Trial Information

A Pilot Study of Robotic Template Guidance for Needle Placement in Transperineal Prostate Brachytherapy

Section 1- Background:

Adenocarcinoma of the prostate will affect over 220,900 U.S. males this year, making it the
most prevalent cancer in the nation.1 Prostate specific antigen (PSA) is a very useful tumor
marker in early detection of this malignancy, as well as a reliable marker for control after
definitive therapy with either surgery or irradiation.2,3,4 Widespread use of
prostate-specific antigen (PSA) screening has resulted in approximately 45% of patients
being detected with early stage disease. For this group of patients, brachytherapy or
implantation of radioactive sources into the prostate is a treatment option that has risen
dramatically in use over the last several years due to its effectiveness and convenience.5
The use of brachytherapy or implantation of radioactive sources into the prostate for
adenocarcinoma has advantages over external beam radiation in that a very high dose can be
delivered to the tumor while limiting the doses to the surrounding normal tissue (i.e.,
bowel and bladder). It is well established that outcomes after treatment with brachytherapy
are critically related to the technical quality of source placement within the gland. A
spatially desirable placement of the radioactive sources with achievement of optimum dose
distributions within the prostate is key to the success of brachytherapy with regard to both
killing tumor as well as minimizing toxicity.6,7,8 The development of transrectal ultrasound
(TRUS) of the prostate, with the ability to map the prostate in several planes, as well as
the associated development of trans-perineal implantation of the prostate, has allowed the
development of the modern prostate implantation method. Ultrasound images are taken before
or during the implant procedure, and a source distribution plan is developed that optimizes
dose to the prostatic tissues while sparing the urethra and rectum. Needles are placed into
the prostate via a transperineal template, and the sources are placed into the prostate
according to the source distribution plan.

Currently, the template utilized for needle guidance is limited to 0.5 centimeter x-axis and
y-axis grid spacing, limiting the ability of the needle positions to conform to the shape of
the prostate, which is spherical (Fig 1). The most commonly utilized method of dosimetric
planning involves placing needles around the periphery of the prostate capsule, in order to
best cover potential microscopic extracapsular extension as well as to avoid the dose
sensitive urethra which runs through the center.9 The grid arrangement of the current
template limits the ability of these needle positions to best approximate the external
contour of the prostate (Fig 2). Also, placement of sources in the most posterior row
adjacent to rectum is critical. Sources too close to rectum may cause increased risk of
rectal bleeding, whereas source too far from the capsule may result in risk of underdosing
disease in that area.10,11 Greater freedom in needle positioning would allow for more
optimum placement of sources.

Figure 1. Transperineal template device 3 Figure 2. Grid positions available with
traditional template (white dot grid on screen). Prostate outline is seen on the image.

Researchers in the JHU School of Engineering have developed a robotic needle positioning
device which will allow greater flexibility in choosing needle positions for prostate
brachytherapy. The device consists of a motor attached to a needle guidance hole. The entire
apparatus attaches to the ultrasound 'stepper' device similar to the standard transperineal
template. For each needle position, the motor moves to the predetermined location and the
physician places the needle through the hole. Visual verification of acceptable needle
position is performed by viewing the needle on the real-time ultrasound. A secondary means
of verification will be the use of an Optical Tracking device, which will verify needle
orientation and position prior to insertion. Rather than having the probe positioned at the
desired endpoint of the needle insertion within the prostate, the ultrasound unit will be
mechanically coupled with the needle (via the optical tracking system) as it is being
inserted, such that the needle tip will be continuously visualized as it is progressing into
the prostate.

Another problem frequently encountered in brachytherapy is pubic arch interference. Given
the proximity of the prostate to the pubic arch, the anterior aspect of the prostate often
abuts this structure. If pubic arch curves posteriorly around the inferior aspect of the
prostate, then access to the anterior prostate with transperineal needles is limited. Some
patients may not be eligible for brachytherapy due to this problem with their anatomy.12
This device will allow for angulation of needles such that pubic arch interference may be
circumvented by inserting more posteriorly and then angling the needle anteriorly such that
the pubic arch is not in the needle path as it travels toward the anterior prostate.

We will use the CMS Interplant system software (St Louis, MO), which has the capability of
calculating treatment plans using sources off of the usual template grid positions.

Section 2 -Objectives:

This will be a feasibility trial of a therapeutic device. The purpose of the study is to
demonstrate the clinical feasibility of using the needle positioner device in a cohort of 5
patients. This will involve demonstrating the feasibility of using the system in an actual
operating room environment and determining acceptable positioning effectiveness by assessing
needle position during insertion on the live ultrasound image, as well as by using an
optical tracking device.

Section 3- Study Population:

The eligible population will be patients with a diagnosis of adenocarcinoma of the prostate
who are seen in consultation at the Johns Hopkins Hospital.

We currently perform 1-2 brachytherapy procedures per week on average; therefore patient
accrual (5 patients) is expected to complete within 3-5 months.

Section 4 - Protocol Design:

This will be a feasibility study with a cohort of 5 patients. 4.1. Subject Identification:
Patient confidentiality will be maintained in accordance with Health Information Portability
and Accountability Act (HIPAA) guidelines. All participants must sign an informed consent
that will describe the objectives of the study and potential risks. All patient data
reported on the case reports forms will be identified by the patient's initials and study
code number only. Patients shall not be identified by name. This should serve to protect the
confidentiality of subjects enrolled on the trial. Clinical data and records for all
subjects studied including history and physical

findings, laboratory data, and results of interventions are to be maintained by the
investigators in a secure, locked location. Computerized data will require password
authorization(s) for access.

