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High Intensity Focused Ultrasound for Radiorecurrent Prostate Cancer: A North American Clinical Trial
Author's Accepted Manuscript High-Intensity Focused Ultrasound for Radio-recurrent Prostate Cancer: A North American Clinical Trial Tonye A. Jones , Joseph Chin , David Mcleod , Jack Barkin , Allan Pantuck , Leonard S. Marks
PII: DOI: Reference:
S0022-5347(17)76734-1 10.1016/j.juro.2017.06.078 JURO 14826
To appear in: The Journal of Urology Accepted Date: 17 June 2017 Please cite this article as: Jones TA, Chin J, Mcleod D, Barkin J, Pantuck A, Marks LS, High-Intensity Focused Ultrasound for Radio-recurrent Prostate Cancer: A North American Clinical Trial, The Journal of Urology® (2017), doi: 10.1016/j.juro.2017.06.078. DISCLAIMER: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our subscribers we are providing this early version of the article. The paper will be copy edited and typeset, and proof will be reviewed before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to The Journal pertain.
Embargo Policy All article content is under embargo until uncorrected proof of the article becomes available online. We will provide journalists and editors with full-text copies of the articles in question prior to the embargo date so that stories can be adequately researched and written. The standard embargo time is 12:01 AM ET on that date. Questions regarding embargo should be directed to [email protected].
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High-Intensity Focused Ultrasound for Radio-recurrent Prostate Cancer: A North American Clinical Trial Runninghead: Salvage HIFU for Radio-recurrent Prostate Cancer
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Authors: Tonye A. Jonesa, Joseph Chinb, David Mcleodc, Jack Barkind, Allan Pantucka, Leonard S. Marksa a
Department of Urology, David Geffen School of Medicine, Los Angeles, CA, 90095, USA Division of Urology, London Health Sciences Center, London, ON, Canada c Center for Prostate Cancer Disease Research: Department of Surgery, Uniformed Services University of the Health Sciences and Walter Reed National Medical Military Center, Bethesda, MD 20814 d Can-Am HIFU, Toronto, ON, Canada
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Keywords: focal therapy, prostate, cancer, high-intensity focused ultrasound
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Corresponding Author: Leonard S. Marks, M.D. Department of Urology David Geffen School of Medicine at UCLA 300 Stein Plaza, 3rd Floor Los Angeles, California 90095 Ph: 310-794-3070 Fax: 310-794-0987 Email: [email protected]
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Abstract Purpose: To determine the safety and efficacy of whole-gland HIFU in men with radio-recurrent prostate
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cancer (CaP).
Materials and Methods:
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100 men with clinically localized recurrence of CaP at least 2 years after EBRT received wholegland HIFU in an open-label trial (2009 to 2012). Treatments were performed at 16 sites in the
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U.S. (14) and Canada (2). Primary endpoint was a combination of both PSA nadir ≤0.5 ng/ml and negative biopsy at 12 months. Validated questionnaires were used to monitor changes in urinary and sexual function.
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Results:
Of the 100 men treated (mean age 70, range, 53-83 years), 78 completed 12-month biopsy, of which 63 (81%) were negative. Mean PSA was 4.9ng/ml (range, 0.4-14) and median Gleason
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score was 7. 50 men achieved 1-year endpoint of both PSA nadir ≤0.5ng/ml and negative biopsy. In post-trial follow-up, mean PSA at 2 years was 1.1 ng/ml, range 0.1-17 (N=33). Adverse events
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(AEs) occurred in 91 men through 12 months: grade 1 in 67, grade 2 in 80, and grade 3 in 20 (CTCAE). Treatment-related grade 3 AEs included rectal fistulae in 5 (3 required surgery), osteitis pubis in 3, and hematuria requiring intervention in 3. Treatment-related Grade 3 AEs occurred early in the trial and appeared related to operator experience. There were no lifethreatening AEs or treatment-related deaths.
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Conclusions: Whole-gland HIFU appears reasonably safe and effective for treatment of radio-recurrent prostate cancer. Rate of complications, which are potentially severe, was acceptable, especially
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considering the advanced, refractory nature of the disease and limited treatment options.
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Introduction Biochemical recurrence after external beam radiation therapy (EBRT) for clinically localized prostate cancer (CaP) occurs in up to 60% of men (1). The majority of these men
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receive androgen-deprivation therapy (ADT) alone, which is not curative and entails adverse effects on cardiovascular health, metabolic function, and bone strength (2). A fraction of men with biochemical recurrence after EBRT have localized disease that may be amenable to curative
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salvage therapy. In such cases, treatment options include prostatectomy, cryotherapy,
and bowel complications (1).
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brachytherapy, and high-intensity focused ultrasound (HIFU); all involve risk of urinary, sexual,
Koch and associates from Indiana University reported the use of HIFU for CaP in 2007, showing in previously untreated men that the procedure could be safe and effective (3). The goal of HIFU is to induce coagulative necrosis and cavitation of cancerous prostate tissue by use of
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ultrasonic waves (4). In a study evaluating salvage HIFU treatment for 22 men with radiorecurrent CaP, Uchida et al. reported biochemical disease-free survival rates of 100% and 86% at 5 years in men with low and intermediate risk CaP, respectively (5).
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Several studies have since evaluated the safety and oncological effectiveness of HIFU as a salvage therapy for men with localized cancer recurrence after EBRT (1,2,6,7). These studies
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were performed in European and British centers, where regulatory approval has been in place for many years. The present ‘registration’ study was conducted at centers primarily in the U.S. The goal of this prospective, open-label study was to determine the safety, feasibility, and early cancer control rates of whole-gland prostate ablation using HIFU following failed radiation therapy.
