SALVAGE RADICAL PROSTATECTOMY FOR RADIORECURRENT PROSTATE CANCER: : MORBIDITY REVISITED

0022-5347/00/1646-1998/0 THE JOURNAL OF UROLOGY® Copyright © 2000 by AMERICAN UROLOGICAL ASSOCIATION, INC.®

Vol. 164, 1998 –2001, December 2000 Printed in U.S.A.

SALVAGE RADICAL PROSTATECTOMY FOR RADIORECURRENT PROSTATE CANCER: MORBIDITY REVISITED ANIL VAIDYA

AND

MARK S. SOLOWAY

From the Department of Urology, University of Miami, Miami, Florida.

ABSTRACT

Purpose: With the advent of prostate specific antigen (PSA) testing and transrectal ultrasound guided prostate biopsy there has been stage migration in the diagnosis of prostate cancer, so that more younger men are being diagnosed with organ confined prostate cancer. Many patients elect radiation therapy, while some have recurrent or new prostate cancer with absent systemic disease and life expectancy greater than 10 years. We present our experience with salvage radical prostatectomy in these cases. Materials and Methods: Between 1995 and 2000, 6 men treated with curative intent with radiotherapy for prostate cancer were subsequently treated with salvage surgery for clinically localized prostate cancer. All men had biopsy proved recurrent or persistent prostate cancer, increasing serum PSA, no evidence of systemic disease at surgery and life expectancy greater than 10 years. We assessed the morbidity associated with this procedure and compared results to those in the contemporary literature. Results: Six patients underwent salvage radical prostatectomy. Initial pre-radiation PSA was 4.5 to 15.7 ng./ml. Pre-radiation disease was clinical stage T1c in 5 cases and B2 in 1. The interval from radiotherapy to repeat biopsy was 12 to 48 months. A mean of 6.3 months after local recurrence was detected and before salvage radical prostatectomy was performed 4 patients underwent androgen deprivation therapy. Mean operative time was 195 minutes, intraoperative blood loss was 680 cc, and hospital stay and catheterization time were 3.2 and 13.8 days, respectively. There were no rectal injuries. All 6 patients are impotent, 5 are continent and 1 has mild stress incontinence. There was biochemical failure in 1 case 36 months after salvage radical prostatectomy and no evidence of recurrence in the remaining 5 at a mean followup of 27 months. Conclusions: Salvage radical prostatectomy is a technically challenging procedure. In the past it was associated with a high incidence of rectal injury, urinary incontinence and anastomotic stricture. The results of our relatively small series are encouraging and concur with those of recent studies that the morbidity of salvage radical prostatectomy is lower than previously reported. We believe that salvage radical prostatectomy may be considered a reasonable treatment option in appropriate patients with radiorecurrent prostate cancer. KEY WORDS: prostate, prostatectomy, prostatic neoplasms, salvage therapy, morbidity

Since 1913 when Pasteau and Degrais pioneered the use of ionizing radiation for prostate cancer,1 reports of improved survival and tumor control have become common, establishing radiotherapy as an accepted treatment modality for localized prostate cancer.2–5 According to the Surveillance, Epidemiology and End Results program radiation therapy is often given to treat clinically localized prostate cancer.6, 7 The advent of prostate specific antigen (PSA) testing and transrectal ultrasound guided prostate biopsy has dramatically increased the number of men diagnosed with prostate cancer.8 Patients are being diagnosed with prostate cancer at a younger age and many undergo radiotherapy as primary treatment. Local recurrence remains a problem.9 The rate of recurrence and/or persistence of prostate cancer after radiotherapy is unclear. Post-radiation therapy prostate biopsy has been positive for cancer in as many as 20% to 50% of cases.10, 11 Thus, there exists a cohort of patients with radiorecurrent prostate cancer, no evidence of systemic disease and life expectancy greater than 10 years.12, 13 These cases represent a challenging therapeutic dilemma. Therapy alternatives include androgen deprivation, cryotherapy, brachytherapy, radical cystoprostatectomy and radical prostatectomy. Ideally treatment would provide potential cure with minimal morbidity. In properly selected Accepted for publication July 21, 2000.

