Detection of High Grade Prostate Cancer With Subharmonic Ultrasound Imaging, A Pilot Study

Background: Prostate cancer (PCa) is the most frequently diagnosed cancer among American
males, accounting for 27 % of new cancer diagnoses, but it is directly responsible for only
9.5 % of cancer related deaths. Two recently published clinical trials suggest that
overdiagnosis and overtreatment of potentially insignificant cancer is a major drawback of
prostate cancer screening, and point to the need for a more specific screening tool that can
identify clinically significant prostate cancer. The US-based Prostate, Lung, Colorectal, and
Ovarian (PLCO) Cancer Screening Trial failed to show a mortality benefit from screening and
treatment of prostate cancer. The European Randomized Study of Screening for Prostate Cancer
(ERSPC) suggests that with the current standard of care, 1410 men must be screened and 48
additional cases of prostate cancer treated to prevent one death from prostate cancer. Based
upon these trials, the U.S. Preventive Services Task Force (USPSTF) has issued a grade "D"
recommendation against PSA-based screening for PCa.

Contrast-Enhanced Ultrasound: Recent studies have demonstrated that contrast-enhanced
harmonic imaging (HI) can identify enhancement related to vascular flow in higher grade PCa,
and that HI can selectively detect patients with "clinically significant" PCa that are most
likely to benefit from therapy. Subharmonic imaging (SHI) is a newer technology for
contrast-enhanced ultrasound imaging that provides a 10-fold improvement in the signal to
background ratio for visualization of small vascular structures, but has not been previously
implemented on a transrectal ultrasound probe. SHI of the prostate is expected to advance the
imaging of prostatic neovascularity and to improve selective biopsy of clinically significant
PCa.

Objective: To adapt SHI to a transrectal probe appropriate for prostate imaging and biopsy
(over the first 6 months of this study). The subsequent 18 month pilot clinical study will
enroll 50 participants who have a clinical indication for prostate biopsy to quantify SHI for
the detection of clinically significant PCa (defined as: Gleason score ≥ 7, a single core
with > 50 % involvement, or > 25 % of biopsy cores positive for PCa).

Approach: Each participant will undergo a transrectal ultrasound evaluation of the prostate
with conventional grayscale and color Doppler imaging, as well as contrast-enhanced imaging
with color Doppler, HI and SHI approaches. Imaging results from each of these techniques will
be recorded, but only the SHI findings will be used to guide a targeted biopsy of the
prostate. A maximum of 6 targeted biopsy cores will be obtained from each participant, based
upon suspicious areas identified with SHI. Following the targeted biopsy, each participant
will also receive a 12-part systematic biopsy consisting of 6 laterally directed biopsy cores
and 6 medially directed biopsy cores. The pilot study is designed to estimate the detection
of clinically significant cancer that will be obtained with targeted biopsy based upon SHI
along with the medially directed systematic sextant biopsy cores (≤ 12 cores total).

Inclusion Criteria:

1. Subject must be scheduled for a clinically indicated needle biopsy of the prostate
based upon an elevated PSA, abnormal digital rectal examination, or based upon active
surveillance of prostate cancer.

2. Subject must be able and willing to give written informed consent for a contrast
enhanced ultrasound study of the prostate.

3. Subject must be a male at least 18 years of age when informed consent is obtained.

4. Subject must have a life expectancy that exceeds the duration of the clinical trial.

Exclusion Criteria:

1. Participant in a clinical trial involving an investigational drug within the past 30
days.

2. Prior allergic reaction to the ultrasound contrast agent Definity™

3. Previous treatment for PCa.

4. Clinically unstable, severely ill, or moribund.