Phase II Study Assessing the Potential for Reduced Toxicity Using Focal Brachytherapy Early Stage, Low Volume in Prostate Cancer
Phase: PHASE2
Conditions: Prostate Cancer
Sponsor: Memorial Sloan Kettering Cancer Center

 
 
MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 11-056 A(3) 
 
 
Phase II Study Assessing the Potential for Reduced Toxicity Using Focal Brachytherapy in Early 
Stage, Low Volume Prostate Cancer 
 
 
 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
 
 
Principal Investigator/Department: 
Michael Zelefsky, MD 
Radiation Oncology 
Co-Principal 
Investigator(s)/Department: 
Jonathan Coleman, MD 
Surgery 
Investigator(s)/Department: 
Marisa Kollmeier, MD 
Yoshiya Yamada, MD 
Marco Zaider, PhD 
Gilad Cohen, BS 
James Eastham, MD 
Brett Carver, MD 
Victor Reuter, MD 
Samson Fine, MD 
Oguz Akin, MD 
Stephen Solomon, MD 
Zhigang Zhang, PhD 
Radiation Oncology 
Radiation Oncology 
Medical Physics 
Medical Physics 
Surgery 
Surgery 
Pathology 
Pathology 
Radiology 
Radiology 
Epidemiology and 
Biostatistics 
Consenting Professional(s)/Department: Michael Zelefsky, MD 
Marisa Kollmeier, MD 
Yoshiya Yamada, MD 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
 
 
 
 
 
Participating Institutions 
PI's Name 
Site's Role 
University of Colorado 
David Raben, MD 
Data Collection 
MD Anderson Cancer Center 
Steven Frank, MD 
Data Collection 
North Shore- LIJ Health System 
Louis Potters, MD 
Data Collection 
 
 
 
 
 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
 
 
 
 
 
 
Amended: 11/06/12 
Page 1 of 27 

MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 11-056 A(3) 
Amended: 11/06/12 
- 2 - 
 
 
Table of Contents 
 
 
 
 
 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ......................................................................... 3 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS .................................................................................. 4 
 
Primary Objective .......................................................................................................................... 4 
 
3.0 
BACKGROUND AND RATIONALE ....................................................................................... 5 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION................................................................ 7 
 
4.1 
Design................................................................................................................................. 7 
 
4.2 
Intervention ......................................................................................................................... 7 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ............................................................................... 7 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ............................................................................... 8 
 
6.1 
Subject Inclusion Criteria..................................................................................................... 8 
 
6.2 
Subject Exclusion Criteria ................................................................................................... 8 
 
7.0 
RECRUITMENT PLAN ........................................................................................................... 8 
 
8.0 
PRETREATMENT EVALUATION .......................................................................................... 9 
 
9.0 
TREATMENT/INTERVENTION PLAN.................................................................................... 9 
 
9.1 Re-staging Prostate Biopsy.................................................................................................... 10 
 
9.2 Focal Brachytherapy of the Prostate ...................................................................................... 11 
 
9.3 Assessment of QOL............................................................................................................... 12 
 
10.0 EVALUATION DURING TREATMENT/INTERVENTION ..................................................... 13 
 
11.0 TOXICITIES/SIDE EFFECTS ............................................................................................... 13 
 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ......................... 14 
 
13.0 CRITERIA FOR REMOVAL FROM STUDY ......................................................................... 15 
 
14.0 BIOSTATISTICS .................................................................................................................. 15 
 
15.0 RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES.... 16 
 
15.1 Research Participant Registration ..................................................................................... 16 
 
15.2 Randomization .................................................................................................................. 17 
 
16.0 DATA MANAGEMENT ISSUES ........................................................................................... 17 
 
16.1 Quality Assurance ............................................................................................................. 19 
 
16.2 Data and Safety Monitoring ............................................................................................... 20 
 
17.0 PROTECTION OF HUMAN SUBJECTS .............................................................................. 22 
 
17.1 Privacy .............................................................................................................................. 23 
 
17.2 Serious Adverse Event (SAE) Reporting ........................................................................... 23 

MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 11-056 A(3) 
Amended: 11/06/12 
- 3 - 
 
 
18.0 INFORMED CONSENT PROCEDURES .............................................................................. 24 
 
19.0 REFERENCES ..................................................................................................................... 26 
 
20.0 APPENDICES ...................................................................................................................... 27 
 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
Men diagnosed with early stage, low volume prostate cancer (defined as clinical stage T1c-T2a, 
prostate-specific antigen (PSA) <10 ng/mL, biopsy with a minimum of 10 cores, Gleason grade  7 in 
two cores or less with no primary Gleason grade 4 or 5 in any core, no individual biopsy core with 
>50% cancer, unilateral cancer and no more that 25% of cores containing cancer) and a total 
prostate volume of < 60 cc at the time of treatment are eligible for this study. Patients will undergo a 
repeat transrectal or transperineal ultrasound-guided prostate biopsy (minimum of 12 cores) to 
confirm the early stage, low volume nature of their cancer. In order to be enrolled into this study, 
patients must meet the original pathology entry criteria on this repeat biopsy. If the patient meets the 
eligibility criteria as stated above, he will be treated with focal brachytherapy to the involved lobe of 
the prostate containing cancer. 
 
As the primary endpoint of this study is to determine if this treatment approach would be associated 
with significantly less late grade 2 and higher urinary or rectal toxicities compared to whole gland 
brachytherapy, patients will be monitored at 3 month intervals during the first two years. Efficacy is a 
secondary endpoint of this study and is defined as all negative biopsy cores in the treated lobe on a 
repeat biopsy 12 and 24 months after completion of focal brachytherapy. 
 
At baseline (prior to the transrectal or transperineal biopsy) and at 3, 6, 12, 18, and 24 months (prior 
to the repeat biopsies used to define efficacy), the patient will be monitored for side effects including 
urinary and rectal related effects as well as sexual function and serial quality-of-life (QOL) 
questionnaires will be administered. Digital rectal examination (DRE) and PSA tests will be 
performed at the 3 (DRE optional at 3 months) and 6 month follow-up visits and every 6 months for 
24 months. Transrectal or transperineal ultrasound-guided biopsies will be performed at the 12 and 
24 month follow-up visit. Imaging (endorectal or pelvic coil MRI) will be performed at baseline and at 
6 (optional), 12, and 24 months after the completion of focal brachytherapy procedure. Endorectal 
coil MRI is preferred, though not required. 
 
Following completion of the study, patients will undergo standard care procedures, including a DRE 
and serum PSA level every 6 months for 5 years and annually thereafter. The need for any future 
prostate biopsies will be at the physician’s discretion. 
 
Target accrual for this study is 80 patients, approximately 20 per site, to be achieved in 2-3 years of 
accrual. 

MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 11-056 A(3) 
Amended: 11/06/12 
- 4 - 
 
 
 
 
 
 
 
 
 
Schema 
 
 
Patient with early stage, low volume 
prostate cancer at diagnosis1 
 
 
Baseline endorectal or pelvic coil MRI 
Transrectal or Transperineal prostate biopsy 
 
 
 
Early stage, low volume prostate 
cancer confirmed 
 
 
QOL Survey 
 
 
Registration 
 
 
Focal 
brachytherapy2 
 
Endorectal or pelvic coil MRI at baseline, 6 (optional), 12, and 24 months 
QOL survey at baseline, 3, 6, 12, 18 and 24 months 
Transrectal or transperineal prostate biopsy at baseline, 12 and 24 months after brachytherapy 
 
1Clinical stage T1c-T2a, PSA <10 ng/mL, unilateral cancer, biopsy with a minimum of 10 cores, 
Gleason grade 7 in two cores or less with no primary Gleason grade 4 or 5 in any core, no 
individual biopsy core with >50% cancer, and no more than 25% of cores containing cancer. 
 