cases salvage radical prostatectomy represents a chance of cure but it has been described as associated with significant morbidity due to the effects of radiotherapy.14 –18 We present our experience with such cases. MATERIALS AND METHODS

Between 1995 and 2000, 6 men treated with curative intent with radiotherapy for prostate cancer were subsequently treated with salvage surgery for locally recurrent prostate cancer. Patients were considered candidates for surgery when they had biopsy proved recurrent prostate cancer associated with increasing serum PSA, no evidence of systemic disease at surgery and life expectancy greater than 10 years. Radiation treatment consisted of external beam radiation only in 3 cases, external beam radiation followed by interstitial radioactive 125iodine (125I) seed placement in 1 and interstitial radioactive seed placement in 2 (table 1). All patients underwent physical examination, serum PSA testing, computerized tomography of the abdomen and pelvis, bone scan and flexible cystoscopy in the office setting. Hospital charts were evaluated under certain headings, including patient characteristics (age, weight and body habitus), tumor characteristics (year of prostate cancer diagnosis, and preradiation PSA, biopsy Gleason score and clinical stage),

1998

1999

SALVAGE RADICAL PROSTATECTOMY FOR RADIORECURRENT PROSTATE CANCER TABLE 1. Morbidity associated with salvage radical prostatectomy References Mador et al19 Thompson et al20 Neerhut et al21 Rainwater and Zincke22 Moul and Paulson23 Link and Freiha24 Stein et al25 Ahlering et al26 Pontes et al27 Rogers et al28 Lerner et al13 Present series

No. Pts.

No. Rectal Injuries (%)

4

2 (50)

5 16 13 22 14 13 34 43 40 79

0 3 (19) 0 3 (10) 0 1 (8) 0 4 (9) 6 (15) 5 (6.3), 1 required fecal diversion 0

6

No. Anastomotic Leakage (%)

No. Incontinence (%)

0

0

Unknown 3 (19) 0 0 Unknown 0 Unknown Unknown Unknown 15 (19)

treatment characteristics (dates of interstitial therapy and external beam radiation, number of interstitial seeds, interval from radiotherapy to biochemical failure, tumor pathology at repeat biopsy and information on any adjuvant therapy after radiation failure), operative morbidity (operative time, intraoperative blood loss and transfusion, alteration of surgical planes, rectal and/or ureteral injury, hospital stay and catheterization duration), tumor pathology (lymph node status, Gleason score, seminal vesicles and margins) and followup (biochemical failure and continence). Continence was determined by chart review and telephone interview. Patients were defined as continent when they had no urinary leakage and did not wear pads. Incontinence was considered mild when no more than 1 pad was required daily and severe when 2 or more were required. A PSA of 0.5 to 1.0 ng./ml. by the Hybritech* assay was considered the required nadir after radiation therapy for prostate cancer.10 Biochemical failure after irradiation was defined as serum PSA greater than 1 ng./ml. at a minimum 2-year followup or serum PSA that increased by more than 10% compared with a previous PSA value less than 2 years after treatment.10 Thus, a sequential increase in PSA over the nadir of 0.5 to 1.0 ng./ml. or failure of PSA to attain a nadir and/or no evidence of decreasing PSA 1 year after radiation therapy was considered biochemical failure. Gleason score after radiation therapy was assigned by a single pathologist using areas in the biopsy specimen not affected by radiation. These parameters were compared with the results of earlier series (table 1).13, 19 –28 RESULTS

