Long-Term Outcome and Toxicity of Salvage Brachytherapy for Local Failure After Initial Radiotherapy for Prostate Cancer

Int. J. Radiation Oncology Biol. Phys., Vol. 77, No. 5, pp. 1338–1344, 2010 Copyright Ó 2010 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/$–see front matter

doi:10.1016/j.ijrobp.2009.06.061

CLINICAL INVESTIGATION

Prostate

LONG-TERM OUTCOME AND TOXICITY OF SALVAGE BRACHYTHERAPY FOR LOCAL FAILURE AFTER INITIAL RADIOTHERAPY FOR PROSTATE CANCER RYAN J. BURRI, M.D.,* NELSON N. STONE, M.D.,y PAM UNGER, M.D.,z AND RICHARD G. STOCK, M.D.* Department of * Radiation Oncology, y Urology, and z Pathology, Mount Sinai School of Medicine, New York, NY. Purpose: To describe long-term outcomes and toxicity after salvage brachytherapy (BT) for local failure after initial radiotherapy for prostate cancer. Methods and Materials: Between 1994 and 2008, 37 men with local failure after initial prostate radiotherapy (32 external-beam radiation therapy [EBRT] and 5 BT) underwent salvage BT with 103Pd or 125I. Estimates of freedom from biochemical failure (FFbF, Phoenix definition) and cause-specific survival (CSS) were calculated using the Kaplan-Meier method. Toxicities were graded using CTCv3.0. Results: Median follow-up was 86 months (range, 2–156). The median dose to 90% of the prostate volume was 122 Gy (range, 67–166). The 10-year FFbF and CSS were 54% and 96%, respectively. On univariate analysis, prostatespecific antigen (PSA) >10 ng/mL at initial diagnosis was significantly associated with FFbF (p = 0.01), and there were trends for both age <70 years (p = 0.08) and PSA <6 ng/mL (p = 0.08) at the time of salvage BT. On multivariate analysis, only presalvage PSA <6 ng/mL (p = 0.046) was significantly associated with improved FFbF. There were three Grade 3 toxicities and one Grade 4 toxicity. Pelvic lymph node dissection before salvage BT was the only variable significantly associated with Grade $2 toxicity (p = 0.03). Conclusion: With a median follow-up of 86 months, salvage prostate BT was associated with a 10-year FFbF of 54% and CSS of 96%. Improved FFbF was associated with a presalvage PSA <6 ng/mL. Toxicity was worse in patients who had undergone pelvic lymph node dissection before salvage BT. Careful patient selection for salvage BT may result in improved outcomes and reduced toxicity. Ó 2010 Elsevier Inc. Prostate cancer, Brachytherapy, Salvage therapy. brachytherapy [BT]) underwent salvage BT with either 103Pd (36 patients) or 125I (1 patient) at the Mount Sinai Medical Center. The patients who made up this cohort were, for the most part, referred to Mount Sinai after local failure after EBRT at outside institutions. Of the 5 upfront brachytherapy patients, 4 were treated in the very early years of the prostate brachytherapy program at Mount Sinai and were deemed at the time of local failure to have had a lowerquality implant initially based on dosimetric analysis. The fifth brachytherapy failure occurred in a patient who underwent a suboptimal implantation at an outside institution and was referred to Mount Sinai at the time of local failure. The extent of disease workup included a thorough history and physical examination followed by routine laboratory studies, pelvic computed tomography (CT), bone scan, and serum prostate-specific antigen (PSA) determinations. In addition, 30 men underwent 6-core seminal vesicle (SV) biopsy at the discretion of the treating urologist before salvage implant; one had a positive SV biopsy, and all others had negative SV biopsies. Thirty-one of the 37 men were Caucasian. Three patients had a history of transurethral resection of the prostate (TURP) before undergoing initial treatment for prostate cancer, and 1 patient underwent suprapubic prostatectomy before EBRT. In this latter patient, the surgery was performed for a history of