2 If there is greater than 30 days between consent and treatment start, patients will need to be re- 
consented prior to treatment. 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
Primary Objective 
To assess the late, 6 months to 2 years, toxicity outcomes of focal brachytherapy in patients with 
early stage, low volume prostate cancer. Given the reduced volume of the treated region, we 
expect significantly less rectal, urinary and sexual dysfunction among treated patients compared to 
expected tolerance outcomes with whole gland brachytherapy. 
 
Secondary Objectives 
 
1.  To evaluate the local tumor control after focal brachytherapy as measured by the ability to 
obtain all negative biopsy cores 12 and 24 months after completion of therapy in the hemi- 

MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 11-056 A(3) 
Amended: 11/06/12 
- 5 - 
 
 
gland of where the focal therapy was administered. “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, or adenocarcinoma with 
severe treatment effect) it will be considered negative for study purposes. 
 
2.  To evaluate the change from baseline in QOL indicators following focal brachytherapy in 
patients with low-risk localized prostate cancer. 
 
3.  To correlate post-treatment MRI  findings with post-treatment biopsy outcomes 
 
 
 
3.0 
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 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 (1). Among 2,950 men with negative DRE and PSA levels <4.0 ng/mL, 15.2% 
harbored prostate cancer by biopsy, as did 6.2% of men with PSA levels ≤ 0.5 ng/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 the Memorial Sloan-Kettering 
Cancer Center (MSKCC) radical prostatectomy series suggests 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 <0.5 cm3, 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. 
 
There are ongoing studies in various institutions exploring the role of focal therapy for early stage 
prostate cancer (2-8). While the tumor control outcomes for such therapy should be comparable to 
whole gland therapy, it has not been established or tested whether these highly selected early stage 
tumors require treatment to the whole gland. Indeed, the irradiation of the whole gland subjects the 
patients to increased risks of morbidity including chronic urethritis, rectal bleeding and erectile 
dysfunction. Given the fact that the dominant reasons patients with early stage therapy select a 
specific treatment intervention such as surgery or irradiation is often based on quality of life and 
psychological issues, exploring modes of treatment intervention for early stage of disease which 
could be associated with significantly lower rates of morbidity and impairment on their quality of life 
is important. 
 
Advantages of Focal Therapy: 

MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 11-056 A(3) 
Amended: 11/06/12 
- 6 - 
 
 
While deferring definitive therapy (active surveillance, watchful waiting, expectant management) until 
evidence that the cancer is sufficiently aggressive to warrant therapy may be appropriate for many 
patients with a favorable (early stage, low volume) cancer, most 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 
major disadvantage of watchful waiting is that the cancer is not treated, while the major 
disadvantage of surgery/radiation is that there is a significant risk of urinary, bowel, and sexual side 
effects. Using real-time intraoperative techniques, brachytherapy is amenable and well suited for 
focal treatments. 
 
The other advantage for focal brachytherapy which is the primary objective of our study is to 
corroborate reduced toxicity outcomes with the treatment of a smaller target volume. Such an 
approach can more easily spare the urethra, rectum and neurovascular bundles more effectively 
from the high doses of irradiation. Many studies have demonstrated that the volume of irradiated 
normal tissue correlates with morbidity outcomes. In these studies higher doses to the urethra, 
rectum and neurovascular bundle were directly associated with increased rates of dysfunction and 
morbidity (9-11). In our published experience using whole gland brachytherapy in 448 patients the 
incidence of late grade 2 rectal bleeding is 5%, the risk of late grade 2 chronic urethritis is 15% and 
the incidence of erectile dysfunction is approximately 40% (12). We hypothesize that treatment of a 
hemilobe of the prostate rather than whole gland treatment for selected early stage tumors will 
reduce by >30% these respective morbidities. A future goal is also to compare these side effect 
profiles to contemporarily treated patients who receive whole gland brachytherapy. Once we obtain 
from this study the incidence of side effects experienced with focal brachytherapy we would consider 
the design of a randomized trial to compare to similar patients who receive standard whole gland 
brachytherapy. 
 
This protocol will investigate the tolerance profile of focal brachytherapy in a well-defined, early 
stage, low volume prostate-cancer population and in addition will examine treatment efficacy 
(elimination of the cancer) as well as changes from baseline in QOL. While PSA is often used to 
assess the response of treatment and while biochemical control is considered a surrogate for local 
tumor control, this marker is recognized to be insufficient to assess the response after focal therapy. 
For this reason serial MRI studies as well as 12 and 24 month biopsies will be used to monitor the 
response of focal therapy. Local control will also be considered negative if the biopsy contains 
inflammation or pre-cancerous changes (high-grade prostatic intraepithelial neoplasia and/or 
atypical small acinar proliferation, or adenocarcinoma with severe treatment effect). It will also be 
considered negative for study purposes if no recurrence of cancer is noted within the irradiated lobe. 
Given the limited scope of the irradiated area we would not anticipate significant risk or morbidity if 
the area was subsequently treated with whole gland irradiation or salvage surgery. 
 
Our QOL survey is based on the previously validated MSKCC prostate cancer QOL outcomes 
instrument (13). Erectile function will be assessed using the six-question version of the International 
Index of Erectile Function, a validated and widely used measure. For urinary function, we will use a 
five-question scale that constitutes a subset of the urinary outcomes on the MSKCC instrument: 
correlation between the score on these five questions and the scores on the complete instrument is 
0.9. In a limits-of-agreement analysis, the difference was 1.7, with an 80% confidence interval of 
−7.5, 10.8. We feel that these are acceptable properties for a 0-100 scale. The Cronbach’s α for 

MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 11-056 A(3) 
Amended: 11/06/12 
- 7 - 
 
 
these six items was also good, at 0.82. Two bowel questions from the full questionnaire, "How often 
have bowel problems or bowel pain made it difficult to enjoy your life?" and "How big a problem have 
your bowel habits been for you?" had a high Pearson's rho (0.91) compared to the full domain score 
(limits of agreement difference of −2.3; 80% confidence interval −13.9, 9.3). These two questions will 
therefore be used in the questionnaire. Finally, we will ask a general health-related QOL question 
using a 0-10 scale. The full instrument is given in appendix A. 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.1 
Design 
 
This is a multi-center, non-randomized, Phase II study examining the tolerance profile (primary 
endpoint) as well as the secondary endpoints of QOL changes, efficacy and the correlation of post- 
treatment MRI findings with post-treatment biopsy outcomes in men with early stage, low volume 
prostate cancer treated with focal brachytherapy. We will test the hypothesis that the 2-year 
probability of rectal bleeding, grade 2 urethritis or erectile dysfunction for patients treated with focal 
ablation will be reduced by 30% or greater compared to our aforementioned published experience of 
whole gland brachytherapy. 
 
4.2 
Intervention 
 
Patients will undergo a re-staging transrectal or transperineal ultrasound-guided prostate biopsy as 
currently performed at participating institutions. Prostate biopsy will be performed under general or 
local anesthesia using a standard transrectal or transperineal approach that obtains no fewer than 
12 biopsy cores. For patients to be eligible for treatment with focal brachytherapy under this 
protocol, they must meet the original entry criteria on this re-staging biopsy. 
 
If after the re-staging biopsy the patient does not meet the criteria for focal brachytherapy, he will be 
considered for other treatment options for prostate cancer including active surveillance, radical 
prostatectomy, external beam radiation therapy, or whole-gland brachytherapy. 
 