Salvage radical prostatectomy was done in 6 men 58 to 74 years old (mean age 64.4) for radiorecurrent prostate cancer. Mean patient weight was 174 pounds. Pre-radiation PSA was 4.5 to 15.7 ng./ml. The year of initial prostate cancer diagnosis was 1991 to 1997. Pre-radiation biopsy Gleason score was known in 2 cases, while in 5 and 1 pre-radiation clinical stage was T1c and B2, respectively. The interval from radiotherapy to biochemical failure was 12 to 48 months (mean 36). Biochemical failure developed at 12 to 24, 24 to 36 and 36 to 48 months in 1, 4 and 1 men, respectively. Table 2 shows the details of radiation treatment. Post-radiation PSA nadir was 0.4 ng./ml. in 5 patients, while serial PSA testing showed a progressive increase in 1 who failed to achieve a nadir within a year after radiation treatment. Androgen deprivation was administered in 5 cases a mean 6.3 months after biochemical failure was detected and before salvage radical prostatectomy was done. In all patients 6 to 10 biopsy cores were obtained and 2 to 5 were positive. None of the patients had cardiovascular, pulmonary or endocrine

1 (16.6)

1 (20) 4 (25) 3 (17) 0 0 2 (15) Unknown 5 (11) 11 (27.5) 0 0

Other Postop. pulmonary edema ⫹ death in 1 0 Ureteral transection Lymphedema in 11% 0 0 0 0 0 0 Deep vein thrombosis in 5%, pulmonary embolism in 1% 0

disease, while 3 had undergone previous operative procedures not related to the urological tract and 1 had undergone transurethral resection of a superficial bladder tumor. Operative time was 180 to 220 minutes (mean 195) and blood loss was 400 to 1,000 cc (mean 680). All patients received 1 unit of previously donated autologous blood and 1 required 2 additional units of blood. There was adherence of the rectourethral and posterior prostate fascia in 2 cases but no rectal or ureteral injuries. Sharp rather than blunt finger dissection was required. Postoperative hospital stay was 3 to 4 days (mean 3.2) with no prolonged drainage or wound infection. Mean catheterization time was 13.8 days (range 10 to 17). There was no perioperative morbidity, such as myocardial ischemia, pulmonary embolism or deep vein thrombosis. Pathological evaluation revealed seminal vesicle invasion in 2 patients. Gleason score was 7 to 9. There were negative resection margins in 5 men and a positive urethral margin in 1. All 6 patients are impotent, 5 are continent and 1 has mild stress incontinence. Postoperative followup was 2 to 48 months (mean 27). There was no anastomotic stricture, lymphocele or ureterovesical stricture. Biochemical failure developed in 1 case 36 months after salvage radical prostatectomy, requiring androgen deprivation. There is no evidence of disease and PSA is undetectable in 5 patients. DISCUSSION

The role of salvage surgery for managing local failure after radiotherapy for prostate cancer has received limited attention in the urological literature. In 1974 Gill et al reported on 2 patients in whom carcinoma was down staged from C to B after external beam radiotherapy.29 Radical prostatectomy was then performed. Each patient had a temporary urethrocutaneous fistula postoperatively but convalescence was otherwise uneventful and subsequent urinary continence was not mentioned.

TABLE 2. Radiation treatment characteristics in 6 patients Pt. No. 1 2 3 4 5 6

* Hybritech Beckman-Coulter Corp., San Diego, California.

0

4 (80) 4 (25) 2 (10) 0 8 (55) 8 (64) 21 (63) 20 (46) 23 (58) 33 (41.7)

0

No. Bladder Neck Contracture (%)

Radiation Type External beam, 6,660 cGy. in 37 fractions, 10 Mvx. energy, 4-field box technique External beam, 6,660 cGy. in 37 fractions, 10 Mvx. energy, 4-field box technique External beam, 6,660 cGy. in 39 fractions, 3-dimensional conformal technique External beam, unknown dose, 3-dimensional conformal technique, 56 125I interstitial radioactive seeds, unknown mCi. 74 Interstitial 125I seeds, 31.39 mCi. of 125I, 16,000 cGy. 57 Interstitial 125I seeds, 31.39 mCi. of 125I, 16,000 cGy.

