A Phase II, Prospective Study of MRI in the Reclassification of Men Considering Active Surveillance in Prostate Cancer
Phase: NA
Conditions: Prostate Cancer
Sponsor: Dana-Farber Cancer Institute

Status Page 
 
 
 
PROTOCOL 13-056 
 
 
 
 
Closed To New Accrual 
 
 
 
Closure Effective Date: 06/05/2017 
No new subjects may be enrolled in the study as described above. 
Any questions regarding this closure should be directed to the 
study’s Principal Investigator 

CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
Protocol Version Date: November 25, 2014 
 
Local Protocol #:13-056 
 
Title: A phase II, prospective study of MRI in the reclassification of men considering active 
surveillance in prostate cancer 
 
Principal Investigator: 

MRI in active surveillance for prostate cancer 
11/25/2014 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
 
 
 
 
 
 
 
 
 
SCHEMA 
 

MRI in active surveillance for prostate cancer 
11/25/14 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
 
 
TABLE OF CONTENTS 
1. 
OBJECTIVES .................................................................................................................................................... 4 
1.1 
Study Design .................................................................................................................................................... 4 
1.2 
Primary Objectives .......................................................................................................................................... 4 
1.3 
Secondary Objectives ...................................................................................................................................... 4 
o 
Determine the frequency of MP-erMRIs which appear to reclassify men with low risk disease considering 
AS 
4 
2. 
BACKGROUND ................................................................................................................................................ 4 
2.1 
Study Disease .................................................................................................................................................. 4 
2.2 
Rationale ......................................................................................................................................................... 9 
3. 
PARTICIPANT SELECTION ........................................................................................................................ 10 
3.1 
Eligibility Criteria ......................................................................................................................................... 10 
3.2 
Exclusion   Criteria ....................................................................................................................................... 10 
3.3 
Inclusion of Women, Minorities and Other Underrepresented Populations ................................................. 11 
4. 
REGISTRATION PROCEDURES ................................................................................................................ 12 
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions .......................................................................... 12 
4.2 
Registration Process for DF/HCC and DF/PCC Institutions ................................................................. 12 
4.3 
General Guidelines for Other Participating Institutions .................................................................... 13 
4.4 
Registration Process for Other Participating Institutions............................................................................ 13 
5. 
TREATMENT PLAN ...................................................................................................................................... 13 
5.1 
Patient-reported health states ..................................................................................................................... 13 
5.2 
Multiparametric MRI ............................................................................................................................... 14 
5.3 
Prostate biopsy ........................................................................................................................................ 15 
5.4 
PSA ................................................................................................................................................................ 17 
5.5 
Duration of Follow Up/End of Study Visit .................................................................................................... 17 
5.6 
Criteria for Removal from Study ................................................................................................................... 17 
6. 
EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS .................................... 17 
6.1 
Anticipated Toxicities .................................................................................................................................... 18 
7. 
STUDY CALENDAR ...................................................................................................................................... 19 
8. 
ADVERSE EVENT REPORTING REQUIREMENTS ............................................................................... 20 
8.1 
Definitions ..................................................................................................................................................... 20 
8.2 
Procedures for AE and SAE Recording and Reporting ................................................................................. 21 
8.3 
Reporting to the Study Sponsor ..................................................................................................................... 22 
8.4 
Reporting to the Institutional Review Board (IRB) ........................................................................................ 23 

MRI in active surveillance for prostate cancer 
11/25/14 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
8.5 
Reporting to Hospital Risk Management ....................................................................................................... 23 
8.6 
Monitoring of Adverse Events and Period of Observation ............................................................................ 23 
9. 
DATA AND SAFETY MONITORING .......................................................................................................... 24 
9.1 
Data Reporting .............................................................................................................................................. 24 
9.2 
Safety Meetings ............................................................................................................................................. 25 
9.3 
Monitoring ..................................................................................................................................................... 25 
10. 
REGULATORY CONSIDERATIONS .......................................................................................................... 26 
10.1 
Protocol Review and Amendments ........................................................................................................... 26 
10.2 
Informed Consent ..................................................................................................................................... 26 
10.3 
Ethics and Good Research Practice ......................................................................................................... 26 
This study is to be conducted according to the following considerations, which represent good and sound 
research practice .................................................................................................................................................... 26 
10.4 
Study Documentation ................................................................................................................................ 27 
10.5 
Records Retention ..................................................................................................................................... 27 
11. 
STATISTICAL CONSIDERATIONS ............................................................................................................ 28 
11.1 
Study Design/Primary Objective .............................................................................................................. 28 
11.2 
Hypothesis assumptions ............................................................................................................................ 28 
11.3 
Power and sample size calculation ........................................................................................................... 28 
11.4 
Primary Analysis ...................................................................................................................................... 29 
11.5 
Secondary Objectives ............................................................................................................................... 29 
11.6 
Secondary Analysis ................................................................................................................................... 29 
12. 
REFERENCES ................................................................................................................................................. 29 

MRI in active surveillance for prostate cancer 
11/25/14 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
4 
 
 
 
 
1. OBJECTIVES 
 
This study’s primary objective is to determine the sensitivity and specificity of multiparametic, endorectal- 
magnetic resonance imaging (MP-erMRI) in classifying prostate cancer disease extent and grade relative to 
transrectal ultrasound-guided (TRUS) biopsy in men considering active surveillance (AS). We hypothesize MP- 
erMRI prior to AS for men with low risk disease can identify men who harbor more extensive or higher-risk 
prostate cancer. Identifying and treating these higher risk men early may result in better outcomes for both 
groups. Specifically, more men will remain on AS in follow up and those who are treated early will have better 
outcomes. We anticipate that correctly identifying individuals likely to remain on AS will make this initial 
treatment approach more appealing to men with newly diagnosed low-risk prostate cancer and to their 
physicians. 
 
1.1 Study Design 
 
A prospective, single arm study assessing the sensitivity and specificity of multi-parametric magnetic 
resonance imaging in identifying men whose disease will be upgraded on subsequent repeat biopsy in 
individuals with previously untreated prostate cancer considering AS. 
 
1.2 Primary Objectives 
 
Determine the sensitivity and specificity of MP-erMRI relative to repeat 12 core TRUS biopsy for 
classifying upgrading of disease extent or Gleason grade in men considering AS 
 
1.3 Secondary Objectives 
 
o Determine the frequency of MP-erMRIs which appear to reclassify men with low risk disease 
considering AS 
o Determine effect of MP-erMRI and rebiopsy on patient-reported health states 
o Correlate the pathology findings from a targeted biopsy with the MP-erMRI findings for those 
men who fall into the reclassified category. 
 
2. BACKGROUND 
 
 
2.1 Study Disease 
 
Prostate cancer is a major cause of morbidity and mortality among men in the United States. Many men with 
prostate cancer have a slow growing tumor and experience an indolent course even without curative therapy [1]. 
The Scandinavian trial of radical prostatectomy versus watchful waiting [2, 3] demonstrated that definitive local 
therapy compared to observation alone decreases subsequent risk of metastases and prostate cancer death. 
However, 15 men had to have a surgical resection to prevent one cancer-specific death during a median 12 
years of follow-up. Conversely, some men with apparently localized disease die of their cancer despite initial 
therapy because of the presence of undiagnosed micrometastases. 
This biologic heterogeneity in prostate cancer has been brought into sharp focus as a result of widespread 
adoption of prostate specific antigen (PSA) screening in many countries, with a resulting marked migration 
towards the diagnosis of lower-risk prostate cancer [4].  There are now more than 240,000 men in the United 

MRI in active surveillance for prostate cancer 
11/25/14 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
5 
 
 
 
 
States diagnosed with prostate cancer each year [5], and 90 percent of prostate cancers are clinically localized at 
time of diagnosis [4]. Data from the randomized trials of PSA screening [6, 7] highlight the considerable 
overdiagnosis and overtreatment of men with screen-detected prostate cancer with very low prostate-cancer 
specific mortality rates in modern series [8-10]. 
In this setting, there is an increasing recognition that some men may defer or even avoid treatment. This strategy 
of AS focuses on closely monitoring patients and intervening only when their disease becomes clinically 
significant. This stands in contrast to the watchful waiting approach used in the Scandinavian study, where men 
are simply observed and palliative treatments are instigated when necessary [3]. For AS, the aim is to intervene 
with curative intent at the time of disease progression. Given the long natural history of low-risk disease [11], 
this strategy could both spare many men the morbidity associated with surgery or radiation and provide 
significant cost savings [12] without negatively affecting cancer-related death rates. 
While many groups have prospectively explored AS [13-18] with generally excellent clinical outcomes, 
significant questions remain regarding which men are most suitable for AS and what thresholds for treatment 
should be utilized. 
The success of AS is predicated on several assumptions. The ability to reliably: (1) identify men who are at a 
low-risk of having incurable disease at diagnosis, (2) identify men unlikely to progress to incurable disease in 
the interval between visits, and (3) identify clinical or pathologic features from biopsy suggesting the need for 
immediate definitive local treatment. All three of these remain challenging and likely reduce the number of 
clinicians and patients who feel comfortable with AS. In this protocol, we aim to better identify men most likely 
to continue on AS, and therefore those most likely to benefit from this approach. 
As summarized in the tables, several groups have published their experience with AS. Typically, men with low- 
risk disease have been selected for AS (Table 1), followed with PSAs and rebiopsies every 1-2 years (Table 2), 
and with limited follow-up, have been shown to have excellent cause-specific survival rates (Table 3). 
 
Table 1: Eligibility Criteria for Reported Prospective Studies (after[23]) 
 
Disease 
Extent 
Broadly, 
two types 
of failure 
of AS as an 
initial 
manageme 
nt strategy 
can be 
considered: 
(1) 
developme 
nt of 
incurable disease or (2) relatively rapid reclassification of the patient from low-risk to higher risk necessitating 
definitive treatment. Longer follow-up will be needed to better identify the first group as most series have 
reported low rates of metastatic disease or prostate cancer specific mortality. Lacking randomized studies 
comparing follow up approaches, the second group has been identified variously (Table 2) but typically with 
either a rise in the PSA or an increase in the tumor grade or volume. Both markers are associated with disease 
progression but decision making around small changes in PSA rely on untested assumptions [24] regarding the 
relationship between PSA and tumor volume, location or aggressiveness. Unlike PSA, where one would have to 
T stage 
Gleason 
PSA 
cores positive 
PSA density 
Royal Marsden 
[16] 
T1c-T2a 
≤ 3+4 
≤ 15 
≤ 50% 
NA 
University of 
Miami [19] 
T1-T2 
≤ 6 
≤ 10 
≤ 2 cores; ≤ 20% of any core 
pos 
NA 
Johns Hopkins 
[18] 
T1 
≤ 3+3 
NA 
≤ 2 cores; ≤ 50% of any core 
≤ 0.15 
ng/mL/mL 
UCSF [17] 
≤ T2 
≤ 3+3 
≤ 10 
≤ 33% of cores pos; ≤50% 
of any core 
NA 
University of 
Toronto [20] 
NA 
≤ 6 (age >70 ≤ 
3+4) 
≤ 10 (age>70, ≤ 
15) 
NA 
NA 
European 
Randomized 
Screening 
Study [21] 
Tc-2 
≤ 3+3 
≤ 10 
≤ 2 cores pos 
≤ 0.2 ng/mL/mL 
MSKCC [22] 
≤ T2a 
≤ 3+3 
≤ 10 
≤ 3 cores pos; ≤ 50% of any 
core 
NA 

MRI in active surveillance for prostate cancer 
11/25/14 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
6 
 
 
 
 
predict future trends, the amount and grade of disease present at diagnosis is thought to be simply undersampled 
using current diagnostic approaches [25-27]. 
 
