Focal Prostate Radio-Frequency Ablation for the Treatment of Prostate Cancer
Phase: NA
Conditions: Prostate Cancer
Sponsor: H. Lee Moffitt Cancer Center and Research Institute

 
 
Focal Prostate Radio-Frequency Ablation for the Treatment of Prostate Cancer  
 
NCT02328807 
 
Version 7.0 
October 12, 2015 

 
MCC #17753 
 
Protocol Version 7/ October 12, 2015 
 
Table of Contents 
 
 
 
       Page 
 
INTRODUCTION……………………………………………………………………….............4  
 
STUDY SCHEMA .........................................................................................................................5 
 
1. OBJECTIVES ..........................................................................................................................6 
 
2. BACKGROUND AND RATIONALE ...................................................................................7 
 
3. THERAPEUTIC AND Diagnostic Agents ...........................................................................10 
 
3.1 
Imaging .......................................................................................................................10 
 
3.2 
Transperineal Mapping Biopsy ................................................................................10 
 
3.3 
RFA .............................................................................................................................10 
 
4. CRITERIA FOR SUBJECT ELIGIBILITY .......................................................................11 
4.1 
Subject Inclusion Criteria .........................................................................................11 
4.2 
Subject Exclusion Criteria ........................................................................................12 
4.3       Inclusion of Minorities and Women  ........................................................................12 
4.4 
Recruitment Plan .......................................................................................................12 
 
5. PRE-TREATMENT and IMAGING ...................................................................................13 
 
6. TREATMENT/INTERVENTION PLAN............................................................................14 
 
 
7. EVALUATION DURRING TREATMENT INTERVENTION .......................................14 
 
8. TOXICITIES/SIDE EFFECTS ............................................................................................15 
8.1 
Definitions ..................................................................................................................16 
 
8.2 
Adverse Event Assessment ........................................................................................16 
8.3 
Routine Reporting .....................................................................................................17 
8.4 
Potential Adverse Events ..........................................................................................17 
 
9. CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ..............18 
 
 
10. CRITERIA FOR REMOVAL FROM STDUY...................................................................18 
 
11. BIOSTATISTICS ...................................................................................................................18 
11.1 
Study Design/Endpoints ............................................................................................18 
11.2 
Sample Size/Accrual Rate  ........................................................................................18 
11.3     Stratification Factors……………………………………………………………….18  
      11.4 Analysis of Primary Endpoint………………………………………………………...18   
      11.5 Analysis of Secondary Endpoints……………………………………………………...19  
 
 
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12.0 RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION   
PROCEDURES…………………………………………………………………………20 
13.0 DATA MANAGEMENT ISSUES………………………………………………………..21 
 
13.1 Quality Assurance…………………………………………………………………21 
 
13.2 Data Collection and Record Keeping ……………………………………………21 
14.0 
ETHICS………………………………………………………………………………….22 
15.0 FUNDING………………………………………………………………………………….24 
16.0 REFERENCES …………………………………………………………………………...25 
APPENDICIES………………………………………………………………………………...26 
Appendix A  Sexual Health Inventory for Men……………………………………..26 
Appendix B Rectal Assessment Scale………………………………………………..27 
Appendix C American Urological Symptom Score………………………………....28 
Appendix D EPIC QOL survey……………………………………………………....29 
 
Appendix E Medical Resource Utilization (MRU) forms………………….............38 
 
 
 
 
 
 
 
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INTRODUCTION: 
 
Men diagnosed with non-palpable, unilateral, low-intermediate risk localized prostate 
cancer (defined as clinical stage T2a, PSA<10ng/ml, Gleason score <=7, in only one side 
of the prostate) and multi-parametric endo-rectal MRI with no lesions or lesions less than 
1cm. in diameter and only on one side of the prostate are eligible for this study. Initial 
biopsy would need to have a minimum of 10 cores.  
 
After enrollment, patients will undergo endo-rectal, multi-parametric 1.5 Tesla MRI with 
Dynamic contrast enhancement and Diffusion Weighted images.  Areas on MRI that have 
a high level of suspicion for prostate cancer will be identified (right or left, Central or 
peripheral gland) and categorized from 1 Negative to 5 highly suspicious. 
 
For study purposes, the prostate is divided into four regions: RIGHT CENTRAL, RIGHT 
PERIPHERAL, LEFT CENTRAL and LEFT PERIPHERAL.  Patients must meet the 
original entry criteria on this repeat mapping biopsy and have unilateral prostate cancer. 
If the patients meet the mapping-biopsy enrollment criteria, they are treated with focal 
bipolar radiofrequency ablation (RFA) meaning RFA of the sites where the biopsies 
were positive but no more than one prostate side. Efficacy is defined as negative biopsy 
cores at the sites of the focal ablation on repeat extended biopsies at 6 months after RFA. 
A second MRI will be performed just prior to the 6 month repeat saturation biopsy 
performed identical to the original pre-treatment biopsy.   
 
At baseline (prior to pre-treatment biopsy) and at 6 months (prior to the repeat biopsy 
used to define efficacy) the patient will complete an American Urologic Association 
lower urinary tract symptom score assessment (AUA score), Rectal Assessment Scale 
(RAS), International Index of Erectile Function (IIEF-5), and the EPIC quality of life 
questionnaires. 
 
Following completion of the focal prostate radio-frequency ablation study at 6 months 
from treatment, patients will undergo standard/routine care including serum PSA level 
every 6 months and as needed digital rectal examinations; any future prostate biopsies 
will be performed at the discretion of the treating physician. 
 
Patients will also be required to complete a medical resource utilization (MRU) form to 
capture resource utilization between study visits, which can be used to estimate costs 
associated with procedure related complications and health care visits. Patients will 
requested to complete a weekly diary of medical resource utilization to limit recall bias 
that may occur between study visits. 
 