Focal brachytherapy will be performed at least 8 weeks following the transrectal or transperineal 
biopsy, though it may be performed sooner if the patient has recovered from the repeat biopsy and 
the treating physician determines it is safe to proceed with treatment. Focal brachytherapy is 
performed under a spinal or general anesthesia and will include the hemilobe of the prostate 
containing cancer, based on the re-staging biopsy. The regions will be targeted with the prescription 
dose and receive 144 Gy of Iodine-125 (I-125). This is an outpatient procedure. Prior to discharge, 
the Foley catheter (inserted routinely during the brachytherapy procedure) will be removed. 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
Whole-gland brachytherapy is a standard and accepted treatment for clinically localized prostate 
cancer. Focal brachytherapy will merely entail the treatment of the involved lobe where the biopsy 
cores are positive and sparing the rest of the gland from the high-dose therapy. The actual 
brachytherapy procedure itself will be otherwise identical to standard whole-gland brachytherapy 
procedure in technique, treatment-planning aspects, and treatment delivery as described in section 
9.0. 

MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 11-056 A(3) 
Amended: 11/06/12 
- 8 - 
 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.1 
Subject Inclusion Criteria 
 
• 
Men ≥ 21 years of age with a life expectancy estimated to be > 10-years 
• 
Diagnosis of adenocarcinoma of the prostate confirmed by MSKCC or participating 
site pathology review 
• 
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1(Appendix 
C) 
• 
Prostate cancer clinical stage T1c-T2a 
• 
PSA < 10ng/mL (this will be the PSA level prompting the prostate biopsy) 
• 
MRI evidence of one-sided disease performed within 3 months of registration 
• 
Prostate size <60 cc at time of treatment- if the prostate is larger, hormonal therapy is 
allowed to achieve the required size 
 
Screening biopsy parameters: 
 
• 
Minimum of 10 biopsy cores 
• 
Gleason grade 7 in two cores or less, with no primary Gleason grade 4 or 5 in any 
cores 
• 
Unilateral cancer (only right-sided or left-sided, not bilateral) 
• 
No more than 50 % cancer in any one biopsy core 
• 
No more than 25 % of cores containing cancer 
 
Repeat transrectal or transperineal prostate biopsy that must meet the following parameters: 
 
• 
Minimum of 12 biopsy cores 
• 
Unilateral cancer (only right-sided or left-sided, not bilateral) 
• 
Gleason grade 7 in two cores or less, with no primary Gleason grade 4 or 5 in any 
cores 
• 
No more than 50 % cancer in any one biopsy core 
• 
No more than 25 % of cores containing cancer 
 
6.2 
Subject Exclusion Criteria 
 
• 
Medically unfit for anesthesia 
• 
Evidence or suspicion of extracapsular extension on MRI 
• 
IPSS score > 18 
• 
Unable to receive MRI 
• 
Prior radiotherapy for the current disease 
 
7.0 
RECRUITMENT PLAN 
 
Recruitment Plan (with Limited waiver of Authorization) 
 
Investigators and their research teams at University of Colorado, MD Anderson Cancer Center and 
North Shore-LIJ Health Systems will recruit patients at their respective sites. 
 
Potential research subjects will be identified by a member of the patient’s treatment team, the 
protocol investigator, or research team at Memorial Sloan-Kettering Cancer Center (MSKCC). If the 
investigator is a member of the treatment team, s/he will screen their patient’s medical records for 
suitable research study participants and discuss the study and their potential for enrolling in the 

MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 11-056 A(3) 
Amended: 11/06/12 
- 9 - 
 
 
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 for the limited purpose of identifying patients who would be 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 MSKCC 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 and medical records 
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 PHI will be maintained as part of a screening log. For these reasons, 
we seek a (partial) limited waiver of authorization for the purposes of (1) reviewing medical records 
to identify potential research subjects and obtain information relevant to the enrollment process; (2) 
conversing with patients regarding possible enrollment; (3) handling of PHI contained within those 
records and provided by the potential subjects; and (4) maintaining information in a screening log of 
patients approached (if applicable). 
 
 
We plan to accrue 80 patients (approximately 20 per site) within 2-3 years. 
 
 
 
8.0 
PRETREATMENT EVALUATION 
 
The baseline clinical evaluation is to be completed before the transrectal or transperineal, 
ultrasound-guided prostate biopsy. These procedures, which are standard of care, will include: 
 
• 
Medical history 
• 
Physical examination including DRE 
• 
Review of prostate biopsy information including Gleason score and clinical staging 
(TNM staging). Note: If the patient had his diagnostic biopsy performed at an outside 
institution, these biopsy slides must be reviewed at either MSKCC or one of the 
participating centers prior to determining patient eligibility. If there is a discrepancy 
between the pathology reviews, we will rely on the MSKCC or participating center 
review to determine eligibility. 
• 
QOL assessment 
• 
Endorectal or pelvic coil MRI (within 3 months of registration) 
• 
PSA 
 
9.0 
TREATMENT/INTERVENTION PLAN 

MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 11-056 A(3) 
Amended: 11/06/12 
- 10 - 
 
 
9.1 Re-staging Prostate Biopsy 
9.1.1 Transrectal Prostate Biopsy: 
 
Preparation/anesthesia: The patient will be administered prophylactic antibiotics as per 
standard of care. The biopsy is performed by the urologist on an outpatient basis under local 
anesthesia. With the patient in the left lateral decubitus position, 2% lidocaine gel is instilled 
per rectum followed by the ultrasound probe. Serial images of the prostate are taken in 
transverse and sagittal planes. 
 
Approximately 5 cc of lidocaine may be injected in the angle between the seminal vesicle 
and base of the prostate on each side. 
 
A minimum of 12 prostate biopsy specimens are obtained. Cores are placed in the same 
specimen container containing formalin and submitted to pathology for histologic 
examination. 
 
Required equipment and setup: Techniques for transrectal prostate biopsy will employ an 
endocavity ultrasound probe with biopsy needle guide. The lubricated probe will be placed in 
the rectum and the prostate gland will be imaged manually by hand to identify the base, mid 
and apex anatomy. Core biopsies will be taken from medial and lateral portions of the 
prostate. The biopsy needle is capable of obtaining core lengths of 2.2 cm. 
 
9.1.2 Transperineal Prostate Biopsy: 
 
The location and grade of the subject’s prostate cancer may be documented via transrectal 
ultrasound guided transperineal 3-dimensional prostate mapping biopsy as described by 
Crawford et al. (Clinical Staging of Prostate Cancer: A Computer-simulated Study of 
Transperineal Prostate Biopsy, BJU Intl., Vol. 96, pp. 999-1004, 2005). 
 
This procedure is performed under general anesthesia.  A Foley catheter may be placed to 
mark the location of the urethra and assess the subject for post-biopsy hematuria for a 
recommended 2-5 days.  A biplane transrectal ultrasound probe may be placed in the rectum 
to visualize the prostate and assist in needle guidance and placement. 
 
The G x axis of the brachytherapy grid may be placed in the midline urethral plane for 
ultrasound prostate orientation. A 5mm Civco Brachytherapy Grid with coordinates of A-M on 
the x axis and 0-12 on the y axis may be used to identify biopsy location and to guide biopsy 
needles in relation to the ultrasound generated biopsy grid. To assist in this location, two 
fiducial markers may be placed, one in each hemisphere approximately midline within the 
prostate, in an apex/base relationship. Prior to placement of the fiducial seeds, the two 
coordinates selected for these markers may be biopsied in the appropriate fashion. The 
fiducial seeds may be dropped in their respective locations as described, and the fiducial 
needles may be left in place to stabilize the prostate throughout the remaining biopsy 
procedure. Prior to biopsy, multiple jpeg images may be sampled under ultrasound guidance 
at 5mm increments from extreme apex to extreme base utilizing the mounted stepping unit in 
order to aid in 3D reconstruction. These images may be saved to a removable storage 
device.  Using a 22mm, 18 gauge automated biopsy gun with a 2 cm specimen size, biopsies 
may be obtained every 5 mm throughout the volume of the prostate under transrectal 

MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 11-056 A(3) 
Amended: 11/06/12 
- 11 - 
 
 
ultrasound guidance. 
 
