Evaluation of a Novel High-Resolution Diffusion-Weighted MRI Sequence
Phase: NA
Conditions: Prostate Cancer
Sponsor: Cedars-Sinai Medical Center

 
 
 
CONFIDENTIAL 
This material is the property of Cedars-Sinai Medical Center. Do not disclose or use except as authorized in writing by the study sponsor. 
 
 
 
 
Evaluation of a Novel High-Resolution Diffusion-Weighted MRI Sequence 
 
Principal Investigator:           Hyung Kim, M.D. 
 
 
 
         Urology/Surgery 
                                 Cedars-Sinai Medical Center 
                                 8635 West Third Street, 1070W 
                                 Los Angeles, CA  90036 
                                 Email: kimhl@cshs.org 
                                 Tel: 310-423-4700 
                                 Fax: 716-423-4711 
 
 
Sub-Investigator(s): 
 
 
Name 
Department/Division 
Tim Daskivich, M.D.  
Urology/Surgery 
Steve Freedland, M.D. 
Urology/Surgery 
Amit Gupta, M.D. 
Urology/Surgery 
Rola Saouf, M.D. 
Radiology 
Dan Luthringer, M.D. 
Pathology 
Chris Nguyen, M.D. 
Biomedical Imaging Research Institute 
Dibiao Li, Ph.D. 
Biomedical Imaging Research Institute 
 
 
 
 
 
Biostatistician: 
             Mourad Tighiouart, Ph.D. 
 
 
 
             Cedars Sinai Medical Center 
 
 
 
 
 
 
Study Intervention: 
 
High-resolution MRI 
 
 
Funding Source:  
NIH 
 
Amended version: 
 
4/7/2020 
 
Initial version:  
 
1/8/2017 
 
 
 
 
 
 
 

 
 
 
CONFIDENTIAL 
This material is the property of Cedars-Sinai Medical Center. Do not disclose or use except as authorized in writing by the study sponsor. 
 
 
Signature Page 
 
 
The signature below constitutes the approval of this protocol and the attachments, and provides the 
necessary assurances that this trial will be conducted according to all stipulations of the protocol, including 
all statements regarding confidentiality, and according to local legal and regulatory requirements and 
applicable U.S. federal regulations and ICH guidelines. 
 
 
 
Principal Investigator (PI) Name: _____________________________ 
 
 
 
PI Signature: _____________________________ 
 
 
 
Date: ____________________ 
 

________________________________________________________________________ 
i 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ...........................................................................................1 
STUDY SCHEMA .............................................................................................................2 
STUDY SUMMARY ..........................................................................................................2 
1.0 
STUDY ABSTRACT .............................................................................................3 
2.0 
BACKGROUND AND RATIONALE .................................................................4 
3.0 
STUDY DESIGN: ..................................................................................................5 
A. 
Overview .......................................................................................................................... 5 
B. 
Study Population .............................................................................................................. 6 
C. 
Inclusion/Exclusion Criteria ............................................................................................. 6 
D. 
Study endpoints ............................................................................................................... 6 
E. 
Study Design ................................................................................................................... 6 
F. 
Study Risks ...................................................................................................................... 7 
G. 
Statistical Analysis ........................................................................................................... 9 
4.0 
REFERENCES .....................................................................................................10 

________________________________________________________________________ 
1 
LIST OF ABBREVIATIONS 
ADC 
Apparent diffusion coefficient 
AS 
Active surveillance 
AUC 
Area under the curve 
DCE 
Dynamic contrast enhanced 
DWI 
Diffusion-weighted imaging 
EPI 
Echo-planar imaging 
hrMRI 
High resolution MRI 
mpMRI 
Multiparametric MRI 
MRI 
Magnetic resonance imaging 
PI-RADS 
Prostate Imaging-Reporting and Data System 
ROI 
Region of interest 
TRUS 
Transrectal ultrasound 
 
 
 
 
 
 
 
 
 
 
 
 
 