INTRODUCTION The ideal treatment of the prostate cancer patient who experiences a local failure after definitive radiotherapy is controversial. Radical prostatectomy, cryotherapy, and brachytherapy have been attempted with varying degrees of success (1). Several series have been published in the literature describing the short-term and intermediate-term biochemical control of these potentially curative local approaches, but long-term outcomes and toxicity data are limited (2–15). Herein we report the long-term oncologic and quality of life outcomes in a cohort of patients with locally recurrent prostate cancer treated with salvage brachytherapy. METHODS AND MATERIALS Patient characteristics Between June 1994 and February 2008, 37 men with biopsyproven local failure after prostate radiotherapy (32 treated with initial external-beam radiotherapy [EBRT] and 5 treated with initial Reprint requests to: Richard G. Stock, M.D., Department of Radiation Oncology, Box 1236, 1 Gustave L. Levy Place, New York, NY 10029. Tel: (212) 241-7500; Fax: (212) 410-7194; E-mail: [email protected]

Conflict of interest: N.N. Stone is owner, Prologics LLC; consultant, Nihan Medi-Physics; and consultant; B & K Medical. The authors report no other conflicts of interest. Received April 21, 2009, and in revised form June 3, 2009. Accepted for publication June 23, 2009. 1338

Long-term outcome of salvage prostate brachytherapy d R. J. BURRI et al.

obstructive uropathy before his initial EBRT for prostate cancer; at the time of local recurrence, the patient was noted on physical examination and on transrectal ultrasound to have locally recurrent prostatic tissue in the prostate bed and was thought to be a good candidate for salvage brachytherapy. Patients were staged according to the 1992 American Joint Committee on Cancer staging system before their original treatment (16). All prostate and SV biopsy specimens were reviewed by a pathologist (P.U.) with experience in interpreting postirradiation prostate tissue. Written informed consent was obtained from patients for participation in this retrospective review, which was approved by the Institutional Review Board. Both initial and salvage patient characteristics are shown in Table 1. Patients were followed up every 6 months, and toxicities were recorded and graded using Common Toxicity Criteria version 3.0. The median patient age was 65 years (range, 48–73 years) at the time of initial treatment and 70 years (range, 51–79 years) at the time of salvage therapy. Cancer control outcomes were calculated using the actuarial methods of Kaplan and Meier (17). Outcomes measured include freedom from biochemical failure (FFbF) using the Phoenix definition (18); local recurrence-free survival (LRFS) using postsalvage prostate biopsy and/or digital rectal examination; distant metastasis-free survival (DMFS) based on a combination of imaging studies and clinical examination findings; cause-specific survival (CSS) based on deaths attributed to prostate cancer; recurrence-free survival (RFS) combining biochemical, local, and distant events; and overall survival (OS). Variables were analyzed for association with outcomes using log rank and Cox regression analyses and toxicity using the chi-square test. Two-sided p values <0.05 were considered significant.

Initial treatment characteristics Initially, 32 men were initially treated with EBRT to a median dose of 67.8 Gy (range, 63.0–75.6 Gy). Six of these patients were treated with concurrent hormonal ablation therapy. Sixteen men received prostate-only radiation, 5 received whole pelvic RT, and the details were insufficient to determine the initial treatment volume in 11 patients. Three men underwent pelvic lymph node dissection (PLND) to rule out regional metastases before EBRT. Five patients underwent initial BT with either full-dose 125I (3 patients), full-dose 103Pd (1 patient) or combined modality therapy with partial-dose 103Pd and EBRT (1 patient). Four of these 5 patients underwent PLND before BT to rule out regional metastases. None of these men received hormonal therapy at the time of their initial treatment. The D90 (dose to 90% of the prostate volume) for these implants was available from postimplant CT-based dosimetry for 4 of the 5 patients and ranged from 47.5 to 113.1 Gy. To compare doses between different isotopes and between implant alone and EBRT or combined BT and EBRT, biologically effective dose (BED) equations were used. The rationale and methodology for using BED calculations have been previously described in detail (19). An alpha/beta for prostate cancer of 2 Gy was used for these equations (20–23). The initial treatment BED calculations could be performed for 33 of the 37 patients. The median initial BED was 128.8 Gy2 (range, 48.3–143.6 Gy2). The median time to salvage BT after the completion of initial radiation therapy was 62 months (range, 26–171 months).