Radiotherapy Yr. 1991 1993 1993 1997 1994 1998

2000

SALVAGE RADICAL PROSTATECTOMY FOR RADIORECURRENT PROSTATE CANCER

In 1982 Carson et al reported on 18 patients who underwent radical prostatectomy after radiotherapy, of whom only 2 had local progression before salvage surgery.30 Most patients in this series received planned, staged bimodal therapy rather than true salvage radical prostatectomy for radiorecurrent cancer. Nevertheless, the lack of surgical morbidity with regained continence reported in all patients and subsequent metastatic disease in only 3 at the last followup were encouraging. These studies led us to believe that radiotherapy was being performed to down stage disease before surgical extirpation in the pre-PSA and transrectal ultrasound biopsy era, when detecting early prostate cancer and followup for monitoring progression were rather crude by the standards of today. With the advent of serial PSA monitoring and transrectal ultrasound biopsy the incidence of prostate cancer peaked and younger patients were being diagnosed with prostate cancer.31 There was also a trend toward radical radiotherapy as primary treatment of prostate cancer due to the perceived lower risk of urinary incontinence and impotence. This trend resulted in a large cohort of patients in the mid and late 1980s who with the help of PSA testing and transrectal ultrasound guided prostate biopsy were diagnosed with radioresistant or radiorecurrent prostate cancer. These men were younger and had no evidence of distant metastasis or significant morbid factors that would have caused death within the next decade. Various treatment modalities were available for these patients with variable outcomes but few offered an opportunity for cure. Other aspects were considered in these cases, such as pain, gross hematuria, bladder outlet obstruction and ureteral obstruction as well as distant metastasis. In the series of Schellhammer et al up to 30% of men with recurrent tumor required surgical intervention, including transurethral prostatic resection or urinary diversion.32 Moreover, Green et al reported incontinence in a third of patients who underwent transurethral prostatic resection for symptoms of bladder outlet obstruction due to post-irradiation tumor progression.33 In those with locally recurrent cancer after full dose radiation therapy the 10-year rate survival was 35%, whereas survival in those with local control was 90% for the same interval.34 Studies in the last 10 years have described salvage radical prostatectomy as a procedure that may achieve local control but has been associated with significant morbidity compared with standard radical prostatectomy.13 Notable is the high incidence of intraoperative rectal injury, prolonged urine extravasation and urinary incontinence. Despite this morbidity others have suggested that this operation is feasible with acceptable risks. Rainwater and Zincke performed radical prostatectomy with curative intent in 13 men after neoadjuvant radiotherapy and in 17 who had previously undergone full dose radiotherapy with curative intent.22 The most significant complications were vesical neck contracture in 17% of cases, lymphedema in 10% and incontinence in 10%. Spaulding and Whitmore described 38 patients with locally advanced, clinical stage C prostate cancer treated with cystoprostatectomy or pelvic exenteration, including 6 in whom definitive radiotherapy failed.35 They concluded that if neither the rectum nor the bladder was involved with tumor, surgical excision may be done with acceptable morbidity and cure was possible. Nevertheless, only a few surgeons advocate this extensive surgery. Mador et al reported on 4 patients who underwent salvage radical prostatectomy and 3 who underwent cystoprostatectomy after local failure following external beam radiation therapy.19 There were 2 intraoperative rectal injuries. Average operative time was 4.75 hours, average hospital stay was 7.6 days and average transfusion was 4.7 units. One man died immediately postoperatively of pulmonary edema. The remaining 3 patients had no significant complications and are continent.