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2 
STUDY SCHEMA 
 
STUDY SUMMARY 
Title 
Evaluation of a Novel High-Resolution MRI Sequence 
Short Title 
High resolution MRI  
Protocol Number 
 
Phase 
 Not applicable 
Methodology 
 Single arm, paired imaging 
Study Duration 
3 years 
Study Center(s) 
Cedars Sinai Medical Center 
Objectives 
To determine if enhanced prostate imaging (high resolution MRI) will detect 
prostate lesions not seen on standard MRI. 
Number of Subjects 
80 Study Subjects  
Diagnosis and Main Inclusion 
Criteria 
 
Inclusion Criteria: 
• 
Age over 18 years 
• 
Patients diagnosed with clinically localized prostate cancer  
• 
Low or Low-intermediate Risk Prostate cancer1 defined as: 
o 
Pre-operative PSA ≤ 20.0 ng/ml 
o 
Clinical stage cT1 or cT2  
o 
Gleason score 3+3 or 3+4  
• 
Patients choosing AS or already on AS as primary management 
strategy 
• 
No previous treatment for prostate cancer with radiotherapy, 
chemotherapy, or hormonal therapy 
• 
No contraindications for gadolinium enhanced MRI 
Study Imaging 
Standard multiparametric prostate MRI with high resolution diffusion weighted 
imaging  
Control Imaging 
Standard multiparametric prostate MRI 
Reference standard  
Evidence of disease progression on standard 12-core ultrasound-guided prostate 
biopsy.   
Statistical analysis 
Our hypothesis is that changes in tumor size or apparent diffusion coefficient 
(ADC) on high resolution MRI will predict presence of biopsy criteria for disease 
progression. 
 
59 patients achieve 91% power to detect a 0.285 cm3 difference (between 
patients progressing and patients not progressing) in the mean change in tumor 
volume at the two-sided two-sample t-test with a 0.05 level of significance. With 
respect to change in ADC, 59 patients achieve 80% power to detect a difference 
in the mean change ADC around 0.07 at the two-sided two-sample t-test with a 
0.05 level of significance. This corresponds to about a 50% increase in ADC 
between the two groups of patients.  
 
Registration
Imaging (standard 
and experimental 
MRI)
Imaging (standard 
and experimental 
MRI)
Standard prostate 
biopsy
 

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3 
1.0 
STUDY ABSTRACT 
 
We developed 3D magnetization-prepared high resolution diffusion weighted imaging (DWI) to 
overcome the major problems associated with 2D conventional single-shot echo-planar imaging 
(EPI) technique for prostate imaging. Major technical novelties are: 
• 
Magnetization-prepared DWI was optimized to improve image quality. Standard DWI uses 
single-shot EPI acquisition, which inherently results in relatively poor image quality with 
apparent image artifacts, such as streaking (high image intensity bands) and geometric 
distortion (round objects may appear oval)2, which may hinder the detection of small lesions. 
Magnetization-prepared DWI allows separate diffusion-preparation and data acquisition, 
which in turn allows segmented/multi-shot (vs single-shot) data acquisition and more robust 
acquisition techniques such as steady-state free precession (SSFP) or turbo-spin-echo (TSE) 
(vs EPI), which eliminate typical image artifacts associated with single-shot EPI.2 An 
optimized first-order motion-compensated diffusion preparation scheme was developed 
to minimize the diffusion preparation time, which reduced T2 decay and minimize signal loss 
due to motion. 
• 
3D DWI was developed to achieve high and isotropic spatial resolution: While single-shot EPI 
acquisition is limited to 2D imaging with low in-plane resolution and thick slices (2.1x2.1x3.5 
mm3), segmented/mult-shot SSFP or TSE acquisitions allow for contiguous slices of the entire 
prostate in one scan volume with isotropic resolution of 1.2x1.2x1.2 mm3, represents a 9-fold 
increase over the conventional protocol. 3D DWI with high and isotropic spatial resolution is 
critically important for accurate measurement of lesion size and reducing partial voluming for 
more accurate ADC quantification.   
• 
Hybrid Cartesian-radial readout and real-time-feedback self-gating minimized the effects of 
motion: Radial sampling was used to provide inherent motion robustness of images and allow 
for additional accelerated data acquisition through iterative non-Cartesian reconstruction. A 
self-gating signal was acquired to keep track of patient motion and data acquired during 
apparent motion was excluded from image reconstruction prospectively and the data was 
immediately reacquired.  
 