Salvage treatment characteristics All men were treated with salvage permanent prostate BT using either 103Pd (36 patients) or 125I (1 patient) seeds and a real-time transrectal ultrasound-guided transperineal technique. The original

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Table 1. Initial and salvage patient characteristics Characteristic Age PSA, ng/mL #10 >10 – 20 >20 Unknown Gleason score #6 7 8-10 Unknown T stage #T2a T2b $T2c Unknown Recurrent D’Amico risk group Low Intermediate High Unknown Hormone use Smoking history Yes No Unknown IPSS score

At initial presentation

Median, 65 70 (range, 51–79) (range, 48–73) Median, 10.9 5.6 (range, 1.7–35.0) (range, 4.4–81.0) 13 (55%) 28 (76%) 11 (30%) 8 (22%) 5 (14%) 1 (3%) 8 (22%) 0 Median, 6 7 (range, 4–9) (range, 4–8) 20 (54%) 7 (19%) 7 (19%) 17 (46%) 4 (11%) 12 (32%) 6 (16%) 1 (3%) 7 (19%) 3 (8%) 3 (8%) 24 (65%) 37 (100%) 9 (24%) 12 (32%) 9 (24%) 7 (19%) 6 (16%)

Not available

QOL score 0 -1 2–3 Unknown Mt. Sinai Erectile Function Score 0 1 2 3 Unknown

At salvage

6 (16%) 18 (49%) 13 (35%) 0 31 (84%) 18 (49%) 17 (46%) 2 (5%) Median, 3 (range, 0–14) Median, 1 (range, 0–3) 19 (51%) 12 (32%) 6 (16%)

Not available 9 (24%) 8 (22%) 7 (19%) 9 (24%) 4 (11%)

Abbreviations: PSA = prostate-specific antigen; AJCC = American Joint Committee on Cancer; IPSS = International Prostate Symptom Score. technique as described in 1995 and the impact of subsequent innovations have been previously reported (24–26). The activity range per seed was 0.9–1.7 mCi for 103Pd and was 0.4 mCi for the single 125 I implant. The prescription dose for the implants was 110 Gy for 103 Pd (NIST-99 [27]) and 135 Gy for 125I. Neoadjuvant and adjuvant hormonal therapy was used in 31 of the 37 men for an average of 6 months. Hormonal therapy consisted of a gonadotropin-releasing hormone agonist (either leuprolide acetate or goserelin acetate) with or without an antiandrogen (either flutamide or bicalutamide). PLND was performed in 4 men before salvage implantation to rule out regional metastases. One patient with positive seminal vesicle involvement on seminal vesicle biopsy underwent salvage BT with planned SV seed implantation using a technique that has previously been described (28).

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Table 2. Univariate analysis of factors that may influence FFbF following salvage brachytherapy Factor

Fig. 1. Freedom from biochemical failure (FFbF) after salvage brachytherapy for local failure after initial radiotherapy. Postimplant CT-based dosimetry was performed on the 32 patients who were not previously treated with seed implantation. The median D90 to the prostate for these 32 implants was 122.0 Gy (range, 44.0–166.0 Gy). The median BED for the salvage implant was 140.8 Gy2 (range, 46.3–199.7 Gy2).