Table 2: Follow-up Protocol 
PSA/DRE 
Rebiopsy 
Indication for Radical Treatment 
 
 
Entry 
Criteria 
Critical to 
University of 
Miami[19] 
q3-4 mo x 2 yr; 
q6mo after 2 yr 
At 6-12 mo and as 
clinically indicated 
thereafter 
Gleason >3 
Increase in tumor volume (% of cores pos or 
amount of tumor within a core) 
avoiding 
reclassificat 
ion based 
on disease 
UCSF[17] 
q3mo 
U/S: q6-12 mo 
bx: q12-24 mo 
PSA velocity >0.75 ng/mL/yr 
Gleason grade increase 
grade or 
University of 
Toronto[20] 
q3mo x 2 yr; 
q6mo after 2 yr 
At 6-12 mo; q3-4 yrs 
until pt 80 
PSADT <3yr 
Gleason upgrade 
Clinical progression (volume) 
extent is 
the ability 
European 
Randomized 
Screening 
Study[21] 
Per center 
Per center 
Per center 
to 
accurately 
select men 
MSKCC[22] 
q6mo 
 Immediate confirmatory 
At 12-18mo and then q2- 
3 yrs 
PSA >10ng/mL 
Gleason >6 
T>2a 
>3 cores positive or >50% of any core positive 
likely to 
harbor low- 
risk 
disease. 
Early work 
by Epstein et al at. at Johns Hopkins found clinical factors associated with very low volume, low grade disease 
[28] which are now incorporated into practice guidelines from the National Comprehensive Cancer Network. 
These factors include a T category of T1c, Gleason grade of 6 or lower, two or fewer prostate biopsy cores 
positive for cancer, none of which have >50 percent tumor involvement and a PSA density ([PSA]/prostate 
volume on transrectal ultrasound) of less than 0.15 ng/mL/mL. While Johns Hopkins has adopted similar 
criteria for entry into their AS protocol, other groups have been less restrictive (Table 1). Nomograms now 
exist which predict men likely to harbor low volume, low risk disease [29-31] though how these should be 
applied to selecting men for AS remains to be determined. 
The challenge at the time of diagnosis remains that the standard 12 biopsy is inadequate to accurately predict 
the final Gleason score secondary to sampling errors [25-27]. Reported rates vary widely but it is estimated that 
approximately one-third of cases are upgraded on Gleason between the diagnostic biopsy and a radical 
prostatectomy [26]. Confidently identifying men at diagnosis likely to have organ-confined disease at the outset 
is thought to be important as extracapsular extension (ECE) or seminal vesicle invasion (SVI) at the time of 
local therapy are associated with a poor outcome [32]. A systematic review of surgical outcomes for men with 
very limited disease extent on diagnostic biopsy suggests that adverse pathologic findings such 
 
Table 3: Reasons for active treatment and outcomes across reported series (after[23]) 
as ECE are present in up to 50% of cases though much of the data was from 10 or more years ago with fewer 
biopsy samples taken [33]. Exploring the rates of ECE or SVI among large surgical cohorts categorized by 
whether they met entrance criteria for the various AS protocols, groups have found rates of 7 percent ECE for 
the Johns Hopkins criteria which is the most restrictive to 18 percent for the Royal Marsden criteria which is 
Royal 
Marsden[16] 
q3mo x 2 yr; 
at 1 yr and then q 3 yr 
q6mo after 2 yr 
PSA velocity >1ng/mL/yr 
Gleason ≥4+3 
>50% Cores positive 
Johns 
Hopkins[18] 
q6mo 
q1yr 
Gleason >6 
> 2 cores; >50% of any core 

MRI in active surveillance for prostate cancer 
11/25/14 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
7 
 
 
most permissive [25]. Taking the same approach of retrospectively comparing a surgical cohort to the various 
published AS protocol entry criteria, Gleason upgrading was noted in 23-35 percent of men and seminal vesicle 
involvement was seen in between 2 and 9 percent depending on the study entrance criteria. Other recent studies 

MRI in active surveillance for prostate cancer 
11/25/14 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
8 
 
 
 
 
have found that using the Epstein criteria, more than 10% of men treated with prostatectomy have disease 
reclassification [25, 34] highlighting the need for additional markers of disease extent. 
 
 
 
 
 
Royal 
Marsden[16] 
326 
22 
27 
10 
13 
2 
98 
100 
73 
5 
University of 
Miami[19] 
230 
32 
~7 
10 
NA 
NA 
100 
100 
86 
0 
Johns 
Hopkins[18] 
633 
32 
20 
14 
NA 
9 
98 
100 
54 
9 
UCSF[17] 
376 
47 
15 
9 
7 
8 
97 
100 
54 
1 
University of 
Toronto[20] 
450 
82 
16 
9 
14 
3 
68 
97 
70 
50 
European 
Randomized 
Screening 
Study[21] 
616 
52 
~18 
NA 
12 
18 
91 
99 
68 
NA 
MSKCC[22] 
238 
22 
16 
13 
14 
11 
NA 
NA 
NA 
NA 
 
Rebiopsy 
 
In light of the significant sampling errors in the classification of men considered appropriate for active 
surveillance, repeat biopsy in follow up has been used as a component of surveillance protocols. Memorial 
Sloan Kettering Cancer Center adopted a strategy of recommending immediate rebiopsy for all men considering 
AS at their institution [35]. Between 2002 and 2007, 104 men who met eligibility criteria for AS at Memorial 
Sloan Kettering Cancer Center (Table 1) underwent immediate 14-core rebiopsy [35]. Among these rebiopsies, 
26% had no cancer identified. For those with cancer on the rebiopsy, 77% had Gleason ≤6, 22% had Gleason 7 
and one man had Gleason 9. From the standpoint of upstaging of disease extent, 13% were found to have >3 
cores positive and 16% had >50% of any core involved. In total, 27% had either upstaging or up-grading on the 
biopsy. A subset of these men, 64%, had an erMRI prior to re-biopsy with 27% showing a finding concerning 
for ECE. None of the men without evidence of ECE were up-staged or upgraded compared to 39% among those 
with concerning MRI features. A subsequent analysis showed that those men without cancer identified on the 
confirmatory biopsy were less likely to progress to definitive treatment over the course of the study [22]. Other 
retrospective analyses show similar results [36, 37]. In line with these results, the first biopsy following 
diagnosis has tended to result in the greatest number of men being upgraded on AS protocols [38, 39]. 
Though biopsy remains the gold standard for reclassification, it carries what appear to be increasing risks [40, 
41]. Highlighting the short-term effects, in one recent report of nearly one thousand men who had undergone 
biopsy, 44% noted pain, 66% had hematuria, 37% had hematochezia, 93% had hemoejaculate and 18% had 
fever in the days following the procedure [42]. Many of these symptoms were not considered moderate or 
serious problems by the participants though 15% had some pain and 3% had fever two weeks or more after the 
biopsy. Significantly, the rates of hospitalization for infections following prostate biopsies appear to be 
increasing [40, 43, 44]. Though the absolute rates of sepsis following biopsy remain low [42, 43], the 
increasing risk appears to be related to resistance to antibiotics used in pre-biopsy prophylaxis [41, 45]. These 
findings highlight that approaches other than frequent, repeated biopsies will be necessary to classify men as 
candidates for AS. 
 
Prostate MRI 
Reason for treatment overall - % 
Outcomes - % 
n 
Median 
F/U - mo 
Treatment at 
2 yrs - % 
Gleason 
PSA 
No progression 
OS 
CSS 
PFS 
Failure 
after local 
therapy 

MRI in active surveillance for prostate cancer 
11/25/14 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
9 
 
 
 
 
MRI has been investigated as a non-invasive method to determine disease extent and provide insights into 
disease progression in prostate cancer [46]. Endorectal MRI has been shown to have variable sensitivity and 
specificity for tumor localization, extracapsular extension and seminal vesicle invasion [47-51]. While MRI can 
provide excellent morphologic information regarding the prostate, it also has the capacity to evaluate 
physiologic properties. Using diffusion-weighted images (DWI) and dynamic contrast-enhanced (DCE) 
imaging, multi-parametric (MP)-MRI may be better at correlating with disease risk [52] and localization [52- 
54]. Several groups have published on the use of MP-MRI in active surveillance populations [55]. MP-MRI 
may be better at correlating with disease risk and localization [56]. 
The group at the Royal Marsden reported on 80 men in their cohort of 326 on AS who had a diffusion-weighted 
(DW) MRI and a repeat biopsy as part of the protocol [55]. They found that the apparent diffuse coefficients 
(ADCs) were significantly correlated with adverse findings on repeat biopsy and on univariate analysis, was 
associated with a hazard ratio of 3.38 (95% CI 1.65-6.94) for progression to radical treatment. Ploussard 
reported a series of 96 patients who had low, but not very low risk disease who had undergone 21 core biopsies 
and subsequent erMRI prior to prostatectomy [57]. This was a T2-weighted MRI without contrast. Of the 68 
men (82%) with radiographic T1 or T2 disease, 18% had pathologic T3 or T4 disease and 39% had Gleason 
upgrading. These data suggest that in slightly higher risk men, a standard T2-weighted MRI may be insufficient 
to accurately reclassify men considering AS. 
More specifically, the group from Princess Margaret Hospital reported on a prospective AS protocol in which 
all men received multi-parametric MRI at the time of enrollment to assess its role in reclassifying their disease 
[58]. In this study, 60 men with T1c, Gleason 6, PSA <10 ng/mL, ≤3 cores involved and <50% involvement of 
any one core were enrolled. The 1.5 Tesla MRI was interpreted to classify men into three groups: (1) those with 
no visible tumor, (2) those with tumor ≤1 cm in size, and (3) those with tumor >1 cm (used to correspond to 
Epstein criterion for clinically significant disease). Those with either no tumor visible or with a tumor ≤1 cm in 
size were asked to undergo a repeat biopsy at approximately one year after initial diagnosis. Those with lesions 
larger than 1 cm were asked to undergo an immediate repeat biopsy using a TRUS approach targeting the area 
of interest [59]. Reclassification was defined as Gleason 7, more than 3 positive cores or more than 50% of any 
one core involved. The overall reclassification rate was 32%, with 77%, 25% and 9% in groups 3, 2, and 1 
respectively. Groups 3 and 2 had a higher mean number of biopsies than group 1 (16.2, 15.3 and 12.3 
respectively). Half of the reclassifications were for Gleason 7 disease on rebiopsy and this finding was 
significantly more common among those with larger MRI lesions. 
Given differences in how the groups were treated in this study, more biopsies in those with larger lesions and 
targeted biopsies for those with larger lesions, we aim to further clarify the role of MP-MRI in reclassifying 
men considering AS. We will specifically evaluate the accuracy of MP-MRI relative to standard TRUS biopsy 
as that has remained the gold standard for disease classification in men followed on surveillance in the 
published literature. If MP-MRI could replace repeat biopsy for men considering AS, it could have a dramatic 
impact on successfully selecting men likely to safely remain on surveillance. 
 