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Materials and Methods This federally registered study (NCT00772317) was a non-randomized, prospective, open-label trial performed at 16 trial sites in the U.S. (14) and Canada (2) *. Investigative sites
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are shown in Table 1. 100 men with biopsy-proven (12-core), localized recurrence of CaP at least 2 years after EBRT were subjects. Average number of biopsy cores positive was 4 per patient and median Gleason score was 7. All men who received ADT within 3 months of
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treatment were excluded. Entry criteria included a PSA level between 0.5 ng/mL and 10 ng/mL, clinical stage T1c-T2 prior to EBRT, and bone scan and CT (chest, abdomen, pelvis) negative for
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metastatic disease upon enrollment. Patient characteristics are shown in Table 2. The study treatments were performed between February 2009 and July 2012. All patients provided written informed consent and were placed in a prospectively maintained HIFU registry, following issuance of an Investigational Device Exemption from the U.S. Food and Drug
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Administration (FDA) (G080057) in 2008. At each participating institution, participants signed a consent form approved by the institutional review board. Complete inclusion and exclusion criteria are shown in Table 3. The primary endpoint was a combination of PSA nadir ≤0.5 ng/mL
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within 12 months of treatment and a negative prostate biopsy at 1 year. Secondary endpoints were changes in urinary and sexual function compared to baseline.
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* The trial reported here was the basis of a 510k application by SonaCare Medical, LLC to the U.S. FDA. An FDA panel hearing was held October 1, 2014, and the Sonablate-450 device was approved “for ablation of prostatic tissue” via the de novo route on October 9, 2015.
Treatment protocol
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All men underwent HIFU using the Sonablate 450 device (Sonacare, Charlotte, NC, USA) under general anesthesia. A HIFU-experienced physician and engineer proctored each treatment. Following placement of a suprapubic and urethral catheter, patients were placed in the lithotomy
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position for rectal insertion of the treatment probe. Real-time ultrasound images of the prostate in sagittal and transverse planes were obtained to ensure treatment would be technically feasible (e.g., anterior gland is accessible, absence of acoustic shadowing).
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Treatment planning was performed using custom software, which allowed the prostate to be divided into three zones: anterior, middle, and posterior (8). The software moved the
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transducer automatically to allow treatment of the entire prostate. Just prior to each treatment, the urethral catheter, which is used to identify anatomical landmarks (e.g., bladder neck, apex), was removed.
During treatment, real-time ultrasound of the apex of the prostate allowed identification
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and avoidance of the external urinary sphincter. HIFU energy was applied for 3 second intervals followed by a 6 second pause to avoid overheating of prostate tissue outside the targeted zone. Power settings were determined using rectal wall distance and adjustments were made if
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unfavorable tissue changes were observed.
After a two-hour observation period, patients were discharged home with an antibiotic
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and oral analgesics. Each patient had a suprapubic catheter in place for 2-4 weeks, with planned removal dependent on voiding function following treatment.
Follow-up
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Follow-up clinic visits were conducted at 6 weeks, 3 months, 6 months, 9 months, and 12 months. A subset of men underwent PSA testing at 24 and 36 months. Each visit included a detailed history and physical examination, screening for adverse events (CTCAE, v4.03), medication
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reconciliation, PSA, and health-related quality of life (HRQOL) questionnaires (e.g., IPSS, IIEF). At 12 months, a systematic transrectal ultrasound-guided (TRUS) biopsy of the prostate was
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performed.
Results
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100 patients with mean age 70 years (range, 53-83) were enrolled in this study and treated with HIFU. Treatment was successfully completed in all men. Baseline characteristics are shown in Table 2. Two patients died during their follow-up interval, neither related to HIFU. One patient died due to respiratory aspiration during elective esophageal surgery, and the other
treatment.
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Primary outcomes
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died during treatment for uncontrolled hypertension 10 months after uncomplicated HIFU
Of the 100 men treated, 78 underwent 12-month biopsy; 63 (81%) had no cancer on
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systematic 12-core prostate biopsy (Table 4). PSA nadir ≤0.5 ng/ml was observed in 70 men within 12 months. 50 men achieved the 1-year combined primary endpoint of PSA nadir and negative biopsy. Of the patients followed after 12 months, mean PSA was 1.1 ng/ml (range, 0.117; N=33) at 2 years and 1.2 ng/ml (range, 0.1-5.0; N=16) at 3 years.
Clinical effects of salvage HIFU
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HRQOL questionnaires (IPSS, IIEF-5) were performed at 6 weeks, 3 months, 6 months, 9 months, and 12 months following HIFU. At 12 months, urinary incontinence was reported as mild in 18 men, moderate in 25 men, and severe in 4 men. 21 patients required pads at 12 months.
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Of the 47 men who reported potency prior to HIFU treatment, 12 (26%) remained potent at 12 months. Figure 1 displays the MRI changes seen in the prostate two weeks after whole-gland
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HIFU treatment.
Adverse Events
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Adverse events (AEs) occurred in 91 men through 12 months: grade 1 in 67, grade 2 in 80, and grade 3 in 20 (CTCAE, v4.03). Urinary retention and urinary tract infection were the most commonly reported AEs after HIFU treatment, with each occurring in 49 patients. Most frequent adverse events are shown in Table 5.
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Treatment-related grade 3 AEs included osteitis pubis in 3 men, gross hematuria requiring intervention in 3 men, and rectal fistulae in 5 men. Osteitis pubis was managed with rest, analgesics, and nonsteroidal anti-inflammatory drugs. Of the patients with rectal fistulae, 2
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men had a class III fistula requiring surgical management and 3 men had resolution with medical intervention only. The rectal fistulae occurred early in the study; at study mid-point, a retraining
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of the operators was performed and only one fistula was observed thereafter. There were two unrelated deaths and no life-threatening AEs or treatment-related deaths.
Discussion
Management of men with localized recurrence of CaP following EBRT is a challenging clinical problem, for which no consensus on appropriate treatment exists (9). In 2008, a review
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of the Cancer of the Prostate Strategic Urological Research Endeavor (CAPSURE) database revealed a biochemical failure rate of 63% in patients treated with EBRT for CaP (10). Moreover, men with recurrent disease had substantial rates of death and bone metastases (10).
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Due to the poor prognosis for patients with biochemical recurrence after EBRT, there remains a need for curative salvage therapy in these patients. Most men with biochemical
recurrence are managed with ADT, which may delay metastatic disease but is not curative(2).