Thompson et al noted 20% bladder neck contracture and 20% total urinary continence rates in 5 cases after salvage radical prostatectomy.20 One patient used an external collecting device and no rectal injuries were reported. In 1991 Moul and Paulson described 22 patients with 100% continence, of whom 3 (10%) had rectal injury.23 Link and Freiha reported a 45% continence rate without any rectal injury or bladder neck contracture in 14 patients who underwent salvage surgery.24 Aherling et al observed a continence rate of 36% without any rectal injury or bladder neck contracture in 34 men.26 Stein25 and Pontes27 et al described a similar incidence of rectal injury, continence and bladder neck contracture (8% and 9%, 36% and 54%, and 15% and 11%) in 13 and 43 cases, respectively. In a series of 40 patients Rogers et al noted a 15% incidence of rectal injury, a continence rate of 42% and bladder neck contracture in 27.5%.28 Except for these anatomical and physiological drawbacks of salvage radical prostatectomy, in the past others have also described greater intraoperative and perioperative morbidity than that of standard radical prostatectomy. Neerhut et al reported rectal injury in 19%, bladder neck contracture in 25% and continence in 73% of 16 men, including 15 who underwent interstitial radioactive gold seed placement in addition to external beam irradiation.21 Mean operative time was 4.4 hours and mean blood loss was 900 cc. Of the 3 patients (19%) with rectal injury 1 had a vesicourethral rectal fistula that required diverting colostomy with subsequent fistula repair. In another case ureteral transection was recognized intraoperatively and successfully reimplanted. Ureteral stenosis developed in 1 patient, requiring repeat implantation. Three patients had prolonged anastomotic leakage and 4 (25%) required internal urethrotomy for anastomotic stricture. Operative time and average hospital stay were longer than those for standard radical prostatectomy but blood loss was less. In 1995 Lerner et al reported on 79 men who underwent salvage radical prostatectomy, including 5 with rectal injury, 1 who required fecal diversion and 15 with prolonged urinary extravasation.13 The continence rate was 59.3%, defined as no pads or a safety pad used. They also noted an overall 5% incidence of deep vein thrombosis, 1% incidence of pulmonary embolism and a median transfusion of 1 unit of blood. Results in recent studies indicate that the morbidity of salvage radical prostatectomy is lower than reported earlier. This observation may reflect surgeon experience or the development of newer techniques of radiotherapy with decreased nontarget organ damage and less periprostatic fibrosis. CONCLUSIONS

Salvage radical prostatectomy is a technically challenging procedure. In the past there was a high incidence of rectal injury, postoperative urinary incontinence and anastomotic stricture. Rectal injury was attributed to the effects of radiotherapy, which resulted in fibrosis and obliteration of the normal tissue plane between the prostate and rectum. To counteract these concerns thorough preoperative mechanical and antibiotic bowel preparation was a common practice. Others performed antegrade dissection of the prostate from bladder neck to apex when there was any difficulty in mobilizing the prostate from the rectal wall. The results of our small series are encouraging. There has been no rectal injury or anastomotic stricture. In our patients the rate of continence, defined as no pad use, is 80%, and mean operative time and transfusion requirements were consistent with those of standard radical prostatectomy. We do not insist on bowel preparation preoperatively and have used bladder neck preservation techniques, which we believe may improve continence and decrease the incidence of anastomotic stricture. Radical prostatectomy was performed in

SALVAGE RADICAL PROSTATECTOMY FOR RADIORECURRENT PROSTATE CANCER

standard retrograde fashion from apex to bladder neck by sharp dissection. We did not observe any postoperative morbidity and hospital stay was consistent with that of standard radical prostatectomy. We removed the urethral catheter at an average of 14 days, which is 4 more than for standard radical prostatectomy, and we did not evaluate the anastomosis by cystography before catheter removal. We believe that salvage radical prostatectomy may be considered reasonable treatment in appropriate patients with radiation recurrent prostate cancer. Patients are considered appropriate when they are candidates for radical prostatectomy at the initial diagnosis of prostate cancer but elect radiation therapy. In addition, PSA attains a nadir and thereafter begins to increase or PSA does not attain a nadir 1 year after radiation treatment is done with curative intent for prostate cancer but increases on serial testing. In appropriate patients repeat biopsy confirms a positive diagnosis of prostate cancer after radiation and there is no evidence of systemic dissemination of prostate cancer or any co-morbid medical problems that would contribute to death in the next 10 years. REFERENCES

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