 
 
 
 
 
 
 
 
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SCHEDULE OF EVALUATIONS / STUDY CALENDAR 
 
 
 
Parameter 
 
 
Prestudy 
 
 
Week 
0  
 
             
 
Week 
6 
 
 
3 
months 
 
 
6 
months 
 
End of 
Study 
Visit 
History  
X 
 
 
 
 
 
Physical examination including DRE  
X 
 
X 
X 
X 
 
QOL questionnaires 
(EPIC,IIEF,AUA,RAS) 
X 
 
 
 
X 
 
MRU (Recording weekly by patients; 
collected at the following visits by 
study coordinator) 
 
 
X 
X 
X 
 
Toxicity assessment  
 
 
X 
X 
X 
 
ECOG Performance Status 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
Laboratory  Investigations 
 
 
 
 
 
 
PSA 
X 
 
X 
X 
X 
 
CBC, differential, platelet count  
X 
 
 
 
X 
 
Serum Chemistries (must include, 
bilirubin, Alk Phos, ALT and AST) 
X 
 
 
 
X 
 
Glucose and Electrolytes (Na, K, C1, 
CO2), BUN, Creatinine 
X 
 
 
 
X 
 
PT /PTT /INR 
X 
 
 
 
X 
 
U/A 
X 
 
 
 
X 
 
EKG  
X 
 
 
 
X 
 
 
 
 
 
 
 
 
Imaging Studies 
 
 
 
 
 
 
Chest X-Ray 
X 
 
 
 
X 
 
MRI and Mapping Biopsy 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
Procedures 
 
 
 
 
 
 
RFA 
 
X 
 
 
 
 
Discussion of final biopsy result and 
assessment of AEs 
 
 
 
 
 
X 
 
 
 
 
1.0  OBJECTIVES AND SCIENTIFIC AIMS    
 
Primary Objective: To assess the local oncologic efficacy of focal RFA in men with 
unilateral, clinically localized prostate cancer as measured by the ability to obtain all 
negative biopsy cores at the sites of focal ablation of the cancer, “all negative” means no 
prostate cancer; if the biopsy contains inflammation, or pre-cancerous changes (high-
grade prostatic intraepithelial neoplasia and /or atypical small acinar proliferation it will 
be considered negative for study purposes). 
 
Secondary Objective: To evaluate the safety of the procedure and change in quality-of-
life indicators from baseline to 6 months following focal RFA in patients with localized 
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prostate cancer. To understand and evaluate imaging characteristics of treated prostate 
cancer by bipolar RFA. 
 
Tertiary Objective:  To assess the potential health economic impact of focal RFA based 
on medical resource utilization data. 
 
BACKGROUND AND RATIONALE  
 
Epidemiological data demonstrate a marked increase in the number of men diagnosed 
with prostate cancer, and a profound migration towards earlier stage disease at the time of 
diagnosis. Implementation of large-scale serum prostate-specific antigen (PSA) screening 
programs and more extensive biopsy strategies are largely responsible for the increase in 
diagnosis. An analysis of the control group in the Prostate Cancer Prevention Trial 
illustrates the potential for extensive biopsy to result in over –diagnosis, of prostate 
cancer (Thompson et al.2004).  Among 2,950 men with negative digital rectal 
examination (DRE) and PSA levels <4.0ng/ml, 15.2% harbored prostate cancer by 
biopsy, as did 6.2% of men with PSA levels<1.5ng/ml. In an era of increasing prostate 
cancer incidence and stage migration towards earlier disease, appropriate management of 
the disease requires assessment of risk; how likely is a given man’s cancer to progress or 
metastasize over his remaining lifetime? What is the probability of success with 
treatment? What are the risks of side effects and complications with each treatment?   
Prostate cancer is relatively slow growing, with doubling times for local tumors estimated 
at 2 to 4 years. Some prostate cancers prove to be so small, low-grade, and noninvasive 
that they appear to pose little risk to the life or health of the host. A recent review of 
radical prostatectomy series suggest that 25-30% of men undergoing radical 
prostatectomy have pathologic features in the radical prostatectomy specimen consistent 
with an insignificant or “indolent” cancer that posed little threat to life or health (organ-
confined cancer < 0.5cc, no Gleason grade 4 or 5 component). However, the biological 
potential of histologically detectable cancers is difficult to characterize with certainty, 
and a traditional 10 to 12 core transrectal prostate biopsy may underestimate the extent of 
cancer in the prostate in up to 50% of men with low-risk cancer. With alternative risk-
assessment strategies (including extended or mapping prostate biopsies) some men have 
focal cancers that would not warrant complete gland treatment with radical 
prostatectomy, brachytherapy or external beam radiation therapy. While deferring 
definitive therapy (active surveillance) until progression of disease is an option in patients 
with low-risk and some with intermediate  cancer, some men with a diagnosis of “cancer” 
do not accept this approach, As such there appears to be a role for therapy solely 
targeting the cancer (focal therapy; the male “lumpectomy”). This has the theoretical 
advantage of treating/curing the cancer while at the same time having fewer side effects 
than traditional whole-gland treatments.   
The mechanism of action of bipolar RFA is complex. It has been proposed that RFA 
exerts its efficacious effect by: (1) the induction of protein denaturation by 
thermocoagulation (2) the rupture of cell membranes from heating, (3) the transfer of 
water from intracellular to extracellular spaces, (4) vascular stasis, and (5) the induced 
apoptosis. The introduction of ultrasound guidance and the bi-polar design of the probe, 
allowed the heating process to be controlled and monitored in real time.  
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PRIMARY OBJECTIVE 
 
This protocol will investigate the role of focal bipolar RFA in a defined prostate cancer 
population examining treatment efficacy (elimination of the cancer) based on repeat 
biopsy at six months from treatment. 
 