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Alternative treatment options include salvage prostatectomy, brachytherapy, HIFU, and
cryotherapy. However, long-term clinical data regarding cancer control rates and HRQOL
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outcomes remain sparse for these options.
In the present study, whole-gland salvage HIFU appeared to have encouraging short-term cancer control rates with reasonable morbidity. Of the 78 men who underwent prostate biopsy after HIFU, 63 (81%) had no evidence of cancer at 12 months. Further, there were 50 men (50%)
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who achieved the 1-year combined primary endpoint of negative biopsy and PSA nadir ≤0.5. A correlation between pre- and post-treatment Gleason scores was not present. Similarly, Ahmed et al. observed favorable oncologic outcomes with salvage HIFU in
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men with localized recurrence after EBRT (1). In that study, 28 of the 49 men (57%) biopsied had no residual cancer found after HIFU treatment (1), and using the ASTRO-Phoenix criteria to
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define biochemical failure, 77 of the 84 patients (92%) treated had a PSA level consistent with treatment success (1). In another study, Siddiqui et al. found that 22 of the 63 men (35%) biopsied had residual CaP after salvage HIFU (7). We recorded adverse events in 91 men during the 12 months after salvage HIFU
treatment. However, there were no life-threatening adverse events or treatment-related deaths. Rectal fistulas occurred in 5 men following treatment. Of the 5 fistulas recorded, 4 occurred
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early in the study. Only one fistula occurred after a mid-study retraining of the surgeons performing the procedures. During the mid-study retraining, extra treatment time was allocated for each case. During these sessions, the proctoring physician and engineer increased vigilance
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regarding pre-focal zone heating and evidence of rectal wall heating. The importance of stopping treatment when rectal wall heating occurred was re-emphasized and the role of tissue change monitoring was further clarified.
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Rectal fistula rates for alternative salvage treatments such as radical prostatectomy,
cryotherapy, and brachytherapy have been reported as 7%, 11%, and 12%, respectively (11).
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Siddiqui et al. reported 223 complications in 81 men following salvage HIFU (7). In that study, 3 of the 81 men (3.7%) treated developed a rectal fistula (7). Crouzet et al. recently observed 9 rectal fistulas in 418 men treated with salvage HIFU (12). Of the 9 rectal fistulas, only 2 occurred after implementation of specific treatment parameters (12). Thus, this major
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complication appears largely avoidable via meticulous performance of the treatment. Ahmed et al. have raised the possibility of focal HIFU for recurrent CaP (2). All men in the present study received whole-gland HIFU. However, limiting treatment volume to cancer-
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containing foci might result in fewer complications and deserves study. Focal therapy would require specific labeling and tracking of cancer-containing biopsy cores, as reported elsewhere
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(13,14).
The findings of the present study should be interpreted within the scope of some
methodological limitations. First, the trial extended for only 12 months after HIFU treatment; long-term success rates declined in unstructured follow-up beyond that point. Moreover, only 78 men underwent 12-month biopsy. Second, the validity of using PSA nadir ≤0.5 for appropriate treatment response may be questioned given the lack of general consensus on defining treatment
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success in the salvage setting. Third, there were 13 men who did not demonstrate a PSA nadir after treatment despite a negative biopsy at 12 months, suggesting the possibility of micrometastatic disease undetected by prior imaging. Although CT and bone scan were employed to
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screen for metastatic disease, the performance characteristics of these tests is reported to be poor (15). Improvements in current imaging modalities may provide better selection of patients for HIFU treatment.
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Nevertheless, these data demonstrate reasonable safety and efficacy of salvage HIFU for localized, radio-recurrent CaP and add to the growing body of evidence that supports the
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expanded use of this procedure. Further establishment of salvage HIFU as an acceptable treatment alternative will await long-term follow-up regarding oncological effectiveness and quality of life outcomes.
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Conclusion
In a multicenter, prospective trial, whole-gland HIFU proved to be reasonably safe and effective for treatment of radio-recurrent prostate cancer. Rate of complications, which are
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potentially severe, was acceptable, especially considering the advanced, refractory nature of the
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disease and limited treatment options.
Acknowledgements
The trial was sponsored by SonaCare Medical, LLC (Charlotte, North Carolina). The company furnished the data, but the manuscript was published independently by the authors.
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References 1.
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Uchida T, Shoji S, Nakano M, et al. High-intensity focused ultrasound as salvage therapy for patients with recurrent prostate cancer after external beam radiation, brachytherapy or proton therapy. BJU Int. 2011 Feb;107(3):378–82.
Gelet A, Chapelon JY, Poissonnier L, et al. Local recurrence of prostate cancer after
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Agarwal PK, Sadetsky N, Konety BR, et al. Treatment failure after primary and salvage therapy for prostate cancer: likelihood, patterns of care, and outcomes. Cancer. 2008 Jan 15;112(2):307–14. Peters M, Moman MR, van der Poel HG, et al. Patterns of outcome and toxicity after
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Crouzet S, Blana A, Murat FJ, et al. Salvage high-intensity focused ultrasound (HIFU) for
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locally recurrent prostate cancer after failed radiation therapy: Multi-institutional analysis of 418 patients. BJU Int. 2017 Jan 7; 13.
Natarajan S, Marks LS, Margolis DJA, et al. Clinical application of a 3D ultrasoundguided prostate biopsy system. Urol Oncol Semin Orig Investig. 2011 May;29(3):334–42. Sonn GA, Filson CP, Chang E, et al. Initial experience with electronic tracking of specific
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Bjurlin MA, Rosenkrantz AB, Beltran LS, et al. Imaging and evaluation of patients with
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high-risk prostate cancer. Nat Rev Urol. 2015 Oct 20;12(11):617–28.
Legends/Titles for Figures and Tables
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Figure 1. Example of MRI changes following HIFU treatment for radio-recurrent prostate cancer (courtesy of Hashim Ahmed, Imperial College London). Axial T2 – weighted MRI of prostate. (A) Pretreatment MRI shows an irregular hypo-intense lesion
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with invasive margins in the right peripheral zone (white arrows). (B) Two weeks posttreatment MRI reveals hypo-perfusion of the entire prostate gland consistent with
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treatment effect. MRI was not part of the present study.
