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A prospective study of salvage high-intensity focused ultrasound for locally radiorecurrent prostate cancer: early results

Scandinavian Journal of Urology and Nephrology, 2010; Early Online, 1–5 A prospective study of salvage high-intensity focused ultrasound forlocally radiorecurrent prostate cancer: Early results VIKTOR BERGE1, EDUARD BACO1 & STEINAR JOHAN KARLSEN1,2 1Department of Urology, Oslo University Hospital, Aker, Oslo, Norway, and 2Faculty of Medicine, University of Oslo,Norway AbstractObjective. After radical external beam radiation therapy (EBRT), local recurrence may benefit from definitive local therapy.
The objective of this study was to evaluate the safety and short-term biochemical results and morbidity after salvage high-intensity focused ultrasound (HIFU) treatment in patients with biopsy-proven local prostate cancer recurrence after EBRT.
Material and methods. From October 2006 46 patients were treated with HIFU. Bone scan and abdominal CT/MRI scan werenegative. Median follow-up was 9 months (range 3–24 months). Results. The median prostate-specific antigen (PSA) nadir was0.3 ng/ml (range 0–24 ng/ml). Eighteen patients (39.1%) were classified as failures. In addition, there were four patients (8.7%)with post-HIFU PSA nadir > 0.5 ng/ml. No patients died during follow-up. One patient developed urethrorectal fistulae andwas successfully treated conservatively. Two patients developed urethrocutaneous fistulae. Seven patients (15.2%) and onepatient (2.1%) developed grade 2 and grade 3 incontinence, respectively. Seven men (15.2%) had erectile function sufficientfor intercourse pre-HIFU and only two men (4.3%) post-HIFU. Conclusions. Early results of salvage HIFU in patients withlocal recurrence of prostate cancer after radical EBRT indicate the procedure to be a reasonable treatment option, but betterpatient selection criteria are needed. The side-effects are not negligible.
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Key Words: HIFU, prostate cancer, salvage treatment to this group of patients owing to the severe morbidityprofile [6].
External beam radiation treatment (EBRT) and rad- Salvage HIFU of radiorecurrent prostate cancer has ical surgery are the most common radical treatments been offered at this centre as a minimally invasive for localized prostate cancer. Following EBRT up to treatment option for this cohort since October 2006.
60% of patients may experience disease progression Since they are working in the first urological clinical within 10 years [1]. About one-third of these patients unit in Scandinavia to have used this treatment have local recurrence only [2,3]. Patients with local modality for patients with local recurrence of disease Scand J Urol Nephrol Downloaded from by Ms Emeline Gleitz on 05/03/10 recurrence or persistence of cancer have a higher risk of after EBRT, the authors feel obliged to present their disease progression and metastases [4]. In a recent early, preliminary results. The aim of this study is to review on published data of salvage therapies following report the short-term biochemical results and mor- radiation failure, Touma et al. reported local recur- bidity after this procedure.
rence to be a strong predictor of distant metastasis [5].
There is no agreement on the optimal management Material and methods for local recurrence after radiotherapy. Treatmentoptions with curative intent include salvage prosta- tectomy, cryoablation and high-intensity focusedultrasound (HIFU). Treatment decisions are often Since October 2006 salvage HIFU treatment has been based on patient comorbidities and physician exper- used in 46 patients with prostate-specific antigen tise and preference. Few centres offer salvage surgery (PSA) recurrence after radical EBRT. The patient Correspondence: V. Berge, Department of Urology, Oslo University Hospital, Aker, NO-0514 Oslo, Norway. E-mail: (Received 9 November 2009; accepted 24 February 2010) ISSN 0036-5599 print/ISSN 1651-2065 online  2010 Informa UK Ltd. (Informa Healthcare, Taylor & Francis AS)DOI: 10.3109/00365591003727551 V. Berge et al.
characteristics before ERBT and at the time of HIFU Table I. Characteristics of 46 patients treated with salvage HIFU are shown in Table I. Minimal requirements for following radiorecurrent prostate cancer.
treatment were a positive prostate biopsy a minimum Mean age (range) at EBRT (years) 60.8 ± 4.9 (51–73) of 18 months after EBRT, a negative bone scan and a Risk group (EAU definition) at EBRT, n (%) (CT) or magnetic resonance imaging (MRI) scan.