Depth of the needle placement may be monitored with the ultrasound longitudinal view in 
order to sample the entire length of the prostate and avoid punctures to the bladder base. 
The axial ultrasound view may be checked periodically to confirm that samples are taken in 
the correct x y coordinates, corresponding to the grid rendered on the BK Falcon (or newer) 
ultrasound machine. Where the length of the prostate is greater than the specimen size of a 
single biopsy at a given coordinate, additional biopsies may be obtained at that location in 
order to sample the full length of the prostate.  Biopsies in the area of the urethra or 
neurovascular bundles may be avoided in order to prevent any subsequent damage. 
 
Biopsy samples may be inked utilizing Davidson Marking Systems # 1003-3 ink at their distal 
end (distal in relation to the biopsy needle body), placed in a formalin biopsy jar,  labeled with 
their respective x y brachytherapy grid coordinates, and sent to a respective pathology lab for 
analysis.  If more than one biopsy is taken at a given x y coordinate, it may also be labeled 
as to whether it was base, apex, or midline. 
 
Dependent on the size of the prostate, the number of biopsy samples may vary between 30- 
150 samples. The whole procedure can last anywhere between 60-90minutes. 
 
Patients meeting our definition of early stage, low volume prostate cancer (clinical stage T1c-T2a, 
PSA <10 ng/mL, Gleason grade 7 in two cores or less, with no primary Gleason grade 4 or 5 in any 
core, unilateral cancer, no single biopsy core containing >50% cancer, no more than 25% of cores 
containing cancer) will undergo focal brachytherapy of the regions/lobe containing cancer on the 
biopsy. 
 
9.2 Focal Brachytherapy of the Prostate 
The focal brachytherapy procedure will be performed in the Department of Radiation Oncology 
Brachytherapy Suite 8 weeks following the transrectal or transperineal biopsy, or sooner if the 
patient has recovered from the repeat biopsy and the treating physician determines it is safe to 
proceed with treatment. The procedure is performed in the exact fashion as conventional whole 
gland brachytherapy except the target is restricted to the involved lobe of the prostate. The patient is 
placed in the extended lithotomy position and transrectal ultrasound is placed as well as a urinary 
catheter. Axial ultrasound images are obtained with peripherally placed needles through the 
perineum into the involved hemilobe. The images are downloaded into the brachytherapy planning 
computer and a computer-based conformal treatment plan is generated which will determine the 
optimal seed loading to treat the involved lobe of the prostate to 144 Gy with I-125 while minimizing 
the dose to the urethra (V100<130% of the prescription dose) and rectum (V100 < 100% of the 
prescription dose). A mobile cone-beam computed tomography (CT) unit, which is routinely used in 
the department for intraoperative planning of permanent I-125 implants, may be employed for the 
focal brachytherapy procedure. The procedure itself will take about 60-90 minutes to perform, similar 
to a standard whole gland brachytherapy procedure. 
 
The information/coordinates from the biopsy as to the dominant visible tumor on the pre-operative 
endorectal or pelvic coil MRI may be fused to the intraoperative ultrasound images. This visible area 
will constitute the gross tumor volume. The clinical target volume (CTV) will represent a 3 mm 
margin beyond the GTV and the planning target volume will represent the involved hemi-lobe of the 

MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 11-056 A(3) 
Amended: 11/06/12 
- 12 - 
 
 
prostate gland. The 144 Gy prescription dose may be prescribed to the isodose line from the 
intraoperative computer plan which completely encompasses the PTV. 
 
Routine intraoperative planning methods may be used to treat the designated hemilobe of the 
prostate. 
 
An intraoperative cone-beam CT scan may be used to confirm accurate placement of the seeds. If it 
is determined based on this scan that there is a deficient dose region, this will be corrected with the 
placement of additional seeds after regeneration of the treatment planning prior to reversal of 
anesthesia. Several hours later, a routine post-implantation CT scan will be obtained for quality- 
assurance assessment of the adequacy of the implanted region. 
 
9.3 Assessment of QOL 
The quality-of-life assessment will focus on erectile function, urinary function, bowel function, and 
general health related quality of life (See Appendix A). The scales to measure these domains were 
derived from the previously validated MSKCC Prostate-Health Related Quality of Life Questionnaire 
(PHRQOLQ (13)). The patients will complete this assessment at baseline and then approximately 3 
± 1 months, 6 ± 1 months, 12 ± 2 months, 18 ± 2 months, and 24 ± 2 months after treatment. 
Consistent with Wagner and colleagues’ discussion of methodological issues associated with 
collection of patient-reported outcomes in Phase II studies (8), these measure will provide pilot data 
which will help describe these symptoms/side effects of brachytherapy and determine general effect 
sizes to appropriately power quality of life outcomes in future studies. 
 
Erectile Function: Erectile function will be assessed using 7-questions from the sexual function 
subscale of the MSKCC Prostate Health-Related Quality-of-Life Questionnaire (PHRQOLQ (13)). 
The PHRQOLQ includes items from the Erectile Function Doman (EFD) of the International Index of 
Erectile Function Questionnaire (IIEF (6)). The 7-item EFD subscale has demonstrated Cronbach's 
alpha values greater than 0.73 and strong test-retest reliability. The EFD also displayed a high 
degree of sensitivity and specificity to the effects of treatment. One additional question has been 
added to the EFD for this study, and asks men if they have been using medication to treat erectile 
dysfunction. This question is for descriptive purposes only, and will not be included in the total score 
for the EFD. 
 
Urinary Function: To assess urinary function, we will use 5-questions which come from the urinary 
function subscale of the MSKCC Prostate Health-Related Quality-of-Life Questionnaire (PHRQOLQ 
(13)). The validation of this subscale is based on data from MSKCC prostate cancer patients. The 
correlation between the scores on these 5-question subscales used in this study and the scores on 
the full urinary subscale is 0.9. In a limits-of-agreement analysis, the difference was 1.7, with an 80% 
confidence interval of −7.5, 10.8. The Cronbach’s α for these five-items was also good, at 0.82. 
 
Bowel Function: Bowel function will be assessed with two 2 questions from the bowel function 
subscale of the PHRQOLQ questionnaire. These questions are: "How often have bowel problems or 
bowel pain made it difficult to enjoy your life?" and "How big a problem have your bowel habits been 
for you?” These two questions produced a high Pearson's rho (0.91) compared to the full bowel 
domain of the PHRQOLQ (limits of agreement difference of −2.3; 80% confidence interval −13.9, 
9.3). 
 
General Healthy Related Quality-of-Life: This will be assessed with 1 question which asks the 

MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 11-056 A(3) 
Transrectal or transperineal prostate biopsy 
Amended: 11/06/12 
- 13 - 
 
 
subjects to rate their general health status on a 0-10 scale. As with the urinary function and bowl 
function, this 1-item assessment is from the PHRQOLQ. 
 