This high resolution MRI (hrMRI), along with stand MRI (sMRI) will be obtained at baseline and 
again in approximately 1 year in patients on prostate cancer active surveillance.  Changes in 
lesion size and ADC values will be assessed on the serial studies.  This study evaluates the 
hypothesis that hrMRI will detect changes that sMRI cannot detect and that these changes will 
correlate with prostate cancer progression as determined on prostate biopsy. 

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4 
2.0 
BACKGROUND AND RATIONALE 
 
Multiparametric MRI 
Multiparametric MRI combining T2-weighted, diffusion-weighted, and dynamic contrast enhanced 
(DCE) images is commonly employed for detection and localization of prostate lesions.3, 4 
Diffusion-weighted imaging (DWI) is sensitive to the diffusion of water molecules interacting with 
surrounding macromolecules.  DWI, which provides a quantitative biological parameter called 
apparent diffusion coefficient (ADC) value, is a robust MRI parameter for differentiating benign 
and malignant prostate tissue.5, 6 In fact, the latest version of the Prostate Imaging-Reporting and 
Data System (PI-RADS) scoring system relies almost exclusively on DWI to identify tumors in the 
peripheral zone, which is where the vast majority of prostate cancers form. Findings on T2 images 
are not used to identify cancer, and DCE images are only used to differentiate between some PI-
RADS 3 and 4 lesions. In a pilot study of prostate cancer AS, DW-MRI was useful for detecting 
progression of Gleason score based on changes in ADC value.7  Tumor size is another important 
clinical criterion for defining low risk prostate cancer, and tumor size based on DWI has been 
shown to crudely predict low risk prostate cancer.8 However, conventional DWI using single-
shot echo-planar imaging is unable to detect small tumors9, low grade tumors, or small 
changes in tumor size on serial imaging. Approximately 20% of small, low grade tumors found 
in men on AS are detected on modern prostate MRI. 10 
 
High Resolution MRI 
We introduce a new three-dimensional (3D) high-resolution diffusion-weighted imaging 
sequence (HR-DWI), which improves image quality while conferring at least a 5-fold 
improvement in resolution when compared to standard two-dimensional (2D) DWI (S-DWI). 
This novel 3D DWI technique has been developed by our team and can be applied on existing 
1.5T or 3T MRI systems.  S-DWI suffers from two important limitations. a) It uses single-shot 
echo-planar imaging (EPI) for data acquisition, which produces magnetic susceptibility induced 
streaking artifacts and geometric distortions so that round objects may appear oval.  b) The 
relatively low signal-to-noise ratio and 2D image acquisition with S-DWI limit spatial resolution, 
which is defined by the minimum distance between two objects required to resolve them uniquely. 
Our HR-DWI overcomes these limitations by using magnetization prepared, multi-shot, turbo-
spin-echo acquisition, which improves signal-to-noise ratio (SNR), spatial resolution, and image 
quality, and eliminates geometric distortions and streaking artifacts associated with EPI.   
 
Preliminary studies 
In preliminary studies assessing the performance of our HR-DWI in a prospective pilot trial of 
prostate cancer AS patients, the technique could detect tumors not seen on S-DWI and measure 
ADC, which correlates with grade.2, 11 This is important because the long-term natural history of 
small prostate cancers invisible to S-DWI has never been prospectively defined, in part due to 
lack of adequate imaging technology.  In the era of molecular diagnostics and next-generation 
sequencing, an important step in understanding the biology of these lesions is to develop 
technologies to image and characterize these lesions. Importance of HR-DWI includes: 
• 
Better imaging will allow these lesions to be monitored serially and targeted for biopsy, 
providing tissue for both histologic and molecular characterization.  
• 
Higher resolution imaging will better delineate tumor boundaries, which can improve tumor 
staging and identify margins during partial-gland ablation by cryotherapy or high intensity 
focused ultrasound (HIFU), which was approved in 2015 by the U.S. FDA. 

