Prostate Cancer in the Era of Focal Therapy: Is Image Guided Therapy

Effective?

Cary N Robertson MD FACS Associate Professor Division of Urology

Department of Surgery Duke Cancer Institute

Duke University Medical Center Durham, North Carolina

Disclosures

EDAP TMS, Inc.

Principal Investigator and Consultant

High Intensity Focused Ultrasound

• Heat effects on tissue known throughout history

• Coagulation effects begin with temperature of 60 C

• Focused ultrasound waves may raise core tissue temperature to 85 C at focal point

• Gradient of temperature protects adjacent tissues and organs

HIFU

Advantages of HIFU: Non-invasive surgery Repeated treatment Palliative therapy

ISPTA > 1,000 W/cm2

HIFU • Indications for use in GU cancers:

• Kidney cancer:

– Small renal masses

• Prostate cancer:

– Radiation failure salvage therapy

– Primary cancer treatment

The Common Foundation of All HIFU Devices

Focusing a beam of high intensity ultrasound waves can result in the ablation of a discrete volume of tissue

The desired effect: Heating Lipid membranes melt

Proteins denature

Persona non grata: Cavitation Air bubbles cause reflection of the US beam

Cavitation the consistency of ablation volume

Prostate Transrectal HIFU: Basic Engineering Goal

• Create a device that :

– Fits into the rectum

– Renders a high quality image for planning

– Creates high quality and reproducible ablation volumes

– Avoids cavitation

Safety features EDAP TMS

Ablatherm Rectal wall cooling Rectal wall temperature monitoring Rectal wall distance measurement Infrared movement detection

Sonablate Rectal wall cooling

Rectal wall temperature monitoring

Rectal wall distance measurement

Visual Movement detection

Reflectivity measurement

Lesion Size EDAP TMS

Ablatherm

19-24 mm focal length

Allows for treatment with one pass

Larger prostates can be downsized with hormones or per op TURP

Sonablate

10 mm focal length

Multiple passes needed for treatment

Allows for enhanced conformity

History of HIFU development

Therapeutic Ultrasound Research Laboratory,Universite´ de Lyon,INSERM,U556,Lyon,France

Department of Urology, Edouard Herriot Hospital,Lyon,France

Kilinikum Harlaching, Munich, Germany

EDAP TMS Inc., Lyon, France

•1989: Start of technical development and animal experiments

•1990: Dunning tumor studies

•1991: Endorectal applicator test in rabbit prostates

•1992: BPH treatment as first human HIFU treatment

•1993: PCa treatment with adapted treatment parameters

•1995: from prototype to serial device

•1995: European PCa Multicenter study

•2000: CE labeling of Ablatherm® with TUR before HIFU-

•2003: 26 hospitals > 4.000 treatments

•2013: > 250 hospitals, > 30.000 treatments world wide

HIFU and Prostate Cancer European Multicenter Study

risk groups negative biopsies

low risk (31,2 %) T1 - T2a and PSA 10 ng/ml and Gleason 6

middle risk (48,2 %) T2b or PSA 10.1-20 ng/ml or Gleason = 7

high risk (20,6 %) T2c or PSA > 20 ng/ml or Gleason 8

72,1 % Nadir PSA 0,27 ng/ml

81,8 %

Nadir PSA 0,26 ng/ml

86,2 % Nadir PSA 0,40 ng/ml

Thueroff, S., Chaussy, C., Vallancien,G. et al. , J Endourol. 2003; 17:673-677

Patients at risk:

152 140 101 70 37 14 Low

270 240 174 121 65 33 Intermed.

282 244 167 109 53 26 High

Munich data update

maximum 14 years follow up (n = 702)

Thüroff S, Chaussy C: J Urol. 2013 Aug;190(2):702-10.

High Risk Prostate Cancer

• Adjuvant radiation therapy in high risk prostate cancer may be beneficial..yet..

• Focally positive margin patients exhibited similar failure patterns as negative margin patients in the control group of the EORTC randomized trial of adjuvant radiation therapy

Bolla M, van Poppel H, Collette L, et al.: Postoperative radiotherapy after radical prostatectomy: a randomised controlled trial (EORTC trial 22911). Lancet 366 (9485): 572-8, 2005 Aug 13-19.