Contraindications were inflammatory rectal disease and anal or rectal stenosis. Initially rectal wall thick- ness > 6 mm was a contraindication, but with Median radiation dose (Gy) improved software technology, this contraindication Median time lapse (range) between EBRT 68.1 (18.2–171.2) limit was increased to > 8 mm. Prostate volume and HIFU (months) > 40 ml was a contraindication, and then the gland had to be downsized. This was achieved by transure- Mean age (range) (years) 67.8 ± 5.0 (53–78) thral resection of the prostate (TURP) 3 monthsbefore HIFU in one patient and by androgen depri- Mean (median) PSA (ng/ml) vation treatment (ADT) in seven patients. Twenty- Gleason score at EBRT, n (%) nine patients (63%) had a history of ADT as an adjuvant therapy in association with EBRT.
HIFU was performed with an Ablaterm second gen- eration HIFU device (EDAP TMS, Vaulx-en-Velin, France). Primary HIFU treatment of localized pros-tate cancer consists of standard treatment parameters which entail 100% acoustic power with a 5 s pulse of Mean prostate volume (range) before 20 ± 5.1 (12–37) energy to create each discrete HIFU lesion, with a 5 s delay between the formation of each lesion. Specific HIFU = high-intensity focused ultrasound; EBRT = external beam For personal use only.
postradiation treatment parameters developed by the radiation therapy; EAU = European Association of Urology; group of Gelet in Lyon [7] were used. These post- PSA = prostate-specific antigen.
radiation treatment parameters consist of a 4 s pulseand 6 s waiting period with 95% of the acoustic institution. The patients received one treatment ses- power. The parameters were developed in the light sion only. Routinely, the patients were discharged on of the decreased vascularity of the previously irradi- the first postoperative day (Table II). Trimethoprim– ated tissue.
sulfamethoxacol was administered preoperatively andprophylaxis was continued with trimethoprim 160 mgtwice daily until urinary catheter removal.
PSA was measured every 3 months after HIFU at the urological outpatient clinic or at the referral hos- Scand J Urol Nephrol Downloaded from by Ms Emeline Gleitz on 05/03/10 General anaesthesia was administered during the pro- pital. Repeated biopsy after HIFU was not routinely cedure. In all patients, a bladder neck incision was performed just before HIFU to reduce the postopera- Information on urinary continence was based on tive catheterization period and to avoid bladder outlet the UCLA-Prostate Cancer Index (PCI) quality of life obstruction. In addition, a limited TURP was carried questionnaire, which each patient was invited to out in 30 (65%) of these patients. A three-way catheter answer before HIFU and a minimum of 3 months was inserted at the end of the endoscopic procedure.
after HIFU. Gradation of incontinence is depicted The HIFU protocol included the treatment of the in Table III, as are the parameters concerning erectile entire gland. There were four treatment sections and general sexual function.
defined by the ultrasound, two sections in eachlobe. Before treating the part containing the urethra,the catheter was removed. The lower limit for treat- ment was 6 mm from the apex of the gland, to reducethe possibility of stress incontinence. Upon comple- Medians and ranges were given for continuous non- tion of the procedure, the catheter was reinserted and normally distributed variables. Percentages were esti- then removed 3–5 days later at the referring mated by frequency tables and cross-tabs. Association Salvage HIFU for recurrent prostate cancer Table II. Operative factors and complications in 46 patients treated localized prostate cancer (PCa): cT1–T2a and Gleason with salvage HIFU following radiorecurrent prostate cancer.
score 2–6 and PSA < 10 ng/ml; intermediate-risk local- Discharge time (days after HIFU) (range) ized PCa: cT2b–T2c or Gleason score = 7 or PSA Follow-up (months) (range) 10–20 ng/ml; high-risk localized PCa: cT3a or Gleasonscore 8 Dilatation for stricture, n (%) –10 or PSA > 20 ng/ml) [8].
PSA doubling time (PSAdt) was calculated with at Requiring intervention for stricture/necrotic least two measurements of PSA with a 3 month interval, using log calculations at the website of the Memorial Sloan Kettering Cancer Center (http:// Rectourethral fistulae Two-sided p values < 0.05 were considered signif- icant. The analyses were performed in SPSS 17(SPSS, Chicago, IL, USA) for Windows.
HIFU = high-intensity focused ultrasound; UTI = urinary tractinfection.
between two categorical variables was assessed byFisher's exact test.
The median follow-up period was 9 months (range Failure was defined as initiated ADT or increasing 3–24 months). The median PSA nadir was 0.3 ng/ml PSA value at last follow-up. The failure rate was strat- (range 0–24 ng/ml). Eight patients (17.4%) had ified according to the pretreatment European Associa- started ADT initiated by the referring institution at tion of Urology (EAU) risk group classification [low-risk the last evaluation owing to increasing PSA or Table III. Self-assessment of urinary continence and erectile function before and after HIFU.