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Table 1. Clinical sites, investigators, and number of patients enrolled.
Table 2. Baseline characteristics of 100 men treated.
*One patient had a PSA level of 14 which was above the cutoff limit.
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Table 3. Inclusion and exclusion criteria.
Table 4. Gleason score before and after HIFU treatment.
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*Inclusion criteria specified only that study endpoint was a biopsy showing any cancer at least 2 years after EBRT. In some cases (19 before, 2 after) the treating physician’s
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notes were used to confirm the positive biopsy, but the actual pathology report was not available, for various reasons (change of doctors, change of residence, length of time, loss of records, etc).
Table 5. Percent of patients with most common adverse events (N=100).
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Table 1. Clinical sites, investigators, and number of patients enrolled. Site
Location
Investigator
London Health Sciences Center University of California, Los Angeles Walter Reed Army Medical Center Can-Am New York University Fox Chase Cancer Center Metropolitan Urology University of Wisconsin MD Anderson Cancer Center Indiana University Urologic Consultants of Southeastern Pennsylvania Tulane University Specialists in Urology Tower Urology University Hospitals of Cleveland University of Cincinnati
London, ON
Joseph Chin
Los Angeles, CA Bethesda, MD
Leonard Marks Allan Pantuck David Mcleod
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Toronto, ON New York, NY Philadelphia, PA
Jack Barkin William Huang David Chen
10 8 8
Jeffersonville, IN Madison, WI
James Bailen David Jarrard
6 5
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John Ward
5
Indianapolis, IN Bala Cynwyd, PA
Michael Koch Laurence Belkoff
5 4
New Orleans, LA Naples, FL Los Angeles, CA Cleveland, OH
Benjamin Lee Earl Gurevitch Matthew Bui Robert Abouassaly
3 2 2 1
Cincinnati, OH
James Donovan
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Houston, TX
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Number of Patients Enrolled 20
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Table 2. Baseline characteristics of 100 men treated.
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Mean age (range) 70 (53-83) Race (no.) White 76 African-American 16 Hispanic 5 Other 3 Mean PSA (range) 4.9 (0.4-14)* Pre-EBRT Gleason Score (no.) ≤6 29 7 40 ≥8 12 Unknown 19 Pre-HIFU Clinical Stage (no.) T1a 1 T1c 65 T2a 20 T2b 8 T2c 6 *One patient had a PSA level of 14 which was above the cutoff limit.
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Table 3. Inclusion and exclusion criteria. Inclusion criteria:
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Clinical stage ≤ T2c treated with EBRT two or more years prior to HIFU Previous radiation therapy must be to a documented therapeutic dose of 60 to 81Gy Negative bone scan within 6 months Negative CT scan of chest, abdomen, and pelvis within 6 months
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Age between 40 and 85 years
Prostate volume ≤40cc
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>10 core prostate biopsy demonstrating 1 or more positive cores within 6 months
Serum PSA between 0.5ng/ml and 10ng/ml
> 90 days post androgen deprivation therapy
Exclusion criteria:
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Life expectancy > 12 months
Intra-prostatic calcifications >1.0 cm
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Active, uncorrected bleeding disorder
American Society of Anesthesiologists (ASA) criteria of IV or higher
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Use of any 5-alpha-reductase inhibitors within 3 months Prior treatment for prostate cancer, other than EBRT or hormone therapy Inability to visualize the prostatic tissue adequately on transrectal ultrasound imaging Functional bladder problems defined as IPSS > 19 History of inflammatory bowel disease History of any other malignancy treated within the last 5 years History of significant rectal surgery, rectal fistula, rectal fibrosis or rectal stenosis
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Table 4. Gleason score before and after HIFU treatment.
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Pre-HIFU Gleason Score N 6 11 7 39 ≥8 31 Not specified* 19 Post-HIFU Gleason Score 6 7 7 3 ≥8 3 Not specified* 2 *Inclusion criteria specified only that study endpoint was a biopsy showing any cancer at least 2
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years after EBRT. In some cases (19 before, 2 after) the treating physician’s notes were used to confirm the positive biopsy, but the actual pathology report was not available, for various
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reasons (change of doctors, change of residence, length of time, loss of records, etc).
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Table 5. Percent of patients with most common adverse events (N=100). Grade 2
Grade 3
Total
18 0
25 11
4 2
47 13
3
42
4
6
8
3
12
26
0
33 7
6 19
3 0
9 2
11 13
0 0
0
16
1
44
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Grade 1
49
17
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38
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Adverse Event Incontinence Urethral stricture Urinary retention Urinary tract obstruction Urinary Frequency Hematuria Urinary urgency Dysuria Bladder spasms Erectile dysfunction Urinary tract infection
42 26 20 15
0
16
4
49
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Androgen deprivation therapy Adverse event Prostate cancer Common Terminology Criteria for Adverse Events External Beam Radiation Therapy High-Intensity Focused Ultrasound Health-related quality of life International Index of Erectile Function International Prostate Symptom Score Prostate-specific antigen Trans-rectal ultrasound
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ADT: AE: CaP: CTCAE: EBRT: HIFU: HRQOL: IIEF: IPSS: PSA: TRUS:
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Abbreviations
PII: DOI: Reference:
S0022-5347(17)76734-1 10.1016/j.juro.2017.06.078 JURO 14826
To appear in: The Journal of Urology Accepted Date: 17 June 2017 Please cite this article as: Jones TA, Chin J, Mcleod D, Barkin J, Pantuck A, Marks LS, High-Intensity Focused Ultrasound for Radio-recurrent Prostate Cancer: A North American Clinical Trial, The Journal of Urology® (2017), doi: 10.1016/j.juro.2017.06.078. DISCLAIMER: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our subscribers we are providing this early version of the article. The paper will be copy edited and typeset, and proof will be reviewed before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to The Journal pertain.
Embargo Policy All article content is under embargo until uncorrected proof of the article becomes available online. We will provide journalists and editors with full-text copies of the articles in question prior to the embargo date so that stories can be adequately researched and written. The standard embargo time is 12:01 AM ET on that date. Questions regarding embargo should be directed to [email protected].