10.0 EVALUATION DURING TREATMENT/INTERVENTION 
 
3 ± 1 month after focal brachytherapy: 
 
• 
DRE (optional) 
• 
Assessment of toxicity relevant to the protocol therapy 
• 
QOL questionnaires 
 
6 ± 1 month after focal brachytherapy: 
 
 
• 
DRE 
• 
PSA 
• 
QOL questionnaires 
• 
Assessment of toxicity relevant to the protocol therapy 
• 
Endorectal or pelvic Coil MRI (optional) 
 
12 ± 2 months after focal brachytherapy: 
 
• 
Endorectal or pelvic Coil MRI 
• 
DRE 
• 
PSA 
• 
QOL questionnaires 
• 
Assessment of toxicity relevant to the protocol therapy 
• 
Second transrectal or transperineal ultrasound-guided prostate biopsy 
 
18 ± 2 months after focal brachytherapy: 
 
• 
DRE 
• 
PSA 
• 
QOL questionnaire 
• 
Assessment of toxicity relevant to the protocol therapy 
 
24 ± 2 months after focal brachytherapy: 
 
• 
DRE 
• 
PSA 
• 
QOL questionnaire 
• 
Assessment of toxicity relevant to the protocol therapy 
• 
Endorectal or pelvic Coil MRI 
• 
Third transrectal or transperineal -guided prostate biopsy 
 
 
11.0 TOXICITIES/SIDE EFFECTS 
 
This study will utilize the toxicity grading scale Common Terminology Criteria for Adverse Events 
(CTCAE) Version 4.0 for the following: 

MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 11-056 A(3) 
Amended: 11/06/12 
- 14 - 
 
 
• 
Blood in semen (50%) 
• 
Bleeding from the rectum, bladder (<3%) 
• 
Anemia (<1%) 
• 
Pelvic pain (<5%) 
• 
Infection (1%) 
• 
Urinary retention (5%)- which would be temporary and require a catheter for several 
days 
 
Focal brachytherapy 
• 
Bleeding (1%) 
• 
Infection (<1%) 
• 
Blood in the stools (3%) 
• 
Defecation urgency (1%) 
• 
Defecation incontinence (1%) 
• 
Urinary retention (5%) 
• 
Urinary incontinence (< 1%) 
• 
Erectile dysfunction (25%) 
• 
Urinary urgency (10%) 
• 
Urinary frequency (10%) 
• 
Dysuria (20%) 
• 
Rectal fistula (<1%) 
 
Endorectal or pelvic Coil MRI 
• 
Discomfort of placing probe in rectum and exacerbation of hemorrhoids if present 
 
This type of prostate radiation can affect an unborn baby and thus birth control methods must be 
used during participation in this study. Patients will be instructed not to father a baby for two years 
following implantation of the seeds. If a patient’s partner should become pregnant during this 
period, the patient must notify the study team as soon as possible. The progress of the pregnancy 
and delivery will be monitored by the study team to ensure that any complications are properly 
documented and reported. 
 
If the patient’s partner is currently pregnant, at the time of protocol treatment, they must be 
instructed to use a condom for at least the first 5 ejaculations after treatment. They should also 
be reminded not father any other children for two years following protocol treatment. 
 
 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
12 ± 2 months and 24 ± 2 months following focal brachytherapy the patient will undergo a second 
and third biopsy to assess the local tumor response, as well as to assess treatment efficacy. The 
rationale for a complete (bilateral) biopsy after brachytherapy, rather than just sampling the regions 
that were treated, is to confirm a prostate cancer-free status, since prostate cancer is commonly 
found to be multifocal and the remainder (non-treated portion) of the prostate remains at risk for the 
presence of cancer. If all biopsies are found to be negative within the hemi-gland where the focal 
therapy was administered this will be considered for the purposes of this study as a complete 
response after therapy and indicative of a successful outcome. In addition, the post-treatment MRI 
studies will be correlated with the biopsy findings to determine the specificity and sensitivity of this 
diagnostic study as a tool to follow patients who were treated with this focal therapy approach. 

MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 11-056 A(3) 
Amended: 11/06/12 
- 15 - 
 
 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
 
The patient may withdraw consent from the study at any time. 
 
The study will be terminated if there is a 3% or greater incidence of rectal fistula as a result of 
treatment. 
 
If at any time the patient develops progressive disease he will be withdrawn from the study and 
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 Subject Eligibility (i.e., a change in diagnosis), the patient will be removed from the study. 
 
 
14.0 
BIOSTATISTICS 
 
The primary objective of this study is to assess for the reduction of treatment related long-term 
morbidity rates associated with focal brachytherapy, compared to our published historical morbidity 
rates associated with whole gland brachytherapy for patients with low-risk, clinically localized 
prostate cancer. The treatment would be considered to have achieved the study’s primary objective 
if a 30% or greater (relative) reduction in either rectal, urinary toxicities or sexual dysfunction is 
observed between 6 months and 2 years after treatment compared to our published toxicity profile of 
whole gland brachytherapy. 
 
Our published data showed that the late toxicity rate (patients having either grade 2 or higher rectal 
or urinary toxicity after 6 months but within 2 years of the treatment, or having sexual dysfunction 
after 6 months but within 2 years of the treatment) was 53% for whole gland brachytherapy. 
Therefore, a late toxicity or sexual dysfunction rate of 53% or higher is considered definitely 
unacceptable while a late toxicity or sexual dysfunction rate of 37% or less is definitely acceptable. 
Using a cohort of 70 patients, we will claim the focal brachytherapy procedure significantly reduces 
the late toxicity/sexual dysfunction rate if no more than 31 patients have grade 2 or higher rectal or 
urinary toxicity or sexual dysfunction after 6 months but within 2 years of the treatment. For this 
decision rule we have a type I error rate as 9% and a power of 92%. 
 
We will also report the sample proportions of the acute toxicity rate (occurred within 6 months of the 
treatment) and the late toxicity and sexual dysfunction rates with its confidence interval and tabulate 
and summarize all tolerance profiles based on all patients. 
 
We expect to accrue 2-3 patients per month. Thus the trial should be completed within 2-3 years. 
Efforts will be made to follow-up every patient for at least 2 years. Since patients may drop off (for 
reasons not related with toxicity or sexual dysfunction) or be lost to follow-up, we will enroll an extra 
15% of patients to make a total of 80 patients, approximately 20 per site, for our accrual goal. 
However, only the first 70 patients who have been followed for at least 2 years will be analyzed 
towards the primary objective. 
 
For secondary objectives, the local control rate will be examined using proportions of patients who 
obtain all negative biopsy cores 12 and 24 months after completion of therapy in the hemi-gland of 
where the focal therapy was administered. QOL data will be presented descriptively, giving summary 
statistics for the change in sexual, erectile, bowel, and QOL scores over time. Post-treatment MRI 

MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 11-056 A(3) 
Amended: 11/06/12 
- 16 - 
 
 
outcome is defined as a 3-level categorical variable: positive, negative and undetermined. Post- 
treatment biopsy outcome is defined as a binary variable: positive and negative. We will examine the 
correlation between the 12-month MRI and 12-month biopsy, and between the 24-month MRI and 
24-month biopsy. The correlation will be assessed by a Fisher exact test. We will also examine the 
sensitivity and specificity of MRI by using biopsy as the gold standard (for this analysis we will omit 
patients with undetermined MRI results). All patients enrolled will be used for the analysis of 
secondary objectives. 
 
 
 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.1 
Research Participant Registration 
 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
 
Obtain informed consent, by following procedures defined in section entitled Informed Consent 
Procedures. 
 
During the registration process registering individuals will be required to complete a protocol specific 
Eligibility Checklist. 
 
All participants must be registered through the Protocol Participant Registration (PPR) Office at 
Memorial Sloan-Kettering Cancer Center. PPR is available Monday through Friday from 8:30am – 
5:30pm at 646-735-8000. The PPR fax numbers are (646) 735-0008 and (646) 735-0003. 
Registrations can be phoned in or faxed. The completed signature page of the written consent and a 
completed Eligibility Checklist must be faxed to PPR. 
 