Urinary continence, n (%) For personal use only.
Occasional dribbling (grade I) Frequent dribbling (grade II) No urinary control whatsoever (grade III) Erectile function, n (%) How would you describe the usual quality of your erections during the last 4 weeks? Not firm enough for any sexual activity Scand J Urol Nephrol Downloaded from by Ms Emeline Gleitz on 05/03/10 Firm enough for masturbation and foreplay only Sufficient for sexual intercourse How would you characterize your sexual function the last 4 weeks? HIFU = high-intensity focused ultrasound.
V. Berge et al.
detection of metastasis. The median time for initiating untreated prostatic tissue [10,11]. Repeated PSA ADT after HIFU was 7.5 months (range 1–15 months).
measurement over time may therefore be the best In addition, 10 patients (21.7%) had a rising PSA at criterion for defining disease progression.
the last follow-up. Accordingly, the failure rate was Correct staging of radiorecurrent prostate cancer 39.1%. Four patients (8.7%) had a post-HIFU PSA still represents a great problem. There is at present no nadir > 0.5 ng/ml.
reliable diagnostic modality for the detection of There was no difference in failure rate between micrometastasis. Patients suitable for local salvage high- and intermediate-risk groups (p = 0.351).
therapy may therefore harbour micrometastasis at Twelve high- (42.9%) and five intermediate-risk the time of treatment. After radiotherapy the PSAdt patients (31.3%) failed to reach a post-HIFU PSA correlates with the site of recurrence. In a study by nadir < 0.5 ng/ml.
Hancock et al. [12] patients with local recurrence had Median PSAdt was 10.3 months (range 1.7–179 a doubling time of 13 months compared with months) in the high- and 15.7 months (range 1.9– 3 months for those with distant failure. Heidenreich 50.9 months) in the intermediate-risk group. PSAdt et al. [13] found that PSAdt > 12 months was a was unknown in eight high- (28.6%) and four predictor of organ- and specimen-confined prostate intermediate-risk (23.5%) patients.
cancer after salvage prostatectomy (p < 0.002). In the There was no difference in failure rate in patients present series there was no statistical significant asso- with pre-HIFU PSAdt < 12 months compared with ciation between PSAdt before HIFU and failure, patients with PSAdt > 12 months (p = 0.721). Regard- probably owing to the small size of the cohort. How- ing the relationship between post-HIFU PSA nadir ever, in the intermediate-risk group there was a ten- and pre-HIFU PSAdt stratified for high- and dency towards an association between PSAdt and intermediate-risk patients there was a tendency PSA nadir (p = 0.072). Further studies with a longer towards higher PSAdt in patients with a PSA nadir follow-up time are necessary to reveal whether PSAdt < 0.5 ng/ml in the intermediate-risk group (p = 0.072), is a marker for better selection of patients.
but not in the high-risk group (p = 0.691).
Complications and side-effects are shown in intermediate-risk patients failed to reach a PSA nadir Tables II and III. A detailed evaluation of the quality < 0.5 ng/ml after HIFU. Recurrence after all salvage of life data from the UCLA-PCI questionnaires, therapies seems to be higher for patients who are high which were offered to the patients before and after risk before radiotherapy than for intermediate- and For personal use only.
HIFU, is currently being performed.
low-risk patients [13,14]. This is probably due to ahigher risk of disseminated tumour cells at the timeof primary radiotherapy [15]. Undiagnosed metasta- sis before HIFU is certainly part of the explanationfor the poor results observed in the high-risk popu- This study reports on short-term results only after salvage HIFU treatment. At 9 months' median HIFU caused a significant deterioration in voiding follow-up the failure rate was 39.1%, defined as and erectile function (Table III). The rate of incon- increasing PSA value or initiated ADT at the last tinence may be reduced in some patients by not follow-up. This compares well with other reports treating the apex of the prostate in cases proven cancer Scand J Urol Nephrol Downloaded from by Ms Emeline Gleitz on 05/03/10 [7], even though 28 (60.9%) of the patients were in negative by biopsies from this region. Erectile func- the high-risk group before radiation therapy. Murat tion was considerably reduced before salvage HIFU, et al. [7] reported the progression-free survival probably owing to advanced age and previous rate (PFSR) to be 53% and 42% in high- and Since the introduction of new treatment parameters The additional four patients who did not achieve a in 2002 [7], urethrorectal fistulae are rare after salvage PSA nadir < 0.5 ng/ml after treatment may also be in HIFU. In the patient who developed a rectourethral danger of disease recurrence in the future. Seo et al.