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High-Intensity Focused Ultrasound for Radio-recurrent Prostate Cancer: A North American Clinical Trial Runninghead: Salvage HIFU for Radio-recurrent Prostate Cancer
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Authors: Tonye A. Jonesa, Joseph Chinb, David Mcleodc, Jack Barkind, Allan Pantucka, Leonard S. Marksa a
Department of Urology, David Geffen School of Medicine, Los Angeles, CA, 90095, USA Division of Urology, London Health Sciences Center, London, ON, Canada c Center for Prostate Cancer Disease Research: Department of Surgery, Uniformed Services University of the Health Sciences and Walter Reed National Medical Military Center, Bethesda, MD 20814 d Can-Am HIFU, Toronto, ON, Canada
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b
Keywords: focal therapy, prostate, cancer, high-intensity focused ultrasound
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Corresponding Author: Leonard S. Marks, M.D. Department of Urology David Geffen School of Medicine at UCLA 300 Stein Plaza, 3rd Floor Los Angeles, California 90095 Ph: 310-794-3070 Fax: 310-794-0987 Email: [email protected]
Word count: 2,017
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Abstract Purpose: To determine the safety and efficacy of whole-gland HIFU in men with radio-recurrent prostate
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cancer (CaP).
Materials and Methods:
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100 men with clinically localized recurrence of CaP at least 2 years after EBRT received wholegland HIFU in an open-label trial (2009 to 2012). Treatments were performed at 16 sites in the
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U.S. (14) and Canada (2). Primary endpoint was a combination of both PSA nadir ≤0.5 ng/ml and negative biopsy at 12 months. Validated questionnaires were used to monitor changes in urinary and sexual function.
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Results:
Of the 100 men treated (mean age 70, range, 53-83 years), 78 completed 12-month biopsy, of which 63 (81%) were negative. Mean PSA was 4.9ng/ml (range, 0.4-14) and median Gleason
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score was 7. 50 men achieved 1-year endpoint of both PSA nadir ≤0.5ng/ml and negative biopsy. In post-trial follow-up, mean PSA at 2 years was 1.1 ng/ml, range 0.1-17 (N=33). Adverse events
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(AEs) occurred in 91 men through 12 months: grade 1 in 67, grade 2 in 80, and grade 3 in 20 (CTCAE). Treatment-related grade 3 AEs included rectal fistulae in 5 (3 required surgery), osteitis pubis in 3, and hematuria requiring intervention in 3. Treatment-related Grade 3 AEs occurred early in the trial and appeared related to operator experience. There were no lifethreatening AEs or treatment-related deaths.
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Conclusions: Whole-gland HIFU appears reasonably safe and effective for treatment of radio-recurrent prostate cancer. Rate of complications, which are potentially severe, was acceptable, especially
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considering the advanced, refractory nature of the disease and limited treatment options.
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Introduction Biochemical recurrence after external beam radiation therapy (EBRT) for clinically localized prostate cancer (CaP) occurs in up to 60% of men (1). The majority of these men
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receive androgen-deprivation therapy (ADT) alone, which is not curative and entails adverse effects on cardiovascular health, metabolic function, and bone strength (2). A fraction of men with biochemical recurrence after EBRT have localized disease that may be amenable to curative
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salvage therapy. In such cases, treatment options include prostatectomy, cryotherapy,
and bowel complications (1).
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brachytherapy, and high-intensity focused ultrasound (HIFU); all involve risk of urinary, sexual,
Koch and associates from Indiana University reported the use of HIFU for CaP in 2007, showing in previously untreated men that the procedure could be safe and effective (3). The goal of HIFU is to induce coagulative necrosis and cavitation of cancerous prostate tissue by use of
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ultrasonic waves (4). In a study evaluating salvage HIFU treatment for 22 men with radiorecurrent CaP, Uchida et al. reported biochemical disease-free survival rates of 100% and 86% at 5 years in men with low and intermediate risk CaP, respectively (5).
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Several studies have since evaluated the safety and oncological effectiveness of HIFU as a salvage therapy for men with localized cancer recurrence after EBRT (1,2,6,7). These studies
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were performed in European and British centers, where regulatory approval has been in place for many years. The present ‘registration’ study was conducted at centers primarily in the U.S. The goal of this prospective, open-label study was to determine the safety, feasibility, and early cancer control rates of whole-gland prostate ablation using HIFU following failed radiation therapy.
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Materials and Methods This federally registered study (NCT00772317) was a non-randomized, prospective, open-label trial performed at 16 trial sites in the U.S. (14) and Canada (2) *. Investigative sites
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are shown in Table 1. 100 men with biopsy-proven (12-core), localized recurrence of CaP at least 2 years after EBRT were subjects. Average number of biopsy cores positive was 4 per patient and median Gleason score was 7. All men who received ADT within 3 months of
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treatment were excluded. Entry criteria included a PSA level between 0.5 ng/mL and 10 ng/mL, clinical stage T1c-T2 prior to EBRT, and bone scan and CT (chest, abdomen, pelvis) negative for
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metastatic disease upon enrollment. Patient characteristics are shown in Table 2. The study treatments were performed between February 2009 and July 2012. All patients provided written informed consent and were placed in a prospectively maintained HIFU registry, following issuance of an Investigational Device Exemption from the U.S. Food and Drug
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Administration (FDA) (G080057) in 2008. At each participating institution, participants signed a consent form approved by the institutional review board. Complete inclusion and exclusion criteria are shown in Table 3. The primary endpoint was a combination of PSA nadir ≤0.5 ng/mL
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within 12 months of treatment and a negative prostate biopsy at 1 year. Secondary endpoints were changes in urinary and sexual function compared to baseline.
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* The trial reported here was the basis of a 510k application by SonaCare Medical, LLC to the U.S. FDA. An FDA panel hearing was held October 1, 2014, and the Sonablate-450 device was approved “for ablation of prostatic tissue” via the de novo route on October 9, 2015.