4.2. Description of the Recruitment Process: Potential subjects will be identified at the
time of consultation in the Department of Radiation Oncology by Dr. Song. All patients
meeting above stated eligibility criteria will be offered participation in the study by the
consulting physician.

4.3. Description of the Informed Consent Process: Only physicians who are investigators on
this project will perform the informed consent interview. The informed consent interview
will take place prior to the day the patient is to be treated to ensure that the patient has
adequate time to discuss the research project with family, friends, and/or other Health Care
providers. During the informed consent interview the interviewer (investigator) will take as
much time as needed to ensure that the potential subject understands the research project
and also clearly understands that he does not have to participate in this project to receive
his cancer treatment at Johns Hopkins. If the patient decides to enroll into the research
project he will sign three copies of the informed consent form. One will be for his own
records, one will be kept in the Clinical Research Office at Johns Hopkins, and the third
one will be kept in his medical records.

4.4. Subject Assignment: Five patients will be enrolled onto the trial. 4.5. PATIENT
ASSESSMENTS Assessments Pre-Study Entry Post Brachytherapy Month 3 (+/- 4 weeks)
History/physical Exam Xa X KPS Xa PSA Xa X Chest X-ray Xa Xb CT of pelvis Xa Xb Ultrasound
volume Xa Bone scan (if clinically indicated) Xa

1. within 6 weeks prior to day 1 of brachytherapy

2. up to 1 day post brachytherapy RADIATION THERAPY AND RESEARCH INTERVENTIONS The patient
population who will be offered this protocol are those who are currently offered
brachytherapy as standard treatment at our institution. The clinical protocol will not
affect what patients experience during the procedure.

Implant procedure As is our routine, within the week prior to implantation the patient will
undergo a transrectal ultrasound study to determine the volume of the prostate and estimate
the number of sources required. A preliminary implant plan will be developed based on the
pre-operative ultrasound.

On the day of implantation, the patient will be brought into the operating room and
'timeout' performed. He will be placed in dorsal lithotomy position after anesthetic (either
general or spinal) is administered. A foley catheter will be placed into the urethra.
Ultrasound images will be acquired and a dosimetric plan developed based on the
intraoperative ultrasound. Computerized dosimetric algorithms are used to assist the
physician in creating a plan which adequately treats the prostate while minimizing dose to
urethra and rectum.

Given that the needle positioner device will allow an infinite number of positions rather
than being limited to predetermined holes, the source placement will be planned by the
physician with this in mind. Sources are placed with immediate feedback from software as to
dosimetric ramifications on normal tissues and prostate coverage. If a source position does
not correspond to the usual template grid, the software allows the user to 'drag' the
closest grid needle position to the desired location.

Instead of a standard template with pre-drilled holes mounted on the ultrasound support
mechanism, the needle positioner device will be attached to the stepper unit. Needles are
inserted through the needle positioner, through the perineum and into the prostate, using
positions dictated by the dosimetric plan. Ultrasound guidance is used to visualize and
guide the needle placement. An optical tracking system (Northern Digital Inc, Waterloo
Canada) with measured accuracy of 0.1 millimeter, will be used to track the needle position
and angle prior to insertion into tissue.

The correctness of the needle position produced by the NPD will be ascertained at two
levels, before committing the needle to insertion and during insertion. The tracker will be
placed in the field of surgery. The tracker will be calibrated to the coordinate space of
the template. Then the template is removed and the NPD is placed. The tracker will be
calibrated to the coordinate space of the NPD too. Assuming that the tracker does not move
during the procedure, this establishes a direct spatial co-registration between the
coordinate space of a template and NPD. At any time during the procedure, the current
position of the NPD and needle guide can be reported to the responsible physician in
template coordinates. Thus the physician will compare the current needle position (reported
in template space) to the desired needle position determined by the treatment plan (also in
template space). In case of any discrepancy between the reported and desired needle
positions, the NPD is removed and replaced by the template, and the procedure continues
without delay.

During needle insertion, the ultrasound will move in synch with the needle insertion (via
optical tracking and motorized control of the ultrasound probe) in order to allow constant
visualization of the needle tip during insertion. The depth of insertion of the ultrasound
probe is limited by the stepper unit which it is attached to. After each needle insertion,
C-arm fluoroscopy is briefly used to assess and confirm the positioning, and a Mick
applicator (Mick Radio-Nuclear Instruments, Mount Vernon NY) will be used to place sources
into the prostate via the needle. Following source placement the needle is removed, the
needle positioner moves to the next needle position, and the procedure is repeated until all
sources have been placed. After all sources are placed, a final set of fluoroscopic images
is taken for confirmation and documentation.

When using the standard transperineal template, the template is calibrated to the ultrasound
probe prior to the implant procedure by using a phantom, such that the grid on the template
accurately correlates to the grid as seen on ultrasound. However, during the actual
procedure it is not uncommon for the needle position as visualized on ultrasound to be
slightly displaced from the predicted location. This is due to needle bending from tissue
forces during insertion. When this occurs the physician removes the needle and repeats the
insertion with mild force on the needle at the point of tissue entry in order to achieve the
desired position. The needle guide may also be recalibrated if successive needle attempts
show consistent deviation in one direction, which is indicative of slight errors in
calibration. This is not an unusual finding in typical practice.

For purposes of this study, the needle positioning system will also be calibrated prior to
each implant. However, if during the procedure the physician finds that the needle
positioner is inaccurate in a non- systematic fashion (not related to slight calibration
error) relative to the intended position, the system can be quickly replaced by the standard
template during the procedure, since it mounts to the stepper in identical fashion.

Other treatment Patients who have either Gleason score of 7 or PSA 10-20 will be treated
with external beam radiation in addition to brachytherapy in accordance with our usual
practice.