of RALP include reduced blood loss and a shorter hospital stay with a more rapid convalescence, and oncological, continence and potency outcomes comparable to those of the open approach. 12 16 As more experience is gained with robotic techniques, surgeons have expanded its application to more technically challenging procedures. In fact, recent case reports have described the feasibility of salvage RALP. 17 19 We report on the largest series of patients to our knowledge to undergo salvage RALP for radiation resistant prostate cancer. This evaluation of perioperative complications as well as functional and oncological outcomes contributes significantly to the small yet growing body of literature for salvage RALP. MATERIALS AND METHODS After institutional review board approval a retrospective chart review was performed to identify all patients who underwent RALP for biopsy proven prostate cancer after primary RT from June 2004 to April 2008. Biochemical failure after irradiation was defined according to the American Society for Therapeutic Radiology and Oncology criteria. 20 All recurrences were diagnosed based on 3 consecutive increases in PSA. Systematic transrectal ultrasound guided prostatic biopsies were performed to document the persistence of cancer. All patients underwent a thorough evaluation before surgery with appropriate imaging including bone scan and computerized tomography to rule out the presence of metastases. Data were collected on all aspects of care including patient demographics, pre-radiotherapy tumor characteristics, radiotherapy treatment features, preoperative tumor characteristics, operative parameters, intraoperative and perioperative complications, surgical specimen characteristics, and oncological and functional outcomes. BCR after salvage therapy was defined as PSA 0.2 ng/ml or greater. Continence was defined as no pad use or 1 small liner used for security purposes only. All RALPs were performed transperitoneally with our institutional modifications to the Montsouris technique. 21 Our specific technique for RALP has been previously described. 22 A 4-arm da Vinci S robot with 2 assistant ports for 6 ports in all was used. All patients underwent standard bilateral obturator PLND. All patients underwent a cystogram typically 10 to 14 days after surgery to evaluate for anastomotic urinary extravasation before catheter removal. If urine leak was present the cystogram was repeated weekly until there was no evidence of extravasation, at which time the catheter was removed. RESULTS Salvage RALP was performed in 18 patients from June 2004 to April 2008. Patient characteristics are shown in table 1. Before salvage RALP 4 patients received ADT. Two patients continued the ADT that was given in combination with the initial RT and 2 were placed on ADT after biochemical failure. Median preoperative PSA was 6.8 ng/ml and 3 patients had a PSA greater than 10 ng/ml before undergoing salvage RALP. Median (range) operative parameters for estimated blood loss, surgery length and length of hospital stay were 150 ml (50 to 350), 2.6 hours (1.7 to 3.7) and 2 days (1 to 5), respectively. Operative duration was calculated as the time from placing the Veress needle until skin closure. There was no conversion to an open approach. One patient experienced an enterotomy during lysis of adhesions at the beginning of the operation because he had undergone repair of a perforated gastric ulcer 23 years earlier. The injury was repaired intraoperatively and the patient did not experience any adverse sequelae except for the slow advancement of his diet postoperatively, which led to the longest hospitalization in our series of 5 days. There were no rectal or ureteral injuries and no patient required a blood transfusion during hospitalization. There was no perioperative mortality or morbidity such as myocardial infarction or pulmonary embolism. Median catheterization time for the entire cohort was 14 days (range 8 to 61). All patients underwent a cystogram to evaluate for urinary leak at the scheduled catheter removal. Leak was present in 6 patients (33%) at the initial cystogram which led to prolonged catheterization. Mean catheterization time for the 12 patients without urine leak was 11.7 days, whereas the 6 with urine leak had a mean catheterization time of 38 days. Oncological Outcomes Table 2 lists oncological and functional outcomes. Postoperative followup ranged from 4.5 to 40 Table 1. Patient characteristics No. pre-radiation biopsy Gleason score: 6 or Less 13 7 5 8 or Greater 0 No. ADT: With external beam RT 2 With interstitial RT 1 Median ng/ml post-radiation PSA nadir 0.7 No. ng/ml PSA nadir: 0.5 or Less 8 1.0 or Less 12 No. post-radiation biopsy Gleason score: 6 or Less 4 7 5 8 or Greater 6 Unable to be graded 3