SECONDARY OBJECTIVES 
 
1.  Changes from baseline in quality-of-life. 
2.  Image characteristics of treated prostate cancer by bipolar RFA 
3.  To evaluate the safety of the procedure 
 
TERTIARY OBJECTIVE: Evaluate the health economic impact of focal RFA. 
 
OVERVIEW OF STUDY DESIGN/INTERVENTION        
 
1.1 Design  
 
This is a pilot study examining the efficacy (primary endpoint) and quality-of-life 
changes, safety, and image characteristics by MRI (secondary endpoint) in men 
with unilateral prostate cancer treated with focal RFA. In addition, the study will 
collect medical resource utilization data to assess the health economic impact of 
focal RFA (tertiary endpoint). We estimated the negative biopsy rate at 6 months 
after focal bipolar RFA is greater than or equal to 90%. 
 
1.2 Intervention  
 
Before any study procedures are performed (which includes all screening 
procedures, pre-treatment, treatment/intervention procedures, etc.), all patients will 
be asked to sign an informed consent form.  
 
Eligible patients will have been diagnosed with unilateral prostate cancer, with PSA <10, 
Gleason score 6 or 7, up to clinical stage T2a, and prostate volume<60 cc. At enrollment, 
patients will undergo 1.5T MRI with DCE and DWI imaging. The prostate is divided into 
four regions: RIGHT CENTRAL, RIGHT PERIPHERAL, LEFT CENTRAL and LEFT 
PERIPHERAL. Then they will undergo a pre-treatment transrectal mapping prostate 
biopsy as currently performed at our institution. This procedure is performed under 
general anesthesia as an outpatient procedure. For study purposes, the prostate biopsy 
cores will be obtained from four regions: RIGHT CENTRAL, RIGHT PERIPHERAL, 
LEFT CENTRAL and LEFT PERIPHERAL. For patients to be eligible for treatment 
with focal bipolar RFA under this protocol they must meet the original entry criteria on 
this pre-treatment mapping biopsy. 
 
Those men meeting the mapping-biopsy criteria will subsequently be treated with focal 
bipolar RFA. Treatment is performed under general anesthesia and will include the 
regions of the prostate containing cancer based on the mapping biopsy. If there are 
multiple unilateral areas of the prostate involved with cancer, a hemi-ablation will be 
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performed.  This is an outpatient procedure, that takes between 1 and 2 hours, with the 
patient arriving 1-2 hours prior to the procedure and remaining in the recovery room for 
1-2 hours after the procedure. The patient is given a voiding trial. If the patient fails same 
day voiding trial a Foley catheter will be placed with a second trial performed 
approximately one week after treatment. Clinical follow-up visits will be scheduled at 6 
weeks, 3 months, and 6 months after focal bipolar RFA at which time a digital rectal 
examination and PSA test will be performed. These follow-up visits and procedures are 
part of this study protocol.  
 
The primary endpoint of the trial is assessed at 6 months after focal bipolar RFA by 
repeat MRI imaging and post treatment mapping biopsy performed the same as pre-
treatment. Treatment efficacy, defined as all negative biopsy cores at the site of the focal 
ablation, will be determined by the results of this mapping biopsy that will include 
complete biopsy of all regions of the prostate. Secondary endpoints will be evaluated 
through the standard quality-of-life questionnaires. For those patients not enrolled on this 
study protocol, their data from completion of the quality-of-life questionnaires will not be 
included in this investigation.  Any adverse events that occur as a result of this study will 
be recorded and reported to the regulatory committees at Moffitt and IRB.  
 
If after the mapping biopsy the patient does not meet the criteria for focal RFA, he will be 
excluded from this study protocol but considered and offered other management options 
for prostate cancer including active surveillance, radical prostatectomy or radiation 
therapy. 
 
Stopping rules: 
 
Criteria for stopping the Study: 
1. If at the second mapping biopsy done at 6 months, more than 4 patients have a 
positive biopsy in the ablated area, the study will be stopped.  This is based on the 
current treatment failure rate of 20% for radical prostatectomy. 
2. If even one patient develops hematuria after the procedure requiring a second 
procedure to be performed, the study will be terminated. 
3. If even one patient requires a Foley catheter for greater than 2 weeks following 
the procedure, the study will be terminated. 
4. If even one patient develops an infection requiring inpatient hospitalization, the 
study will be terminated. 
5. If even one patient develops a rectal fistula the study will be terminated. 
 
 
 
 
 
 
 
 
 
 
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3.0 THERAPEUTIC/DIAGNOSTIC AGENTS  
 
Before any study procedures are performed (which includes all screening 
procedures, pre-treatment, treatment/intervention procedures, etc.), all patients will 
be asked to sign an informed consent form.  
 
3.1  Imaging 
 
After the informed consent is signed, the patient will be scheduled for an MRI (dynamic 
contrast enhanced and diffusion weighted imaging using a 1.5 Tesla endorectal MRI.  
The regions where both imaging sets indicate the potential for disease will be identified 
and categorized to one or more of 4 possible regions of the prostate as defined below. 
 
 
3.2  Mapping Prostate Biopsy    
 
Transrectal ultrasound-guided prostate biopsies will be performed to determine study 
eligibility as well as to assess treatment efficacy.  The two biopsy sessions (one pre-
treatment and the other 6 months after focal RFA) will follow the same method. The 
rational for a complete mapping biopsy after RFA, rather than just sampling of the 
regions that were treated, is to identify cancer lesions not found in initial MRI/biopsy 
(thus, not treated) or cancer that may have developed after RF treatment. 
 
Preparation/anesthesia: The patient will be given a Fleet enema prior to the procedure and 
administered prophylactic antibiotics. With the patient in the lithotomy position and 
under general anesthesia, transperineal saturation biopsies are obtained and separated in 
four sections: RIGHT CENTRAL, RIGHT PERIPHERAL, LEFT CENTRAL and LEFT 
PERIPHERAL.  
 