Patient-reported outcomes in active surveillance 
Up to one-third of men who initially opt for AS for management of their low risk prostate cancer may seek 
definitive treatment in the absence of clinical progression; instead citing patient preference, progression of 
urinary symptoms such as lower urinary tract symptoms (LUTS), or due to anxiety and distress [60-64]. Van 
den Bergh and colleagues hypothesized that men with prostate cancer on AS, who essentially live with 
untreated disease, may experience overwhelming feelings of anxiety and distress [65]. They found than in a 
population of 150 men with recently diagnosed prostate cancer who had selected AS, that patients reported 
lower anxiety and distress scores than anticipated. Of the 7% of men who opted to cease AS and move onto 
definitive therapy for personal reasons, cited causes included anxiety and fear of prostate cancer 

MRI in active surveillance for prostate cancer 
11/25/14 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
10 
 
 
 
 
progression[66]. Recently, AS protocols are increasingly incorporating validated assessments of health-related 
quality of life (HRQOL) including urinary and sexual function, as well as psychosocial measures including 
uncertainty, anxiety, distress, satisfaction with cancer care into their evaluations of patients as they present for 
their prostate cancer monitoring. 
Dall’Era reported that 33 percent of men on AS protocols at large oncology centers in multiple countries will 
subsequently switch to active treatment within 3-5 years of diagnosis, but also found that patient-reported 
HRQOL outcomes in men on AS are similar or better than those reported by men having undergone immediate 
radical therapy [67]. Kakehi and colleagues found no differences in general HRQOL between men who 
remained on AS and those undergoing radical prostatectomy after one year [62]. However they did note that the 
men on AS reported worse urinary function, sexual function, and bowel bother scores in comparison to their 
baseline levels after one year. Arredondo and colleagues found that, over 5 years, decreases were noted in all 
domains of HRQOL in 224 men on AS or watchful waiting [68]. Even when controlling for age, men on 
conservative management regimens appeared to have worsening perception of overall health and sexual 
function. Most recently, Vasarinen and colleagues reported that AS dose not provoke short-term disturbances in 
HRQOL and found that no patients in their series changed treatments due to anxiety; nor did they find changes 
in urinary function by the IPSS or in erectile function using the IIEF-5 questionnaire [68]. In comparison to an 
age-stratified Finnish population, patients with prostate cancer on AS reported better general mental and 
physical HRQOL at diagnosis and after 1 year of follow-up. Although more recent studies suggest that the 
impact of AS on a patient’s overall health and psychosocial wellness may not be as great as was previously 
hypothesized, evaluation of patient’s baseline HRQOL may predict better adherence with AS in the absence of 
clinical progression as certain factors such as baseline poor perception of physical health, high neuroticisim 
scores on personality assessments, high depression, and baseline anxiety scores appear to correlate with 
increased likelihood of changing from AS to definitive treatment, even without objective evidence of clinical 
progression [66]. 
Indeed, understanding of the morbidity of the surveillance measures employed in prostate cancer AS protocols 
is increasing and the importance of tracking these measures is being increasingly appreciated. Objective 
measurement of bowel, bladder, and erectile function in patients undergoing serial examination and biopsy may 
be helpful in predicting which men may not tolerate AS well, thereby assisting patient counseling and 
facilitating decision-making. There are few studies which have tracked HRQOL metrics over time in men on 
AS to better understand the magnitude of the role that HRQOL and psychosocial factors play in decision 
making as well as selection of treatment choices. To our knowledge, no studies to date assessing the 
incorporation of MRI into the patients’ selection calculus for AS have incorporated patient-reported HRQOL in 
their analysis. 
 
2.2 
Rationale 
 
In this study, our aim is to determine the sensitivity and specificity of MP-erMRI as it relates to initial re-biopsy 
among men with low-risk disease considering AS. Of the criterion used to take men off of AS, disease extent 
and grade appear to be under-assessed using current approaches. Lacking the full surgical specimens available 
from prostatectomy, repeat biopsies are the existing gold standard for classifying disease extent and grade. 
Comparing MP-MRI to the current standard of care, TRUS biopsy, we will specifically address the role of MP- 
erMRI in assessing men with low-risk disease for AS. We anticipate that the MRI will identify lesions of 
concern in up to one quarter of men. To assess the MRI accuracy, men with non-concerning MRIs and MRIs 
suggesting more extensive or higher-grade disease will both undergo TRUS biopsy. Men whose MRI shows an 
abnormal lesion will also have an immediate for-cause, guided biopsy to assess the lesion at the time of the 

MRI in active surveillance for prostate cancer 
11/25/14 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
11 
 
 
 
 
standard TRUS biopsy. This approach both addresses the scientific question of the study and safely identifies 
men with more extensive or aggressive disease. 
 
3. PARTICIPANT SELECTION 
 
 
3.1 
Eligibility Criteria 
 
Participants must meet the following criteria on screening examination to be eligible to participate in 
the study: 
 
 
3.1.1 The subject will have histologically confirmed prostate cancer with all of the following features: 
 
3.1.1.1 Minimum 10 core prostate biopsy showing histologically-confirmed prostate cancer 
within 12 months of enrollment reviewed by a pathologist from one of the DF/HCC 
associated hospitals 
 
3.1.1.2 Gleason ≤3+3 
 
3.1.1.3 No tertiary Gleason grade ≥4 
 
3.1.1.4 ≤3 total cores positive 
 
3.1.1.5 ≤50% of any given core involved with cancer 
 
3.1.1.6 No evidence on biopsy of extracapsular extension 
 
3.1.2 
PSA within 4 months prior to study consent or within 30 days after study consent: <10 ng/mL 
 
3.1.3 Clinical stage: ≤T2a & N0 or NX & M0 or MX 
 
3.1.4 The subject is able and willing to abide by the study protocol or cooperate fully with the 
investigator or designee 
 
3.1.5 The subject is capable of understanding and complying with the protocol requirements and has 
signed the informed consent document 
 
3.1.6 Age ≥18 
 
3.1.7 Life expectancy of greater than 10 years 
 
3.1.8 Ability to understand and the willingness to sign a written informed consent document. 
 
3.2 
Exclusion Criteria 

MRI in active surveillance for prostate cancer 
11/25/14 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
12 
 
 
 
 
Participants who exhibit any of the following conditions at screening will not be eligible for admission 
into the study. 
 
3.2.1 First diagnosis of prostate cancer > 12 months prior to enrollment 
3.2.2 Prior prostate cancer-directed therapy including: 
 
3.2.2.1 androgen deprivation therapy 
 
3.2.2.2 radiation therapy to the prostate (external beam or brachytherapy) 
 
3.2.2.3 cryotherapy 
 
3.2.2.4 high-intensity focused ultrasound (HIFU) 
 
3.2.2.5 chemotherapy for prostate cancer 
 
3.2.3 Prior transurethral resection of prostate 
 
3.2.4 Subject who is deemed by the treating physician to have a contraindication to definitive treatment 
 
3.2.5 Subjects with a contraindication to an MRI including those with a pacemaker, ferromagnetic 
aneurysm clip, or cochlear implants 
 
3.2.6 Subjects with a contraindication to receiving Gadolinium containing contrast for the MRI 
 
3.2.7 Conditions which make repeat TRUS biopsies not feasible 
 
3.3 
Inclusion of Women, Minorities and Other Underrepresented Populations 
 
 
The only patient population which is excluded from this study is women by virtue of the fact women do not 
get prostate cancer.  All other populations are potentially eligible for enrolment 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
0 
+ 
10 
= 
10 
Not Hispanic or Latino 
0 
+ 
120 
= 
120 
Ethnic Category: Total of all subjects 
0 
+ 
130 
= 
130 
Racial Category 
American Indian or Alaskan Native 
0 
+ 
0 
= 
0 
Asian 
0 
+ 
8 
= 
8 
Black or African American 
0 
+ 
8 
= 
8 
Native Hawaiian or other Pacific Islander 
0 
+ 
0 
= 
0 
White 
0 
+ 
114 
= 
114 
Racial Category: Total of all subjects 
0 
+ 
130 
= 
130 

MRI in active surveillance for prostate cancer 
11/25/14 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
13 
 
 
 
 
4. REGISTRATION PROCEDURES 
 
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions 
 
Institutions will register eligible participants with the DF/HCC Quality Assurance Office for 
Clinical Trials (QACT) central registration system. Registration must occur prior to the initiation 
of therapy. Any participant not registered to the protocol before treatment begins will be considered 
ineligible and registration will be denied. 
 
A member of the study team will confirm eligibility criteria and complete the protocol-specific 
eligibility checklist. 
 
Following registration, participants may begin protocol treatment. Issues that would cause 
treatment delays should be discussed with the Principal Investigator. If a participant does not receive 
protocol therapy following registration, the participant’s protocol status must be changed. Notify the 
QACT Registrar of participant status changes as soon as possible. 
 
4.2 
Registration Process for DF/HCC and DF/PCC Institutions 
 
The QACT registration staff is accessible on Monday through Friday, from 8:00 AM to 5:00 PM Eastern 
Standard Time. In emergency situations when a participant must begin treatment during off-hours or 
holidays, call the QACT registration line at and follow the instructions for registering participants after 
hours. 
 
The registration procedures are as follows: 
 
1. 
Obtain written informed consent from the participant prior to the performance of any study 
related procedures or assessments. 
 
2. 
Complete the protocol-specific eligibility checklist using the eligibility assessment documented 
in the participant’s medical/research record. To be eligible for registration to the study, the 
participant must meet each inclusion and exclusion criteria listed on the eligibility 
checklist. 
 
Reminder: Confirm eligibility for ancillary studies at the same time as eligibility for the 
treatment study. Registration to both treatment and ancillary studies will not be completed if 
eligibility requirements are not met for all studies. 
 
3. 
Fax the eligibility checklist(s) and all pages of the consent form(s) to the QACT. 
 
4. 
The QACT Registrar will (a) validate eligibility, (b) register the participant on the study, and 
(c) randomize the participant when applicable. 

MRI in active surveillance for prostate cancer 
11/25/14 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
14 
 
 
 
 
5. 
The QACT Registrar will send an email confirmation of the registration and/or randomization 
to the person initiating the registration immediately following the registration and/or 
randomization. 
 
4.3 
General Guidelines for Other Participating Institutions 
 
N/A 
 
4.4 
Registration Process for Other Participating Institutions 
 
N/A 
 
5. TREATMENT PLAN 
 
This is a single arm, prospective protocol investigating the sensitivity and specificity of MP-erMRI in assessing 
disease extent and grade relative to initial re-biopsy in men with low-risk prostate cancer who select AS as their 
initial treatment strategy. Following enrollment and registration, subjects will complete baseline patient- 
reported health state questionnaires. 
Between 2 and 14 months following initial diagnostic biopsy, they will undergo a MP-erMRI. This will be 
systematically reviewed and men will be characterized into three groups: (1) “not reclassified” characterized by 
findings consistent with small, low-Gleason grade organ-confined tumors, (2) “reclassified” characterized by 
large, higher-Gleason grade organ-confined tumors, and (3) radiographic T3 and/or N1 disease. Those in group 
3 will come off of protocol and proceed to management as per their treating physician. Those in groups 1 and 2 
will proceed within 3 months of the MRI to a standard 12-core TRUS biopsy. For those in group 2 at the time of 
TRUS biopsy, they will also have a for-cause targeted biopsy of the lesion seen on MP-MRI. All men in groups 
1 and 2 who do not have their disease reclassified with the TRUS biopsy or for-cause biopsy will proceed with 
AS as per their treating physician. Those who are pathologically reclassified will be managed per their treating 
physician. All study participants will come off study after the end of study visit that occurs within 60 days 
following the final biopsy. 
 