(years)

0 2 4 6 8 10

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk :

Extracapsular extension

40 124 101 62 31 9

14 36 30 16 6 2

64 118 79 36 16 8

No

Focal

Extensive

Clinical or biological PFS

p=0.0006

Focal

Extensive

Negative

ENLIGHT Clinical Trial in Low Risk, Low Stage Prostate Cancer 2006 - 2014

USA FDA IDE: G050103

135 HIFU subjects enrolled at 13 sites in the USA and 1 in Canada

D’Amico Low risk patients only

No previous PCa treatment

HIFU Performed without TURP

EFFICACY OF HIGH INTENSITY FOCUSED ULTRASOUND (HIFU) AS A PRIMARY MONOTHERAPY FOR LOW RISK LOCALIZED PROSTATE CANCER: OUTCOMES FROM THE ENLIGHT TRIAL

Cary Robertson*, Durham, NC, Anthony Sliwinski, Richmond, VA, Eric Wallen, Chapel Hill, NC, John Ward, Houston, TX, William Orovan, Hamilton, Canada, Donald Locke, Ocala, FL, E David Crawford, Paul Maroni, Aurora, CO, Robert Donnell, Milwaukee, WI, Ivan Grunberger, Ivan Colon, Brooklyn, NY, Richard Bevan-Thomas, Arlington, TX, Ravi Munver, Ihor Sawczuk, Hackensack, NJ, Sam Chang, Nashville, TN, Inderbir Gill, Los Angeles, CA

Source of Funding: EDAP TMS, Inc.

ABSTRACT 16-1890

High-intensity focused ultrasound utilized Ablatherm® Integrated Imaging (EDAP Technomed, Lyon, France). Subjects were administered either spinal or general anesthesia. The subject was positioned on the treatment module (table) in a right decubitus manner. A single endorectal probe capable of both ultrasonography and treatment HIFU was carefully inserted into the rectal cavity after manual dilation of the rectal sphincter to accept three fingers. Ultrasound imaging was used to detect the contour of the prostate and the target treatment volume was defined on the computer screen. Treatment volume encompassed greater than 100% of the prostate volume. Under robotic control, the treatment delivery head was systematically moved within the endorectal probe to deliver HIFU energy in consecutive blocks defined by the operating surgeon using computer planning software. A 4mm margin of safety at the prostatic apex remained untreated. After the prescribed treatment volume was completed, bladder drainage was provide through (in-dwelling urethral Foley catheter or suprapubic tube). All patients subjects were prescribed a course of prophylactic antibiotics. Patients were either discharged the same day or remained overnight.

Mean prostate volume post-HIFU was 9.0 ± 6.3 cc. 84.4% (118/135) of subjects underwent biopsy for a total of 1127 post HIFU biopsy cores and 87 (7.7%) were positive. A per core negative biopsy rate was calculated as Per Core Negative Biopsy Rate (PCNBR) = 100 - % Positive Cores and a Biopsy Survival Rate (BSR) calculated as BSR = 100 - % Subjects with positive biopsy. Of the 1251 baseline pre-HIFU biopsy cores taken, 365 (29.2%) were positive for prostate cancer. Per core negative biopsy rate (PCNBR) was 70.8%. Post-HIFU Per Core Negative Biopsy Rate (PCNBR) was 92.3%. The increase of the per core negative biopsy rate (PCNBR) from 70.8% to 92.3% was statistically significant (p<0.0001). Post-HIFU, 38 (28%) subjects had at least one positive biopsy yielding a 72% Biopsy Survival Rate (BSR). The mean time to positive biopsy for all subjects was 21.0 ± 5.5 months(range: 9.4 - 32.6). Pre-HIFU mean PSA was 4.60 ng/ml; 6 month post-HIFU mean PSA nadir was 0.53 ng/ml. In 116 evaluable subjects, PSA obtained between 6 and 24 months post-HIFU ablation demonstrated that 90.5% of subjects met the definition of the Phoenix Biochemical Survival (less than PSA nadir + 2 ng/ml).