3.3 Focal RFA of the Prostate  
 
The equipment for whole-gland RFA of the prostate is FDA cleared for clinically 
localized prostate cancer, and the focal RFA equipment is also commercially available. 
The focal RFA equipment used in this study is cleared for radiofrequency soft tissue 
ablation by the FDA.   
 
Description of procedure use for the Focal RFA of the Prostate:  
The patient is given a Fleets enema prior to the procedure and administered prophylactic 
antibiotics. The procedure is performed on an outpatient basis under general.  With the 
patient in the lithotomy position a Foley catheter is inserted into the bladder and the 
scrotum is elevated toward the abdomen either by taping or with a rolled towel. Perineal 
shave is optional. The rectum is irrigated with normal saline to ensure adequate bowel 
preparation. The perineum is prepared sterilely.  
 
The bipolar RFA procedure is performed under transrectal ultrasound guidance.  
Transrectal ultrasound probe is inserted into the rectum.  The probe is then connected to a 
stepper stabilizer and the pelvis is visualized at 5mm stepping increments so that the 
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prostate, urethra, bladder, seminal vesicles, and anterior rectal wall can all be 
appropriately visualized. The ultrasound images and probe driving mechanism template 
are mated to allow accurate position of the probe so as to precisely target the regions of 
the prostate that were mapped during the biopsy. The desired target will be defined by 
which of the previously defined four regions of the prostate had positive biopsies as 
described above.  An appropriate insertion location of the bipolar RFA probes are 
designed in the planning process to target the regions of the prostate to be ablated (the 
number of probes will depend upon the size/shape of the prostate and the location of the 
lesions to be ablated.  
 
Designated regions of the prostate will be ablated via the ENCAGE™ (Trod Medical® 
Bradenton, FL) RFA system.  ENCAGE™ has FDA clearance for percutaneous RF soft 
tissue / tumor ablation.  The system consists of percutaneous probes connected to a RF 
bipolar generator which precisely controls the ablation.  Once the target areas for ablation 
have been identified on TRUS the ENCAGE™ RFA probe will be inserted 
percutaneously through the skin of the perineum into the prostate under ultrasound 
guidance.  Once the probe is positioned containing the prostate region designated for 
ablation, ablation will be initiated.  RFA will occur at 0.5 cm increments along the 
longitudinal axis of the prostate under ultrasound guidance initiating cranially towards 
the prostate base and moving caudally towards the apex.  The number of probes inserted 
percutaneously into the prostate will be predefined based on the target size and shape.  
Only one probe will be inserted at any time with prior probes removed before inserting 
the next.  Once ablation has been completed the prostate and bladder neck will be 
surveyed with the TRUS.  The TRUS probe will then be removed from the rectum and 
the Foley catheter will be deflated and removed from the bladder.  
 
3.4 Assessment of Quality-of-Life  
 
Assessment of quality of life (via completion of the questionnaires) will correlate with 
AUA symptom score, RAS, IIEF-15, and EPIC QOL. 
 
Medical Resource Utilization 
 
Medical resource utilization (MRU) will be recorded weekly through patient self-
report using a patient MRU diary. These MRU data will allow for a health economic 
evaluation of the ENCAGETM technology. 
 
 
4.0 CRITERIA FOR SUBJECT ELIGIBILITY  
 
4.1 Subject Inclusion Criteria  
             Subject Population: 
 Men 18 years of age or older  
 Diagnosis of adenocarcinoma of the prostate, confirmed by H.L. Moffitt 
Cancer Center  review 
 No prior treatment for prostate cancer  
 ECOG performance status of 0 or1 
 Prostate Cancer Clinical Stage T2a and below 
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 PSA <10 ng/ml (this will be the PSA level prompting the initial prostate 
biopsy) 
 Prostate size <60 cc on transrectal ultrasound 
 
Pre-enrollment biopsy parameters (as per H.L. Moffitt C.C. review) 
 Minimum of 10 biopsy cores 
 Gleason score 6 or 7 
 Unilateral cancer (only right-sided or left-sided, not bilateral) 
 
 
4.2      Subject Exclusion Criteria  
 Men less than 18 years of age  
 Medically unfit for anesthesia 
 Histology other than adenocarcinoma 
 Biopsy does not meet inclusion criteria 
 Men who have received any hormonal manipulation (antiandrogens; LHRH 
agonist; 5-alpha-reductase inhibitors) within the previous 6 months  
 
4.3    Inclusion of Women and Minorities:  All participants will be men without 
previous treatment for prostate cancer.   Men of all ethnic groups and races are 
eligible for the study. Thus women will not be included in this study.  
 
 
 
4.4 Recruitment Plan  
 
Potential research subjects will be identified by a member of the patient’s treatment team, 
the protocol investigator, or research team at H. L. Moffitt Cancer Center. If the 
investigator is a member of the treatment team, he/she will screen their patient’s medical 
records for suitable research study participants and discuss the study and their potential 
for enrolling in the research study. Potential subjects contacted by their treating physician 
will be referred to the investigator/research staff of the study. 
 
The principal investigator may also screen the medical records of patients with whom 
they do not have a treatment relationship with, for the limited purpose of identifying 
patients who are eligible to enroll in the study and to record appropriate contact 
information in order to approach these patients regarding the possibility of enrolling in 
the study.  
 
During the initial conversation between the investigator/research staff and the patient, the 
patient may be asked to provide certain health information that is necessary to the 
recruitment and enrollment process. The investigator/research staff may also review 
portions of their medical records at H. L. Moffitt Cancer Center in order to further assess 
eligibility. They will use the information provided by the patient and /or medical record 
to confirm that the patient is eligible and to contact the patient regarding study 
enrollment. If the patient turns out to be ineligible for the research study, the research 
staff will destroy all information collected on the patient during the initial conversation 
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and medical review, except for any information that must be maintained for screening log 
purposes.  
 