ROBOTIC SALVAGE PROSTATECTOMY 135 Table 2. Oncological and functional outcomes No. Pts (%) Pathological stage: T2 9 (50) T3a 4 (22) T3b 5 (28) Pathological Gleason score: 6 or Less 0 7 8 (44) 8 or Greater 4 (22) Unable to be graded 6 (33) months with a median followup of 18. Surgical margins were positive in 5 patients (28%). Three patients had unifocal margin involvement while 2 had multifocal surgical margin positive disease. Of these 5 patients 3 had extraprostatic disease, 2 with T3a and 1 with T3b. There was no consistent location for margin positivity. Of 18 patients 12 (67%) were free of biochemical progression. Of the 6 patients in whom BCR developed 2 had a preoperative PSA greater than 10 ng/ml, 2 had multifocal surgical margin positive disease and 2 had unifocal margin involvement. All 6 patients were placed on ADT. Of these patients 1 had lymph node metastasis at salvage RALP and preoperative PSA of 17.7 ng/ml remained increased postoperatively. One patient with no evidence of BCR died of nonprostate cancer related causes 18 months after surgery. Functional Outcomes Of 18 patients 6 (33%) were continent. Mean time to continence for these 6 patients was 7 months (range 3 to 18). Two patients underwent placement of an artificial urinary sphincter for urinary incontinence at 16 and 24 months after salvage RALP. Of the remaining 10 patients 3 used 2 pads daily, 4 used 3 to 4 pads daily and 3 used 5 or more pads daily. A urethrovesical anastomotic stricture developed in 3 patients (17%) requiring at least 1 procedure for treatment. All 3 patients had urine leak requiring prolonged postoperative catheterization. Before salvage RALP 8 patients could achieve an erection adequate for sexual activity, including 4 men who did not require any type of medical assistance. All men had erectile dysfunction after surgery. DISCUSSION Based on the approximate 40% to 60% BCR rates after RT for clinically localized prostate cancer, an estimated 30,000 men will present with disease recurrence annually in the United States. 2,3,5 Of the many treatment options salvage RP has consistently demonstrated a benefit for long-term disease-free survival. 4 8 Grossfeld et al recently reported from the CaPSURE database that 92% of men with post-rt BCR will receive systemic ADT, which is of palliative benefit only. 9 Although local salvage therapy represents the only treatment approach with curative potential, in this same study only 2% of men underwent salvage RP. It is likely that many urologists are dissuaded from performing salvage RP due to the historically high complication rate and significant morbidity of this technically challenging procedure. Historical series of the open approach have reported an incidence of intraoperative rectal injuries of up to 19%, urinary incontinence in up to 73% and bladder neck contracture rates of up to 30%. 6,10,11,23 With technique modification and improvement in perioperative care, more recent studies have shown a decrease in the morbidity of this procedure. 4 8,11,24 In our series of 18 patients who underwent salvage RALP for radiation resistant prostate cancer, we report complication rates and functional outcomes comparable to or better than those of open salvage RP series. None of our patients required conversion to an open approach. No rectal or ureteral injuries occurred and no patient required a blood transfusion throughout the entire hospitalization. Median blood loss was 150 ml, which is substantially less compared to the mean estimated blood loss of 992 ml in contemporary open salvage RP series. 6 We performed a cystogram on all patients to evaluate for urine leak before catheter removal. If urinary extravasation was seen the catheter was left indwelling and the process was repeated 1 week later. Urine leak was present in 6 patients (33%) at the initial cystogram which led to prolonged catheterization. A urethrovesical anastomotic stricture developed in 3 patients (17%) who required at least 1 procedure for treatment. All 3 of these patients experienced urine leak requiring prolonged catheterization. This bladder neck contracture rate is comparable to the mean of 18% reported in contemporary open salvage RP series. 6 Of the 18 patients 6 (33%) were continent. We attribute this lower continence rate to limited patient followup. The majority of open salvage RP series report followup periods of at least 5 years, with continence rates ranging from 20% to 90% (mean 45%). 6 The 3 largest open salvage RP series report continence rates of 50% to 68%. 5,24 Mean time to continence for the 6 continent patients in our series was 7 months. Of the 10 incontinent patients who did not undergo placement of an artificial urinary sphincter 5 had a followup of less than 10 months. Of these 10 patients only 3 used 5 or more pads daily. Therefore, we expect that the continence rates in our series will improve with a longer followup period. Before salvage RALP 8 of the 18 men could achieve an erection adequate for sexual activity, in-