Information about participants will be gathered according to the study calendar. 
 
5.1 
Patient-reported health states 
 
Participants will be asked to complete patient-reported health state questionnaires at enrollment and 
following the final on-protocol biopsy. The questionnaire that will be provided to participants for self- 
administration will include the following: 
• The Mishel Uncertainty in Illness Scale Community Form for Active Surveillance (MUIS-AS, 
Appendix A). The MUIS-AS will evaluate uncertainty, anxiety, and distress associated with the 
patient’s cancer diagnosis. 
• The Service Satisfaction Scale for Cancer Care (SSS-Ca, Appendix B). The SSS-Ca will evaluate 
the patient’s satisfaction with both the process and outcome of their cancer related care. 
• The Expanded Prostate Cancer Index Composite – Clinical Practice (EPIC-CP, Appendix C). 
The EPIC-CP is used to evaluate urinary and sexual function following treatment for prostate 
cancer. This will specifically be useful in order to assess the progression of urinary symptoms 

MRI in active surveillance for prostate cancer 
11/25/14 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
15 
 
 
 
 
overtime in these participants who may be required to undergo serial prostate biopsies, endorectal 
MRI, etc. 
• The American Urological Association Symptom Index (AUA SI, Appendix D), which will be used 
to evaluate overall urinary bother and function 
 
Questionnaires will be given to participants at their enrollment visit and at the end of study visit following 
biopsy. Participants will be instructed to complete them independently and to return them by mail to the 
project coordinator. 
 
 
5.2 Multiparametric MRI 
 
Between 2-14 months following the initial diagnostic biopsy, participants will undergo an endorectal 
prostate MRI. A 2-month delay from the initial biopsy is preferred to minimize the effects of post-biopsy 
hemorrhage. All MR examinations will be performed on a 3T whole-body scanner possessing a whole- 
body gradient coil set with sufficient strength and speed to perform an optimized MP-MRI, a whole body 
transmit/receive coil, an external rigid phased-array torso coil, and an MR-compatible power injector for 
administering intravenous contrast. A compatible endorectal coil will be used for phased-array/ecoil 
measurements. All studies will be obtained with the image plane perpendicular to the rectal wall/prostate 
interface. 
 
5.2.1 Protocol: 
 
5.2.1.1 The standardized 3T pulse sequences we will use will include fast spin echo (FSE) for T2 
weighted-images (FOV: 14-18cm; slice thickness: 3mm; spacing: 3mm; TR/TE: 
3000/102 msec; Matrix: 384x256; NEX=3). Dynamic Contrast Enhanced (DCE) imaging 
will be performed with 3D-Fast spoiled gradient (FSPGR) images using FOV: 26 cm; 
slice thickness: 6mm; spacing: 6mm; Matrix: 256x160; contrast (Gadolinium 
gadopentetate (Gd)) injection rate of 3mL/sec; slab thickness 16-20 slices, 5 sec/volume, 
repeat 60 times, with a total scan time of 5 minutes. Pharmacokinetic analyses of each 
slice will be performed using a custom research tool (OncoQuant, GE Global Research) 
using a population averaged bi-exponential arterial input function augmented with a first 
pass peak[69]. Single shot echo planar diffusion weighted imaging (DWI) will be 
performed using b values of 0 and 500, and 0 and 1400 with trace ADC maps generated 
at all b values. 
 
5.2.2 Image Interpretation: 
 
5.2.2.1 Images will be reviewed within the radiology department where the scans were obtained 
as per current protocols and a standard clinical report will be produced. Images will 
subsequently be analyzed by study radiologists with extensive experience in GU imaging. 
The images will be evaluated according to the proposed PIRADS scoring system 
guidelines. This will specifically look at signal intensity on T2 weighted image (with a 
discrete, homogenous low signal focus being suspicious for tumor). For DCE, both semi- 
quantitative and quantitative parameters will be evaluated, with particular attention paid 
to the dynamic enhancement curve type [70]: ( type 1, persistent increase; type 2, plateau; 
and type 3, decline after initial upslope; type 3 being considered the most suspicious for 

MRI in active surveillance for prostate cancer 
11/25/14 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
16 
 
 
 
 
prostate cancer, particularly in the presence of a focal asymmetric enhancing lesion). 
Pharmacokinetic modeling, which will produce quantitative indices [such as Ktrans 
(forward volume transfer constant) and ve (fractional extracellular space)], will be 
incorporated into the analysis. DWI will also be scored according to signal intensity on 
high b value image (≥b1000) and values obtained on ADC map. Index lesion size will be 
measured on T2WI to categorize those ≥ or< 1 cm in size. Extracapsular extension (ECE) 
and seminal vesicle invasion (SVI) will also be evaluated for. 
The interpretation of the MRI will place participants into the following categories: 
1. Not-reclassified: any identified abnormality of the MRI is confined to the gland 
without definitive evidence of ECE or SVI. Additionally, no lesion is greater than 
1 cm in size nor do any identifiable lesions have characteristics of high Gleason 
grade. 
2. Reclassified: Disease appears to be confined to the prostate (no ECE or SVI) but 
one or more lesions appear either >1 cm in size or have imaging characteristics 
concerning for higher Gleason grade disease. 
3. T3 or N1: disease appears to be clearly extending outside the prostate and/or into 
the seminal vesicles or there is evidence of pathologic involvement of lymph 
nodes. 
If the MRI places a subject into the T3/N1 category, they will meet criteria for coming 
off protocol and will then receive further treatment per their treating physician. If a 
participant is in either the not-reclassified or the reclassified categories, they will 
proceed with the planned biopsy. 
 
5.3 
Prostate biopsy 
 
All subjects who remain on protocol following the MP-MRI will undergo an on-protocol TRUS biopsy 
within 3 months of the MRI. This biopsy will therefore take place between approximately 2-17 months 
following their initial diagnostic biopsy. 
 
5.3.1 Prophylaxis 
 
5.3.1.1 Participants will be recommended to receive oral or IV antibiotic prophylaxis according 
the American Urologic Association Guidelines 
(http://www.auanet.org/content/media/antimicroprop08.pdf) and as per the standard of 
the institution. Further, anticoagulant or antiplatelet directed therapy will be managed 
prior to biopsy as per the standard of the participating institution. 
 
5.3.2 TRUS Biopsy Sampling 
 
A 12-core biopsy will be performed without specific targeting of lesions noted at the time 
of MRI. This approach is intended to provide an unbiased assessment of the accuracy of 
MP-MRI in predicting men reclassified based on the current gold standard TRUS re- 
biopsy. Each core will be individually labeled with laterally and anatomic site within the 
prostate. 

MRI in active surveillance for prostate cancer 
11/25/14 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
17 
 
 
 
 
5.3.3 Targeted rebiopsy 
 
Participants in the reclassified category will have both a 12-core TRUS biopsy unguided 
by the results of the MRI and a biopsy targeting the lesion(s) of concern from the scan. The 
rationale for doing both biopsies is that to compare the MRI findings to the current gold- 
standard, a non-targeted TRUS biopsy, we need to include this regardless of the MRI 
findings. Because this biopsy may not capture the lesion noted on the scan, a targeted 
biopsy will be performed at the same time. The targeted biopsy will be performed 
according to the practices of the treating institution but will generally consist of conscious 
sedation with either an MRI-guided biopsy or a TRUS-guided biopsy directed based on 
images fused to the MRI. The number of cores taken will be at the discretion of the 
physician performing the biopsy. Standard of care transrectal ultrasound imaging (TRUS) 
may be augmented with the setup needed for spatial tracking of the TRUS images. The 
purpose of this is to facilitate research in spatial mapping biopsy samples within the 
prostate gland, and to aid with correlation of pathology analysis of the samples with TRUS 
and MRI imaging data. The tracking setup would be enabled by a tracking system 
consisting of an electromagnetic field transmitter that establishes the coordinate frame for 
tracking volume, and several sensors. The transmitter would be mounted on an articulated 
arm to the patient bed. One sensor will be attached to the handle of the TRUS probe before 
the procedure. The sensor will remain on the handle outside the patient at all times. The 
second sensor will be attached with the medical tape to the back of the patient. Prior to 
TRUS imaging, a calibration procedure may be necessary. If needed, such procedure would 
involve placing the TRUS probe in a water bath and imaging of a phantom, prior to the 
patient procedure. This component of the biopsy is not anticipated to add any additional 
risk or toxicity to the protocol. 
 
 
 
5.3.4 Pathologic assessment 
 
5.3.4.1 All specimens will be formalin fixed and paraffin embedded as per usual clinical care. 
Pathology will be reviewed by a pathologist with GU expertise for Gleason grade, disease 
extent, and number of cores positive. Additional features such as perineural invasion and 
high-grade PIN will be noted though these will not be used to determine continued 
protocol eligibility. Each of the cores will be labeled for biopsy location at the time of 
procedure and will be individually reported. Pathology will be reviewed at the treating 
center. Specimens will also be labeled as to whether they came from the TRUS biopsy or 
the targeted biopsy 
 
5.3.4.2 TRUS Biopsy: Participants will come off study if they no longer meet eligibility criteria 
following rebiopsy: 
• >3 cores positive for cancer 
• >50% of any single core containing cancer 
• any Gleason >3+3 

MRI in active surveillance for prostate cancer 
11/25/14 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
18 
 
 
 
 
5.3.4.3 Targeted Biopsy: Participants will be considered pathologically reclassified if either of 
the following criteria are met on the targeted biopsy: 
• Gleason >3+3 
• >7mm of any core involved with cancer 
In this situation, using the criteria of number of cores involved with cancer will no longer 
be comparable across participants as the number of cores sampled will be variable based 
on the situation. 
 
5.4 
PSA 
 
During the time that participants are on study, a PSA will be drawn as per the treating physician 
(typically every 3-6 months). A change in PSA will not be a criterion for discontinuation of this 
protocol though may be used clinically to change management at the discretion of the treating 
physician. 
 
5.5 
Duration of Follow Up/End of Study Visit 
 
Participants will also be followed until their final study visit which will occur up to 60 days after the 
final biopsy. 
5.6 
Criteria for Removal from Study 
Participants will be removed from the study when any of the criteria in section 5.3.3 or 5.3.4 applies. 
Additional criteria for removal from the study: 
• Participant withdraws from the study 
• The patient proceeds to prostate-cancer directed therapy 
• Death from any cause 
• General or specific changes in the participant’s condition which render them unacceptable for 
completion of the protocol in the opinion of the treating investigator. 
• Intercurrent illness that prevents completion of the protocol 
• Investigator discretion 
 
6. EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS 
 
Toxicity assessments will be done using CTEP Version 4.0 of the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) which is identified and located on the CTEP website at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
If possible, symptoms should be managed symptomatically. In the case of toxicity, appropriate medical 
treatment should be used (including anti-emetics, anti-diarrheals, etc.). 
 
All adverse events experienced by participants will be collected from the time of the enrollement, through 
the study and until the final study visit. Participants continuing to experience toxicity at the off study visit 
may be contacted for additional assessments until the toxicity has resolved or is deemed irreversible. 