In most cases, the initial contact with the prospective subject will be conducted either by 
the treatment team, investigator or the research staff working in consultation with the 
treatment team. The recruitment process outlined presents no more than minimal risk to 
the privacy of the patients who are screened and minimal patient health information 
(PHI) will be maintained as part of a screening log.  
 
 
5.0 PRE-TREATMENT EVALUATION AND IMAGING 
 
The pre-enrollment clinical evaluation will include a complete medical history, physical 
examination including digital rectal examination, review of prostate biopsy information 
including Gleason score, review of any imaging studies, and clinical staging (TNM 
staging). Patients with up to clinical stage T2a prostate cancer meeting the 
aforementioned clinical and biopsy criteria are eligible for enrollment. If the patient had 
their diagnostic biopsy performed at an outside institution, these biopsy slides must be 
reviewed at our center prior to determining patient eligibility. If there is a discrepancy 
between the outside and H. L. Moffitt Cancer Center pathology reviews, we will rely on 
the H. L. Moffitt Cancer Center review to determine eligibility. 
Baseline visit: determine patient eligibility. If patient’s diagnostic prostate biopsy has not 
yet been reviewed at pathology, a request will be made to have pathology review the 
slides and provide a review for diagnosis. Once eligibility is confirmed and patient agrees 
to participate in the study an informed consent is signed. Pre-mapping imaging and 
biopsy assessment #1 (week 0 to 12): After the informed consent is signed, the patient 
will be scheduled for an MRI (DCE and DWI using a 1.5T MRI if possible with a 
Sentinal Endorectal coil).  The regions where both imaging sets indicate the potential for 
disease will be identified.  During the initial transrectal-guided mapping prostate biopsy, 
all acquired ultrasound images will be registered to the MRI images. Baseline laboratory 
studies including serum electrolytes, UA, PT/PTT/INR, CBC, electrocardiogram and 
chest xray will be performed on patients prior to the procedure. A consent (separate from 
the informed consent to participate in the study) for the biopsy procedure will be obtained 
per the Cancer Center’s policy for any procedure conducted for treatment/diagnosis.    
Patients will also be asked to complete an assessment (see appendixes A-D) of urinary, 
sexual and bowel functioning, as well as overall quality of life, at baseline.  These 
assessments will be completed at the beginning of the study and at 6 months after the 
RFA procedure during their clinic visit.  
6.0 TREATMENT/INTERVENTION PLAN  
Before any study procedures are performed (which includes all screening 
procedures, pre-treatment, treatment/intervention procedures, etc.), all patients will 
be asked to sign an informed consent form.  
Prior to the mapping prostate biopsy, patients will be required to have an EKG and Chest 
X-Ray. Eligible patients are evaluated with a transrectal-guided transperineal mapping 
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prostate biopsy. Patients meeting our definition of low-risk or intermediate prostate 
cancer (up to clinical stage T2a, PSA< 10ng/ml, Gleasons score 6 or 7), will undergo 
RFA of the regions containing cancer on the mapping biopsy (focal bipolar RFA). Six 
months following focal bipolar RFA the patient will undergo a second mapping biopsy. 
 
7.0 EVALUATION DURING TREATMENT/INTERVENTION   
Before any study procedures are performed (which includes all screening 
procedures, pre-treatment, treatment/intervention procedures, etc.), all patients will 
be asked to sign an informed consent form.  
Focal bipolar RFA will be done (after 4 weeks and no more than 12 weeks of initial 
mapping biopsy): a separate informed consent for this procedure will be obtained (which 
is separate from the informed consent to participate in the study), per the Cancer Center’s 
policy for any procedure conducted for treatment/diagnosis.  If the laboratory studies 
obtained at the pre-mapping biopsy assessment are still valid (within 6 months), they will 
not be repeated.  
Six weeks after focal bipolar RFA; DRE, PSA, assessment of toxicity will be done. 
Toxicity of transperineal prostate biopsy includes bleeding, infection, urinary retention. 
Toxicity of focal bipolar RFA includes bleeding, infection, urinary incontinence, urinary 
retention, erectile dysfunction, urinary urgency, urinary frequency and rectal fistula. 
Three months after focal RFA; DRE, PSA, assessment of toxicity will be done as 
mentioned in the preceding paragraph. 
 
Six months after focal bipolar RFA; DRE, PSA, QOL questionnaire, assessment of 
toxicity; obtain serum electrolytes, UA, EKG and chest x-ray in preparation for repeat 
mapping biopsy to be done. The patient will be scheduled for the second MRI imaging 
and transrectal-guided mapping prostate biopsy # 2 to be completed within 6-8 months 
after focal bipolar RFA. After a biopsy is requested we will have a patient follow up in 1-
2 weeks for discussion of results and assessment of any adverse events (this will be the 
end of study visit).   
 
Patients will record weekly medical resource utilization data to share with their study 
coordinator at routine scheduled visits. 
 
 
 
8.0 Adverse Event Reporting and Safety Monitoring 
 
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protocol.   
8.0.4  Non-protocol therapy is defined as any treatment or procedure not 
described in the protocol 
 
8.1 Adverse event assessment: 
8.11The type of event using NCI Common Toxicity Criteria for Adverse 
Events (CTCAE) version 4.0 will be identified and graded for 
severity. 
8.12 The relationship of the adverse event to the therapy or procedure will 
be determined as follows:  Unrelated; Unlikely; Possible; Probable; 
Definite 
8.13  For reporting purposes, an adverse event is considered unexpected 
when either the type of event or severity of the event is not listed in the 
study consent 
 
8.2 Serious Adverse Events (SAEs): 
8.2.1 All study-related, unexpected Grade 3 or 4 SAEs will be 
immediately reported to the IRB.  These toxicities will be reviewed 
by the principal investigator and appropriate measures taken in 
terms of delaying, modifying or stopping therapy. 
8.2.2 The descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.0 will be utilized for adverse event reporting 
(http://ctep.cancer.gov/reporting/ctc.html).  
8.2.3 SAEs must be followed until resolution or deemed irreversible.   
 