SUBJECTS Inclusion criteria were age ≥ 50 years; low-risk, localized PCA (stage T1-T2a, PSA <10 ng/mL and Gleason score <6); prostate volume <40 cc; normal rectal anatomy and mucosa; rectal wall thickness ≤6 mm; and prostate AP diameter <25 mm. Pre HIFU transurethral resection of the prostate gland (TURP) was not performed. Exclusion criteria included previous treatment for PCA (including both hormone therapy and radiation therapy), current or recent anatomical, functional or malignant anomalies of the rectum or urinary tract; prostatic seroma, abscess, large median lobe, or prostatic calcifications with posterior shadowing; previous PCA treatment; bleeding disorders; and use of finasteride within 6 months.

METHODS A 24-month, prospective, non-randomized, multi-center study was conducted. Inclusion criteria: age 50 years or greater; low-risk, localized PCA (stage T1-T2a, PSA < 10 ng/ml, Gleason score < 6); prostate AP diameter < 25 mm. Prostates were treated with transrectal HIFU (Ablatherm, EDAP TMS, Inc. Lyon, France). Prostate biopsy for cause and 24-month post-HIFU biopsy results as well as serum prostate specific antigen (PSA) values were analyzed. Assignment to study groups was in a 1:1 ratio. Subject accrual spanned the time period 2007 to 2010. This report is limited to subjects treated with HIFU . All subjects provided written informed consent before participating.

Between 2007 and 2010 transrectal ultrasound guided high intensity focused ultrasound (HIFU) was employed in a FDA approved IDE registration clinical trial (ENLIGHT Trial) in men with low grade, low risk prostate cancer. Efficacy outcomes are reported.

INTRODUCTION

RESULTS

For cause biopsy was performed in the event of three consecutive rises in PSA regardless of magnitude. An end of study biopsy, regardless of PSA was included in the 24-month visit. During each prostate biopsy session, multiple, systematic random cores were obtained using standard transrectal ultrasound guided technique. Two biopsy rates were calculated: the per core negative biopsy rate and the biopsy survival rate. The per core negative biopsy rate reports the number of positive cores by discrete location and thus is a more sensitive indicator of effective tissue ablation than the biopsy survival rate, which reports a subject as a failure if only 1 core is positive and the rest (typically 7-9) are negative. The per core negative biopsy rate is calculated by subtracting the percentage of biopsy cores which are positive from 100:

Per Core Negative Biopsy Rate = 100 - %Positive Cores

The Biopsy Survival rate is calculated by subtracting the percentage of subjects with positive biopsy findings from 100:

Biopsy Survival Rate = 100 - %Subjects with Positive Biopsy

Biochemical failure was defined according to the Phoenix definition of biochemical failure (PSA nadir + 2 ng/ml )

MATERIALS AND METHODS

PROCEDURE

Adverse events were obtained from signs and symptoms detected during each examination, observed by the study personnel, or spontaneous reports from the study patients. Adverse event reporting on each patient started from the screening visit and continued with each study contact. Severity of adverse events were categorized by the investigators at each site as mild, moderate or severe. If, subsequent to the reporting of an adverse event, a status of ‘resolved’ in the CRFs was recorded the adverse event was considered resolved. The rates of unresolved adverse events were analyzed.

Post-HIFU follow-ups were conducted at 5 days (phone interview), 1, 3, 6, 9, 12 15, 18, 21 and 24 months. All adverse events were collected during the IDE study regardless of their perceived relationship to the HIFU procedure. During each telephone call and office visit, patients were questioned about any health problems they may have had since their last visit.

STATISTICAL ANALYSIS Subject demographics, procedure parameters and study outcomes were summarized using summary statistics including the mean, standard deviation, median and range for continuous parameters and the frequency and percent for categorical outcomes. No formal statistical hypothesis tests were defined for this single arm report.

CONCLUSIONS Cancerous tissue ablation efficacy of transrectal HIFU was demonstrated in this clinical trial and compares favorably with previously published HIFU outcomes.

Variable N Mean Std Dev Median Minimum Maximum

Baseline Volume 134 22.7 12.5 21.6 9.7 152.0

First post-HIFU Biopsy

(with volume):

Volume (cc) 113 9.0 6.3 7.8 1.2 33.0

Volume

change from

Baseline (cc)

1121 -13.62 14.4 -12.7 -145.0 7.0

1 Subject 120-013’s baseline volume was recorded as <30, post-HIFU the volume was 5.24

cc.