136 ROBOTIC SALVAGE PROSTATECTOMY cluding 4 who did not require any type of medical assistance. All men had erectile dysfunction after surgery. Due to the combination of periprostatic fibrosis from radiation at surgery and a desire to obtain negative surgical margins, we typically perform a wide, nonnerve sparing resection at salvage RALP. It is our goal to avoid compromising cancer control in an attempt to preserve what is more often than not poor erectile function. Salvage RP has been demonstrated to provide cancer control for up to 10 years or more in a substantial proportion of patients. 4 8 The 5 and 10-year PSA progression-free probability after salvage RP ranges from 47% to 69%, and 25% to 43%, respectively. 5,6 Many series have demonstrated that the outcome of salvage RP improves substantially when surgery is performed early in the course of recurrent disease, when PSA is low. Of patients who underwent salvage RP with a preoperative PSA of 10 ng/ml or less, up to two-thirds had organ confined disease and an estimated 70% were free of progression at 5 years. 4,5,7,23 For patients with a preoperative PSA less than 4, 4 to 10 and greater than 10 ng/ml Bianco et al found a 5-year progression-free probability after salvage RP of 86%, 55% and 28%, respectively. 4 In our series 12 of 18 patients (67%) were free of biochemical progression with a median followup of 18 months. Of the 6 patients with BCR 4 had positive surgical margins while 2 had preoperative PSA greater than 10 ng/ml. As has been previously well documented, preoperative PSA values (especially those greater than 10 ng/ml) and margin involvement are strong predictors of progression-free survival. 4 7,23 Although the followup in our series was limited, the oncological outcomes were comparable to those of open salvage prostatectomy series which demonstrated the highest success for cancer control. Our series adds to the small body of literature on minimally invasive approaches for salvage prostatectomy. In 2003 Vallancien et al presented the feasibility of transperitoneal laparoscopic salvage RP. 25 Jamal et al reported on the first case of salvage RALP with an operative time of 150 minutes, blood loss of 100 ml and discharge home on postoperative day 1. 17 This patient was reported as continent at 3 months with no evidence of BCR. Kaouk et al evaluated 4 patients who underwent salvage RALP. 18 Mean operative duration was 125 minutes, blood loss was 117 ml and hospital stay was 2.7 days. Of the 4 patients 2 had positive surgical margins. At a mean followup of 9 months 3 patients were continent and 1 had BCR. Boris et al recently reported data on 11 patients who underwent salvage RALP. 19 Mean operative duration was 183 minutes with an estimated blood loss of 113 ml and a mean hospital stay of 1.4 days. With a mean followup of 20.5 months 27% of patients experienced BCR. One patient experienced an anastomotic leak and an anastomotic stricture developed in 1 who required surgical intervention. With a minimum followup of 2 months they reported that 8 of 10 patients were continent. Our data are similar to these smaller series of salvage RALP. We report a median operative time of 156 minutes, blood loss of 150 ml and length of stay of 2 days. Our study shows that salvage RALP is a technically feasible operation with decreased operative morbidity, and functional and oncological outcomes comparable to those of large series of open salvage RP. A benefit of this surgical approach is the magnified 3-dimensional vision in the deep pelvis. The presence of pneumoperitoneum also results in minimal blood loss, further improving visualization in such critical areas of dissection as the prostatic apex. An additional advantage for salvage RALP arises from the antegrade dissection of the prostate, which allows for the early separation of the anterior rectum from the prostate. A well-defined plane can often be established, thereby minimizing the risk of rectal injury. A potential disadvantage for salvage RALP is the lack of tactile sensation. While tactile feedback can be of particular importance for open salvage RP, we believe that in the hands of experienced robotic surgeons the magnified 3-dimensional visualization allows for compensation of this handicap. A potential criticism of our series is that we performed a limited rather than an extended PLND at salvage RALP. However, the indications and surgical extent of PLND for prostate cancer are still controversial. Although recent literature supports extended PLND at RP to improve diagnostic accuracy and cancer control, these studies include nonrandomized patients who are not in a salvage setting. 26,27 For salvage RP the issue is local recurrence of cancer and not distant disease. We also have concerns for the increased morbidity of extended PLND in a salvage setting, which can lead to devastating and severely debilitating lower extremity lymphedema. As a result we elected not to perform extended PLND at salvage RALP. CONCLUSIONS Although BCR develops in a large number of patients after radiation therapy for localized prostate cancer, few undergo local salvage treatment. Salvage RP represents an established option for patients with curative potential. With the largest reported series to date, we showed that salvage RALP is technically feasible, with outcomes similar to those of open salvage RP. We hope that with this increased application of robotic assisted surgery, urologists will consider more patients for this potentially curative surgical treatment of radiation resistant prostate cancer.