8.3   Routine reporting: 
8.3.1 Serious and/or unexpected adverse events will be reported to the 
IRB according to current IRB policy as well as Moffitt’s Protocol 
Monitoring Committee (PMC) according to current PMC policy.   
 
8.4 Potential Adverse Events that may occur as part of conducting this study 
include:  
Transperineal prostate biopsy: 
 Bleeding 
 Infection 
 Urinary retention 
 
 
Focal Bipolar RFA 
 Bleeding  
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 Infection 
 Urinary Incontinence  
 Urinary Retention 
 Erectile Dysfunction 
 Urinary Urgency 
 Urinary Frequency 
 Rectal Fistula 
 
9.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT  
The primary endpoint of this study is a negative prostate biopsy in the region that was 
radio frequency ablated 6 months after treatment. 
 
10.0 CRITERIA FOR REMOVAL/ WITHDRAWAL FROM STUDY   
 The study will be terminated if a rectal fistula develops in any patient as a result 
of treatment. 
 The patient may withdraw consent for the study at any time. If at any time the 
patient develops progressive disease he will be taken off the study and referred for 
alternative therapy. 
 If the participant is not following the study procedures as outlined in the protocol/ 
informed consent, he may be removed from the study.  If the participant is 
removed from the study, he will be referred for alternative therapy.  
 If at any time the patient is found to be ineligible for the protocol as designated in 
the section on Criteria for Patient/Subject Eligibility (i.e., a change in diagnosis, 
etc.), the patient will be removed from the study. 
 
 
 
 
11.0 BIOSTATISTICS  
 
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11.0 Statistical Consideration  
 
11.1 
Study Design/Endpoints 
 
 
This is a prospective study. The primary endpoint is safety of the procedure negative 
prostate biopsy rate at six months. The secondary endpoint is quality of life and safety of 
the procedure. 
 
11.2 Sample Size/Accrual Rate 
 
 
This is a pilot study so the sample size justification is based on providing reasonable 
precision of the primary efficacy endpoint, the negative biopsy rate at 6 months after 
focal bipolar RFA. We estimated the negative biopsy rate at 6 months after focal bipolar 
RFA is greater than or equal to 90%. If the negative biopsy rate at the 6-month visit is 
90%, a sample size of 20 patients provides a two-sided 95% confidence interval of 68.3-
98.8%. If the negative biopsy rate at the 6-month visit is 95%, the 95% corresponding 
confidence interval is 75.1-99.9%. Thus, the total sample size for this study will be 20 
patients. We estimate an accrual rate of 4 patients a month. We anticipate completion of 
this study over a one year time period.   
 
11.3 
Stratification Factors 
 
No stratification factors will be applied.  
 
 
 
11.4 Analysis of Primary Endpoint 
 
Descriptive statistics will be used to summarize patients’ demographic and clinical 
characteristics collected at each visit. Mean, standard deviation and range will be 
calculated for continuous variables, and frequency and percentage will be generated for 
categorical variables. The primary objective is to assess the local oncologic efficacy of 
focal RFA in men with low-risk prostate cancer. The primary efficacy endpoint is 
negative biopsy rate at 6 months after focal bipolar RFA. The point estimate and its 95% 
confidence interval will be calculated using the exact binominal method.  
 
11.5 Analysis of Secondary Endpoints 
 
The secondary objective is to evaluate the change from baseline in quality-of-life 
indicators following focal RFA in patients with low-risk localized prostate cancer. The 
patients will complete the EPIC, AUA, RAS, and IIEF-5 questionnaires at baseline, 3- 
and 6-month visit. The QOL will be primarily based on the EPIC, developed to measure 
health related quality of life among men with prostate cancer. The EPIC assesses the 
disease-specific aspects of prostate cancer and its therapies and comprises four summary 
domains (Urinary, Bowel, Sexual and Hormonal) [Wei et al, 2000]. The EPIC summary 
score and subscale characteristics at each time-point will be calculated based on its 
scoring instruction (http://roadrunner.cancer.med.umich.edu/epic/epicmain.html). The 
summary score of the AUA, RAS and IIEF-5 questionnaires will be also calculated. 
Descriptive statistics (mean, median, standard deviation and inter-quartile range) will be 
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applied to summarize the QOL scores at each time-point and the score change between 
the 3- or 6-month visit and baseline. The normal distribution assumption of these score 
changes will be evaluated. The QOL score change from baseline will be evaluated using 
either the paired t-test if the original or transformed data are normally distributed, or the 
Wilcoxon signed-rank test whenever the normality assumption cannot be justified. 
 
For safety analyses, the definitions of adverse event and serious adverse event were listed 
in Section 8.0. adverse event will be summarized by worst NCI CTCAE version 4.0 
grade and serious adverse event will be listed separately. Safety data, such as toxicity and 
laboratory test, will be summarized by time point of collection. Descriptive statistics will 
be calculated for quantitative safety data and frequency counts will be summarized for 
classifications of qualitative safety data.  
 
The image characteristics will be summarized using descriptive statistics. Mean, standard 
deviation and range will be calculated for continuous variables, and frequency and 
percentage will be generated for categorical variables. 
 
Analysis of Tertiary Endpoint 
 
The tertiary objective is to assess the potential health economic impact of focal RFA 
through the collection of medical resource utilization (MRU) data. Patients will collect 
weekly data on health care visits including clinician seen, indication for visit and any 
procedures associated with the visit. Descriptive statistics will summarize the frequency 
of visits by indication and will consider both visits captured in the MRU form as well as 
data collected on the adverse event form.  
 