RESULTS Outcomes The median follow-up after salvage BT was 86 months (range, 2–156 months). The 5- and 10-year actuarial FFbF rates were 65% and 54%, respectively (Fig. 1). For the other outcomes, 5- and 10-year rates were as follows: LRFS, 84% and 76%; DMFS, 94% and 79%; CSS, 96% and 96%; RFS, 65% and 46%; and OS, 94% and 74%. Ten patients had died by the time of last follow-up. One death was attributable to prostate cancer. Eleven of the 37 patients underwent prostate needle biopsy at a median of 38 months after salvage BT (range, 10–83 months). The reasons for undergoing biopsy were as follows: planned biopsy (no symptoms, no PSA failure; 4 of 6 were positive for local failure); TURP for obstructive symptoms (2 of 2 were negative for local failure); and PSA failure (3 of 3 were positive for local failure). The effect of the following factors on FFbF were tested using univariate analysis: initial radiation dose (BED), salvage radiation dose (BED), initial hormone use, salvage hormone use, time to salvage therapy from initial therapy, Gleason score at original diagnosis, Gleason score at salvage, D’Amico risk group at initial treatment (29), PSA at original diagnosis, PSA at salvage, initial treatment type (EBRT vs. BT), and age at salvage therapy (Table 2). The only factor significantly associated with improved FFbF was PSA at original diagnosis >10 ng/mL (5- and 10-year FFbF of 85% and 74%, respectively, in patients with PSA >10 ng/mL vs. 5- and 10-year FFbF of 24% and 24%, respectively, in patients with initial PSA #10 ng/mL; p = 0.010). There were

Initial radiation dose BED #128.8 Gy2 BED >128.8 Gy2 Salvage radiation dose BED #140.8 Gy2 BED >140.8 Gy2 Initial hormone use Yes No Salvage hormone use Yes No Time to salvage therapy from initial treatment (mo) #62 >62 Gleason score at original diagnosis #6 $7 Gleason score at salvage #7 $8 D’Amico risk group at initial treatment Low or intermediate High PSA at initial diagnosis (ng/mL) #10 >10 PSA at salvage (ng/mL) <6 $6 Initial treatment type BT EBRT Age at salvage (y) <70 $70

5-y FFbF (%) 10-y FFbF (%) p value 58.2 67.1

58.2 53.7

0.854

68.8 69.6

34.4 69.6

0.670

75.0 62.7

50.0 55.7

0.906

65.5 60.0

60.0 30.0

0.613

56.2 71.0

49.2 71.0

0.388

61.2 57.1

61.2 38.1

0.479

62.5 73.3

62.5 40.7

0.989

48.3 87.5

48.3 65.6

0.359

23.9 84.6

23.9 74.0

0.010

78.7 53.3

65.6 45.7

0.081

25.0 70.6

25.0 58.6

0.239

80.0 49.5

71.1 37.1

0.079

Abbreviations: FFbF = freedom from biochemical failure; BED = biologic effective dose; PSA = prostate-specific antigen; BT = brachytherapy; EBRT = external beam radiation therapy.

trends for both age at salvage therapy <70 years (p = 0.079) and PSA at the time of salvage therapy <6 ng/mL (p = 0.081) and improved FFbF. Multivariate analysis of these three factors (age at salvage therapy, PSA at initial diagnosis, and PSA at salvage) revealed that only PSA <6 ng/mL at the time of salvage therapy was significantly associated with an improved FFbF: p = 0.046, hazard ratio 8.44 (95% confidence interval, 1.04–68.79) (Table 3). Toxicity Seventeen of the 37 patients did not develop any toxicity, and 3 patients developed Grade 1 urinary symptoms not requiring medication during follow-up. Thirteen patients

Long-term outcome of salvage prostate brachytherapy d R. J. BURRI et al.

Table 3. Multivariate analysis of factors that may influence FFbF Factor

HR (95% CI)

Table 4. Analysis of factors that may influence Grade $2 toxicity

p value Factor

PSA at initial diagnosis (#10 vs. >10 ng/mL) PSA at salvage (<6 vs. $6 ng/mL) Age at salvage (<70 vs. $70 y)

0.27 (0.07–1.07)

0.062

8.44 (1.04–68.79)

0.046

2.22 (0.59–8.38)

0.241

Abbreviations: FFbF = freedom from biochemical failure; HR = hazard ratio; CI = confidence interval; PSA = prostate-specific antigen.