fistula in the present study, MRI imaging 4 months [9] found that the PSA nadir level > 0.5 ng/ml was the after HIFU confirmed the fistula to be healed by only significant predictor on multivariate analysis prolonged bladder catheterization. It is also highly associated with failure of salvage HIFU therapy. How- probable that the urethrocutaneous fistula formation ever, there is not yet a definition of successful salvage to the symphysis pubis and groin is related to the HIFU treatment based on PSA nadir. After primary HIFU procedure, although the authors are not aware HIFU, as is the case with primary cryotherapy, com- of these complications being reported in previous plete ablation of the prostate may not be attained, publications. Both of these complications occurred at resulting in the release of measurable PSA from referral institutions in patients with concomitant Salvage HIFU for recurrent prostate cancer urinary infection and it is hypothesized that they have Coen JJ, Zietman AL, Thakral H, Shipley WU. Radical were precipitated by catheterization of the urethra with radiation for localized prostate cancer: local persistence ofdisease results in a late wave of metastases. J Clin Oncol a very vulnerable mucosa after HIFU, causing an infec- tious fistula. The rare problem of urethrocutaneous Touma NJ, Izawa JI, Chin JL. Current status of local salvage fistula formation may favour bladder drainage with therapies following radiation failure for prostate cancer.
suprapubic catheter during the postoperative period.
J Urol 2005;173:373–9.
In conclusion, early results of salvage HIFU in Rukstalis DB. Treatment options after failure of radiationtherapy – a review. Rev Urol 2002;4:S12–7.
patients with local recurrence of prostate cancer after Murat F-J, Poissonnier L, Rabilloud M, Belot A, Bouvier R, radical EBRT indicate the procedure to be a reason- Olivier R, et al. Mid-term results demonstrate salvage able treatment option, but better patient selection high-intensity focused ultrasound (HIFU) as an effective criteria are still requires. However, the side-effects are not negligible.
locally radiorecurrent prostate cancer. Eur Urol 2009;55:640–9.
EAU guidelines address:
Seo SI, Jeon SS, Jo MK, Lee HM, Choi HY. Salvage high-intensity focused ultrasound (HIFU) therapy for locally -recurrent prostate cancer after primary HIFU or external The authors acknowledge statistician Lien My Diep at beam radiotherapy (EBRT). Eur Urol Suppl 2008;7:119.
the Research Department, Aker University Hospital, Chin JL, Touma N, Pautler SE, Guram KS, Bella AJ,Downey DB, et al. Serial histopathology results of salvage for help in preparation of the manuscript cryoablation for prostate cancer after radiation failure. J Urol2003;170:1199–202.
Declaration of interest: The authors report no Izawa JI, Morganstern N, Chan DM, Levy LB, Scott SM, conflicts of interest. The authors alone are responsible Pisters LL. Incomplete glandular ablation after salvage cryo-therapy for recurrent prostate cancer after radiotherapy. Int J for the content and writing of the paper.
Radiat Oncol Biol Phys 2003;56:468–72.
Hancock SL, Cox RS, Bagshaw MA. Prostate specific anti-gen after radiotherapy for prostate cancer: a re-evaluation of long-term biochemical control and the kinetics of recurrencein patients treated at Stanford University. J Urol 1995;154: Kupelian PA, Martinez AA, et al. Long-term multiinstitu- Heidenreich A, Richter S, Thu D, Pfister D. Prognostic tional analysis of stage T1–T2 prostate cancer treated with parameters, complications, and oncologic and functional For personal use only.
radiotherapy in the PSA era. Int J Radiat Oncol Biol Phys outcome of salvage radical prostatectomy for locally recur- rent prostate cancer after 21st-century radiotherapy. Eur Crook J, Malone S, Perry G, Bahadur Y, Robertson S, Abdolell M. Postradiotherapy prostate biopsies: what do Langenhuijsen JF, Eveline MP, Broers EWP, Vergunst H.
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Pollack A, Zagars GK, Antolak JA, Kukan DA, Rosen II.
Berg A, Berner AA, Lilleby W, Bruland ØS, Fossa SD, Prostate biopsy status and PSA nadir level as early surrogates Nesland JM, et al. Impact of disseminated tumor cells in for treatment failure: analysis of a prostate cancer randomized bone marrow at diagnosis in patients with nonmetastatic radiation dose escalation trial. Int J Radiat Oncol Biol Phys prostate cancer treated by definitive radiotherapy. Int J Scand J Urol Nephrol Downloaded from by Ms Emeline Gleitz on 05/03/10


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