15.1.1 For Participating Sites: 
 
Central registration for this study will take place at Memorial Sloan Kettering Cancer Center 
(MSKCC). 
 
To complete registration and enroll a participant from another institution, the study staff at 
that site must contact the designated research staff at MSKCC to notify him/her of the 
participant registration. The site staff then needs to fax registration/eligibility documents to 
the Radiation Oncology department at MSKCC 212-639-2417. 
 
The following documents must be sent for each enrollment within 24 hours of the informed 
consent form being signed: 
 
• The completed or partially completed MSKCC eligibility checklist 
• The signed informed consent and HIPAA Authorization form 
• Supporting source documentation for eligibility questions (pathology report, radiology 
reports, MD notes, physical exam sheets, medical history and prior treatment records). 
 
 
Upon receipt, the research staff at Memorial Sloan Kettering Cancer Center will conduct an 
interim review of all documents.  If the eligibility checklist is not complete, the patient will be 

MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 11-056 A(3) 
participant. 
Amended: 11/06/12 
- 17 - 
 
 
registered PENDING and the site is responsible for sending a completed form within 30 days 
of the consent. 
 
If the eligibility checklist is complete, participant meets all criteria, all source documentation is 
received, the participating site IRB has granted approval for the protocol, and the site is in 
good standing with MSKCC, the MSKCC research staff will send the completed registration 
documents to the MSKCC Protocol Participant Registration (PPR) Office to be enrolled as 
stated in section 15.1. The participant will be registered. 
 
Once eligibility has been established and the participant is registered, the participant will be 
assigned an MSKCC Clinical Research Database (CRDB) number (protocol participant 
number). This number is unique to the participant and must be written on all data and 
correspondence for the participant. This protocol participant number will be relayed back to 
study staff at the registering site via e-mail and will serve as the enrollment confirmation. 
 
 
15.2 
Randomization 
 
There is no randomization for this trial. 
 
16.0 
DATA MANAGEMENT ISSUES 
 
A Research Study Assistant (RSA) will be assigned to the study. The responsibilities of the RSA 
include project compliance, data collection, abstraction and entry, data reporting, regulatory 
monitoring, problem resolution and prioritization, and coordination of the activities of the protocol 
study team. 
 
The data collected for this study will be entered into CRDB. Source documentation will be available 
to support the computerized patient record. 
 
 
16.0.1  Data and Source Documentation for Participating Sites 
 
Data 
Standardized Case Report Forms (CRFs), directions for use and sign off requirements have been 
generated for this study. Blank case report forms will be sent to the study staff at each 
participating site for use. The participating Site PI is responsible for ensuring these forms are 
completed accurately, legibly and in a timely manner. 
 
Source Documentation 
Source documentation refers to original records of observations, clinical findings and evaluations 
that are subsequently recorded as data. Source documentation should be consistent with data 
entered into CRFs. Relevant source documentation to be submitted throughout the study 
includes: 
o Baseline measures to assess pre–protocol disease status (ex. MRI, PSA) 
o Treatment records 
o Toxicities/adverse events not previously submitted with SAE Reports 
o Response designation 
 
16.0.2 Data and Source Documentation Submission for Participating Sites 
Participating sites should email CRFs and source documentation to MSKCC to the contact 
provided below. Submissions should include a cover page listing all CRFs enclosed per 

MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 11-056 A(3) 
Amended: 11/06/12 
- 18 - 
 
 
 
 
EMAIL: Michael Zelefsky, MD,  zelefskm@mskcc.org and 
Rebekah Dunn, CRC,  dunnr@mskcc.org 
 
16.0.3 Data and Source Documentation Submission Timelines for Participating Site 
Data and source documentation to support data should be transmitted to MSKCC according to 
the following chart: 
 
 
 
 
 
 
Baseline 
Biopsy 
Visit 
Treatment 
Visits 
Follow 
Up 
SAE 
Off 
Study 
SUBMISSION SCHEDULE 
Source 
Documentation 
Within 24 
hours 
(see section 
15.1.1) 
within 14 days of 
visit 
Within 14 
days of 
visit 
(see 
section 
10.0 for 
schedule) 
Within 3 
days of 
event (see 
section 17.3; 
updates to be 
submitted as 
available 
Within 
14 days 
of visit 
CRFs 
Within 7 
days of 
enrollment 
Required Forms 
Demographics Form 
X 
Medical History 
Form 
X 
Treatment Form 
X 
Disease Status Form 
X 
X 
X 
Biopsy Form 
X 
X 
X 
X 
Adverse Event Form 
X 
X 
X 
Serious Adverse 
Event Form 
X 
Off Study Form 
X 
Questionnaires 
X 
X 
 
 
16.0.4 Data Review and Queries for Participating Site Data 
 
Research staff at MSKCC will review data and source documentation as it is submitted. Data will 
be monitored against source documentation and discrepancies will be sent as queries to the 
participating sites. Queries will be sent by MSKCC Research staff twice a month. 

MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 11-056 A(3) 
Amended: 11/06/12 
- 19 - 
 
 
Participating sites should respond to data queries within 14 days of receipt 
 
16.1 
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 and 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. 
 
16.1.1 Quality Assurance for Participating Sites 
 
Each site participating in the accrual of participants to this protocol will be audited by the staff of the 
MSKCC study team for protocol and regulatory compliance, data verification and source 
documentation.  Audits may be accomplished in one of two ways: (1) selected participant records 
can be audited on-site at participating sites or (2) source documents for selected participants will be 
sent to MSKCC for audit. Audits will usually be determined by participant accrual numbers and rate 
of accrual, but can also be prompted by reported SAEs or request of MSKCC PI. 
 
Audits will be conducted at least once shortly after initiation of participant recruitment at a site, 
annually during the study (or more frequently if indicated), and at the end or closeout of the trial. The 
number of participants audited will be determined by available time and the complexity of the 
protocol. 
 
The audit will include a review of source documentation to evaluate compliance for: 
 
• 
Informed consent documents and procedures 
• 
Adherence to eligibility criteria 
• 
Protocol defined treatment 
• 
Required baseline, on study and follow-up protocol testing 
• 
IRB documents (submitted amendments, annual continuing review reports, SAEs) 
• 
Case Report Form submissions to MSKCC: time lines and accuracy 
 
A wrap-up session will be conducted at the participating site and preliminary findings will be 
discussed with the participating site PI and research team. The preliminary results will be sent to the 
MSKCC PI. 
 
Each audit will be summarized and a final report will be sent to the PI at the audited participating site 
within 30 days of the audit. The report will include a summary of findings, participant by participant 
case review, specific recommendations on any performance and/or shortcomings and request for 
corrective action, when necessary. When corrective action is required, the participating site must 
reply within 45 days of receipt of audit report with their corrective action plan. 
 
A copy of the audit report and corrective action plan (if applicable) submitted by the participating site 
must be sent to the MSKCC IRB/PB, CRQA and maintained in the department’s protocol regulatory 
binder. 

MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 11-056 A(3) 
Amended: 11/06/12 
- 20 - 
 
 
16.2 
Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center were 
approved by the National Cancer Institute in September 2001.  The plans address the new policies set 
forth by the NCI in the document entitled “Policy of the National Cancer Institute for Data and Safety 
Monitoring of Clinical Trials” which can be found 
at: http://www.cancer.gov/clinicaltrials/conducting/dsm-guidelines/page1. The DSM Plans at 
MSKCC were established and are monitored by the Office of Clinical Research.  The MSKCC Data 
and Safety Monitoring Plans can be found on the MSKCC Intranet at: 
http://smskpsps9/dept/ocr/OCR%20Website%20Documents/Clinical%20Research%20Quality%20As 
surance%20(CRQA)/MSKCC%20Data%20and%20Safety%20Monitoring%20Plan.pdf 
There are several different mechanisms by which clinical trials are monitored for data, safety, and 
quality. There are institutional processes in place for quality assurance (e.g., protocol monitoring, 
compliance and data verification audits, therapeutic response, and staff education on clinical 
research quality assurance) and departmental procedures for quality control, plus there are two 
institutional committees that are responsible for monitoring the activities of our clinical trials 
programs. The committees, Data and Safety Monitoring Committee (DSMC) for Phase I and II 
clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III clinical trials, report to 
the Center’s Research Council and Institutional Review Board. 
 