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5 
• 
Improved imaging resolution will allow for more accurate measurement of tumor size and 
ADC, and detection of small changes in size or grade over time.  Standard prostate DWI 
has poor resolution; therefore, tumor growth kinetics have never been accepted as clinical 
criteria for cancer progression while on AS.  If tumor growth kinetics or changes in grade 
determined by ADC prove prognostic, AS can rely less on serial transrectal biopsies, which 
can lead to serious complications.   
 
 
Prostate Cancer 
 
Prostate cancer is the most commonly diagnosed cancer among men and the second 
leading cause of cancer death in US men.12 In the US, there are more than 200,000 newly 
diagnosed cases and nearly 40,000 deaths from prostate cancer annually.  The lifetime risk of 
developing prostate cancer is one in seven men.13  The vast majority of men diagnosed with 
prostate cancer do not die of their disease even when curative therapy is not administered.14, 15 
However, historically approximately 90% of men diagnosed with localized prostate cancer elect 
therapies such as radical prostatectomy or radiotherapy.16  The problem is that definitive therapies 
for prostate cancer can negatively impact quality-of-life by producing side-effects such as 
permanent urinary incontinence (7-14% post-treatment) and erectile dysfunction (44-51% post-
treatment).17 Therefore overtreatment of prostate cancer has broad impact on quality of life and 
health care costs.  The U.S. Preventive Services Task Force (USPSTF) recommends against 
PSA-based screening for all U.S. men; they argue that screening provides little to no benefit for 
most men while harming many men.18  On the other hand, the American Urologic Association 
(AUA) maintains that prostate cancer screening and risk assessment should be offered to 
asymptomatic men 55-69 years of age.19  
Both opponents and advocates of PSA-based screening acknowledge that screening increases 
the detection of prostate cancer.  An important assumption underlying the USPSTF 
recommendation against screening is that men with indolent cancer will continue to receive 
unnecessary treatment.  An important assumption underlying the AUA recommendation for 
screening is that patients and physicians will be able to uncouple the diagnosis of prostate cancer 
from treatment.  For example, men at highest risk for death from prostate cancer will receive 
treatment.  All other men will undergo a period of active surveillance (AS).  During followup on 
AS, men with evidence of high risk disease or cancer progression are offered definitive local 
therapy; however, men who continue to have low risk cancer can delay or completely avoid 
treatment.  A barrier to AS is that clinical tools for risk-stratifying and monitoring men with newly 
diagnosed prostate cancer have limited accuracy.  Prostate cancers are multifocal and biopsies 
are vulnerable to sampling error. Transrectal ultrasound-guided (TRUS) biopsy remains the gold 
standard for diagnosing prostate cancer and monitoring patients on AS.  However, the standard 
prostate biopsy may miss clinically significant disease. TRUS biopsy undergrades and 
understages the cancer in approximately a third of patients.20, 21 Furthermore, TRUS biopsy is 
accompanied by complications such as systemic infection, bleeding, and transient erectile 
dysfunction.22 There is a clear need for innovations to reduce the clinical burden of 
diagnosing and monitoring prostate cancer.  
 
 
 
3.0 
STUDY DESIGN: 
 
A. Overview 

________________________________________________________________________ 
6 
 
Prostate cancer is the rare malignancy where there is no imaging strategy to serially 
monitor the tumor. MRI, which is the best tool we have for imaging the prostate, cannot 
detect most tumors and does not have the resolution to detect subtle changes in tumor 
size or tumor characteristic.  Therefore, followup during AS relies on serial transrectal 
biopsies.  An effective imaging strategy will decrease the clinical burden of AS.  This 
prospective trial will compare the effectiveness of high resolution MRI (hrMRI) and 
standard MRI (sMRI) for serially monitoring prostate tumors for clinical progression, which 
is an indication for definitive local therapies such as radical prostatectomy and external 
beam radiotherapy. We test the hypothesis that hrMRI may detect changes in tumor 
size or ADC value, which will predict clinical progression as defined by biopsy 
criteria.  
 