2 Volume change from baseline statistically significant at p<0.0001

Visit # Cores # Positive % Positive Per Core Negative

Biopsy Rate

Baseline

1251 365 29.2%

70.8%

Follow-up (Unscheduled and/or Month 24 Overall)

1127 87 7.7% 92.3%

Increase in Per Core Negative Biopsy Rate from baseline is statistically significant at p<0.0001

Table 1: Biopsy Results per Core

Table 2: Prostate Volume Post-HIFU at First Biopsy

1. Chaussy CG, Thüroff SF: Robotic high-intensity focused ultrasound for prostate cancer: what

have we learned in 15 years of clinical use? Curr Urol Rep 12: 180-187, 2011

2. Crouzet S, Rebillard X, Chevallier D, et al: Multicentric oncologic outcomes of high-intensity

focused ultrasound for localized prostate cancer in 803 patients. Eur Urol 58: 559–566, 2010

3. Blana A, Murat FJ, Walter B, et al: First analysis of the long-term results with transrectal HIFU

in patients with localized prostate cancer. Eur Urol 53: 1194–1201, 2008.

1, 2, 3

REFERENCES

Event Incidence

Erectile Dysfunction 43.7%

37.8 % Moderate or Severe 5.9 % Mild

Urinary Incontinence 11.1%

3.0 % Moderate or Severe 8.1 % Mild

Urinary Tract Infection 0.0%

Urinary Obstruction 0.7%

Urinary Retention unresolved by day 30 or

onset ≥ 30 days

2.2%

Stricture 1.5%

Bladder Neck Contracture 0.7%

Urinary Retention Resolved by Day 30 0.0%

Bowel Injury 0.0%

Sepsis 0.0%

Table 3: Adverse Events Unresolved at 2 years

Variable N Mean Std Dev Median Minimu

m

Maximu

m

Baseline Volume 134 22.7 12.5 21.6 9.7 152.0

First post-HIFU

Biopsy (with

volume):

Volume (cc) 113 9.0 6.3 7.8 1.2 33.0

Volume change

from Baseline

(cc)

1121 -13.62 14.4 -12.7 -145.0 7.0

1 Subject 120-013’s baseline volume was recorded as <30, post-HIFU the volume was 5.24 cc.

2Volume change from baseline statistically significant at p<0.0001

Visit # Cores # Positive % Positive

Per Core

Negative

Biopsy Rate

Baseline 1251 365 29.2% 70.8%

Follow-up

(Unschedul

ed and/or

Month 24

Overall)

1127 87 7.7% 92.3%

Increase in Per Core Negative Biopsy Rate from baseline is statistically significant at p<0.0001

Morbidity of High Intensity Focused Ultrasound (HIFU) as a Primary Monotherapy for Low-Risk Localized Prostate Cancer: Outcomes from the ENLIGHT Trial

Robertson CN, Sliwinski A, Delisio J, Wallen E, Ward JF, Orovan W, Locke D, Crawford ED, Maroni P, Donnell R, Grunberger I, Bevan-Thomas R, Munver R, Sawczuk I, Chang S, Gill IS: Morbidity of High Intensity Focused Ultrasound (HIFU) as a Primary Monotherapy for Low-Risk Localized Prostate Cancer: Outcomes from the ENLIGHT Trial. Societe d’Urologie Internationale Oct 2011 Berlin. Abstract 1810.0 POD-07.09

Potency (UCLA-PCI Questionnaire)

One Year Two Years

Full recovery (sufficient for penetration)

24.1% 26.8%

Partial recovery 35.1% 24.3%

Continence IPSS

% return to baseline (p>0.05) @ 24 months

High Intensity Focused Ultrasound (HIFU) Clinical Approvals

• FDA approval 10/2015 for the treatment of prostate tissue ablation with HIFU

• Focused ultrasound is currently available in the US to treat uterine fibroids and essential tremor.

• The option for non-invasive treatment of prostate cancer in an ambulatory surgery setting is a significant step forward for patients.