During the protocol development and review process, each protocol will be assessed for its level of 
risk and degree of monitoring required. Every type of protocol (e.g., National Institutes of Health 
sponsored, in-house sponsored, industrial sponsored, National Cancer Institute cooperative group, 
etc.) will be addressed and the monitoring procedures will be established at the time of protocol 
activation. 
 
16.3 
Regulatory Documentation 
 
Prior to implementing this protocol at MSKCC, the protocol, informed consent form, HIPAA 
authorization and any other information pertaining to participants must be approved by the 
MSKCC Institutional Review Board/Privacy Board (IRB/PB). Prior to implementing this protocol at 
the participating sites, approval for the MSKCC IRB/PB approved protocol must be obtained from 
the participating site’s IRB. 
 
The following documents must be provided to MSKCC before the participating site can be 
initiated and begin enrolling participants: 
 
• 
Participating Site IRB approval(s) for the protocol, appendices, informed consent form and 
HIPAA authorization 
• 
Participating Site IRB approved consent form 
• 
Participating Site IRB membership list 
• 
Participating Site IRB’s Federal Wide Assurance number and OHRP Registration number 
• 
Curriculum vitae and medical license for each investigator and consenting professional 
• 
Documentation of Human Subject Research Certification training for investigators and key 
staff members at the Participating Site 
• 
Participating site laboratory certifications and normals for PSA 
 
Upon receipt of the required documents, MSKCC will formally contact the site and grant permission 
to proceed with enrollment 
 
16.3.1 Amendments 

MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 11-056 A(3) 
Amended: 11/06/12 
- 21 - 
 
 
Each change to the protocol document must be organized and documented by MSKCC and first 
approved by the MSKCC IRB/PB. Upon receipt of MSKCC IRB/PB approval, MSKCC will 
immediately distribute all non expedited amendments to the participating sites, for submission to 
their local IRBs. 
 
Participating sites must obtain approval for all non expedited amendments from their IRB within 90 
calendar days of MSKCC IRB/PB approval. If the amendment is the result of a safety issue or 
makes eligibility criteria more restrictive, sites will not be permitted to continuing enrolling new 
participants until the participating site IRB approval has been granted. 
 
The following documents must be provided to MSKCC for each amendment within the stated 
timelines: 
• 
Participating Site IRB approval 
• 
Participating Site IRB approved informed consent form and HIPAA  authorization 
 
 
16.3.2 Additional IRB Correspondence 
 
 
Continuing Review Approval 
The Continuing Review Approval letter from the participating site’s IRB and the most current 
approved version of the informed consent form should be submitted to MSKCC within 7 days of 
expiration. Failure to submit the re-approval in the stated timeline will result in suspension of 
study activities. 
 
Deviations and Violations 
A protocol deviation on this study is defined as a request to treat a research participant who does 
not meet all the eligibility criteria, pretreatment evaluation, or who requires alteration in their study 
plan. If a deviation from this protocol is proposed for a potential or existing participant at MSKCC 
or a participating site, approval from the MSKCC IRB/PB is required prior to the action. 
Participating sites should contact the MSKCC PI who will in turn seek approval from the MSKCC 
IRB/PB. 
 
A protocol violation is anything that occurs with a participant, which deviated from the protocol 
without prior approval from the MSKCC IRB/PB. For protocol violations that are identified after 
they occur, the participating site should report to MSKCC as soon as possible. The MSKCC PI 
will in turn report the violation to the MSKCC IRB/PB. 
 
Participating sites should report deviations and violations to their institution’s IRBs as soon as 
possible per that site’s institutional guidelines. Approvals/acknowledgments from the participating 
site IRB for protocol deviations and violations should be submitted to MSKCC as received. 
 
Other correspondence 
Participating sites should submit other correspondence to their institution’s IRB according to local 
guidelines, and submit copies of that correspondence to MSKCC. 
 
 
16.3.3 Document maintenance 
The MSKCC PI and the Participating Site PI will maintain adequate and accurate records to 
enable the implementation of the protocol to be fully documented and the data to be subsequently 
verified. 

MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 11-056 A(3) 
• Focal brachytherapy 
Amended: 11/06/12 
- 22 - 
 
 
The participating sites will ensure that all participating site IRB correspondence (IRB approval 
letters referencing protocol version date and amendment number, IRB approved protocol, 
appendices, informed consent forms, deviations, violations, and approval of continuing reviews) is 
maintained in the regulatory binder on site and sent to MSKCC. 
 
A regulatory binder for each site will also be maintained at MSKCC; this binder may be paper or 
electronic. 
 
After study closure, the participating site will maintain all source documents, study related 
documents and CRFs for 3 years. 
 
16.4 Noncompliance 
If a participating site is noncompliant with the protocol document, accrual privileges may be 
suspended and/or contract payments may be withheld, until the outstanding issues have been 
resolved. 
 
 
17.0 
PROTECTION OF HUMAN SUBJECTS 
 
This protocol does not include children because children do not develop prostate 
cancer. This statement is based on exclusion 4b of the NIH Policy and Guidelines on the 
Inclusion of Children as Participants in Research Involving Human Subjects. Since only men have 
prostates, participants in the study are limited to this gender. Therefore, women will be excluded 
from the study. In conformity with the National Institute of Health Revitalization Act of 1993 with 
regard to the inclusion of minorities in clinical research, every effort will be made to include 
participants of all ethnicities. There will be no restrictions based on racial/ethnic background. 
The risk of participating in this protocol is related to the risk of prostate biopsy (infection, bleeding, 
pelvic pain, urinary obstruction) and/or the focal brachytherapy (infection, bleeding, pelvic pain, 
urinary obstruction, urinary incontinence, erectile dysfunction) and/or the risk of under-treating the 
patient’s prostate cancer. Each of these risks appears low and certainly appears to have a more 
favorable risk/benefit profile than any active treatment. Alternative treatment options include active 
surveillance (watchful waiting; whereby definitive treatment is delayed until the patient demonstrates 
signs of prostate cancer local progression), radiation therapy or radical prostatectomy. 
 
The subjects will be responsible for all charges associated with the items that are part of the routine 
clinical care, including the prostate biopsy (clinical and pathological charges) as well as the focal 
brachytherapy procedure. The subjects will not be compensated for their participation. If the patient 
is injured as a result of being in this study, emergency care, hospitalization, and outpatient care will 
be made available by the hospital and billed to the patient and his insurance company as part of his 
medical expenses. 
 
The exams, tests or procedures in the study are part of regular cancer care. The patient and/or 
health plan/insurance company will need to pay for the following tests in the study: 
 
• 
Physical exam 
• 
Digital rectal examinations 
• 
Endorectal or pelvic coil MRIs 
• 
Prostate-Specific Antigens (PSA) 
• 
Transrectal and transperineal prostate biopsies 

MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 11-056 A(3) 
Amended: 11/06/12 
- 23 - 
 
 
 
17.1 
Privacy 
 
MSKCC’s Privacy Office may allow the use and disclosure of protected health information pursuant 
to a completed and signed Research Authorization Form. The use and disclosure of protected health 
information will be limited to the individuals described in the Research Authorization Form. A 
Research Authorization Form must be completed by the Principal Investigator and approved by the 
IRB and Privacy Board. 
 