 
B. Study Population 
 
The study population for recruitment will be patients at Cedars-Sinai Medical Center with 
prostate cancer on active surveillance.  
 
C. Inclusion/Exclusion Criteria 
 
Inclusion Criteria: 
• 
Age over 18 years 
• 
Patients diagnosed with clinically localized prostate cancer  
• 
Low or Low-intermediate Risk Prostate cancer1 defined as: 
o Pre-operative PSA ≤ 20.0 ng/ml 
o Clinical stage cT1 or cT2  
o Gleason score 3+3 or 3+4  
• 
Patients choosing AS or already on AS as primary management strategy 
• 
No previous treatment for prostate cancer with radiotherapy, chemotherapy, or 
hormonal therapy 
• 
No contraindications for gadolinium enhanced MRI 
 
D. Study endpoints 
 
Primary Endpoint: evidence of disease progression as defined by any of the following: 
• 
Increase in Gleason score from 3 + 3 to Gleason sum 7 on biopsy 
• 
Gleason score 4+3 on biopsy 
• 
Gleason sum 8-10 on biopsy 
• 
> 3 Increase in number of positive cores  
• 
Progression to nodal or bone involvement 
 
 
 
 
 
E. Study Design 
 

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7 
 
 
The study enrolls patients with low and low-intermediate risk prostate cancer.  The 
National Comprehensive Cancer Network (NCCN) guidelines for prostate cancer list AS 
as an option for these patients.1  There is no proven standard for monitoring patients on 
AS.  The NCCN recommends a standard 12-core prostate biopsy every 1-2 years, at the 
discretion of the treating physicians depending on risk category and length of stable 
followup on AS.  All Patients enrolling on the study will undergo standard (control) MRI 
(sMRI) and experimental High-Resolution MRI (hrMRI) at the time of study enrollment and 
again in 12 months (+/-2 months).  The patients then undergo a standard ultrasound 
guided 12-core prostate biopsy, where prostate ultrasound is used to sample 2 cores from 
the left and right lobes at the base, midgland and apex.  At the discretion of the treating 
physician, the 2nd MRI and biopsy may be performed early if disease progression is 
suspected due to increasing PSA or adverse change in prostate exam.  These for-cause 
MRI and biopsies will be used for the final analysis if the interval between MRIs is at least 
5 months.  
All MRI images will be read according to PI-RADS (version 2).  All lesions with PI-RADS 
greater than or equal to 3 will be considered suspicious for cancer.  A region of interest 
(ROI) application will be used. The circumference of a suspicious lesion will be drawn on 
each individual MRI slice. The lesion volume and average ADC will be calculated from the 
ROI’s. At the discretion of the treating physician, the MRI images may be used to perform 
a MRI-ultrasound fusion biopsy of suspicious lesions, however, only the standard 12-core 
biopsy will be used for the statistical analysis. 
 
Study calendar 
Study Calendar 
 
 
 
Registration/consenting 
 
Standard and experimental MRI 
 
Standard and experimental MRI* 
12 months after first MRI (+/- 2 months) 
Prostate biopsy* 
within 3 months of the 2nd MRI 
* At the discretion of the treating physician, the 2nd MRI and biopsy may be performed 
early if disease progression is suspected due to increasing PSA or adverse change in 
prostate exam. 
 
 
F. Study Risks 
 
All agents administered to patients in this study are approved by the U.S. Food and Drug 
Administration.  This study investigates a novel software-based MRI imaging protocol that 
improves image resolution.   
 