Treatment protocol
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All men underwent HIFU using the Sonablate 450 device (Sonacare, Charlotte, NC, USA) under general anesthesia. A HIFU-experienced physician and engineer proctored each treatment. Following placement of a suprapubic and urethral catheter, patients were placed in the lithotomy
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position for rectal insertion of the treatment probe. Real-time ultrasound images of the prostate in sagittal and transverse planes were obtained to ensure treatment would be technically feasible (e.g., anterior gland is accessible, absence of acoustic shadowing).
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Treatment planning was performed using custom software, which allowed the prostate to be divided into three zones: anterior, middle, and posterior (8). The software moved the
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transducer automatically to allow treatment of the entire prostate. Just prior to each treatment, the urethral catheter, which is used to identify anatomical landmarks (e.g., bladder neck, apex), was removed.
During treatment, real-time ultrasound of the apex of the prostate allowed identification
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and avoidance of the external urinary sphincter. HIFU energy was applied for 3 second intervals followed by a 6 second pause to avoid overheating of prostate tissue outside the targeted zone. Power settings were determined using rectal wall distance and adjustments were made if
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unfavorable tissue changes were observed.
After a two-hour observation period, patients were discharged home with an antibiotic
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and oral analgesics. Each patient had a suprapubic catheter in place for 2-4 weeks, with planned removal dependent on voiding function following treatment.
Follow-up
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Follow-up clinic visits were conducted at 6 weeks, 3 months, 6 months, 9 months, and 12 months. A subset of men underwent PSA testing at 24 and 36 months. Each visit included a detailed history and physical examination, screening for adverse events (CTCAE, v4.03), medication
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reconciliation, PSA, and health-related quality of life (HRQOL) questionnaires (e.g., IPSS, IIEF). At 12 months, a systematic transrectal ultrasound-guided (TRUS) biopsy of the prostate was
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performed.
Results
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100 patients with mean age 70 years (range, 53-83) were enrolled in this study and treated with HIFU. Treatment was successfully completed in all men. Baseline characteristics are shown in Table 2. Two patients died during their follow-up interval, neither related to HIFU. One patient died due to respiratory aspiration during elective esophageal surgery, and the other
treatment.
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Primary outcomes
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died during treatment for uncontrolled hypertension 10 months after uncomplicated HIFU
Of the 100 men treated, 78 underwent 12-month biopsy; 63 (81%) had no cancer on
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systematic 12-core prostate biopsy (Table 4). PSA nadir ≤0.5 ng/ml was observed in 70 men within 12 months. 50 men achieved the 1-year combined primary endpoint of PSA nadir and negative biopsy. Of the patients followed after 12 months, mean PSA was 1.1 ng/ml (range, 0.117; N=33) at 2 years and 1.2 ng/ml (range, 0.1-5.0; N=16) at 3 years.
Clinical effects of salvage HIFU
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HRQOL questionnaires (IPSS, IIEF-5) were performed at 6 weeks, 3 months, 6 months, 9 months, and 12 months following HIFU. At 12 months, urinary incontinence was reported as mild in 18 men, moderate in 25 men, and severe in 4 men. 21 patients required pads at 12 months.
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Of the 47 men who reported potency prior to HIFU treatment, 12 (26%) remained potent at 12 months. Figure 1 displays the MRI changes seen in the prostate two weeks after whole-gland
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HIFU treatment.
Adverse Events
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Adverse events (AEs) occurred in 91 men through 12 months: grade 1 in 67, grade 2 in 80, and grade 3 in 20 (CTCAE, v4.03). Urinary retention and urinary tract infection were the most commonly reported AEs after HIFU treatment, with each occurring in 49 patients. Most frequent adverse events are shown in Table 5.
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Treatment-related grade 3 AEs included osteitis pubis in 3 men, gross hematuria requiring intervention in 3 men, and rectal fistulae in 5 men. Osteitis pubis was managed with rest, analgesics, and nonsteroidal anti-inflammatory drugs. Of the patients with rectal fistulae, 2
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men had a class III fistula requiring surgical management and 3 men had resolution with medical intervention only. The rectal fistulae occurred early in the study; at study mid-point, a retraining
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of the operators was performed and only one fistula was observed thereafter. There were two unrelated deaths and no life-threatening AEs or treatment-related deaths.
Discussion
Management of men with localized recurrence of CaP following EBRT is a challenging clinical problem, for which no consensus on appropriate treatment exists (9). In 2008, a review
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of the Cancer of the Prostate Strategic Urological Research Endeavor (CAPSURE) database revealed a biochemical failure rate of 63% in patients treated with EBRT for CaP (10). Moreover, men with recurrent disease had substantial rates of death and bone metastases (10).
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Due to the poor prognosis for patients with biochemical recurrence after EBRT, there remains a need for curative salvage therapy in these patients. Most men with biochemical
recurrence are managed with ADT, which may delay metastatic disease but is not curative(2).
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Alternative treatment options include salvage prostatectomy, brachytherapy, HIFU, and
cryotherapy. However, long-term clinical data regarding cancer control rates and HRQOL
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outcomes remain sparse for these options.
In the present study, whole-gland salvage HIFU appeared to have encouraging short-term cancer control rates with reasonable morbidity. Of the 78 men who underwent prostate biopsy after HIFU, 63 (81%) had no evidence of cancer at 12 months. Further, there were 50 men (50%)
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who achieved the 1-year combined primary endpoint of negative biopsy and PSA nadir ≤0.5. A correlation between pre- and post-treatment Gleason scores was not present. Similarly, Ahmed et al. observed favorable oncologic outcomes with salvage HIFU in
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men with localized recurrence after EBRT (1). In that study, 28 of the 49 men (57%) biopsied had no residual cancer found after HIFU treatment (1), and using the ASTRO-Phoenix criteria to
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define biochemical failure, 77 of the 84 patients (92%) treated had a PSA level consistent with treatment success (1). In another study, Siddiqui et al. found that 22 of the 63 men (35%) biopsied had residual CaP after salvage HIFU (7). We recorded adverse events in 91 men during the 12 months after salvage HIFU
treatment. However, there were no life-threatening adverse events or treatment-related deaths. Rectal fistulas occurred in 5 men following treatment. Of the 5 fistulas recorded, 4 occurred
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early in the study. Only one fistula occurred after a mid-study retraining of the surgeons performing the procedures. During the mid-study retraining, extra treatment time was allocated for each case. During these sessions, the proctoring physician and engineer increased vigilance
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regarding pre-focal zone heating and evidence of rectal wall heating. The importance of stopping treatment when rectal wall heating occurred was re-emphasized and the role of tissue change monitoring was further clarified.