developed Grade 2 toxicity requiring medications for symptom relief as follows: 9 for obstructive urinary symptoms requiring alpha blockers; 2 with urge incontinence treated with anticholinergics; and 2 with diarrhea requiring antidiarrheal medication. The crude rate of Grade $2 toxicity was 46% (17 of 37). Three patients developed Grade 3 toxicity as follows:2 patients developed obstructive uropathy requiring TURP at 39 and 67 months after salvage therapy; 1 patient required fulguration 9 months after salvage therapy for gross hematuria. One patient developed Grade 4 toxicity, constituting a prostatorectal fistula requiring urinary diversion via an ileal conduit 51 months after salvage BT. Of note, this patient had a history of poorly controlled diabetes mellitus and experienced unexpected Grade 2 perianal skin toxicity requiring a 2-week treatment break during his initial EBRT. In addition, the D90 to the prostate from his salvage implant was 166 Gy, which represented the upper limit of the range of D90 values in this series. Finally, before development of the fistula, he required TURP for obstructive uropathy 21 months after salvage therapy. The crude rate of Grade $3 toxicity was 11% (4 of 37). There were no cases of Grade 5 toxicity. Factors tested using univariate analysis for potential effect on the development of Grade $2 toxicity were as follows: presalvage International Prostate Symptom Score (IPSS) quality-of-life score, presalvage IPSS total score, smoking history, salvage hormone use, initial hormone use, initial treatment type (EBRT vs. BT), salvage radiation dose (BED), age at salvage therapy, race, TURP before salvage therapy, and PLND before salvage therapy (Table 4). Only previous PLND (p = 0.033) was significantly associated with a higher rate of Grade $2 toxicity after salvage BT (73% (8 of 11) had Grade $2 toxicity with a history of PLND versus 35% (9 of 26) with Grade $2 toxicity without a history of PLND). Erectile function Data on erectile function at last follow-up were available on 27 men. Four of the 16 men with adequate presalvage erectile function (Mount Sinai Erectile Function score of 2 or 3) reported either optimal or suboptimal (but sufficient)

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IPSS QOL score 0 or 1 2 or 3 IPSS total score 0 to 3 >3 Smoking history Yes No Hormones at salvage Yes No Hormones with initial RT Yes No Initial treatment type BT EBRT Salvage BED #140.8 Gy2 >140.8 Gy2 Age at salvage BT (y) <70 $70 Race White Nonwhite TURP/prostate surgery before salvage BT Yes No PLND before salvage BT Yes No

Percent with Grade $2 toxicity (n/N)

p value

37% (7/19) 67% (8/12)

0.106

47% (8/17) 50% (8/16)

0.866

39% (7/18) 59% (10/17)

0.238

48% (15/31) 33% (2/6)

0.498

17% (1/6) 52% (16/31)

0.116

60% (3/5) 44% (14/32)

0.498

47% (8/17) 40% (6/15)

0.688

50% (9/18) 42% (8/19)

0.630

52% (16/31) 17% (1/6)

0.116

50% (2/4) 46% (15/33)

0.863

73% (8/11) 35% (9/26)

0.033

Abbreviations: n/N = number with Grade >2 toxicity with factor present / total number with factor present; IPSS = International Prostate Symptom Score; QOL = quality of life; RT = radiation therapy; BT = brachytherapy; EBRT = external beam radiation therapy; BED = biologic effective dose; TURP = transurethral resection of the prostate; PLND pelvic lymph node dissection.

erectile function at last follow-up (crude potency preservation rate of 25%), and 23 men reported either no erectile function or erections insufficient for penetration.

DISCUSSION Local failure after external beam radiotherapy for prostate cancer has been associated with an increased incidence of distant metastatic disease and poorer overall survival (30, 31). Therefore, effective local therapy in this setting could have important implications for the patient. Reports of salvage brachytherapy, cryotherapy, and radical surgery suggest a wide range of outcomes and toxicities (Table 5) and vary according to patient-related and disease-related characteristics. Toxicities that may potentially result from all three local