Registration
Imaging (standard 
and experimental 
MRI)
Imaging (standard 
and experimental 
MRI)
Standard prostate 
biopsy

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8 
 
Magnetic Resonance Imaging (MRI) 
MRI imaging is among the least invasive of all imaging modalities. The U.S. Food and 
Drug Administration has labeled MR systems of up to 4.0 Tesla as having “non-significant 
risk” and currently there is no evidence that MR imaging causes any long-term or 
irreversible effects in human beings. However, there are certain risks, which are detailed 
below. 
 
MRI imaging utilizes magnetic fields and radiofrequency fields, both of which can be 
harmful in certain situations. Magnetic fields can cause ferromagnetic implants or 
ferromagnetic foreign bodies, such as intracranial aneurysm clips, shrapnel, and 
intraocular metal chips to become dislodged and tear the surrounding soft tissue. 
Therefore, MRI imaging is contraindicated in persons with ferromagnetic implants or 
ferromagnetic foreign bodies. It is also contraindicated in persons with electrically, 
magnetically or mechanically activated implants because the magnetic field can cause 
these to function erratically.  In addition, persons wearing metallic objects may be at 
danger for them becoming dangerous projectiles, due to them inadvertently becoming 
introduced into the magnetic field. All subjects will be prescreened carefully and all 
scanners are used in accordance with guidelines set by the Bureau of Radiological Health. 
 
Gadolinium contrast (Gadavist 
The intravenous contrast agent to be used in this study is gadolinium-based. The 
intravenous contrast has an excellent safety profile and is commonly used in MR studies. 
Allergic reactions are extremely rare, but may be more common in persons with a history 
of allergic reactions to iodinated contrast. Studies support a rate of serious allergy 
reactions of 1 in 20,000.  
 
The most common side effect is bruising at the site of vein puncture, inflammation of the 
vein and infection; care will be taken to avoid these complications. Rare side effects are 
headache (5%), a coldness feeling on your arm where the needle was placed (2.8%), 
nausea (2.5%), dizziness (less than 2%), and vomiting (less than 1%). The use of 
gadolinium-based contrast agents in patients who already have serious kidney problems 
or who have a liver transplant may lead to a possibly fatal disease involving the skin, 
muscle and internal organs. This possibly fatal disease is called nephrogenic systemic 
fibrosis (NSF). Prior to giving a gadolinium-based contrast agent, we will ask about any 
history of kidney problems or liver transplant, and will test the health of the participant’s 
kidneys by a blood test. If there are known risk factors for developing this disease, the 
participant will not be eligible to receive contrast. 
 
Cedars Sinai conducted a research study looking for gadolinium deposits in the brain of 
119 patients who underwent at least 7 contrast enhanced scans.  Approximately half the 
patients had all their scans performed with a contrast agent categorized as a macrocyclic 
molecule and the remainder of the patients had all their scans performed with a contrast 
agent categorized as a linear agent.  Patients who received the linear agent had contrast 
agents in their brain but none of the patients who received the macrocyclic agent had brain 
deposits.  All patients in this study will receive the macrocyclic contrast agent for the MRI 
studies. 
 
Hypersensitivity to Medications - Occasionally, people have allergic reactions when 
taking any medication. Subjects may receive medications such as contrast. 
Hypersensitivity reactions may include symptoms such as shortness of breath, wheezing, 

________________________________________________________________________ 
9 
flushing, nasal congestion and skin rash. In most cases, initial symptoms occur within 
minutes of drug administration and quickly reverse themselves or resolve with prompt 
medical treatment.  
 
In general, allergic reactions to medicines are more likely to occur in people who have 
allergies to other drugs, foods, or things in the environment.  Subjects will be asked about 
any pre-existing allergies before administering any medications during the study.  
 
Incidental Findings  
Only noted clinically significant incidental findings will be communicated to the subject, per 
CSMC IRB and Legal Department approved policy, as a result of agreeing to undergo a 
research MRI scan. No reports or images will be provided to subjects and their medical 
records.   
 