Monofocal tumor, treated with safety margin

Focal Therapy of GU Malignancies

• Imaging dependent technology

• Tissue destructive technique

• Cancer detection pre- and post-treatment feasible and reproducible

• Re-treatment an option for treatment failures

Focal Therapy of GU Malignancies

• Cryotherapy

• High Intensity Focused Ultrasound

• Interstitial Laser Therapy

• Photodynamic Laser Therapy

Cryotherapy • Tissue ablation at the time of 2 freeze/thaw

cycles

• Immediate pathology reveals cell ghosts

• Tissue sloughing, fibrosis and shrinkage occurs over 3-6 months

• Urethral preservation with warming catheter

• Tissue effects dramatic on US, CT, MRI

High Intensity Focused Ultrasound

• Heat effects on tissue known throughout history

• Coagulation effects begin with temperature of 60 C

• Focused ultrasound waves may raise core tissue temperature to 85 C at focal point

• Gradient of temperature protects adjacent tissues and organs

Imaging Techniques • Transrectal Ultrasound

– Cryotherapy

– HIFU

– Photodynamic Laser Therapy

• Magnetic Resonance Imaging

– Interstitial Laser Therapy

– HIFU

Duke Clinical Opportunities

– Clinical Lead(Cary Robertson, Tom Polascik) • Integrate Cryotherapy/HIFU into Duke’s prostate cancer

management options by routing patients requesting HIFU through the Multi-D Clinic, thereby ensuring that the patients will receive appropriate treatment and that all service lines have the opportunity to interact with these patients

• Develop algorithms for patient selection and eligibility for HIFU. Provide leadership nationally in the proper application of HIFU in localized prostate cancer.

• Coordinate HIFU with existing programs of Active Surveillance, Radiation Therapy, Surgery and Cryotherapy for localized prostate cancer.

• Build on prior experience with cryoablation, recognizing the leadership role of Duke in the area of Focal Therapy nationally and internationally

• Radiation Oncology (Bridget Koontz, Robert Lee) partnership across therapies for salvage and potentially primary disease

Focal Therapy of GU Malignancies

• Duke Cancer Institute offers single site coordinated care of cancer patients combined with consultative services for survivorship care.

• The Division of Urology supports the patient care mission of Duke Medical Center with innovative research.

• Collaborative efforts across the university expands the potential of basic and clinical research.

Duke Research in HIFU

– Initiatives: • Biomedical Engineering collaboration for device

development- Cary Robertson/Pei Zhong –animal models of HIFU and immunotherapy

• Basic Science (Brant Inman, Bridget Koontz) – review immuno-modulating response

• Clinical Science (Tom Polascik) –thermally based treatment comparisons

• Imaging-pre and post HIFU MRI monitoring (Raj Gupta/Tom Polascik/Cary Robertson)

• Outcomes-Compare whole gland ablation to partial ablation or hemi-ablation of the prostate gland

• Clinical Registry • Survivorship Clinic as and essential component of

patient management (Drew Peterson)

Our Team

Pei Zhong, Ph.D. Biomedical Engineering

Hui-Wen Lo, Ph.D. Cancer Biology

Cary Robertson, M.D. Urologic Surgery

Mari Shinohara, M.D. Immunology

An Interdisciplinary

and Translational

Research Group

Preliminary Results B-scan ultrasound image of tumors during HIFU treatment, indicating

cavitation activities in tumor tissues (arrow points to region of hyperechogenicity)

Photographs of excised tumors after HIFU treatment, showing regions of mechanical damage by cavitation bubbles

Preliminary Results

• No recurrent tumor growth in both groups after surgery

Growth curves for re-challenged tumors

Animal survival rates after re-challenge

Ablation combined with immunotherapy: a new paradigm for prostate cancer?

Future Directions

– Second generation technology accessibility • Fusion imaging and targeted treatment of

small volume intermediate or high risk lesions as early as 2017 (Focal 1 Device)(Uronav/Sonacare)

– Education and Training • East Coast training site for providers • National Center of Excellence • Standard of Care Development and

Thought Leadership

HIFU in Prostate Cancer

The future of HIFU is evolving but extremely important, not only as a primary therapy but also as an adjunct to additional strategies i.e. immunotherapy

HIFU Natural History Hypothesis testing in active surveillance populations will require long term studies

Focal HIFU will be the ideal strategy for such low morbidity treatments and will allow attractive randomization schemes