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Rectal fistula rates for alternative salvage treatments such as radical prostatectomy,
cryotherapy, and brachytherapy have been reported as 7%, 11%, and 12%, respectively (11).
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Siddiqui et al. reported 223 complications in 81 men following salvage HIFU (7). In that study, 3 of the 81 men (3.7%) treated developed a rectal fistula (7). Crouzet et al. recently observed 9 rectal fistulas in 418 men treated with salvage HIFU (12). Of the 9 rectal fistulas, only 2 occurred after implementation of specific treatment parameters (12). Thus, this major
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complication appears largely avoidable via meticulous performance of the treatment. Ahmed et al. have raised the possibility of focal HIFU for recurrent CaP (2). All men in the present study received whole-gland HIFU. However, limiting treatment volume to cancer-
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containing foci might result in fewer complications and deserves study. Focal therapy would require specific labeling and tracking of cancer-containing biopsy cores, as reported elsewhere
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(13,14).
The findings of the present study should be interpreted within the scope of some
methodological limitations. First, the trial extended for only 12 months after HIFU treatment; long-term success rates declined in unstructured follow-up beyond that point. Moreover, only 78 men underwent 12-month biopsy. Second, the validity of using PSA nadir ≤0.5 for appropriate treatment response may be questioned given the lack of general consensus on defining treatment
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success in the salvage setting. Third, there were 13 men who did not demonstrate a PSA nadir after treatment despite a negative biopsy at 12 months, suggesting the possibility of micrometastatic disease undetected by prior imaging. Although CT and bone scan were employed to
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screen for metastatic disease, the performance characteristics of these tests is reported to be poor (15). Improvements in current imaging modalities may provide better selection of patients for HIFU treatment.
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Nevertheless, these data demonstrate reasonable safety and efficacy of salvage HIFU for localized, radio-recurrent CaP and add to the growing body of evidence that supports the
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expanded use of this procedure. Further establishment of salvage HIFU as an acceptable treatment alternative will await long-term follow-up regarding oncological effectiveness and quality of life outcomes.
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Conclusion
In a multicenter, prospective trial, whole-gland HIFU proved to be reasonably safe and effective for treatment of radio-recurrent prostate cancer. Rate of complications, which are
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potentially severe, was acceptable, especially considering the advanced, refractory nature of the
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disease and limited treatment options.
Acknowledgements
The trial was sponsored by SonaCare Medical, LLC (Charlotte, North Carolina). The company furnished the data, but the manuscript was published independently by the authors.
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References 1.
Uddin Ahmed H, Cathcart P, Chalasani V, et al. Whole-gland salvage high-intensity focused ultrasound therapy for localized prostate cancer recurrence after external beam
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radiation therapy. Cancer. 2012 Jun 15;118(12):3071–8. 2.
Ahmed HU, Cathcart P, McCartan N, et al. Focal salvage therapy for localized prostate
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cancer recurrence after external beam radiotherapy. Cancer. Wiley Subscription Services,
Koch MO, Gardner T, Cheng L, et al. Phase I/II trial of high intensity focused ultrasound for the treatment of previously untreated localized prostate cancer. J Urol. 2007
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Perera M, Krishnananthan N, Lindner U, Lawrentschuk N. An update on focal therapy for
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prostate cancer. Nat Rev Urol. 2016 Nov 27;13(11):641–53.
Uchida T, Shoji S, Nakano M, et al. High-intensity focused ultrasound as salvage therapy for patients with recurrent prostate cancer after external beam radiation, brachytherapy or proton therapy. BJU Int. 2011 Feb;107(3):378–82.
Gelet A, Chapelon JY, Poissonnier L, et al. Local recurrence of prostate cancer after
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external beam radiotherapy: early experience of salvage therapy using high-intensity focused ultrasonography. Urology. 2004 Apr;63(4):625–9. Siddiqui KM, Billia M, Arifin A, et al. Pathological, Oncologic and Functional Outcomes
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of a Prospective Registry of Salvage High Intensity Focused Ultrasound Ablation for
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Radiorecurrent Prostate Cancer. J Urol. 2017 Jan;197(1):97–102.
Illing RO, Leslie TA, Kennedy JE, et al. Visually directed high-intensity focused ultrasound for organ-confined prostate cancer: a proposed standard for the conduct of therapy. BJU Int. 2006 Dec;98(6):1187–92.
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Chalasani V, Martinez CH, Lim D, Chin J. Salvage HIFU for recurrent prostate cancer after radiotherapy. Prostate Cancer Prostatic Dis. 2009 Jun 14;12(2):124–9.
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Agarwal PK, Sadetsky N, Konety BR, et al. Treatment failure after primary and salvage therapy for prostate cancer: likelihood, patterns of care, and outcomes. Cancer. 2008 Jan 15;112(2):307–14. Peters M, Moman MR, van der Poel HG, et al. Patterns of outcome and toxicity after
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salvage prostatectomy, salvage cryosurgery and salvage brachytherapy for prostate cancer recurrences after radiation therapy: a multi-center experience and literature review. World
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Crouzet S, Blana A, Murat FJ, et al. Salvage high-intensity focused ultrasound (HIFU) for
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locally recurrent prostate cancer after failed radiation therapy: Multi-institutional analysis of 418 patients. BJU Int. 2017 Jan 7; 13.
Natarajan S, Marks LS, Margolis DJA, et al. Clinical application of a 3D ultrasoundguided prostate biopsy system. Urol Oncol Semin Orig Investig. 2011 May;29(3):334–42. Sonn GA, Filson CP, Chang E, et al. Initial experience with electronic tracking of specific
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tumor sites in men undergoing active surveillance of prostate cancer. Urol Oncol Semin Orig Investig. 2014;32(7):952–7.