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Table 5. Modern salvage series following local failure of radiation therapy for prostate cancer Study, year Vaidya & Soloway, 2000 (4) Stephenson et al., 2004 (7)/ Bianco et al., 2005 (8) Heidenreich et al., 2009 (15) Izawa et al., 2002 (5) Bahn et al., 2003 (6) Ismail et al., 2007 (11) Beyer, 1999 (2) Grado et al., 1999 (3) Wong et al., 2006 (9) Allen et al., 2007 (10) Nguyen et al., 2007 (12) Lee et al., 2008 (13) Aaronson et al., 2009 (14) Present series, 2009

N

Median f/u (mo)

RP RP

6 100

27 (mean) 60

83% 3-y FFbF* 55% 5-y PFPy

RP Cryotherapy Cryotherapy Cryotherapy Brachytherapy Brachytherapy Brachytherapy Brachytherapy Brachytherapy Brachytherapy Brachytherapy Brachytherapy

55 131 59 100 17 49 17 12 25 21 24 37

23 58 84 34 (mean) 62 64 44 45 47 36 30 86

87% 2-y FFSRz 40% 5-y bDFSj 50-62% 7-y bDFSx 59% 3-y FFbF{ 53% 5-y FFSR{ 34% 5-y bDFS** 75% 4-y FFbF{ 63% 4-y FFbF{ 70% 4-y FFbFj 38% 5-y FFbF{ 88% 3-y FFbFj 54% 10-y FFbFj

Salvage therapy

Outcome

Grade 3/4 toxicity 0% 13–33% 15% NR NR 3% NR 16% 47% 0% 30% 0% 4% 11%

Abbreviations: f/u = follow-up; RP = radical prostatectomy; FFbF = freedom from biochemical failure; PFP = progression-free probability; bDFS = biochemical disease-free survival; NR = not reported; FFSR = freedom from second relapse. * Crude rate; failure not defined. y Failure defined as PSA $0.2 ng/mL. z Crude rate; failure defined as PSA >0.2 ng/mL with two subsequent rises. x The 50% rate is for failure defined as PSA >0.5 ng/mL; the 62% rate is for failure defined as PSA >1.0 ng/mL. j Failure defined as Phoenix definition (18). { Failure defined as ASTRO definition (37). ** Failure defined as two PSA rises above nadir.

therapeutic options include rectal injury, incontinence, and impotence. Anastomotic leak and bladder neck contracture are unique to surgery, and obstructive uropathy requiring TURP may occur after either cryotherapy or brachytherapy. In the present series, salvage brachytherapy resulted in a 10-year actuarial FFbF of 54%. To our knowledge, the median follow-up of 86 months is the longest to date for any type of salvage therapy after local failure of initial radiotherapy. The value of this longer follow-up is evident in that men seem to continue to experience biochemical failure even as follow-up extends beyond 5 years from salvage therapy (Fig. 1). Because men with presalvage PSA <6 ng/mL had significantly better FFbF after salvage BT, improvement in outcomes could be further enhanced by careful patient selection in the future. Gleason score at salvage, although not associated with FFbF, seemed to be, on average, higher than on initial presentation—a phenomenon that has been described in the literature (32). Finally, of the 10 men who died during this follow-up period, only one death was attributable to prostate cancer, reflecting that the competing risk of death from other causes remains significant even after local failure of initial therapy for prostate cancer. There have been several recent reports of salvage prostate brachytherapy after local failure following EBRT. In a retrospective series of 49 patients treated with salvage BT by Grado et al. (3) from the Mayo Clinic Scottsdale, the 5year actuarial biochemical disease-free survival was 34%. The median follow-up was 64 months, and failure was based on the definition of two successive rising PSA values above the posttreatment PSA nadir value. Postsalvage PSA nadir <0.5 ng/mL was significantly associated with improved bio-