Cost values will be assigned to health care visits based on the indication and 
procedures/evaluations completed as a part of the visit. These costs will be assigned 
throughout the 6 month duration of the study to estimate the average cost of MRU after 
focal RFA.  
 
12.0 RESEARCH PARTICIPANT REGISTRATION  
Confirm in the electronic medical record that the patient has received the Notice of 
Privacy Practice. This must be obtained before the eligibility confirmation and obtaining 
of the research informed consent. 
 Confirm eligibility as defined in the section entitled Criteria for Patient/Subject 
Eligibility. 
 Obtain written informed consent from each patient 
 
 
 
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13.0 DATA MANAGEMENT ISSUES  
The clinical research nurse/study coordinator responsibilities include: project compliance, 
data collection, abstraction and entry, data reporting, regulatory monitoring, problem 
resolution and prioritization, and coordinate the activities of the protocol study team. 
The data collected for this study will be entered into a secure database at Biomed. Source 
documentation will be available to support the computerized patient record. 
13.1    Quality Assurance  
Weekly registration reports will be generated to monitor patient accruals and 
completeness of registration data. Routine data quality reports will be generated to 
assess missing data and inconsistencies.   Accrual rates and extent and accuracy of 
evaluations and follow-up will be monitored periodically throughout the study 
period and potential problems will be brought to the attention of the study team 
for discussion action. Random-sample data quality and protocol compliance 
audits will be conducted by the study team, at a minimum of two times per year, 
more frequently if indicated 
Data collection and record keeping 
 
13.2  
Data monitoring and sponsor CRFs collection will be 
performed by Biomed Research. The clinical data for this 
protocol will be recorded on patient Case Report Forms 
(CRF’s) printed on 3-part NCR and bound into individual 
patient booklets. Once all data queries are resolved for a given 
data form, the white copy will go to the sponsor (Trod), the 
yellow copy will go to MCC data management, and the pink 
copy will stay with the MCC clinical coordinator for study 
archiving. Biomed will monitor conformance to the protocol 
informed consent, AE’s, etc. as well as verify random CRF’s to 
source documents and work with MCC to resolve data queries. 
Biomed will be responsible to collect the sponsor’s copy 
(white) of the completed/verified/signed CRF’s, but Biomed 
will not retain sponsor CRF’s. 
13.2.1 
Identifying patient information will be kept confidential. CRF’s 
will not contain the patient’s MRN, name, etc. only, a “Subject 
Record ID No (3 digits)” and “Subject Initials” (F, M, L). The 
Clinical Research Nurse/Coordinator at Moffitt will maintain 
the “key” that links patients (with their name, MRN, etc.) to 
their “Subject Record No.” The “key” will be destroyed upon 
completion of data analysis for this study. Identifying patient 
information will be kept confidential. All direct identifying 
(name, medial record number, etc.) will be destroyed and 
removed from the computer upon completion of data analysis for 
this study. 
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13.2.2   
Representatives of the IRB, OHRP, Moffitt Committees and 
Center for Medicare and Medicaid Services (CMS) will have 
access to patient information as it pertains to the study. 
13.2.3    
Privacy and confidentiality of the information will be protected 
to the extent provided by the law. 
13.2.4    
The Principal Investigator and the Clinical Research 
Nurse/Coordinator assigned to the study protocol will be 
primarily responsible for maintaining all study related 
documents including the clinical research forms, as well as for 
providing the sponsor with its copy of each completed CRF.  
All data collection will be performed on hard-copy (3-part 
NCR) CRF’s.  The review of medical records (by the study 
team at Moffitt) within the Cancer Center’s institutional 
database will be done in a manner to assure that patient 
confidentiality (PHI) is protected and maintained at all times.  
 
14. ETHICS/ HUMAN SUBJECT’S PROTECTION  
 
14.1 Patient Consent:  Patients who are candidates for this study at Moffitt Cancer 
Center will be approached for this study.  Patients meeting the eligibility criteria will 
be consented using the IRB approved consent form.  The consent will be verbally 
explained to the participant by a member of the research team, describing the study 
procedures, risks, benefits, etc.  Patients must be freely consenting adults.  Patients 
who meet eligibility criteria and provide informed consent as documented by a signed 
consent form by the clinical note of the consenting investigator will be enrolled in this 
study.  All subjects interested in participating in this study will be given a copy of the 
informed consent form to read and sign. Each subject who is interested in 
participating in this study will be asked to sign and date the IRB approved consent 
form. All discussions related to participating in this study and obtaining informed 
consent will take place in a private room in the clinic at Moffitt to ensure the privacy 
and confidentiality of each subject is protected. Only members of the research team 
will be involved in this process and have access to the signed consent forms. All 
signed consent forms will be stored in a locked file cabinet. 
 
14.2 Regulatory Approval:  The trial will be approved by both the H. Lee Moffitt 
Cancer Center and Research Institute’s Scientific Review Committee (SRC) and the 
Institutional Review Board (IRB).  
 
14.3 Protocol Modifications:  No modifications will be made to the protocol and 
implemented without the agreement of the investigators and approval from the 
Moffitt Scientific Review Committee (SRC) and the Institutional Review Board 
(IRB). Changes that significantly affect the safety of the patients, the scope of the 
investigation, or the scientific quality of the study will require approval from the SRC 
and IRB prior to implementation, except where the modification is necessary to 
eliminate apparent immediate hazard to human subjects. Any departures from the 
protocol will be documented in the case report form and the source documentation 
and reported the SRC and IRB.  
  
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 14.4 Potential Risks: There are risks associating with having any type 
of surgery.  The surgery team will explain these risks to the potential 
participants and inform them they will be asked to sign a separate 
consent form for the standard of care treatment and if they agree to 
participate, an informed consent to participate in this research study. 
These risks include bleeding, infection, urinary incontinence, risk of 
anesthesia 
related 
complications, 
urinary 
retention, 
erectile 
dysfunction, urinary urgency, frequency and rectal fistula. There are 
also psychological risks associated with completing the quality of life 
questionnaires. 
 