ROBOTIC SALVAGE PROSTATECTOMY 137 REFERENCES 1. Cupps RE, Utz DC, Fleming TR et al: Definitive radiation therapy for prostatic carcinoma: Mayo Clinic experience. J Urol 1980; 124: 855. 2. Zelefsky MJ, Kuban DA, Levy LB et al: Multiinstitutional analysis of long-term outcome for stages T1-T2 prostate cancer treated with permanent seed implantation. Int J Radiat Oncol Biol Phys 2007; 67: 327. 3. Kuban DA, Thames HD, Levy LB et al: Long-term multi-institutional analysis of state T1-T2 prostate cancer treated with radiotherapy in the PSA era. Int J Radiat Oncol Biol Phys 2003; 57: 915. 4. Bianco FJ Jr, Scardino PT, Stephenson AJ et al: Long-term oncologic results of salvage radical prostatectomy for locally recurrent prostate cancer after radiotherapy. Int J Radiat Oncol Biol Phys 2005; 62: 448. 5. Stephenson AJ and Eastham JA: Role of salvage radical prostatectomy for recurrent prostate cancer after radiation therapy. J Clin Oncol 2005; 23: 8198. 6. 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Kaouk JH, Hafron J, Goel R et al: Robotic salvage retropubic prostatectomy after radiation/brachytherapy: initial results. BJU Int 2008; 102: 93. 19. Boris RS, Bhandari A, Krane LS et al: Salvage robotic-assisted radical prostatectomy: initial results and early report of outcomes. BJU Int 2009; 103: 952. 20. American Society for Therapeutic Radiology and Oncology Consensus Panel. Consensus statement: guidelines for PSA following radiation therapy. Int J Radiat Oncol Biol Phys 1997; 37: 1035. 21. Guillonneau B and Vallancien G: Laparoscopic radical prostatectomy: the Montsouris technique. J Urol 2000; 163: 1643. 22. Link BA, Nelson R, Josephson DY et al: The impact of prostate gland weight in robot assisted laparoscopic radical prostatectomy. J Urol 2008; 180: 928. 23. Rogers E, Ohori M, Kassabian VS et al: Salvage radical prostatectomy: outcome measured by serum prostate specific antigen levels. J Urol 1995; 153: 104. 24. Stephenson AJ, Scardino PT, Bianco FJ Jr et al: Morbidity and functional outcomes of salvage radical prostatectomy for locally recurrent prostate cancer after radiation therapy. J Urol 2004; 172: 2239. 25. Vallancien G, Gupta R, Cathelineau X et al: Initial results of salvage laparoscopic radical prostatectomy after radiation failure. J Urol 2003; 170: 1838. 26. Burkhard FC and Studer UE: The role of lymphadenectomy in high risk prostate cancer. World J Urol 2008; 26: 231. 27. Jeschke S, Burkhard FC, Thurairaja R et al: Extended lymph node dissection for prostate cancer. Curr Urol Rep 2008; 9: 237. EDITORIAL COMMENT The authors have reported the largest series to date of SRALP in patients with radiation resistant prostate cancer. This series from a high volume center demonstrates the technical feasibility of SRALP. However, since there are few studies detailing RALP in the salvage scenario, oncological and functional outcomes should be compared to those of contemporary open salvage prostatectomy series from large volume centers to consider the procedure comparable to open salvage procedures as suggested by the authors. Updated data from a large case series of open salvage radical prostatectomy demonstrated lower rates of positive surgical margins (16% vs 28%) and incontinence (40% vs 67%) than the current study. 1 Eandi et al provide important data in an area of few published studies. As experience is gained with robotically assisted procedures, hopefully the results of future SRALP series will continue to improve and more closely mimic the outcomes of open salvage prostatectomy. Michael E. Karellas Division of Urologic Oncology The Cancer Institute of New Jersey Robert Wood Johnson School of Medicine New Brunswick, New Jersey REFERENCE 1. 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