MRI in active surveillance for prostate cancer 
11/25/14 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
19 
 
 
 
 
6.1 
Anticipated Toxicities 
 
 
6.1.1 Biopsy 
 
Prostate biopsies are generally well-tolerated outpatient procedures. In addition to anticipatory 
anxiety, participants are at risk of the following complications: 
Common (occurring in 20 to 90 out of 100 participants) 
• mild discomfort (44%) 
• hematuria (66%) 
• hematospermia (93%) 
• hematochezia (37%) 
• fever (20%) 
Occasional (occurring in 1 or 2 our of 100 participants) 
• persistent bleeding (1-2%) 
• urinary retention (<1%) 
• infection requiring hospitalization (1-2%) 
 
6.1.2 MRI 
 
Participants may experience frustration or anxiety related to the time spent obtaining the MRI. 
Participants will also be at risk of the typical reactions from MRI with gadolinium contrast 
administration: 
Occasional (occurring 2 or 3 out of 100 participants) 
• Mild nausea (with or without vomiting), tingling sensation, headache, dizziness, coldness at 
the injection site, headache, warmth or pain at the injection site, paresthesias, dizziness and 
itching. 
Rare (occurring in 1 participant or less out of 100) 
• Severe anaphylactic reaction 
• Severe nephrogenic systemic fibrosis (NSF) in participants with chronic renal insufficiency 

MRI in active surveillance for prostate cancer 
11/25/14 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
20 
 
 
 
 
7. STUDY CALENDAR 
Pre- Study 
MRI Visit 
(2-14 months post 
initial biopsy) 
Final Bx visit 
(within 3 months 
of MRI visit) 
End of Study 
Visit 
(within 60 days 
of final bx) 
Informed consent 
X 
Historya 
X 
Pathology review 
Xb 
Xd 
PSA 
Xc 
Xe 
Concurrent meds 
X 
Height and weight 
X 
Performance Status 
X 
Patient-reported health 
Xf 
X 
Adverse event evaluation 
X ------------------------------------ X 
X 
a: biopsy date, clinical T-category, was the subject staged with a CT of the abdomen and pelvis; was the subject 
staged with a bone scan; ACE-27 Comorbidity index (Appendix E) 
b: DF/HCC pathology review of original biopsy (no. cores taken, no. cores positive for cancer; % involvement for 
each positive core; Gleason grade for each positive core; presence and grade of tertiary Gleason grade; evidence 
of extracapsular extension; evidence of perineural invasion) 
c: last PSA level prior to biopsy diagnosing the prostate cancer 
d: DF/HCC pathology review of “random” and targeted biopsy (as needed) (no. cores taken, no. cores positive for 
cancer; % involvement for each positive core; Gleason grade for each positive core; presence and grade of 
tertiary Gleason grade; evidence of extracapsular extension; evidence of perineural invasion) 
e: most recent PSA value 
f: MUIS-AS, Appendix A; SSS-Ca, Appendix B; EPIC-CP, Appendix C; AUA SI, Appendix D 

MRI in active surveillance for prostate cancer 
11/25/14 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
21 
 
 
 
 
 
 
8. ADVERSE EVENT REPORTING REQUIREMENTS 
 
 
8.1 
Definitions 
 
8.1.1 Adverse Event (AE) 
 
An adverse event (AE) is any undesirable sign, symptom or medical condition or experience that 
develops or worsens in severity after starting the first dose of study treatment or any procedure 
specified in the protocol, even if the event is not considered to be related to the study. 
 
Abnormal laboratory values or diagnostic test results constitute adverse events only if they 
induce clinical signs or symptoms or require treatment or further diagnostic tests. 
 
8.1.2 Serious adverse event (SAE) 
 
A serious adverse event (SAE) is any adverse event, occurring at any dose and regardless of 
causality that: 
• Results in death 
• Is life-threatening. Life-threatening means that the person was at immediate risk of death 
from the reaction as it occurred, i.e., it does not include a reaction which hypothetically 
might have caused death had it occurred in a more severe form. 
• Requires or prolongs inpatient hospitalization (i.e., the event required at least a 24-hour 
hospitalization or prolonged a hospitalization beyond the expected length of stay). 
Hospitalization admissions and/or surgical operations scheduled to occur during the study 
period, but planned prior to study entry are not considered SAEs if the illness or disease 
existed before the person was enrolled in the trial, provided that it did not deteriorate in 
an unexpected manner during the trial (e.g., surgery performed earlier than planned). 
• Results in persistent or significant disability/incapacity. Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions. 
• Is a congenital anomaly or birth defect; or 
• Is an important medical event when, based upon appropriate medical judgment, it may 
jeopardize the participant and require medical or surgical intervention to prevent one of 
the outcomes listed above. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home; blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
 
Events not considered to be serious adverse events are hospitalizations for: 
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition, or for elective procedures 
• elective or pre-planned treatment for a pre-existing condition that did not worsen 
• emergency outpatient treatment for an event not fulfilling the serious criteria outlined 
above and not resulting in inpatient admission 

MRI in active surveillance for prostate cancer 
11/25/14 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
22 
 
 
 
 
• respite care 
 
8.1.3 Expectedness 
 
Adverse events can be 'Expected' or 'Unexpected.' 
 
8.1.3.1 Expected adverse event 
 
Expected adverse events are those that have been previously identified as resulting from 
administration of the agent. For the purposes of this study, an adverse event is 
considered expected when it appears in the current adverse event list, the Investigator’s 
Brochure, the package insert or is included in the informed consent document as a 
potential risk. 
 
Refer to Section 6.1 for a listing of expected adverse events associated with the study 
agent(s). 
 
8.1.3.2 Unexpected adverse event 
 
For the purposes of this study, an adverse event is considered unexpected when it varies 
in nature, intensity or frequency from information provided in the current adverse event 
list, the Investigator’s Brochure, the package insert or when it is not included in the 
informed consent document as a potential risk. 
 
8.1.4 Attribution 
 
Attribution is the relationship between an adverse event or serious adverse event and the study 
treatment. Attribution will be assigned as follows: 
 
• Definite – The AE is clearly related to the study treatment. 
• Probable – The AE is likely related to the study treatment. 
• Possible – The AE may be related to the study treatment. 
• Unlikely - The AE is doubtfully related to the study treatment. 
• Unrelated - The AE is clearly NOT related to the study treatment. 
 
8.2 
Procedures for AE and SAE Recording and Reporting 
 
Participating investigators will assess the occurrence of AEs and SAEs at all participant evaluation 
time points during the study. 
 
All AEs and SAEs whether reported by the participant, discovered during questioning, directly 
observed, or detected by physical examination, laboratory test or other means, will be recorded in the 
participant’s medical record and on the appropriate study-specific case report forms. 

MRI in active surveillance for prostate cancer 
11/25/14 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
23 
 
 
 
 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. All appropriate treatment 
areas should have access to a copy of the CTCAE version 4.0. 
A copy of the CTCAE version 4.0 can be downloaded from the CTEP website at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
8.3 
Reporting to the Study Sponsor 
 
8.3.1 Serious Adverse Event Reporting 
 
All serious adverse events that occur after the initial study procedure, or within 30 days of the 
last study procedure treatment must be reported to the DF/HCC Overall Principal Investigator on 
the local institutional SAE form. This includes events meeting the criteria outlined in Section 
11.1.2, as well as the following: 
 
• Grade 2 (moderate) and Grade 3 (severe) Events – Only events that are unexpected and 
possibly, probably or definitely related/associated with the intervention. 
 
• All Grade 4 (life-threatening or disabling) Events – Unless expected AND specifically 
listed in the protocol as not requiring reporting. 
 
• All Grade 5 (fatal) Events – When the participant is enrolled and actively participating in 
the trial OR when the event occurs within 30 days of the last study intervention. 
 
Note: If the participant is in long term follow up, report the death at the time of continuing 
review. 
 
Participating investigators must report each serious adverse event to the DF/HCC Overall 
Principal Investigator within 24 business hours of learning of the occurrence. In the event that 
the participating investigator does not become aware of the serious adverse event immediately 
(e.g., participant sought treatment elsewhere), the participating investigator is to report the event 
within 24 business hours after learning of it and document the time of his or her first awareness 
of the adverse event. Report serious adverse events by telephone, email or facsimile to: 
 
Within the following 24-48 business hours, the participating investigator must provide follow-up 
information on the serious adverse event. Follow-up information should describe whether the 
event has resolved or continues, if and how the event was treated, and whether the participant 
will continue or discontinue study participation. 

MRI in active surveillance for prostate cancer 
11/25/14 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
24 
 
 
 
 
8.3.2 Non-Serious Adverse Event Reporting 
 
Non-serious adverse events will be reported to the DF/HCC Overall Principal Investigator on the 
toxicity Case Report Forms. 
 
8.4 
Reporting to the Institutional Review Board (IRB) 
 
Investigative sites within DF/HCC will report all serious adverse events directly to the DFCI Office for 
Human Research Studies (OHRS). 
 
Other investigative sites should report serious adverse events to their respective IRB according to the 
local IRB’s policies and procedures in reporting adverse events. A copy of the submitted institutional 
SAE form should be forwarded to: 
 
 
The DF/HCC Principal Investigator will submit SAE reports from outside institutions to the DFCI 
Office for Human Research Studies (OHRS) according to DFCI IRB policies and procedures in 
reporting adverse events. 
 
8.5 
Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any subject safety reports 
or sentinel events that require reporting according to institutional policy. 
 
8.6 
Monitoring of Adverse Events and Period of Observation 
 
All adverse events, both serious and non-serious, and deaths that are encountered from initiation of 
study intervention, throughout the study, and within 30 days of the last study intervention should be 
followed to their resolution, or until the participating investigator assesses them as stable, or the 
participating investigator determines the event to be irreversible, or the participant is lost to follow-up. 
The presence and resolution of AEs and SAEs (with dates) should be documented on the appropriate 
case report form and recorded in the participant’s medical record to facilitate source data verification. 
 
For some SAEs, the study sponsor or designee may follow-up by telephone, fax, and/or monitoring 
visit to obtain additional case details deemed necessary to appropriately evaluate the SAE report (e.g., 
hospital discharge summary, consultant report, or autopsy report). 
 
Participants should be instructed to report any serious post-study event(s) that might reasonably be 
related to participation in this study. Participating investigators should notify the DF/HCC Overall 
Principal Investigator and their respective IRB of any unanticipated death or adverse event occurring 
after a participant has discontinued or terminated study participation that may reasonably be related to 
the study. 

MRI in active surveillance for prostate cancer 
11/25/14 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
25 
 
 
 
 
9. DATA AND SAFETY MONITORING 
 
9.1 
Data Reporting 
 
9.1.1 Method 
 
The QACT will collect, manage, and monitor data for this study. 
 
9.1.2 Data Submission 
The schedule for completion and submission of case report forms (paper or electronic) to the 
QACT is as follows: 

MRI in active surveillance for prostate cancer 
11/25/14 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
26 
 
 
 
Form 
Submission Timeline 
Eligibility Checklist 
Complete prior to registration with QACT 
On Study Form 
Within 14 days of registration 
Baseline Assessment Form 
Within 14 days of registration 
Treatment Form 
Within 10 days of the last day of the cycle 
Adverse Event Report Form 
Within 10 days of the last day of the cycle 
Response Assessment Form 
Within 10 days of the completion of the cycle 
required for response evaluation 
Off Treatment/Off Study Form 
Within 14 days of completing treatment or 
being taken off study for any reason 
Follow up/Survival Form 
Within 14 days of the protocol defined follow 
up visit date or call 
 
 
9.2 
Safety Meetings 
 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity and 
accrual data from this trial. The committee is composed of clinical specialists with experience in 
oncology and who have no direct relationship with the study. Information that raises any questions 
about participant safety will be addressed with the Principal Investigator and study team. 
 