 
 
17.2 
Serious Adverse Event (SAE) Reporting 
 
Any serious adverse event must be reported to the IRB as soon as possible but no later than 5 
calendar days. 
 
An SAE is defined as any untoward medical occurrence that 
 
•  Results in death 
•  Is life threatening 
•  Requires inpatient hospitalization or prolongation of existing hospitalization 
•  Results in persistent or significant disability/incapacity 
•  Results in congenital anomaly and/or birth defects 
•  Is an important medical event that jeopardizes the participant AND requires medical or 
surgical intervention to prevent one of the outcomes above 
The IRB/PB requires a Clinical Research Database (CRDB) SAE report be submitted electronically 
to the SAE Office at sae@mskcc.org. The report should contain the following information: 
 
Fields populated from the CRDB 
 
•  Subject’s name (generate the report with only initials if it will be sent outside of 
MSKCC) 
•  Medical record number 
•  Disease/histology (if applicable) 
•  Protocol number and title 
 
Data needing to be entered 
 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the adverse event was expected 
• 
The severity of the adverse event 
• 
The intervention 
• 
Detailed text that includes the following information: 
o A explanation of how the adverse event was handled 
o A description of the subject's condition 
o Indication if the subject remains on the study 
o If an amendment will need to be made to the protocol and/or consent form 
 
The principal investigator’s signature and the date it was signed are required on the completed 
report. 

MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 11-056 A(3) 
Amended: 11/06/12 
- 24 - 
 
 
17.3 Serious Adverse Event (SAE) Reporting for Participating Sites 
Responsibility of Participating Sites 
 
• 
Participating sites are responsible for reporting all SAEs to the MSKCC PI and CRC by email 
within 24 hours of learning of the event. The SAE form is due to MSKCC via fax or e-mail within 
3  calendar days of learning of the event. 
• 
Participating sites should notify the MSKCC PI of any grade 5 event immediately. 
• 
Participating sites should use the SAE Report Template (in the CRF packet) to report SAEs to 
MSKCC. 
 
SAE contact information for the Coordinating Center is listed below: 
Michael Zelefsky, MD, ZelefskM@mskcc.org and 
Rebekah Dunn, CRC, DunnR@mskcc.org 
 
 
Responsibility of MSKCC 
 
• 
The MSKCC Research Staff is responsible for submitting all SAEs to the MSKCC IRB/PB as 
specified in 17.2 
• 
The MSKCC PI is responsible for informing all participating sites about unexpected SAEs within 
30 days of receiving the stamped SAE from the MSKCC IRB/PB. 
• 
Any report pertaining to a grade 5 event will be distributed to the participating sites as soon as 
possible. 
 
 
17.4 Safety Reports 
• 
MSKCC will distribute outside safety reports to the participating sites immediately upon 
receipt. 
• 
MSKCC must submit outside safety reports to the MSKCC IRB/PB according to institutional 
guidelines. 
• 
Participating sites must submit safety reports to their institution’s IRBs within 30 days of 
receipt from MSKCC or per participating site guidelines. 
 
 
 
18.0 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain full 
details of the protocol and study procedures as well as the risks involved to participants prior 
to their inclusion in the study. Participants will also be informed that they are free to withdraw 
from the study at any time. All participants must sign an IRB/PB-approved consent form 
indicating their consent to participate. This consent form meets the requirements of the Code 
of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. The 
consent form will include the following: 
 
1.  The nature and objectives, potential risks and benefits of the intended study. 
2.  The length of study and the likely follow-up required. 
3.  Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4.  The name of the investigator(s) responsible for the protocol. 

MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 11-056 A(3) 
Amended: 11/06/12 
- 25 - 
 
 
5.  The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
 
Before any protocol-specific procedures can be carried out, the consenting professional will fully 
explain the aspects of patient privacy concerning research specific information. 
 
In addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
18.1 FOR PARTICIPATING SITES 
 
The investigators listed on the protocol cover page and their qualified designees at each 
participating site may obtain informed consent and care for the participants according to good 
clinical practice and protocol guidelines. 
 
 
Signed copies of the informed consent should be distributed as follows: One copy will be given to 
the participant to be retained for their personal records. One copy will be maintained on file at the 
MSKCC. The third copy will be confidentially maintained by the participating institution. 
 
 
A note will be placed in the medical record documenting that informed consent was obtained for this 
study, and that the participant acknowledges the risk of participation. 

MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 11-056 A(3) 
Amended: 11/06/12 
- 26 - 
 
 
19.0 
REFERENCES 
 
1. 
Thompson IM, Pauler DK, Goodman PJ, et al. Prevalence of prostate cancer among men 
with a prostate-specific antigen level < or =4.0 ng per milliliter. N Engl J Med 2004;350:2239- 
2246. 
 
2. 
Ahmed HU, Emberton M. Is focal therapy the future for prostate cancer? Future Oncol 
 
2010;6:261-268. 
 
3. 
Eggener SE, Scardino PT, Carroll PR, et al. Focal therapy for localized prostate cancer: a 
critical appraisal of rationale and modalities. J Urol 2007;178:2260-2267. 
4. 
Lee F, Bahn DK, Badalament RA, et al. Cryosurgery for prostate cancer: improved glandular 
ablation by use of 6 to 8 cryoprobes. Urology 1999;54:135-140. 
5. 
Polascik TJ, Mayes JM, Mouraviev V. Nerve-sparing focal cryoablation of prostate cancer. 
 
Curr Opin Urol 2009;19:182-187. 
 
6. 
Rosen RC, Riley A, Wagner G, et al. The international index of erectile function (IIEF): a 
multidimensional scale for assessment of erectile dysfunction. Urology 1997;49:822-830. 
7. 
Turpen R, Rosser CJ. Focal therapy for prostate cancer: revolution or evolution? BMC Urol 
 
2009;9:2. 
 
8. 
Wagner LI, Wenzel L, Shaw E, et al. Patient-reported outcomes in phase II cancer clinical 
trials: lessons learned and future directions. J Clin Oncol 2007;25:5058-5062. 
9. 
Allen ZA, Merrick GS, Butler WM, et al. Detailed urethral dosimetry in the evaluation of 
prostate brachytherapy-related urinary morbidity. Int J Radiat Oncol Biol Phys 2005;62:981- 
987. 
 
10. 
Han BH, Wallner KE. Dosimetric and radiographic correlates to prostate brachytherapy- 
related rectal complications. Int J Cancer 2001;96:372-378. 
11. 
Snyder KM, Stock RG, Hong SM, et al. Defining the risk of developing grade 2 proctitis 
following 125I prostate brachytherapy using a rectal dose-volume histogram analysis. Int J 
Radiat Oncol Biol Phys 2001;50:335-341. 
12. 
Zelefsky MJ, Yamada Y, Pei X, et al. Comparison of tumor control and toxicity outcomes of 
high-dose intensity-modulated radiotherapy and brachytherapy for patients with favorable 
risk prostate cancer. Urology 2010: (e-pub ahead of print). 
13. 
Befort CA, Zelefsky MJ, Scardino PT, et al. A measure of health-related quality of life among 
patients with localized prostate cancer: results from ongoing scale development. Clin 
Prostate Cancer 2005;4:100-108. 
14. 
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
 
Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-655. 

Amended: 11/06/12 
- 27 - 
MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 11-056 A(3) 
 
 
20.0 
APPENDICES 
 
Appendix A: QOL questionnaire used in the Department of Urology 
Appendix B: QOL directions 
Appendix C: ECOG performance status scale