 
G. Statistical Analysis  
 
Power. The progression rate used for the power calculations comes from the REDEEM 
trial, which was a phase III trial conducted at 65 academic medical centers to assess the 
role of a 5-alpha reductase inhibitor to decrease progression during AS.23  The REDEEM 
trial followed patient for a total of 3 years.  In the placebo group, the progression rate for 
patients already on active surveillance undergoing their 2nd surveillance biopsy was 20%.  
This is expected to be a conservative estimate for progression since the REDEEM trial 
only included low risk patients while our study allows for low intermediate risk patients, 
who have a higher risk of progression. The patients at 20% risk for progression drive our 
power calculation. 
Preliminary data from 13 patients with a total of 14 Gleason score 6 lesions show a mean 
of 0.19 cm3 and standard deviation of 0.19 cm3. We expect to detect at least a 50% 
increase in tumor volume in the group who progress compared to the group of patients 
that do not progress relative to baseline. Assuming that the standard deviation at the 
biopsy/MRI is similar to the baseline biopsy/MRI, group sample sizes of 12 patients who 
progressed and 47 patients that do not progress achieve 91% power to detect a difference 
in the mean change tumor volume around 0.285 cm3 at the two-sided two-sample t-test 
with a 0.05 level of significance. The estimate standard deviation of the difference in tumor 
size in each group (SDdiff) was estimated assuming the correlation coefficient 
measurements is 0. Since this correlation coefficient is likely to be positive, this power 
calculation is very conservative and much smaller mean change tumor volume can be 
detected. In fact, if this correlation coefficient equals to 0.6, then we can achieve 90% 
power to detect a mean change tumor volume around 0.18 cm3. With respect to change 
in ADC, preliminary data show that the mean and SD of ADC are 0.2 and 0.05, 
respectively. Under similar assumptions for the correlation coefficient between the first 
and second measurements (corr = 0), group sample sizes of 12 patients who progressed 
and 47 patients that do not progress achieve 80% power to detect a difference in the mean 
change ADC around 0.07 at the two-sided two-sample t-test with a 0.05 level of 
significance. This corresponds to about a 50% increase in ADC between the two groups 
of patients. 
Multivariable logistic regression model will be used to study the association between 
change in tumor size and ADC from the first and the second biopsy as assessed by 
imaging and disease progression adjusting for potential baseline characteristics such as 
PSA level, clinical stage, NCCN risk category, and size of prostate nodule. Tumor size 

________________________________________________________________________ 
10 
and ADC is measured by averaging the volumes or ADCs of all detectable lesions (PI-
RADS 3 - 5). Secondary analyses include studying this association by considering 
changes of single lesions. Automatic variable selection methods such as backward and 
stepwise selection will be used as a guideline to identify sets of important predictors of 
progression. More rigorous approach based on a 4-step procedure outlined in Collett24 will 
be employed. Several model checking diagnostics will be employed to ensure that the 
logistic model is appropriate.25  
 
4.0 
REFERENCES 
 
 
 
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11 
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Sanda, M. G., Dunn, R. L., Michalski, J. et al.: Quality of life and satisfaction with 
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Screening for Prostate Cancer. 
http://www.uspreventiveservicestaskforce.org/prostatecancerscreening.htm, U.S. 
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http://www.uspreventiveservicestaskforce.org/prostatecancerscreening.htm. Accessed: 
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Carter, H. B., Albertsen, P. C., Barry, M. J. et al.: Early detection of prostate cancer: 
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Cohen, M. S., Hanley, R. S., Kurteva, T. et al.: Comparing the Gleason prostate biopsy 
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Kawachi, M. H., Bahnson, R. R., Barry, M. et al.: NCCN clinical practice guidelines in 
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22. 
Loeb, S., Vellekoop, A., Ahmed, H. U. et al.: Systematic review of complications of 
prostate biopsy. Eur Urol, 64: 876, 2013 

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12 
 
23. 
Fleshner, N. E., Lucia, M. S., Egerdie, B. et al.: Dutasteride in localised prostate cancer 
management: the REDEEM randomised, double-blind, placebo-controlled trial. Lancet, 
379: 1103, 2012 
 
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Collett, D.: Modeling survival data in medical research: Chapman and Hall, 2003 
 
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