The DSMC will meet quarterly and/or more often if required to review toxicity and accrual data. 
Information to be provided to the committee may include: up-to-date participant accrual; current dose 
level information; DLT information; all grade 2 or higher unexpected adverse events that have been 
reported; summary of all deaths occurring within 30 days for Phase I or II protocols; for gene transfer 
protocols, summary of all deaths while being treated and during active follow-up; any response 
information; audit results, and a summary provided by the study team. Other information (e.g. scans, 
laboratory values) will be provided upon request. 
 
 
9.3 
Monitoring 
 
Involvement in this study as a participating investigator implies acceptance of potential audits or 
inspections, including source data verification, by representatives designated by the DF/HCC Overall 
Principal Investigator (or Protocol Chair) or DF/HCC. The purpose of these audits or inspections is 
to examine study-related activities and documents to determine whether these activities were 
conducted and data were recorded, analyzed, and accurately reported in accordance with the 

MRI in active surveillance for prostate cancer 
11/25/14 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
27 
 
 
 
 
protocol, institutional policy, Good Clinical Practice (GCP), and any applicable regulatory 
requirements. 
 
All data will be monitored for timeliness of submission, completeness, and adherence to protocol 
requirements. Monitoring will begin at the time of participant registration and will continue during 
protocol performance and completion. 
 
10. REGULATORY CONSIDERATIONS 
 
 
10.1 Protocol Review and Amendments 
 
This protocol, the proposed informed consent and all forms of participant information related to the 
study (e.g., advertisements used to recruit participants) and any other necessary documents must be 
submitted, reviewed and approved by a properly constituted IRB governing each study location. 
 
Any changes made to the protocol must be submitted as amendments and must be approved by the 
IRB prior to implementation. Any changes in study conduct must be reported to the IRB. The 
DF/HCC Overall Principal Investigator (or Protocol Chair) will disseminate protocol amendment 
information to all participating investigators. 
 
All decisions of the IRB concerning the conduct of the study must be made in writing. 
 
10.2 Informed Consent 
 
All participants must be provided a consent form describing this study and providing sufficient 
information for participants to make an informed decision about their participation in this 
study. The formal consent of a participant, using the IRB approved consent form, must be 
obtained before the participant is involved in any study-related procedure. The consent form 
must be signed and dated by the participant or the participant’s legally authorized 
representative, and by the person obtaining the consent. The participant must be given a copy of 
the signed and dated consent document. The original signed copy of the consent document must 
be retained in the medical record or research file. 
 
10.3 Ethics and Good Research Practice 
 
This study is to be conducted according to the following considerations, which represent good and 
sound research practice: 
 
• 
US Code of Federal Regulations (CFR) governing clinical study conduct and ethical 
principles that have their origin in the Declaration of Helsinki 
 
o Title 21 Part 50 – Protection of Human Subjects 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr50_02.html 

MRI in active surveillance for prostate cancer 
11/25/14 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
28 
 
 
 
 
o Title 21 Part 54 – Financial Disclosure by Clinical Investigators 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr54_02.html 
 
o Title 21 Part 56 – Institutional Review Boards 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr56_02.html 
 
o Title 21 Part 312 – Investigational New Drug Application 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr312_02.html 
 
• 
State laws 
• 
DF/HCC research policies and procedures 
http://www.dfhcc.harvard.edu/clinical- 
research-support/clinical-research-unit-cru/policies-and-procedures/ 
 
It is understood that deviations from the protocol should be avoided, except when necessary to 
eliminate an immediate hazard to a research participant. In such case, the deviation must be 
reported to the IRB according to the local reporting policy. 
 
10.4 Study Documentation 
 
The investigator must prepare and maintain adequate and accurate case histories designed to record all 
observations and other data pertinent to the study for each research participant. This information 
enables the study to be fully documented and the study data to be subsequently verified. 
 
Original source documents supporting entries in the case report forms include but are not limited to 
hospital records, clinical charts, laboratory and pharmacy records, recorded data from automated 
instruments, microfiches, photographic negatives, microfilm or magnetic media, and/or x-rays. 
 
10.5 Records Retention 
 
All study-related documents must be retained for the maximum period required by applicable 
federal regulations and guidelines or institutional policies. 

MRI in active surveillance for prostate cancer 
11/25/14 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
29 
 
 
 
 
11. STATISTICAL CONSIDERATIONS 
 
 
11.1 Study Design/Primary Objective 
The primary objective is to determine the sensitivity and specificity of Mp-erMRI relative to repeated standard 
12-core TRUS biopsy for classifying upgrading of disease extent or Gleason grade in men considering AS. We 
hypothesize MP-erMRI prior to AS for men with low risk disease can identify men who harbor more extensive 
or higher risk prostate cancer. 
 
The study will plan to enroll 130 participants who had diagnostic biopsy less than one year prior to enrollment. 
After enrollment, participants will undergo a MP-erMRI. This will be reviewed and participants will be 
characterized into 3 groups: “not reclassified” characterized by findings consistent with small, low-Gleason 
grade organ-confined tumors, “reclassified” characterized by large, higher-Gleason grade organ-confined 
tumors, and radiographic T3 and or N1 disease. Less than 10% (roughly 10) of participants who belong to group 
3 will be taken off study. Those in groups 1 and 2 will proceed within 3 months of the MP-erMRI to a standard 
12-core TRUS biopsy. 
 
11.2 Hypothesis assumptions: 
Participants in groups 1 and 2 will receive 12 core TRUS re-biopsy within 3 months of undergoing MP-erMRI. 
TRUS re-biopsy will be assumed as the gold standard for determining tumor size and grade. 
 
11.2.1 Null hypothesis: 
TRUS Re-biopsy Results 
MP-erMRI Results No Disease Upgrade Disease Upgrade Total 
Not Reclassified 
72 
9 
81 
Reclassified 
18 (20%) 
21 (70%) 
39 
Total 
90 
30 
120 
 
11.2.2 Alternative hypothesis: 
 
TRUS Re-biopsy Results 
MP-erMRI Results No Disease Upgrade Disease Upgrade Total 
Not Reclassified 
85 
3 
88 
Reclassified 
5 (6%) 
27 (90%) 
32 
Total 
90 
30 
120 
 
 
11.3 Power and sample size calculation: 
A true positive fraction (TPF) is defined as the probability of MP-erMRI tests show disease re-classified results 
when participants truly have upgraded disease according to 12 core TRUS re-biopsies. A false positive fraction 
(FPF) is defined as the probably of MP-erMRI tests show re-classified disease results when no upgrade disease 
was observed on 12 core TRUS re-biopsies. A TPF (sensitivity) of 90% and FPF (1-specificity) of 6% would be 
considered promising, whereas a TPF of ≤70% and a FPF of ≥20% are unacceptable. Sample size is calculated 
using the formula with asymptotic variances as proposed by Pepe [71], followed by a set of 5000 simulation to 
assess that the power is adequate. Simulation was done using STATA scrsize package 
(http://labs.fhcrc.org/pepe/dabs/software.html). Results showed that with 120 participants (25% have upgrade 

MRI in active surveillance for prostate cancer 
11/25/14 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
30 
 
 
 
 
re-biopsy vs. biopsy prior to enrollment), 81% power can be achieved (1-sided alpha 0.1). This ensures that 
there is at least 80% chance of drawing a positive conclusion if the MP-MRI is 94% specific and 90% sensitive. 
 
11.4 Primary Analysis: 
The observed TPF and FPF will be summarized as percentages with 90% CI. Joint CIs for TPF and FPF will 
also be examined. A positive conclusion is drawn if the lower limit of TPF is above the minimally acceptable 
level of 70% and the upper limit of FPF is below the minimally acceptable level of 20%. Table below gives 
80% confidence intervals for the true but unknown TPF and FPF, given possible observed participants with 
reclassified disease by MRI among 30 true reclassified and 90 non-reclassified cases (by re-biopsy). Table 
below is an example of 80% CI given different scenarios observed reclassified participants number. 
Disease Upgrade by Re-biopsy (n=30) 
No Upgrade by Re-biopsy (N=90) 
Observed 
reclassified 
N by MRI 
Observed 
TPF 
80% CI 
Observed 
Reclassified 
N by MRI 
Observed 
FPR 
80% CI 
27 
90% 
(79%, 96%) 
5 
6% 
(3%, 10%) 
25 
83% 
(71%, 92%) 
10 
11% 
(7%, 17%) 
23 
77% 
(64%, 87%) 
15 
17% 
(12%, 23%) 
21 
70% 
(57%, 81%) 
18 
20% 
(15%, 26%) 
 
11.5 Secondary Objectives 
Determine the frequency of MP-erMRIs which appear to reclassify men with low risk disease considering AS. 
Determine the effect of MP-erMRI and repeated 12 core TRUS biopsy on patient-reported health states. 
Correlate the pathology findings from the targeted biopsy with the MP-erMRI findings for those men who fall 
into the reclassified category. 
 
11.6 Secondary Analysis 
Secondary analysis will be summarized descriptively. Number and percentage of participants with reclassified 
disease by MP-erMRI will be summarized as numbers and percentages with 90% CI. Participants will be asked 
to complete self-reported health state questionnaires at enrollment and following the final on-protocol biopsy. 
A score will be given for each questionnaire answered by participants. The scores for the questionnaires will be 
summarized as median and inter-quartile ranges. Descriptive statistics will be utilized to correlate the targeted 
biopsy findings (disease extent in mm and Gleason score) with the findings from the MP-erMRI. 
12. REFERENCES 
 
 
 
1. 
Johansson, J.E., et al., Natural history of early, localized prostate cancer. JAMA, 2004. 291(22): p. 2713-9. 
2. 
Holmberg, L., et al., A randomized trial comparing radical prostatectomy with watchful waiting in early prostate 
cancer. N Engl J Med, 2002. 347(11): p. 781-9. 
3. 
Bill-Axelson, A., et al., Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med, 
2011. 364(18): p. 1708-17. 