chemical disease-free survival. Serious complications (Grade $3) developed in 8 patients (16%). Beyer (2) reported the outcomes of salvage BT in a series of 17 men treated at Arizona Oncology Services after local failure after initial radiotherapy for prostate cancer with a median follow-up of 62 months. The 5-year actuarial freedom from second relapse rate was 53%, with failure defined as either three consecutive rising PSA intervals, clinical progression, or institution of hormonal therapy with backdating to the first interval PSA rise. PSA #10 ng/mL at the time of salvage therapy was associated with an improved freedom from second relapse rate at 5 years (67% vs. 25%, p = 0.15), although the difference was not statistically significant because of the small sample size. Low Gleason score at the time of salvage therapy also seemed to result in improved freedom from second relapse (p = 0.12). Long-term toxicity was reported as a 24% risk of incontinence. No serious (Grade $3) genitourinary or gastrointestinal toxicities were noted during follow-up. The most recently published retrospective data come from the University of California, San Francisco, and were reported by Aaronson et al. (14). Twenty-four men were treated with salvage BT after local failure of EBRT. With a median follow-up of 30 months, biochemical relapse-free survival (Phoenix definition) was 88% at 2–3 years, and one Grade 3 rectal hemorrhage was observed (Grade $3 crude toxicity rate of 4%). A prospective Phase II trial from the Brigham and Women’s Hospital and the Dana Farber Cancer Institute was recently reported by Nyugen et al. (12). Twenty-five men with favorable clinical features (Gleason score #7,

Long-term outcome of salvage prostate brachytherapy d R. J. BURRI et al.

PSA <10 ng/mL) at the time of local failure after initial radiotherapy for prostate cancer underwent MRI-guided salvage BT with a 4-year PSA control rate (Phoenix definition) of 70% and a median follow-up of 47 months. The estimated rate of Grade $3 toxicity at 4 years was 30%. Quality of life is an important consideration (33), and the recent publication of two large prostate cancer screening trials (34, 35) has drawn fresh attention to the potential toxicities of any intervention in the setting of a new diagnosis of prostate cancer. The potential for treatment-related toxicity may be even higher in the setting of locally recurrent disease. Overall, the crude rate of serious complications (Grade $3) was 11% (4/37) in our study, which is lower than the rates published in some (3, 9, 12) but not all (10, 13, 14) recent salvage BT series with median follow-up ranging from 30 to 64 months. Men with a history of PLND had a higher risk of Grade $2 toxicity, indicating that careful patient selection could help improve the toxicity profile after salvage BT in the future. Finally, a 25% potency preservation rate (4 of the 16 men with adequate erectile function before salvage BT reported either normal or suboptimal, but sufficient, erections at last follow-up) may be seen as a modest success in a population of older men who underwent repeat local therapy for a genitourinary malignancy. There are inherent limitations to the present study that are important to point out. Because the study was retrospective, it had the potential for selection bias. Also, the small number of patients, although comparable with that in other published series, may have precluded the identification of certain patientrelated or treatment-related variables that truly have a small or modest effect on outcomes or toxicity. In addition, the population of 11 patients with previous PLND was heteroge-

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neous, and the association with increased toxicity is difficult to explain, given the disparate timing of PLND within this subgroup. Although there can be no definitive explanation for this finding, an association between previous PLND and increased rates of complications after salvage radical prostatectomy has been previously described (36). The heightened toxicity in that series was attributed to increased fibrosis in the pelvis in patients who had undergone PLND at the time of their initial radiotherapy. Finally, because our group has extensive experience in brachytherapy for prostate cancer, the results presented in this study may represent above-average outcomes compared with those that might be expected at smaller community hospitals. A prospective multi-institutional study of salvage brachytherapy (Radiation Therapy Oncology Group 0526) is currently open to accrual to address these very concerns. CONCLUSION With a median follow-up of 86 months, salvage prostate brachytherapy was associated with a 10-year freedom from biochemical failure rate of 54% and a cause-specific survival rate of 96%. Improved freedom from biochemical failure was associated with a presalvage PSA <6 ng/mL. Toxicity seemed to be worse in patients who had undergone pelvic lymph node dissection before salvage therapy. These longterm data suggest that salvage brachytherapy in the setting of local failure may represent an effective and safe therapeutic option for men previously treated with radiation therapy for prostate cancer. Careful patient selection for salvage brachytherapy may result in improved outcomes and reduced toxicity.

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