 As with any research study, there is always a potential risk of unintentional 
disclosure of protected personal health information (PHI); however, every precaution 
will be taken to ensure all PHI and data collected as part of this study is kept 
confidential.  All data will be kept confidential.   
 
14.5: Potential Benefits: Participants will not directly benefit for taking part in this 
study.  We hope that the results of this study will someday benefit future patients with 
prostate cancer. 
 
 
14.6: Payment and Costs:   
 
14.6.1: Payment 
Participants will not be paid to participate in this study.   
 
14.6.2: Costs to Participate 
There will be no extra cost to patients as a result of participating in this study.  
Costs of standard medical care for RFA, including all costs of the surgery, lab 
work, etc. will be charged to the patient and/or their insurance company.  
Participants and/or their insurance company will be financially responsible for 
hospital inpatient, outpatient and follow-up visits that would normally or routinely 
occur in the management of their disease. Inpatient and outpatient visits could include 
charges for treatments, medications, physician visits, laboratory tests and procedures. 
Participants and /or their insurance company will be responsible for paying for the 
charges which are considered routine, since they would have received these services 
even if they were not participating in this study. Participants will be responsible for 
any costs not covered by their insurance company, including deductibles, co-
payments and all out-of-pocket expenses. Participants and/or their insurance company 
will not be responsible for paying for the following testing and procedures that are 
specifically required for this research study and are not considered part of the routine 
management of their disease, if these procedures are performed at Moffitt Cancer 
Center.  
 
 
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 Wei JT, Dunn RL, Litwin MS, Sandler HM, Sanda MG.Development and 
validation of the expanded prostate cancer index composite (EPIC) for 
comprehensive assessment of health-related quality of life in men with prostate 
cancer.Urology. 2000;56(6):899-905. 
 
 
 
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APPENDIX A 
 
 
___________________________________________ 
 
________________ 
Signature of Patient or Legal Representative     
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Signature of Person Completing Form (if not patient)               
Relationship to Patient                         
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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APPENDIX B RECTAL ASSESSMENT SCALE –(RAS) 
 
Date of Visit:   
 
 
 
 
    
 
Total Score:  
 
       
 
Please fill out this short questionnaire to help us find out more about any problems you may 
be having with diarrhea.  Check the statement for each subject that best describes your 
situation during the past 7 days. 
 
 
0 
1 
2 
3 
 
Frequency of 
stools per day: 
 
[  ] 0-1 Stools 
per day 
 
[  ] 2 Stools per 
day 
 
[  ] 3 Stools per 
day 
 
[  ] 4 or more 
stools per day 
 
 
Consistency of 
stools per day: 
 
[  ] All stools 
formed 
 
[  ] Stools formed 
and loose 
 
[  ] Stools loose  
 
[  ] Watery stools 
 
 
Urgency of stools 
 
 
[  ] No 
urgency 
 
[  ] Somewhat 
urgent 
 
[  ] Urgent 
 
[  ] Very urgent 
 
 
Abdominal 
discomfort: 
 
[  ] No 
discomfort 
 
[  ] Mild-
moderate 
discomfort 
 
[  ] Somewhat 
severe 
discomfort 
 
[  ] Very severe 
discomfort 
 
 
Hemorrhoid 
discomfort 
 
[  ] No 
discomfort 
 
[  ] Requires mild 
treatment   
     (e.g. Tucks, 
sitz baths) 
 
[  ] Requires 
topical medication  
     (e.g. 
Preparation H., 
etc.) 
 
[  ] Requires oral 
analgesics or 
narcotics for pain 
relief 
 
Adapted from: RAS 
                  
                     
 
 
___________________________________________ 
 
________________ 
Signature of Patient or Legal Representative     
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Signature of Person Completing Form (if not patient)               
Relationship to Patient                        
 
 
 
 
 
 
 
 
 
 
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APPENDIX C 
 
 
 
 
 
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APPENDIX D 
 
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 ID: ___ ___ - ___ ___ ___ 
INITIALS: ___ ___ ___ 
 
 
Site 
Subject 
F 
M 
L 
 
Medical Resource Utilization Patient Diary 
Patient Instructions:   
Please complete the form below weekly by providing detail on non-study related health care visits. If there 
were multiple visits within a single week, please list out each individual visit. 
 
Date 
Did you 
have a 
health 
care 
visit this 
week 
(Y/N)? 
 
If yes, how 
many 
healthcare 
visits did 
you have 
this week, 
and where 
did you 
visit? 
For each of the 
visits, who did 
you see during 
this visit?  
(e.g., nurse, 
physician 
assistant, or  
physician) 
What was 
the primary 
reason for 
this visit? 
Did the 
healthcare 
personnel 
say the visit 
was related 
to the RFA 
procedure1 
(Y/N)? 
What  
treatment 
did you 
receive 
during this  
visit, if any? 
Week 
13: 
 
 
 
 
 
 
 
Week 
14: 
 
 
 
 
 
 
 
Week 
15: 
 
 
 
 
 
 
 
Week 
16: 
 
 
 
 
 
 
 
Week 
17: 
 
 
 
 
 
 
 
Week 
18: 
 
 
 
 
 
 
 
Week 
19: 
 
 
 
 
 
 
 
Week 
20: 
 
 
 
 
 
 
 
Week 
21: 
 
 
 
 
 
 
 
Week 
22: 
 
 
 
 
 
 
 
Week 
23: 
 
 
 
 
 
 
 
Week 
24: 
 
 
 
 
 
 
 
1. Note to MCC clinical coordinator: If the patient’s response to this question is “Y” an AE form must also be completed. 
CRF: MRU PATIENT DIARY 
CONFIDENTIAL 
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Version 05/23/2014                                                                                                                                                page 2 of 2 
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