MRI in active surveillance for prostate cancer 
11/25/14 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
31 
 
 
 
 
4. 
Shao, Y.-H., et al., Contemporary risk profile of prostate cancer in the United States. J Natl Cancer Inst, 2009. 
101(18): p. 1280-3. 
5. 
Siegel, R., D. Naishadham, and A. Jemal, Cancer statistics, 2012. CA Cancer J Clin, 2012. 62(1): p. 10-29. 
6. 
Andriole, G.L., et al., Mortality results from a randomized prostate-cancer screening trial. N Engl J Med, 2009. 
360(13): p. 1310-9. 
7. 
Schroder, F.H., et al., Screening and prostate-cancer mortality in a randomized European study. N Engl J Med, 
2009. 360(13): p. 1320-8. 
8. 
Stephenson, A.J., et al., Prostate cancer-specific mortality after radical prostatectomy for patients treated in the 
prostate-specific antigen era. J Clin Oncol, 2009. 27(26): p. 4300-5. 
9. 
Zelefsky, M.J., et al., Metastasis after radical prostatectomy or external beam radiotherapy for patients with 
clinically localized prostate cancer: a comparison of clinical cohorts adjusted for case mix. J Clin Oncol, 2010. 
28(9): p. 1508-13. 
10. 
Welch, H.G. and P.C. Albertsen, Prostate cancer diagnosis and treatment after the introduction of prostate- 
specific antigen screening: 1986-2005. J Natl Cancer Inst, 2009. 101(19): p. 1325-9. 
11. 
Draisma, G., et al., Lead time and overdiagnosis in prostate-specific antigen screening: importance of methods 
and context. J Natl Cancer Inst, 2009. 101(6): p. 374-83. 
12. 
Hayes, J.H., et al., Active surveillance compared with initial treatment for men with low-risk prostate cancer: a 
decision analysis. JAMA, 2010. 304(21): p. 2373-80. 
13. 
Klotz, L., Active surveillance with selective delayed intervention for favorable risk prostate cancer. Urol Oncol, 
2006. 24(1): p. 46-50. 
14. 
Roemeling, S., et al., Active surveillance for prostate cancers detected in three subsequent rounds of a screening 
trial: characteristics, PSA doubling times, and outcome. Eur Urol, 2007. 51(5): p. 1244-50; discussion 1251. 
15. 
Soloway, M.S., et al., Active surveillance; a reasonable management alternative for patients with prostate 
cancer: the Miami experience. BJU Int, 2008. 101(2): p. 165-9. 
16. 
van As, N.J., et al., Predicting the probability of deferred radical treatment for localised prostate cancer 
managed by active surveillance. Eur Urol, 2008. 54(6): p. 1297-305. 
17. 
Cooperberg, M.R., et al., Outcomes of active surveillance for men with intermediate-risk prostate cancer. J Clin 
Oncol, 2011. 29(2): p. 228-34. 
18. 
Tosoian, J.J., et al., Active surveillance program for prostate cancer: an update of the Johns Hopkins experience. 
J Clin Oncol, 2011. 29(16): p. 2185-90. 
19. 
Soloway, M.S., et al., Careful selection and close monitoring of low-risk prostate cancer patients on active 
surveillance minimizes the need for treatment. Eur Urol, 2010. 58(6): p. 831-5. 
20. 
Klotz, L., et al., Clinical results of long-term follow-up of a large, active surveillance cohort with localized 
prostate cancer. J Clin Oncol, 2010. 28(1): p. 126-31. 
21. 
van den Bergh, R.C., et al., Outcomes of men with screen-detected prostate cancer eligible for active surveillance 
who were managed expectantly. Eur Urol, 2009. 55(1): p. 1-8. 
22. 
Adamy, A., et al., Role of prostate specific antigen and immediate confirmatory biopsy in predicting progression 
during active surveillance for low risk prostate cancer. J Urol, 2011. 185(2): p. 477-82. 
23. 
Cooperberg, M.R., P.R. Carroll, and L. Klotz, Active surveillance for prostate cancer: progress and promise. J 
Clin Oncol, 2011. 29(27): p. 3669-76. 
24. 
Berglund, R.K., et al., Pathological upgrading and up staging with immediate repeat biopsy in patients eligible 
for active surveillance. J Urol, 2008. 180(5): p. 1964-7; discussion 1967-8. 
25. 
Conti, S.L., et al., Pathological outcomes of candidates for active surveillance of prostate cancer. J Urol, 2009. 
181(4): p. 1628-33; discussion 1633-4. 
26. 
Cohen, M.S., et al., Comparing the Gleason prostate biopsy and Gleason prostatectomy grading system: the 
Lahey Clinic Medical Center experience and an international meta-analysis. Eur Urol, 2008. 54(2): p. 371-81. 
27. 
Epstein, J.I., et al., Upgrading and downgrading of prostate cancer from biopsy to radical prostatectomy: 
incidence and predictive factors using the modified Gleason grading system and factoring in tertiary grades. Eur 
Urol, 2012. 61(5): p. 1019-24. 
28. 
Epstein, J.I., et al., Pathologic and clinical findings to predict tumor extent of nonpalpable (stage T1c) prostate 
cancer. JAMA, 1994. 271(5): p. 368-74. 

MRI in active surveillance for prostate cancer 
11/25/14 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
32 
 
 
 
 
29. 
Kattan, M.W., et al., Counseling men with prostate cancer: a nomogram for predicting the presence of small, 
moderately differentiated, confined tumors. J Urol, 2003. 170(5): p. 1792-7. 
30. 
Nakanishi, H., et al., A nomogram for predicting low-volume/low-grade prostate cancer: a tool in selecting 
patients for active surveillance. Cancer, 2007. 110(11): p. 2441-7. 
31. 
Bangma, C.H., M.J. Roobol, and E.W. Steyerberg, Predictive models in diagnosing indolent cancer. Cancer, 
2009. 115(13 Suppl): p. 3100-6. 
32. 
Stephenson, A.J., et al., Postoperative nomogram predicting the 10-year probability of prostate cancer 
recurrence after radical prostatectomy. J Clin Oncol, 2005. 23(28): p. 7005-12. 
33. 
Harnden, P., et al., The clinical management of patients with a small volume of prostatic cancer on biopsy: what 
are the risks of progression? A systematic review and meta-analysis. Cancer, 2008. 112(5): p. 971-81. 
34. 
Palisaar, J.R., et al., Comprehensive report on prostate cancer misclassification by 16 currently used low-risk and 
active surveillance criteria. BJU Int, 2012. 
35. 
Prisman, E.Z., A. Gafni, and A. Finelli, A stochastic approach to risk management for prostate cancer patients on 
active surveillance. J Theor Biol, 2011. 284(1): p. 61-70. 
36. 
Scher, H.I., et al., Increased Survival with Enzalutamide in Prostate Cancer after Chemotherapy. N Engl J Med, 
2012. 
37. 
Wilt, T.J., et al., Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med, 2012. 
367(3): p. 203-13. 
38. 
Porten, S.P., et al., Changes in prostate cancer grade on serial biopsy in men undergoing active surveillance. J 
Clin Oncol, 2011. 29(20): p. 2795-800. 
39. 
Sheridan, T.B., et al., Change in prostate cancer grade over time in men followed expectantly for stage T1c 
disease. J Urol, 2008. 179(3): p. 901-4; discussion 904-5. 
40. 
Nam, R.K., et al., Increasing hospital admission rates for urological complications after transrectal ultrasound 
guided prostate biopsy. J Urol, 2010. 183(3): p. 963-8. 
41. 
Zaytoun, O.M., et al., Emergence of fluoroquinolone-resistant Escherichia coli as cause of postprostate biopsy 
infection: implications for prophylaxis and treatment. Urology, 2011. 77(5): p. 1035-41. 
42. 
Rosario, D.J., et al., Short term outcomes of prostate biopsy in men tested for cancer by prostate specific antigen: 
prospective evaluation within ProtecT study. BMJ, 2012. 344: p. d7894. 
43. 
Loeb, S., et al., Infectious complications and hospital admissions after prostate biopsy in a European randomized 
trial. Eur Urol, 2012. 61(6): p. 1110-4. 
44. 
Carignan, A., et al., Increasing Risk of Infectious Complications After Transrectal Ultrasound-Guided Prostate 
Biopsies: Time to Reassess Antimicrobial Prophylaxis? Eur Urol, 2012. 
45. 
Batura, D., et al., Adding amikacin to fluoroquinolone-based antimicrobial prophylaxis reduces prostate biopsy 
infection rates. BJU Int, 2011. 107(5): p. 760-4. 
46. 
Shukla-Dave, A., et al., Preoperative nomograms incorporating magnetic resonance imaging and spectroscopy 
for prediction of insignificant prostate cancer. BJU Int, 2011. 
47. 
Wang, L., et al., Prostate cancer: incremental value of endorectal MR imaging findings for prediction of 
extracapsular extension. Radiology, 2004. 232(1): p. 133-139. 
48. 
Sala, E., et al., Endorectal MR imaging in the evaluation of seminal vesicle invasion: diagnostic accuracy and 
multivariate feature analysis. Radiology, 2006. 238(3): p. 929-937. 
49. 
Brajtbord, J.S., et al., Endorectal magnetic resonance imaging has limited clinical ability to preoperatively 
predict pT3 prostate cancer. BJU Int, 2011. 107(9): p. 1419-1424. 
50. 
D'Amico, A.V., et al., Critical analysis of the ability of the endorectal coil magnetic resonance imaging scan to 
predict pathologic stage, margin status, and postoperative prostate-specific antigen failure in patients with 
clinically organ-confined prostate cancer. J Clin Oncol, 1996. 14(6): p. 1770-7. 
51. 
Hegde, J.V., et al., Preoperative 3-Tesla Multiparametric Endorectal Magnetic Resonance Imaging Findings and 
the Odds of Upgrading and Upstaging at Radical Prostatectomy in Men With Clinically Localized Prostate 
Cancer. Int J Radiat Oncol Biol Phys, 2012. 
52. 
Turkbey, B., et al., Multiparametric 3T prostate magnetic resonance imaging to detect cancer: histopathological 
correlation using prostatectomy specimens processed in customized magnetic resonance imaging based molds. J 
Urol, 2011. 186(5): p. 1818-1824. 

MRI in active surveillance for prostate cancer 
11/25/14 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
33 
 
 
 
 
53. 
Hoeks, C.M.A., et al., Prostate cancer: multiparametric MR imaging for detection, localization, and staging. 
Radiology, 2011. 261(1): p. 46-66. 
54. 
Iraha, Y., et al., Diffusion-weighted MRI and PSA Correlations in Patients with Prostate Cancer Treated with 
Radiation and Hormonal Therapy. Anticancer Res, 2012. 32(10): p. 4467-71. 
55. 
van As, N.J., et al., A study of diffusion-weighted magnetic resonance imaging in men with untreated localised 
prostate cancer on active surveillance. Eur Urol, 2009. 56(6): p. 981-7. 
56. 
Tan, C.H., et al., Diffusion-weighted MRI in the detection of prostate cancer: meta-analysis. AJR Am J 
Roentgenol, 2012. 199(4): p. 822-9. 
57. 
Ploussard, G., et al., Magnetic resonance imaging does not improve the prediction of misclassification of prostate 
cancer patients eligible for active surveillance when the most stringent selection criteria are based on the 
saturation biopsy scheme. BJU Int, 2011. 108(4): p. 513-7. 
58. 
Margel, D., et al., Impact of Multiparametric Endorectal Coil Prostate Magnetic Resonance Imaging on Disease 
Reclassification Among Active Surveillance Candidates: A Prospective Cohort Study. J Urol, 2012. 
59. 
Lawrentschuk, N., et al., 'Prostatic evasive anterior tumours': the role of magnetic resonance imaging. BJU Int, 
2010. 105(9): p. 1231-6. 
60. 
Klotz, L., Active surveillance with selective delayed intervention: using natural history to guide treatment in good 
risk prostate cancer. J Urol, 2004. 172(5 Pt 2): p. S48-50; discussion S50-1. 
61. 
Kakehi, Y., et al., Prospective evaluation of selection criteria for active surveillance in Japanese patients with 
stage T1cN0M0 prostate cancer. Jpn J Clin Oncol, 2008. 38(2): p. 122-8. 
62. 
van den Bergh, R.C., et al., Is delayed radical prostatectomy in men with low-risk screen-detected prostate cancer 
associated with a higher risk of unfavorable outcomes? Cancer, 2010. 116(5): p. 1281-90. 
63. 
Kasperzyk, J.L., et al., Watchful waiting and quality of life among prostate cancer survivors in the physicians' 
health study. J Urol, 2011. 186(5): p. 1862-7. 
64. 
Dall'Era, M.A. and P.R. Carroll, Outcomes and follow-up strategies for patients on active surveillance. Curr Opin 
Urol, 2009. 19(3): p. 258-62. 
65. 
van den Bergh, R.C.N., et al., Anxiety and distress during active surveillance for early prostate cancer. Cancer, 
2009. 115(17): p. 3868-3878. 
66. 
van den Bergh, R.C.N., et al., Do anxiety and distress increase during active surveillance for low risk prostate 
cancer? J Urol, 2010. 183(5): p. 1786-1791. 
67. 
Arredondo, S.A., et al., Watchful waiting and health related quality of life for patients with localized prostate 
cancer: data from CaPSURE. J Urol, 2004. 172(5 Pt 1): p. 1830-4. 
68. 
Vasarainen, H., et al., Prostate cancer active surveillance and health-related quality of life: results of the Finnish 
arm of the prospective trial. BJU Int, 2012. 109(11): p. 1614-9. 
69. 
Morgan, B., et al., A simple, reproducible method for monitoring the treatment of tumours using dynamic 
contrast-enhanced MR imaging. Br J Cancer, 2006. 94(10): p. 1420-7. 
70. 
Verma, S., et al., Overview of dynamic contrast-enhanced MRI in prostate cancer diagnosis and management. 
AJR Am J Roentgenol, 2012. 198(6): p. 1277-88. 
71. 
Pepe, M.S., et al., Selecting differentially expressed genes from microarray experiments. Biometrics, 2003. 59(1): 
p. 133-42. 