Bjurlin MA, Rosenkrantz AB, Beltran LS, et al. Imaging and evaluation of patients with
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high-risk prostate cancer. Nat Rev Urol. 2015 Oct 20;12(11):617–28.
Legends/Titles for Figures and Tables
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Figure 1. Example of MRI changes following HIFU treatment for radio-recurrent prostate cancer (courtesy of Hashim Ahmed, Imperial College London). Axial T2 – weighted MRI of prostate. (A) Pretreatment MRI shows an irregular hypo-intense lesion
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with invasive margins in the right peripheral zone (white arrows). (B) Two weeks posttreatment MRI reveals hypo-perfusion of the entire prostate gland consistent with
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treatment effect. MRI was not part of the present study.
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Table 1. Clinical sites, investigators, and number of patients enrolled.
Table 2. Baseline characteristics of 100 men treated.
*One patient had a PSA level of 14 which was above the cutoff limit.
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Table 3. Inclusion and exclusion criteria.
Table 4. Gleason score before and after HIFU treatment.
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*Inclusion criteria specified only that study endpoint was a biopsy showing any cancer at least 2 years after EBRT. In some cases (19 before, 2 after) the treating physician’s
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notes were used to confirm the positive biopsy, but the actual pathology report was not available, for various reasons (change of doctors, change of residence, length of time, loss of records, etc).
Table 5. Percent of patients with most common adverse events (N=100).
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Table 1. Clinical sites, investigators, and number of patients enrolled. Site
Location
Investigator
London Health Sciences Center University of California, Los Angeles Walter Reed Army Medical Center Can-Am New York University Fox Chase Cancer Center Metropolitan Urology University of Wisconsin MD Anderson Cancer Center Indiana University Urologic Consultants of Southeastern Pennsylvania Tulane University Specialists in Urology Tower Urology University Hospitals of Cleveland University of Cincinnati
London, ON
Joseph Chin
Los Angeles, CA Bethesda, MD
Leonard Marks Allan Pantuck David Mcleod
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Toronto, ON New York, NY Philadelphia, PA
Jack Barkin William Huang David Chen
10 8 8
Jeffersonville, IN Madison, WI
James Bailen David Jarrard
6 5
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10
John Ward
5
Indianapolis, IN Bala Cynwyd, PA
Michael Koch Laurence Belkoff
5 4
New Orleans, LA Naples, FL Los Angeles, CA Cleveland, OH
Benjamin Lee Earl Gurevitch Matthew Bui Robert Abouassaly
3 2 2 1
Cincinnati, OH
James Donovan
1
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Houston, TX
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Number of Patients Enrolled 20
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Table 2. Baseline characteristics of 100 men treated.
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Mean age (range) 70 (53-83) Race (no.) White 76 African-American 16 Hispanic 5 Other 3 Mean PSA (range) 4.9 (0.4-14)* Pre-EBRT Gleason Score (no.) ≤6 29 7 40 ≥8 12 Unknown 19 Pre-HIFU Clinical Stage (no.) T1a 1 T1c 65 T2a 20 T2b 8 T2c 6 *One patient had a PSA level of 14 which was above the cutoff limit.
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Table 3. Inclusion and exclusion criteria. Inclusion criteria:
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Clinical stage ≤ T2c treated with EBRT two or more years prior to HIFU Previous radiation therapy must be to a documented therapeutic dose of 60 to 81Gy Negative bone scan within 6 months Negative CT scan of chest, abdomen, and pelvis within 6 months
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Age between 40 and 85 years
Prostate volume ≤40cc
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>10 core prostate biopsy demonstrating 1 or more positive cores within 6 months
Serum PSA between 0.5ng/ml and 10ng/ml
> 90 days post androgen deprivation therapy
Exclusion criteria:
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Life expectancy > 12 months
Intra-prostatic calcifications >1.0 cm
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Active, uncorrected bleeding disorder
American Society of Anesthesiologists (ASA) criteria of IV or higher
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Use of any 5-alpha-reductase inhibitors within 3 months Prior treatment for prostate cancer, other than EBRT or hormone therapy Inability to visualize the prostatic tissue adequately on transrectal ultrasound imaging Functional bladder problems defined as IPSS > 19 History of inflammatory bowel disease History of any other malignancy treated within the last 5 years History of significant rectal surgery, rectal fistula, rectal fibrosis or rectal stenosis
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Table 4. Gleason score before and after HIFU treatment.
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Pre-HIFU Gleason Score N 6 11 7 39 ≥8 31 Not specified* 19 Post-HIFU Gleason Score 6 7 7 3 ≥8 3 Not specified* 2 *Inclusion criteria specified only that study endpoint was a biopsy showing any cancer at least 2
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years after EBRT. In some cases (19 before, 2 after) the treating physician’s notes were used to confirm the positive biopsy, but the actual pathology report was not available, for various
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reasons (change of doctors, change of residence, length of time, loss of records, etc).
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Table 5. Percent of patients with most common adverse events (N=100). Grade 2
Grade 3
Total
18 0
25 11
4 2
47 13
3
42
4
6
8
3
12
26
0
33 7
6 19
3 0
9 2
11 13
0 0
0
16
1
44
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Grade 1
49
17
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Adverse Event Incontinence Urethral stricture Urinary retention Urinary tract obstruction Urinary Frequency Hematuria Urinary urgency Dysuria Bladder spasms Erectile dysfunction Urinary tract infection
42 26 20 15
0
16
4
49
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Androgen deprivation therapy Adverse event Prostate cancer Common Terminology Criteria for Adverse Events External Beam Radiation Therapy High-Intensity Focused Ultrasound Health-related quality of life International Index of Erectile Function International Prostate Symptom Score Prostate-specific antigen Trans-rectal ultrasound
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ADT: AE: CaP: CTCAE: EBRT: HIFU: HRQOL: IIEF: IPSS: PSA: TRUS:
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Abbreviations