MRI in active surveillance for prostate cancer 
11/25/14 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
34 
 
 
 
 
Appendix A: 
 
 
 

MRI in active surveillance for prostate cancer 
11/25/14 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
35 
 
 
 
 
 
Appendix B 
 
 
 
 
 

MRI in active surveillance for prostate cancer 
11/25/14 
Appendix C: 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
36 
 
 
 
 

MRI in active surveillance for prostate cancer 
11/25/14 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
37 
 
 
 
 
Appendix D: 
 
 

MRI in active surveillance for prostate cancer 
11/25/14 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
38 
 
 
 
 
Appendix E: 
 
 

MRI in active surveillance for prostate cancer 
11/25/14 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
39 
 
 
 
 
 
 

 
SERVICES SATISFACTION SCALE – FOR CANCER CARE (SSS--‐Ca) 
 
 
 
Please indicate the answer that best describes your feeling about each aspect of the services you have received. We 
are interested in your overall experience during the last year with care or therapy that you have received related to 
your cancer therapy or its side effects. By "practitioner" we mean the one or more doctors, clinicians, etc., who have 
worked with you in your cancer-­­ related care. 
 
What is your overall feeling about the . . . 
 
Completely 
satisfied 
 
 
Very 
satisfied 
 
 
Somewhat 
satisfied 
 
 
Somewhat 
unsatisfied 
 
 
Very 
unsatisfied 
 
 
Completely 
unsatisfied 
Effect of health care 
services in helping you 
deal with your cancer 
and maintain your 
well being? 
1 
2 
3 
4 
5 
6 
7 
Effect of cancer 
treatment in 
preventing cancer 
progression or 
recurrence? 
1 
2 
3 
4 
5 
6 
7 
How well your 
confidentiality and 
rights as an individual 
have been protected? 
1 
2 
3 
4 
5 
6 
7 
Quality of cancer care 
you have received? 
1 
2 
3 
4 
5 
6 
7 
In an overall general 
sense, how satisfied 
are you with the 
cancer treatment you 
have received? 
1 
2 
3 
4 
5 
6 
7 
 
 
 
Name:  
 
 
 
Signature: 
 
Date:  
 
Mixed 
The following questions are about your satisfaction with the cancer care you received 

 
AUA Symptom Index 
Name:  
 
 
 
 
 
 
 
not at 
all 
less than 
1 in 5 
less than 1/2 
the time 
about 1/2 
the time 
more than 
1/2 the time 
almost 
always 
Over the past month or so, 
how often have you had a 
sensation of not emptying 
your bladder completely after 
you finished urinating? 
0 
1 
2 
3 
4 
5 
During the past month or so, 
how often have you had to 
urinate again less than 2 hours 
after you finished urinating? 
0 
1 
2 
3 
4 
5 
During the past month or so, 
how often have you found you 
stopped and started again 
several times when you 
urinated? 
0 
1 
2 
3 
4 
5 
During the past month or so, 
how often have you found it 
difficult to postpone 
urination? 
0 
1 
2 
3 
4 
5 
During the past month or so, 
how often have you had a 
weak urinary stream? 
0 
1 
2 
3 
4 
5 
During the past month or so, 
how often have you had to 
push or strain to begin 
urination? 
0 
1 
2 
3 
4 
5 
Over the past month, how 
many times per night did you 
most typically get up to 
urinate from the time you 
went to bed at night until the 
time you got up in the 
morning? 
0 times 
1 time 
2 times 
3 times 
4 times 
5 or more 
times 
 
 
 
Delighted 
Pleased 
Mostly 
satisfied 
mixed 
mostly 
dissatisfied 
Unhappy 
Terrible 
How would you feel if you 
had to live with your 
urinary condition the way it 
is now, no better, no worse, 
for the rest of your life? 
0 
1 
2 
3 
4 
5 
6 
 
Signature: 
 
Date:  
 
Please answer the following questions by checking the appropriate check box. All questions are about your health 
and symptoms in the LAST FOUR WEEKS. Select one answer for each question. 

 
Name:  
 
 
MISHEL UNCERTAINTY INDEX – COMMUNITY FORM FOR ACTIVE SURVEILLANCE 
(MUIS--‐AS) 
 
 
 
Please indicate the answer that best describes your feeling about each aspect of the services 
you have received. We are interested in your overall experience during the last year with care 
or therapy that you have received related to your cancer therapy or its side effects 
 
Please respond to the following questions, indicating the extent to which you feel the following 
emotions about your prostate cancer: 
 
 
 
Feeling 
Not at all 
A little 
A moderate 
amount 
A lot 
A great deal 
Worried 
0 
1 
2 
3 
4 
Fearful 
0 
1 
2 
3 
4 
Anxious 
0 
1 
2 
3 
4 
Confident 
0 
1 
2 
3 
4 
Hopeful 
0 
1 
2 
3 
4 
Eager 
0 
1 
2 
3 
4 
Angry 
0 
1 
2 
3 
4 
Sad 
0 
1 
2 
3 
4 
Disappointed 
0 
1 
2 
3 
4 
Guilty 
0 
1 
2 
3 
4 
Disgusted 
0 
1 
2 
3 
4 
Exhilarated 
0 
1 
2 
3 
4 
Pleased 
0 
1 
2 
3 
4 
Happy 
0 
1 
2 
3 
4 
Relieved 
0 
1 
2 
3 
4 
 
 
 
 
Signature: 
 
Date:  
 
The following questions are about your feelings about your cancer diagnosis: 

 
Expanded Prostate Cancer Index Composite for Clinical Practice (EPIC--‐CP) 
A clinical tool to measure urinary, bowel, sexual and vitality/hormonal health 
Patients: Please answer the following questions by checking the appropriate checkbox. All questions are about your health 
and symptoms in the LAST FOUR WEEKS. Select one answer for each question 
1. Overall, how much of a problem has your urinary function been for you? 
1 □ No problem 
2 □ Very small problem 
3 □ Small problem 
4 □ Moderate problem 
5 □ Big problem 
2. Which of the following best describes your urinary control? 
0 □ Total Control 
1 □ Occasional dribbling 
2 □ Frequent dribbling 
4 □ No urinary control 
  
 
3. How many pads or adult diapers per day have you been using for urinary leakage? 
0 □ None 
1 □ One pad per day 
2 □ Two pads per day 
4 □ Three or more pads per day 
  
 
4. How big a problem, if any, has urinary dripping or leakage been for you? 
0 □ No problem 
1 □ Very small problem 
2 □ Small problem 
3 □ Moderate problem 
4 □ Big problem 
  
 
Clinicians: ADD the answers from questions 2-­­4 to calculate the Urinary Incontinence Symptom Score (out of 12):   
 
5. How big a problem, if any, has each of the 
following been for you? 
a. Pain or burning with urination……………………………. 
b. Weak urine stream/incomplete bladder emptying 
c. Need to urinate frequently………………………………… 
Clinicians: ADD the answers from questions 5a-­­5c to calculate the Urinary Irritation/Obstruction Symptom Score (out of 12):    
 
 
6. How big a problem, if any, has each of the 
following been for you? 
a. Rectal pain or urgency of bowel movements…….. 
b. Increased frequency of your bowel movements .. 
c. Overall problems with your bowel habits………….. 
Clinicians: ADD the answers from questions 6a-­­6c to calculate the Bowel Symptom Score (out of 12):   
 
7. How would you rate your ability to reach orgasm (climax)? 
0 □ Very good 
1 □ Good 
2 □ Fair 
3 □ Poor 4 □ Very poor to none 
  
 
8. How would you describe the usual quality of your erections? 
 
0 □ Firm enough for 
1 □ Firm enough for masturbation 
2 □ Not firm enough for 
4 □ None at all 
intercourse 
and foreplay only 
any sexual activity 
  
 
 
9. Overall, how much of a problem has your sexual function or lack of sexual function been for you? 
0 □ No problem 
1 □ Very small problem 
2 □ Small problem 
3 □ Moderate problem 
4 □ Big problem 
  
 
 
Clinicians: ADD the answers from questions 7-­­9 to calculate the Sexual Symptom Score (out of 12):   
 
10. How big a problem, if any, has each of the 
following been for you? 
a. Hot flashes or breast tenderness/enlargement.. 
b. Feeling depressed…………………………………………… .. 
c. Lack of energy…………………………………………………….. 
Clinicians: ADD the answers from questions 10a-­­10c to calculate the Vitality/Hormonal Symptom Score (out of 12):   
 
No 
Problem 
Very small 
problem 
Small 
problem 
Moderate 
problem 
Big 
problem 
0 □ 
1 □ 
2 □ 
3 □ 
4 □ 
0 □ 
1 □ 
2 □ 
3 □ 
4 □ 
0 □ 
1 □ 
2 □ 
3 □ 
4 □ 
No 
Problem 
Very small 
problem 
Small 
problem 
Moderate 
problem 
Big 
problem 
0 □ 
1 □ 
2 □ 
3 □ 
4 □ 
0 □ 
1 □ 
2 □ 
3 □ 
4 □ 
0 □ 
1 □ 
2 □ 
3 □ 
4 □ 
No 
Problem 
Very small 
problem 
Small 
problem 
Moderate 
problem 
Big 
problem 
0 □ 
1 □ 
2 □ 
3 □ 
4 □ 
0 □ 
1 □ 
2 □ 
3 □ 
4 □ 
0 □ 
1 □ 
2 □ 
3 □ 
4 □ 

 
 
Name:  
 Signature:  
 Date: