Prospective Evaluation of Hypofractionation Proton Beam Therapy With Concurrent Treatment of the Prostate and Pelvic Nodes for Clinically Localized, High Risk or Unfavorable Intermediate Risk Prostate Cancer
Phase: PHASE2
Conditions: Prostate Cancer
Sponsor: Mayo Clinic

 
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MC1651 
 
 
 
 
 
Mayo Clinic Radiation Oncology 
 
MC1651: Prospective evaluation of Hypofractionation Proton beam therapy with Concurrent Treatment 
of the Prostate and Pelvic Nodes for Clinically Localized, Intermediate or High Risk Prostate 
Cancer 
 
 
 
Study Chair: 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Co-Chair: 
 
 
 
 
Investigators:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Statistician: 
 
 
 
  
 
 
*Study contributor(s) not responsible for patient care. 
 
 
Document History 
(Effective Date) 
Activation 
6/20/16 
 
Version 2 
12/16/2016 
 
Version 3 
2/14/2019 
 
 
 
Version 4 
          10/24/2019 
 
 
 
 
 
 

 
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Protocol Resources 
Questions: 
Contact Name: 
Patient eligibility*, test schedule, 
treatment delays/interruptions/adjustments, 
dose modifications, adverse events, 
protocol document, consent form, 
regulatory issues,  
forms completion and submission 
Rad Onc, Study Coordinator 
 

 
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Index 
Schema 
  1.0 
Background   
  2.0 
Goals 
  3.0 
Patient Eligibility 
  4.0 
Test Schedule 
  5.0  
Stratification Factors  
  6.0 
Registration Procedures 
  7.0 
Protocol Treatment 
  8.0 
Radiotherapy Dose Modifications Based on Adverse Events  
  9.0 
Ancillary Treatment/Supportive Care 
10.0 
Adverse Event (AE) Reporting and Monitoring  
11.0 
Treatment Evaluation  
12.0 
Descriptive Factors 
13.0 
Treatment/Follow-up Decision at Evaluation of Patient  
14.0 
Body Fluid Biospecimens 
15.0 
Drug Information 
16.0 
Statistical Considerations and Methodology 
17.0 
Pathology Considerations/Tissue Biospecimens 
18.0 
Records and Data Collection Procedures 
19.0 
Study Finances 
20.0 
Publication Plan 
21.0 
References 
Appendix I - ECOG Performance Status 
 
Appendix II- International Index of Erectile Function- Erectile Function Domain 
 
Appendix III- American Urological Association Symptom Index 
 

 
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List of Abbreviations 
 
AE 
Adverse Event/Adverse Experience 
BED 
Biologic equivalent dose 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
DSMB 
Data and Safety Monitoring Board 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal  
GU 
Genitourinary  
HIPAA 
Health Insurance Portability and Accountability Act 
IMRT 
Intensity Modulated Radiation Therapy 
IRB 
Institutional Review Board 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PSA 
Prostate Specific Antigen 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SOP 
Standard Operating Procedure 
RT 
Radiation Therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Registration 
Treatment: 
Hypofractionation proton beam therapy with concurrent irradiation of the 
prostate and pelvic nodes for clinically localized, intermediate or high risk, 
prostate cancer (25 fractions), in conjunction with androgen deprivation therapy 
Active Monitoring Phase: 
Late, radiotherapy-related, grade ≥ 3 gastrointestinal and/or genitourinary 
adverse events during 24 months post-protocol beam therapy 
 
Visits: 3, 6, 12, 18, and 24 months post-RT 
Event Monitoring Phase:  
Up to 5 years post-protocol therapy 
 
Evaluations: 30, 36, 42, 48, 54, and 60 
months post-RT 

 
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1.0 
Background   
 
1.1 
Current status of radiotherapy (RT) when elective pelvic nodal irradiation is considered 
for clinically localized, intermediate and high risk, prostate cancer 
 
Clinically localized prostate cancer is classified as ‘high’ risk, when there is a clinical 
stage T3-4, Gleason score 8-10, or Prostate Specific Antigen (PSA) > 20 ng/mL, and as 
‘intermediate’ risk disease, when there is a clinical stage T2b-2c, Gleason score 7, or 
PSA 10-20 ng/mL.  When such high or intermediate risk prostate carcinoma is treated 
with RT, elective pelvic nodal irradiation is often considered (along with definitive RT to 
the prostate and seminal vesicles), since there is concern that regional pelvic nodes may 
harbor occult metastasis.  
 
When regional pelvic nodes are to be irradiated along with RT to the primary tumor in 
the prostate +/- seminal vesicles, RT is usually delivered in two phases in the current 
clinical practice. The first phase is to irradiate both regional pelvic nodes and the primary 
tumor in the prostate +/- seminal vesicles with a dose of 45 Gy in 25 fractions. The 
second phase involves reducing the clinical target volume to the prostate +/- seminal 
vesicles and delivering an additional dose of 34.2 Gy in 19 fractions. This entails 
delivering daily 1.8 Gy per fraction to a total dose of 79.2 Gy over 8.8 weeks. 
   
Adding androgen deprivation therapy to RT is a standard of care for high risk prostate 
cancer and to a lesser extent for intermediate risk prostate cancer, based on a number of 
phase III studies demonstrating its overall or disease-free survival benefit. The duration 
of androgen deprivation therapy is usually 2-3 years for high risk, and 4-6 months for 
intermediate risk prostate cancer.  
 
1.2 
Hypofractionation as dose escalation 
 
Dose escalation in RT can be achieved either adding more fractions (with the 
conventional dose fraction size of 1.8 to 2 Gy per fraction daily) or altered fractionation 
schedule (with hypo- or hyper-fractionation). Hypofractionation refers to an altered dose 
fractionation scheme in which the daily radiation dose is increased beyond the 
conventional 1.8 to 2 Gy per fraction.  Although a total radiation dose is usually lower 
with hypofractionation, a higher doe per fraction is a method of biologically intensifying 
the radiation dose over a shorter period of time.  
 
Clinical and laboratory studies have suggested that prostate cancer has a relatively slow 
rate of proliferation, characterized by a low α/β value (1.5 to 3 Gy) in a linear quadratic 
model for cell survival after irradiation[1-4].  This implies that a larger radiation dose per 
fraction (i.e. hypofractionation) is more effective in cell killing for prostate cancer than 
simply adding more fractions. Another major advantage of hypofractionation is its 
convenience and lower treatment cost, as it allows a shorter treatment duration with a 
reduced number of RT fractions.  
 
 
1.3 
Proton beam therapy 
 
Proton beam therapy delivers a radiation dose with positively charged atomic particles 
(protons), while conventional external beam RT does with photons. Unlike photons, 
protons have a physical property to deposit most of their energy only when they reach 
their target. This allows protons to deliver a radiation dose to a target more preferentially, 

 
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while minimizing a dose to nearby normal organs. Thus, a delicate balance of delivering 
a high radiation dose to eradicate prostate cancer while largely sparing the nearby normal 
organs (such as rectum, bladder, and small bowel) can be achieved much better with 
proton beam therapy than with conventional RT. A study of dose-volume histogram has 
shown in the treatment of prostate cancer that proton beam therapy delivers less radiation 
dose to the dose-limiting normal organs, in comparison to conventional, photon-based, 
intensity modulated RT (IMRT)[5]. 
    
Several studies have reported that proton beam therapy can provide a therapeutic gain by 
offering at least equivalent (or superior) tumor control while reducing the risk of 
radiation toxicity, in comparison with conventional photon-based external beam RT, for 
clinically localized prostate cancer[6-9]. In these studies, proton beam therapy achieved 
at least equivalent or better biochemical relapse-free rates, while yielding lower 
incidences of acute and late radiation toxicity, in comparison with conventional RT. In a 
study comparing patient-reported quality of life between the two prospectively collected 
databases, Hoppe suggested approximately 50% reduction in significant bowel urgency 
and frequency in patients treated with proton beam therapy compared with IMRT[10].   
 
In the current proton beam therapy of prostate cancer, the target volume has been mostly 
limited to the prostate and the adjacent seminal vesicles. There has been no prospective 
study of proton beam therapy to treat both the primary tumor in the prostate and the 
regional pelvic nodes simultaneously using a hypofractionation regimen.    
 
1.4 
Study proposal 
 
In the proposed study, the prostate +/- seminal vesicles will be treated with a 
hypofractionation regimen using daily 2.7 Gy fractions to 67.5 Gy, while the regional 
pelvic lymph nodes will be simultaneously treated with daily 1.8 Gy fractions to 45 Gy, 
using proton beam therapy.  Assuming a α/β value of prostate carcinoma between 1.5 and 
3 Gy, 67.5 Gy in 2.7 Gy fractions is equivalent to 80.2 Gy to 85.9 Gy in 1.8 Gy fractions. 
The overall treatment time is 5 weeks, which is about 3.8 weeks shorter than the standard 
conventional dose fractionation schedule (44 fractions over 8.8 weeks). A high precision 
RT technique using pencil beam proton therapy and daily on-line targeting of the prostate 
gland is employed to minimize the dose to adjacent normal organs (bladder, rectum, and 
small bowel), which will, in turn, reduce the risk of radiation toxicity.  
 
1.5   
Biologic equivalent dose (BED) calculation for the proposed hypofractionation RT 
 
Using the linear quadratic model for cell survival after irradiation, a numeric value called 
biologic equivalent dose (BED) can be calculated.  BED is often used when different 
fractionation regimens are compared with respect to their radiobiologic effects on acute 
and late responding tissues[11]. A higher BED equates to better tumoricidal effect and, at 
the same time, higher risk of normal tissue toxicity.    
 
 
 
BED = total dose x relative effectiveness 
 
 
 
BED = (nd) x [1+ d / (α/β)] 
 
 
 
n: number of fractions (treatments) 
 
 
 
d: dose per fraction 
 
 
 
α/β: numeric value reflecting acute or late responding tissue 
 

 
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Table 1 shows BEDs for prostate cancer with the proposed hypofractionation regimen 
(67.5 Gy at 2.7 Gy per fraction) versus with the conventional dose fractionation scheme 
(79.2 Gy at 1.8 Gy per fraction), when α/β ratio of prostate cancer = 1.5 or 3. Prostate 
cancer is considered to have a low rate of proliferation similar to late responding tissues 
with a α/β ratio ranging from 1.5 to 3 in the linear quadrantic model[1-4].  This means 
that prostate cancer is more sensitive to a fractionation size (dose per treatment), with a 
higher dose per treatment resulting in more effective tumor control. As depicted in the 
Table 1, the hypofractionation regimen provides a higher BED, which means greater 
tumoricidal effect.    
 
Table 1: BEDs for Prostate Cancer   
α/β values 
79.2 Gy  
at 1.8 Gy/fraction 
67.5 Gy  
at 2.7 Gy/fraction* 
1.5 
174.2 
189.0 
3 
126.7 
128.3 
*Protocol dose 
 
To properly address a potential therapeutic gain of the proposed hypofractionation 
regimen, its impact on acute and late responding normal tissues needs to be also 
addressed. Table 2 compares BEDs between the hypofractionation regimen and the 
conventional dose fractionation scheme with respect to both acute and late responding 
normal tissues. The α/β value of acute responding normal tissues (i.e. cells with high 
turnover) is estimated in the range of 10 (e.g. mucosal tissues), while late responding 
normal tissues (i.e. cells with low turnover) is considered to have a low α/β value in the 
range of 3 (e.g. parenchymal cells)[11].   
 
For acute responding normal tissues, BED of the hypofractionation regimen is slightly 
lower than that of the conventional dose fractionation scheme. This suggests that the 
likelihood of observing a higher incidence of acute radiation toxicity with the 
hypofractionation regimen is unlikely. In contrast, for late responding normal tissues, 
BED of the hypofractionation regimen is slightly higher than that of the conventional 
dose fractionation scheme. This means that the hypofractionation regimen has potentially 
a slightly higher probability of late radiation injury (such as radiation proctopathy or 
cystourethritis), when no other strategy to reduce the risk of radiation toxicity is 
integrated to the regimen. In order to counterbalance this negative effect on the late 
responding normal tissues, the proposed study has incorporated high precision RT 
techniques (pencil beam proton therapy, and daily on-line targeting of the prostate using 
intraprostatic fiducial markers and computed tomography imaging) that reduce the 
volume of normal tissues exposed to a high radiation dose. This reduction in the 
irradiated volume of normal tissues would, in turn, minimize the risk of late radiation 
toxicity.      
 
Table 2: BEDs for Acute and Late Normal Tissue Toxicity 
α/β values 
79.2 Gy  
at 1.8 Gy/fraction 
67.5 Gy  
at 2.7 Gy/fraction* 
10 (Acute Responding Tissues) 
93.5 
85.7 
3 (Late Responding Tissues) 
126.7 
128.3 
*Protocol regimen 
 

 
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1.6  
Other studies evaluating hypofractionation regimens in photon radiotherapy setting 
 
The efficacy of the proposed hypofractionation regimen in a photon RT setting has been 
recently reported by Cheung et al [12, 13]. In this prospective study of 97 patients, a 
hypofractionation regimen of 67.5 Gy in 25 fractions was delivered to the prostate +/- 
seminal vesicles, along with a simultaneous irradiation of regional pelvic nodes with 45 
Gy in 25 fractions, over 5 weeks. The prostate and seminal vesicles were irradiated with 
intensity-modulated radiotherapy (IMRT) technique, while the regional pelvic nodes 
were treated with either three-dimensional conformal radiotherapy (3D-CRT; 67 patients) 
or IMRT (30 patients). The study targeted patients with high risk prostate carcinoma 
(clinical stage T3, Gleason score 8-10, or PSA ≥ 20). Median age of the cohort was 71 
years. The patients received adjuvant androgen deprivation therapy for median duration 
of 29.8 months 
 
Table 3 shows the incidence of the maximal acute gastrointestinal (GI) and genitourinary 
(GU) toxicity in the study, using the National Cancer Common Terminology Criteria for 
Adverse Events (CTCAE), version 3.0. 
 
 
Table 4 shows the incidence of maximal late GI and GU toxicity, using the Radiation 
Therapy Oncology Group (RTOG) late morbidity criteria, with median follow-up of 39 
months. 
 
Table 4: Incidence of maximal late GI and GU toxicity (%) 
 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
GI toxicity 
53.8 
39.8 
6.5 
0 
0 
GU toxicity 
82 
8 
5 
3 
1 
 
 
With median follow-up of 62 months, PSA relapse-free rate and survival was 83.7% and 
92.2%, respectively, at 5 years.  Of the 33 patients who underwent a 5-year prostate 
biopsy, only 4 (12.1%) had a positivity showing viable malignant cells. 
 
Pollack et al. reported a phase III study comparing 76 Gy in 38 fractions (2 Gy per 
fraction; conventional fractionation regimen) with 70.2 Gy in 26 fractions (2.7 Gy per 
fraction; hypofractionation regimen) for low- to high-risk prostate cancer[14]. Clinical 
target volume of radiotherapy was limited to the prostate and seminal vesicles for low- 
and intermediate-risk prostate cancer, while regional pelvic nodes were included, along 
with the prostate and seminal vesicles, for high-risk prostate cancer. Patients were treated 
with IMRT technique. Adjuvant androgen therapy was variable, depending on the risk 
category. There were a total of 307 patients randomized between the two fractionation 
regimens. With median follow-up of 68.4 months, there was no difference in the rate of 
PSA relapse and/or clinical disease recurrence at 5 years: 21.4% for the conventional 
fractionation arm vs. 23.3% for the hypofractionation arm. There were no statistically 
significant differences in acute and late toxicity between the two arms. Table 5 shows late 
 
 
Table 3: Incidence of maximal acute GI and GU toxicity (%) 
 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
GI toxicity 
4.3 
59.1 
36.6 
0 
0 
GU toxicity 
7.5 
49.5 
38.7 
4.3 
0 

 
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GI and GU toxicity, using modified LENT (Late Effects of Normal Tissues)/RTOG 
criteria.   
 
Table 5: Late GI and GU toxicity: Crude incidences (%) 
 
76 Gy in 38 fractions 
70.2 Gy in 26 fractions 
 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
GI 
toxicity 
18.5 
58.9 
20.5 
2 
28.2 
53.7 
16.1 
2 
GU 
toxicity 
2 
50.3 
44.4 
3.3 
3.4 
51.7 
40.9 
4 
 
Another phase III study compared 80 Gy in 40 fractions (2 Gy per fraction over 8 weeks) 
with 62 Gy in 20 fractions (3.1 Gy per fraction over 5 weeks) for high-risk prostate 
cancer[15, 16]. Clinical target volume of radiotherapy was limited to the prostate and 
seminal vesicles. Patients were treated with 3D-CRT technique, and received 9-month 
adjuvant androgen deprivation therapy. A total of 168 patients were randomized between 
the two fractionation regimens. With median follow-up of 70 months, there was no 
statistical difference in the rate of PSA relapse (15% for 62 Gy/20 fractions vs. 26% for 
80 Gy/40 fractions, p = 0.065), local recurrence, and distant metastasis at 5 years. Table 6 
shows acute GI and GU toxicity, using the RTOG/EORTC scale. Table 7 shows late GI 
and GU toxicity, using a modified LENT–SOMA scale.    
 
Table 6: Acute GI and GU toxicity: Crude incidences (%) 
 
80 Gy in 40 fractions 
62 Gy in 20 fractions 
 
Grade ≥ 2 
Grade 3 
Grade ≥ 2 
Grade 3 
GI toxicity 
21 
0 
35 
0 
GU toxicity 
40 
1.2 
47 
1.2 
 
Table 7: Late GI and GU toxicity: Crude incidences (%) 
 
80 Gy in 40 fractions 
62 Gy in 20 fractions 
 
Grade ≥ 2 
Grade 3 
Grade ≥ 2 
Grade 3 
GI toxicity 
12 
0 
14 
1.2 
GU toxicity 
6 
2.4 
8 
0 
 
1.7 
High precision RT techniques in the proposed study 
 
Mayo Clinic conducted a prospective study to examine the motion of the prostate and the 
stability of intraprostatic gold fiducial markers, using an electronic portal imaging 
device[17]. The study found that gold fiducial markers were stable within the prostate 
and that there was a significant prostate motion between radiation fractions (i.e. inter-
fraction motion). It demonstrated that fiducial markers in the prostate gland allowed a 
significant margin reduction for planning target volume (PTV) when used for on-line 
localization of the prostate. Margins of 5-7.3 mm around the prostate for inter-fraction 
prostate motion could be reduced to 3 mm by daily on-line localization of the prostate 
using intraprostatic gold fiducial markers. As a result of this study, the implant of fiducial 
markers in the prostate gland, the application of a reduced margin for PTV, and the use of 
IMRT (to achieve better conformity around the prostate) have been a standard of care for  
photon RT of prostate cancer at Mayo Clinic. 
 

 
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When RT is delivered using daily setup based on prostate position, uncertainty arises 
about the dose coverage of pelvic nodes in the setting of simultaneous irradiation of the 
prostate and pelvic nodes, because the motion of pelvic nodes can be independent of 
prostate motion.  The Stanford group reported that in the absence of a significant 
systemic offset, there were negligible changes in dose coverage of the pelvic nodes or 
normal tissue sparing when prostate fiducial markers were used for daily localization in 
the IMRT setting[18]. In another study, Adamczyk retrospectively evaluated the impact 
of correcting inter-fraction prostate motion upon the dose delivered to pelvic nodes in 28 
patients, based on 253 cone beam computed tomography (CBCT) taken during the 
radiotherapy[19]. In this study, the target (prostate) was matched based on CBCT 
imaging, and there were no fiducial markers in the prostate. Shifting treatment fields on 
CBCT prostate matching influenced minimum, maximum, and mean dose of pelvic nodes 
in the range of 0.17% - 2.63%. At our own center, there are currently two prostate cancer 
patients receiving pencil beam proton beam therapy to the pelvic nodes as well as to the 
prostate. In these patients, proton beam therapy was delivered after a treatment set-up 
was established by matching prostate carbon markers using kV orthogonal imaging. 
During the course of proton beam therapy, they had verification CT scans in order to 
assess whether clinical target volumes including the pelvic nodes were adequately 
covered. One patient had three verification CT scans and the other had one. All of the 
verification scans showed that > 95% of the clinical target volume encompassing the 
pelvic nodes received the prescription dose (45 Gy), and that the standard deviation in the 
volume covered by 45 Gy was 1.5%. These findings as well as the aforementioned 
studies indicate that setting up the RT field using the fiducial markers in the prostate or 
CBCT matching of the prostate does not significantly jeopardize a dosimetric coverage of 
the pelvic nodes, and can be utilized for the simultaneous irradiation of the prostate and 
pelvic nodes.  
 
In the proposed study, high precision RT techniques using pencil beam proton therapy 
and daily on-line targeting of the prostate and pelvic nodal region are employed to ensure 
the accurate delivery of radiation to the intended targets, while minimizing the dose to the 
adjacent normal organs (such as bladder, rectum, and small bowel). The goal of these 
precision RT techniques is to minimize the risk of radiation toxicity as much as possible. 
Proton beam therapy provides a dosimetric advantage, in comparison with photon RT, 
since it deposits the bulk of its energy to the target while delivering minimal dose to 
healthy tissues around the target. The delivery of proton beam therapy is further refined 
by pencil beam scanning technology in which proton is more precisely delivered in 
accordance to the depth and contour of the tumor, thus further reducing unnecessary 
radiation to the surrounding healthy tissues. Daily on-line targeting of the intended 
targets is achieved with two independent methods: 1. Carbon fiducial markers implanted 
into the prostate, which can be visualized on an onboard imaging. Using the carbon 
markers as a surrogate for prostate position, the treatment field is adjusted daily to be 
aligned with the position of the carbon markers in order to ensure that the prostate is in 
the proper treatment coordinates. 2. Limited computed tomography imaging to confirm 
that the prostate and pelvic nodal chains are within the planning target volumes. 
Computed tomography imaging allows a volumetric conformation that the prostate and 
pelvic nodes are within the planning target volumes.  
 
1.8  
Significance of the proposed study 
 
If the proposed RT regimen proves to be safe and effective, it will have a major impact in 
the current radiotherapy of prostate cancer. It may demonstrate not only its therapeutic 

 
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efficacy, but also its cost effectiveness and convenience as it allows a shorter treatment 
duration with a reduced number of RT fractions. This can be particularly appealing to 
prostate cancer patients who otherwise face 8.8 weeks of daily treatment in the 
conventional dose fractionation schedule. A shorter treatment course with a reduced 
number of RT fractions also means substantial cost savings to the health care system. 
Additionally, the outcome of this study can be a basis for a large phase III clinical trial 
comparing the hypofractionation regimen to a standard conventional dose fractionation 
schedule.  
 
2.0 
Goals  
 
2.1 
Primary 
 
2.1.1 
To assess late > grade3 GI and/or GU toxicity of interest with the 
hypofractionation proton beam therapy regimen  
 
2.2 
Secondary 
 
2.2.1. Late grade > 2 GI and/or GU toxicities of interest within 24 months after the 
protocol RT, using the CTCAE v4.0. 
 
2.2.2. Acute grade >3 GI and/or GU toxicities of interest during and within 3 months 
after the protocol RT, using the CTCAE v4.0. 
 
 
 
2.2.3.  Disease-free survival including freedom from PSA relapse at 5 years 
 
 
 
 
 
2.2.4. Disease-specific survival at 5 years 
 
 
 
 
 
2.2.5. Overall survival at 5 years 
 
3.0 
Patient Eligibility    
 
3.1 
Inclusion Criteria  
 
3.1.1. Male; Age ≥ 18 years. 
 
3.1.2. Histological confirmation of adenocarcinoma of the prostate within 6 months of 
study enrollment. 
 
3.1.3. Clinical stage T1-2 N0 M0, Gleason Score  7, PSA 20-100 ng/mL, or 
Clinical stage Any T N0 M0, Gleason Score 8 -10, PSA  100 ng/mL, or  
Clinical stage T3-4 N0 M0, any Gleason Score, PSA  100 ng/mL, or 
Clinical stage T1-2 N0 M0, Gleason Score 4 + 3, PSA 10-20 ng/mL 
 
3.1.4. Zubrod performance score (PS) ≤ 1(Appendix 1). 
 
3.1.5. Total bilirubin, AST,  ALP, and serum creatinine: < 2 x upper normal limit 
 
3.1.6. Signed informed consent. 
 
 
3.2 
Exclusion Criteria  
 

 
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3.2.1. Any known nodal (N1) or distant metastasis (M1) 
 
3.2.2. Previous androgen deprivation therapy lasting more than 6 months 
 
 
3.2.3. History of inflammatory bowel disease 
 
 
 
3.2.4. Presence of a hip prosthesis  
 
3.2.5. Prior pelvic radiotherapy or prostatectomy 
 
3.2.6. Prior or concurrent antineoplastic agents (chemotherapy)  
 
3.2.7. Previous or concurrent malignancy other than non-melanoma skin cancer within 
5 years of diagnosis of prostate cancer. 
 
3.2.8. Inability to start the protocol treatment within 1 month after study enrollment. 
 
3.2.9. Medical or psychiatric conditions that preclude informed decision-making or 
compliance with the protocol treatment or follow-up 
 
4.0 
Test Schedule 
 
 
Active Monitoring Phase 
Event Monitoring 
Phase 
Tests and procedures 
≤ 120 days 
prior to 
registration 
Within 2 
weeks prior 
to RT 
During 
RT 
(weekly) 
End of 
RT 
(+/- 5 
days) 
Post-RT 
month3: 3, 
6, 12, 18, 
and 24 
Post-RT month3: 30, 
36, 42, 48, 54, and 60 
History, Physical exam, 
ECOG 
X 
 
 
 
X 
X7 
PSA 
X 
 
 
 
X 
X 
Serum total testosterone 
X 
 
 
 
X2 
X2 
CBC, AST, ALP, Total 
Bilirubin, Creatinine 
X 
 
 
 
X4 
X4 
Path review1 
X 
 
 
 
 
 
CT scan of abdomen and 
pelvis, or MRI of pelvis 
X 
 
 
 
X4 
X4 
Bone scan 
X 
 
 
 
X4 
X4 
GI and GU toxicity 
assessment (CTCAE v4.0) 
 
X 
X 
X 
X 
X 
Questionnaires5 
X6 
 
 
X 
X 
X 
 
1. Optional; For outside prostate biopsy only 
2. Serum total testosterone: to be performed post-RT month 12, 24, 36, 48, and 60 
3. Month: targeted month +/- 1 month  
4. Only when relapse occurs 
5. Questionnaires [including Patient-Reported Outcomes version of the CTCAE, EPIC-26, American 
Urologic Association Symptom Index score (paper), and International Index of Erectile Function – 
Erectile Function Domain (paper)], which are currently parts of a routine clinical practice, will be 
administered electronically to patient in conjunction with the Registry and IRB# 15-000136. 

 
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6. Baseline questionnaires should be completed prior to patient starting hormone therapy if possible.  
7. Only at 36, 48, and 60 months  
 
5.0 
Stratification Factors  
  
None 
 
6.0  
Registration Procedures 
Registration to the study will take place when a patient has met eligibility criteria, signed an 
informed consent, and has been logged into Research Participant Tracking (Ptrax). 
 
7.0        Protocol Treatment 
Protocol treatment consists of proton beam therapy, in combination with 28 months of androgen 
deprivation therapy (or 4-6 months of androgen deprivation therapy for intermediate risk prostate 
cancer). 
 
7.1. Proton beam therapy 
 
 
7.1.1 
Treatment planning 
 
 
 
7.1.1.1. Preparation prior to simulation 
A minimum of 1 day prior to a scheduled CT simulation, a total of four carbon 
markers are implanted into the prostate gland (two in the left and two in the right 
lobe of the prostate gland), via transperineal approach, under a transrectal 
ultrasound guidance by a radiologist. These implanted carbon markers are used 
for daily image-guided proton beam therapy. 
 
Bladder preparation: A patient is to void one hour before simulation or treatment. 
Right after voiding, he drinks 250 or 500 mL (8.5 or 16.9 oz) of water over the 
following 15 minutes. Then he does not void until he completes a CT simulation 
or treatment. This systemic approach is to minimize day-to-day variation of 
bladder volume as much as possible.  
 
 
 
7.1.1.2. Simulation 
A planning CT scan will be performed with a patient in supine position. A 
custom vacuum lock bag is to be used for immobilization during simulation and 
treatment. It should be built up around the patient’s feet to reduce the variation in 
foot rotation. An indexed knee cushion may be added to the setup, if desired.  
 
An inflated endorectal balloon is optional, and can be used for prostate 
immobilization. An endorectal balloon is to be inflated with 100 mL of diluted 
contrast (consisting of 5 mL Gastroview mixed with 95 mL normal saline). At 
the time of CT simulation, the insertion depth of endorectal balloon will be 
recorded at the level of anal verge. The same insertion depth will be applied 
when an endorectal balloon is inserted during the course of proton beam therapy.  
 
Bladder contrast may or may not be used at the time of CT simulation at the 
discretion of attending physician. When bladder contrast is to be used, the 

 
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MC1651 
 
 
 
 
following steps are to be taken: (1) Insert a Foley catheter into the bladder, (2) 
Drain 40-50 mL of urine, (3) Replace the drained amount of urine with the same 
volume of diluted contrast (made of 5 mL of Omnipaque mixed with 55 mL of 
sterile water) into the bladder via a Foley catheter, (4) Remove the Foley catheter 
thereafter.   
 
A bladder scanner will be used to measure a bladder volume at the time of CT 
simulation. The target bladder volume to be achieved at the time of MR 
simulation and during the course of proton beam therapy will be the measured 
volume at the time of CT simulation +/- 25%. 
 
CT simulation scanning will be performed from immediately above the iliac 
crests through at least the ischial tuberosities with 1 - 2.5 mm slice thickness. 
Shortly after CT simulation is completed, MRI of the pelvis (MR simulation)will 
be obtained with the same set-up described above. No contrast should be used for 
bladder or an endorectal balloon. When an endorectal balloon is used, it should 
be inflated with normal saline (100 mL). MR imaging will be fused with the 
planning CT imaging, using the implanted carbon markers as references.  
 
 
 
 
7.1.1.3. Target volumes 
 
 
 
7.1.1.3.1  
Clinical target volume (CTV) 
 
 
There are two clinical target volumes: CTV1 and CTV2. 
 
 
CTV1 is the prostate plus a portion of or entire seminal vesicles. The 
 
extent of seminal vesicles to be included in CTV1 is at the judgement of 
 
the attending physician and based on clinical and pathologic features of a 
 
given malignancy.  
 
CTV2 is the regional pelvic nodes. CTV2 includes the obturator,  external 
iliac, proximal internal iliac and common iliac nodes, up to a level 
corresponding to the sacral promontory so that most of the common iliac 
nodes are included. Please refer to the pelvic nodal atlas  at the RTOG 
Web site (Pelvic Lymph Node Volumes for Prostate Cancer Atlas; 
 The presacral nodes from the sacral promontory to S3 may be 
included, depending on whether the dose constraints to the rectum are 
achievable. The inferior extent of the external iliac lymph nodes is 
generally at the top of the femoral heads. The inferior extent of the 
obturator lymph nodes is generally at the top of the symphysis pubis. 
CTV2 will include a 7 mm margin in 3-dimensions to the iliac vessels, 
and a 10 mm margin anteriorly from the anterior sacral bone for 
prescaral nodes. Adjacent normal organs (such as small bowel, large 
bowel, bladder, and rectum), pelvic musculature, and bones are carved 
out from CTV2. 
 
 
7.1.1.3.2. 
Internal target volume (ITV) 

 
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ITV is an additional margin around CTV to ensure proper dose coverage 
 
of CTV, given changes in the dose distribution caused by target motion.  
 
 
 
ITV1: CTV1 + 4-5 mm expansion for superior, inferior, anterior, and 
 
posterior directions, and 5-6 mm expansion in the lateral direction. 
 
 
ITV2: CTV2 + 5 mm expansion in all directions 
 
7.1.1.3.3 
Optimization target volume (OTV): A volume constructed by a   
 
 
dosimetrist under the guidance of a physicist.  The OTV is a volume used 
 
 
by the treatment-planning-dose-optimization algorithm to ensure that the  
 
 
ITVs and CTVs are treated with a planned radiation dose.  It includes  
 
 
set-up and range uncertainties of 3 mm and 3 %, respectively. The OTV  
 
 
is to provide a robust coverage of CTV and ITV. The evaluation of a  
 
 
proton plan is based on a robust coverage of CTV and ITV.  The OTV  
 
 
should not be considered when evaluating the treatment plan.  
 
 
7.1.1.4   Normal Critical Structures 
 
Normal critical structures to be defined on the treatment planning CT scan 
include the bladder, rectum, large bowel, small bowel, bilateral femora (to the 
level of ischial tuberosity), penile bulb, and skin. The structures will be 
contoured and considered as solid organs. The bladder should be contoured from 
its base to the dome, and the rectum from the anus (at the level of the ischial 
tuberosity) to the rectosigmoid flexure. Any small bowel within the primary 
beam aperture should be defined. Please refer to the RTOG web site 
 view the normal pelvis atlas for examples of target and normal tissue 
contours. 
 
 
7.1.1.5  Treatment planning for critical structures 
 
Plan quality and acceptability will be assessed in accordance to dose-volume 
histogram (DVH) parameters of target volumes and organs at risk (OAR) using 
the constraints shown in the following Table. 
 
Target DVH Objectives 
Priority 
 
CTV 
Max[Gy]  
 
Report 
Max[%] 
 
Report 
Min[Gy] 
 
Report 
Min[%] 
 
Report 
Mean[Gy] 
 
Report 
D2%[%] 
 
Report 
D5%[%] 
 
Report 
D95%[%] 
 
Report 
D98%[%] 
100% (via 
normalization) 
Report 

 
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V110%[cc] 
 
Report 
V98%[%] 
 
Report 
V99%[%] 
 
Report 
V100%[%] 
98% (via 
normalization) 
1 
V107%[%] 
 
Report 
Volume[cc] 
 
Report 
CV98%[%] 
 
Report 
CV98%[cc] 
 
Report 
ITV 
Max[Gy]  
 
Report 
Max[%] 
< 105% 
1 
Min[Gy] 
 
Report 
Min[%] 
>90% 
3 
Mean[Gy] 
 
Report 
D2%[%] 
<= 104 % 
3 
D5%[%] 
 
Report 
D95%[%] 
>= 95 % 
3 
D98%[%] 
 
Report 
V110%[cc] 
0 cc 
1 
V98%[%] 
>= 98 % 
1 
V99%[%] 
>= 98 % 
2 
V100%[%] 
>= 95 % (or 95%) 
2 (or 1, normalization) 
V107%[%] 
<= 2 % 
1 
Volume[cc] 
 
Report 
CV98%[%] 
<= 2 % 
1 
CV98%[cc] 
 
Report 
 
Normal Tissue DVH Objectives 
Priority 
 
Bladder 
D2cc[Gy] 
< 72.91 Gy 
1 
 
< 72.14 Gy 
2 
V36Gy[cc] 
 
Report 
V57Gy[cc] 
 
Report 
V61Gy[cc] 
 
Report 
V66Gy[cc] 
 
Report 
V36Gy[%] 
 33% 
1 
 
17% 
2 
V57Gy[%] 
15% 
1 
 
9% 
2 
V61Gy[%] 
11% 
1 
 
8% 
2 
V66Gy[%] 
8% 
1 
 
5% 
2 
Volume[cc] 
 
Report 
Right femoral head 
Max[Gy] 
< 34.96 Gy 
1 
 
< 32.69 Gy 
2 
Mean[Gy] 
<= 23.95 Gy 
1 
 
<= 18.28 Gy 
2 
V32Gy[%] 
<= 5%  
1 
 
<= 2% 
2 

 
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V14Gy[%] 
<= 91% 
1 
 
<= 66% 
2 
Left femoral head 
Max[Gy] 
< 34.96 Gy 
1 
 
< 32.69 Gy 
2 
Mean[Gy] 
<= 23.95 Gy 
1 
 
<= 18.28 Gy 
2 
V32Gy[%] 
<= 5%  
1 
 
<= 2% 
2 
V14Gy[%] 
<= 91% 
1 
 
<= 66% 
2 
Rectum 
D2cc[Gy] 
< 71.54 Gy 
1 
 
< 71.19 Gy 
2 
V44Gy[cc] 
 
Report 
V53Gy[cc] 
 
Report 
V57Gy[cc] 
 
Report 
V61Gy[cc] 
 
Report 
V66Gy[cc] 
 
Report 
V44Gy[%] 
24% 
1 
 
18% 
2 
V53Gy[%] 
17% 
1 
 
14% 
2 
V57Gy[%] 
15% 
1 
 
11% 
2 
V61Gy[%] 
 12% 
1 
 
9% 
2 
V66Gy[%] 
9%  
1 
 
6% 
2 
Penile bulb 
Mean[Gy] 
 
Report 
D50%[Gy] 
<= 47 Gy 
2 
D70%[Gy] 
<= 36 Gy 
3 
Large bowel 
D2cc[Gy] 
 
Report 
V44Gy[cc] 
 
 
V53Gy[cc] 
 
 
V57Gy[cc] 
 
 
V61Gy[cc] 
 
 
V44Gy[%] 
24% 
1 
 
18% 
2 
V53Gy[%] 
17% 
1 
 
14% 
2 
V57Gy[%] 
15% 
1 
 
11% 
2 
V61Gy[%] 
12% 
1 
 
9% 
2 
V66Gy[%] 
9%  
1 
 
6% 
2 
Small bowel 
Max[Gy]  
< 52 Gy 
3 
D2cc[Gy] 
 
Report 
V30Gy[cc] 
< 300 cc 
3 
V45Gy[cc] 
< 150 cc 
2 
V50Gy[cc] 
< 2 cc 
3 

 
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Body - OTV 
V50%[cc] 
 
Report 
V100%[cc] 
 
Report 
V105%[cc] 
0 cc 
1 
 
 
For purposes of compliance, up to a 5% absolute increase in the volume of 
critical structure receiving a specified dose (or higher) will be considered 
acceptable and called “minor deviation”. When there is a ≥ 5% absolute increase 
in the volume of critical structure receiving a specified dose (or higher), it will be 
considered unacceptable and called a “major deviation”. [Example: rectum 
V66Gy < 14%, but > 9%: minor deviation; rectum V66Gy ≥ 14% major 
deviation]  
 
Of note, the penile bulb constraint is to be regarded as a guideline, and adherence 
to this should not, in any way, result in a reduction of the prescription dose or a 
compromised dose coverage of the target volume. 
 
The deviations in dose constraints described above are considered planning 
deviations only and will not constitute protocol deviations. Treatment plans that 
include minor planning deviations may be delivered as part of this protocol. 
Treatment plans that include major planning deviations may be delivered on this 
protocol with the review and approval of the attending physician prior to 
treatment. All relevant DVH data regarding doses to critical structures will be 
maintained in the study database for analysis. 
 
7.1.2 
Target Dose 
 
 
A prescribed dose of 67.5 Gy in 25 fractions (2.7 Gy per fraction per day, 5 days a week) 
 
is delivered to ITV1, while ITV2 is concurrently treated to a dose of 45 Gy in 25 
 
fractions (1.8 Gy per fraction). 
 
 
 
7.1.3  
Treatment Administration 
 
 
 
An optimal, pencil beam, proton therapy plan is prepared to achieve proper dose   
 
 
coverage of ITVs. Plan quality and acceptability is assessed, based on dose-volume  
 
 
histogram parameters of target volumes and organs at risk. 
 
7.1.4 
Treatment localization and verification  
 
 
7.1.4.1   Patient set-up for daily proton beam therapy is identical to the CT 
 
simulation set-up, including bladder preparation and the application of 
 
endorectal balloon, if used. An endorectal balloon is inflated with 100 
 
mL of normal saline (or, if necessary, diluted contrast consisting of 10 
 
mL Gastroview mixed with 90 mL normal saline). 
 
 
  
7.1.4.2 On-line target localization and image-guided proton beam therapy: 
 
7.1.4.2.1 Use of implanted carbon fiducial markers 
 
Daily kV orthogonal imaging of the implanted, intra-prostatic,   
 
carbon  markers (from an on-board imager) should be used to  
 

 
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confirm the treatment set-up and to account for inter-fraction  
 
 
motion. A patient’s position should be adjusted, using the  
 
 
fiducial markers as references. 
 
 
 
  
 
7.1.4.1.2 Use of volumetric imaging with CT on a rail 
The use of volumetric imaging with CT on a rail is strongly encouraged, if 
available, but not mandatory. Volumetric imaging is taken with a CT scan on a 
rail, after a treatment set-up is established using kV orthogonal imaging of the 
fiducial markers. This is to verify that ITV is properly covered volumetrically. 
Volumetric imaging is taken daily for the first 5 treatments and then twice 
weekly (every Monday and Thursday) thereafter.   
 
7.2   
Concurrent androgen deprivation therapy 
 
As part of the standard of care, adjuvant androgen deprivation therapy is added to proton 
beam therapy for 2-3 years for high risk prostate cancer, and 4-6 months  for intermediate 
risk prostate cancer. Androgen deprivation therapy usually starts  2 months prior to the 
beginning of proton beam therapy. It consists of  bicalutamide 50 mg PO once daily for 2-
16 weeks (given at the start of androgen deprivation therapy) and a LHRH agonist 
(gosereline or leuprolide). The first injection of a LHRH agonist is usually given within 7 
days after the initiation of bicalutamide. 
 
8.0  
Radiotherapy Dose Modifications Based on Adverse Events  
With judicious use of ancillary treatment (see Section 9.0) and/or treatment interruption, it is 
anticipated that a dose reduction should rarely be necessary. This study has no pre-specified dose 
reduction due to adverse events.  However, if adverse events are severe enough that 
administration of full dose is considered contraindicated by the attending Radiation Oncologist, 
the study chair 
should be notified. 
Treatment interruption(s) are permitted only when radiation-related adverse events are not 
reduced to an acceptable level with the use of ancillary treatment (see Section 9.0), or when acute 
grade ≥3 AEs occur. The reason(s) for the interruption must be documented. The duration of 
treatment interruption should be minimized, but proton beam therapy should not resume until AEs 
are grade <3. 
 
9.0 
Ancillary Treatment/Supportive Care 
 
Supportive measures such as antiemetic or antidiarrheal medications, steroid-containing topical 
preparations, topical bladder analgesic (e.g., phenazopyridine HCl) or anti-spasmodic (e.g., α-
adrenergic blockers) agents may be administered in accordance with manufacturer 
recommendations as deemed necessary.  
 
10.0 
Adverse Event (AE) Reporting and Monitoring 
10.1 
Definitions 
Adverse Event- An untoward or undesirable experience associated with the use of a 
medical product (i.e. drug, device, biologic) in a patient or research subject. 
Serious Adverse Event - Adverse events are classified as serious or non-serious.  
Serious problems/events can be well defined and include; 

 
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• death 
• life threatening adverse experience 
• hospitalization secondary to radiation treatment, RT side effects or 
problem due to prostate carcinoma 
• inpatient, new, or prolonged; disability/incapacity 
• persistent or significant birth defect/anomaly 
 
and/or per protocol may be problems/events that in the opinion of the investigator 
may have adversely affected the rights, safety, or welfare of the subjects or others, 
or substantially compromised the research data. 
 
All adverse events that do not meet any of the criteria for serious, should be 
regarded as non-serious adverse events.  
 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSO) - Any 
unanticipated problem or adverse event that meets the following three criteria:  
• Serious: Serious problems or events that result in significant harm, 
(which may be physical, psychological, financial, social, economic, or 
legal) or increased risk for the subject or others (including individuals 
who are not research subjects). These include: (1) death; (2) life 
threatening adverse experience; (3) hospitalization - inpatient, new, or 
prolonged; (4) disability/incapacity - persistent or significant; (5) birth 
defect/anomaly; (6) breach of confidentiality and (7) other problems, 
events, or new information (i.e. publications, DSMB reports, interim 
findings, product labeling change) that in the opinion of the local 
investigator may adversely affect the rights, safety, or welfare of the 
subjects or others, or substantially compromise the research data, AND 
• Unanticipated: (i.e. unexpected) problems or events are those that are not 
already described as potential risks in the protocol, consent document, or 
not part of an underlying disease. A problem or event is "unanticipated" 
when it was unforeseeable at the time of its occurrence. A problem or 
event is "unanticipated" when it occurs at an increased frequency or at an 
increased severity than expected, AND 
• Related: A problem or event is "related" if it is possibly related to the 
research procedures. 
 
Preexisting Condition- A preexisting condition is one that is present at the start of 
the study.  A preexisting condition should be recorded as an adverse event if the 
frequency, intensity, or the character of the condition worsens during the study 
period. At screening, any clinically significant abnormality should be recorded as 
a preexisting condition.  At the end of the study, any new clinically significant 
findings/abnormalities that meet the definition of an adverse event must also be 
recorded and documented as an adverse event.  
 

 
22  
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10.2 
Recording Adverse Events 
 
 
 
CTCAE term (AE description) and grade: 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 web site: 
 
 
10.2.1 Adverse event monitoring and reporting is a routine part of every clinical 
trial. First, identify and grade the severity of the event using the CTCAE 
version 4.0. Next, determine whether the event is expected or unexpected 
and if the adverse event is related to the medical treatment or procedure. 
With this information, determine whether the event must be reported as an 
expedited report (see Section 10.3). 
 
 
 
10.2.2 Assessment of Attribution 
When assessing whether an adverse event is related to a medical treatment 
or procedure, the following attribution categories are utilized: 
Definite - The adverse event is clearly related to the agent(s). 
Probable - The adverse event is likely related to the agent(s). 
Possible - The adverse event may be related to the agent(s). 
Unlikely - The adverse event is doubtfully related to the agent(s). 
Unrelated - The adverse event is clearly NOT related to the agent(s). 
 
 
10.3 
Reporting of Serious Adverse Events and Unanticipated Problems 
 
When an adverse event has been identified, the study team will take appropriated 
action necessary to protect the study participant and then complete the Study 
Adverse Event Worksheet and log.  The sponsor-investigator will evaluate the 
event and determine the necessary follow-up and reporting required. 
 
Serious Adverse Events will be reported as part of regular adverse event reporting 
mechanisms via the data capture system and logged for review reporting. 
 
10.3.1 Investigator Reporting: Notifying the Mayo IRB: 
 
The IRB requirements reflect the guidance documents released by the 
Office of Human Research Protections (OHRP), and the Food and Drug 
Administration (FDA) in early 2007 and are respectively entitled 
“Guidance on Reviewing and Reporting Unanticipated Problems 
Involving Risks to Subjects or Others and Adverse Events” and “Guidance 
for Clinical Investigators, Sponsors, and IRBs: Adverse Event Reporting – 
Improving Human Subject Protection.” 
 
10.3.1.1 
According to Mayo IRB Policy any serious adverse event 
(SAE) which the Principal Investigator has determined to 

 
23  
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be a UPIRTSO must be reported to the Mayo IRB as soon 
as possible but no later than 5 working days after the 
investigator first learns of the problem/event. 
10.3.1.2 
Non-UPIRTSO – the investigator reports problems or 
events that do NOT meet criteria of an UPIRTSO in 
summary format at the time of the next continuing review. 
The investigator monitors the severity and frequency of 
subsequent non-UPIRTSOs. 
 
Consider the following information to collect when developing any forms 
for documentation of adverse events. 
Example 
Information collected on the adverse event worksheet (and entered in the 
research database):  
• Subject’s name:  
• Medical record number:  
• Disease/histology (if applicable):  
• The date the adverse event occurred:  
• Description of the adverse event:  
• Relationship of the adverse event to the research (drug, procedure, 
or intervention):  
• If the adverse event was expected:  
• The severity of the adverse event: (use a table to define severity 
scale 1-5) 
• If any intervention was necessary:  
• Resolution: (was the incident resolved spontaneously, or after 
discontinuing treatment?) 
• Date of Resolution:  
 
The investigator will review all adverse event reports to determine if 
specific reports need to be made to the IRB and FDA.  The investigator 
will sign and date the adverse event report when it is reviewed.  For this 
protocol, only directly related SAEs/UPIRTSOs will be reported to the 
IRB. 
 
10.4 
CTCAE v4.0 is used for the following AEs to be graded at each evaluation and 
pretreatment symptoms/conditions to be evaluated at baseline: 
 
System Organic Class 
Adverse events/Symptoms 
Gastrointestinal 
Diarrhea 
Fecal incontinence 
Proctitis 
Rectal hemorrhage 
Rectal ulcer 
Small intestinal obstruction 

 
24  
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Stricture/Stenosis: Rectum 
Renal/Genitourinary 
Bladder spasm 
Hematuria 
Urinary frequency 
Urinary incontinence 
Urinary tract obstruction 
Urinary tract pain 
Urinary urgency 
Cystitis noninfective 
Urinary retention 
Sexual/Reproductive function 
Erectile dysfunction 
 
Acute AEs are defined as those that occur from day 1, or commencement of 
radiation therapy, through 3 months after the completion of protocol treatment.  
 
All AEs seen after 3 months after the completion of protocol treatment are 
considered late effects. 
 
 
 
10.4.1 Submit via appropriate reporting mechanisms (i.e., paper or electronic) the 
following AEs experienced by a patient and not specified in Section 10.4: 
 
Grade 5 AEs (Death) 
 
 
10.4.1.1.1 
Any death within 30 days of the patient’s last study 
treatment or procedure regardless of attribution to radiation 
treatment 
 
10.4.1.1.2 
Any death more than 30 days after the patients last study 
treatment or procedure that is felt to be at least possibly 
related to radiation treatment must also be submitted as a 
Grade 5 AE, with a CTCAE type and attribution assigned. 
 
10.5 
Monitoring and Auditing  
The investigator will permit study-related monitoring, audits, and inspections by 
the IRB, the sponsor, and government regulatory agencies, of all study related 
documents (e.g. source documents, regulatory documents, data collection 
instruments, study data etc.).  The investigator will ensure the capability for 
inspections of applicable study-related facilities (e.g. pharmacy, diagnostic 
laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential 
inspection by government regulatory authorities and applicable compliance 
offices 
 
10.5.1 Medical Monitoring  
It is the responsibility of the Principal Investigator to oversee the safety of 
the study at his site.  This safety monitoring will include careful 

 
25  
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assessment and appropriate reporting of adverse events as noted above, as 
well as the construction and implementation of a site data and safety-
monitoring plan.  Medical monitoring will include a regular assessment of 
the number and type of serious adverse events.  Any serious adverse 
events will be followed up by the sentinel event reporting procedure. 
 
 
10.5.2 Internal Data and Safety Monitoring Board  
 
As an interventional study, this study will be reviewed in conjunction with 
the Mayo Clinic Cancer Center DSMB processes. The study will also be 
reviewed by the Radiation Oncology Research Executive Board on a 
yearly basis to assess accrual, adverse events, and any endpoint problems. 
Any safety issues requiring protocol changes will be communicated 
through protocol amendments.   
 
The trial will be reviewed by the Cancer Center Auditing area on a bi-
annual or yearly basis, dependent on random study selection. Accrual, 
adverse events, and any endpoint problems will be assessed. Any safety 
issues requiring protocol changes will be communicated through protocol 
amendments.   
 
 
11.0 
Treatment Evaluation  
 
11.1 
No evidence of disease: No clinical evidence of tumor recurrence including the 
freedom from biochemical (PSA) failure (Section 11.2.2.1) 
 
11.2. Recurrence of disease: The site of recurrence will be collected, and classified as 
biochemical failure, local recurrence, regional recurrence and/or distant 
recurrence.   
 
11.2.1 Biochemical (PSA) failure: PSA nadir is defined as the lowest PSA value reached 
after completion of treatment. Biochemical failure is defined as a PSA value that 
is ≥ PSA nadir + 2.0 ng/mL with the date of biochemical failure set at the date of 
the PSA value that meets this criterion.  
 
11.2.2 Local recurrence: Local recurrence is defined when one or more  of the 
followings occur: (1) ureteric obstruction at the level of the ureterovesical 
junction; urethral obstruction that requires prostatic resection (with resected 
tissue demonstrating prostatic adenocarcinoma) or urinary diversion; or 
hematuria due to prostate cancer progression, (2) positive prostate biopsy at ≥ 24 
months  from the completion of protocol treatment (3) ≥ 20% increase in  the 
longest diameter of a target lesion in the prostate gland (for patients with a 
measurable target lesion at baseline), or a new lesion measuring ≥ 1 cm short axis 
during follow-up (for patients with non-measurable lesion at baseline) in the 
setting of biochemical failure 
 

 
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11.2.3  Regional recurrence: Development of nodal metastasis in the pelvis which 
is defined as a new regional pelvic node that was normal at baseline (< 1.0 
cm short axis) and increased to ≥ 1.0 cm short axis during follow-up. 
Confirmation by biopsy is encouraged.   
 
11.2.4 Distant recurrence: Development of nodal metastasis outside the pelvis,  
 
or a hematogenous (e.g., osseous, hepatic, etc.) lesion. Confirmation by  
biopsy is encouraged.  
 
11.2.5 Disease-free survival: Disease-free survival duration will be measured 
 
from the date of registration to the date of biochemical, local, regional, or 
 
distant recurrence or the date of death from any cause.  
 
11.2.6 Disease-specific survival: Disease-specific survival duration will be 
 
measured from the date of registration to the date of death due to prostate 
 
cancer. Death due to prostate cancer will be defined as:  
 
11.2.6.1 Death attributed to carcinoma of the prostate by the investigator, or 
11.2.6.2 Death due to complications of treatment  
11.2.7 Overall survival: Survival duration will be measured from the date of 
 
registration to the date of death from any cause. 
 
12.0 
Descriptive Factors  
 
12.1. Clinical tumor (T) classification: ≤ T2 vs. ≥ T3  
12.2. Histologic grade: Gleason score ≤ 7 vs. ≥ 8  
12.3. Pre-treatment serum PSA value: ≤ 20 ng/mL vs. >20 ng/mL  
This is the PSA value obtained most immediately before the start of neoadjuvant 
androgen deprivation therapy (see Section 7.2).  
12.4. Patient age: ≤70 years vs. >70 years.  
 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient   
 
 Follow-up data will be collected and entered in accordance to Section 4.0. No follow-up data is 
required beyond 5 years from the date of study enrolment. 
 
13.1 
If a patient fails to complete the entire course of treatment for reasons other than 
toxicity or prostate cancer progression, he will be regarded as inevaluable and 
will be replaced. Baseline characteristics will be collected in the database.  
However, no further data collection will be collected.     
 
13.2      A patient is deemed ineligible if after registration, it is determined that at the time 
of registration, he did not satisfy each and every eligibility criteria for study entry.  

 
27  
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The patient may continue treatment off-protocol at the discretion of the physician 
as long as there are no safety concerns, and the patient was properly registered.  
 
If the patient received treatment, all data up until the point of confirmation of 
ineligibility must be submitted, and collection of follow-up data will continue in 
accordance to Section 4.0. Event monitoring will be required per Section 18.0 of 
the protocol.  
 
13.3 
A patient is deemed a cancel if he is removed from the study for any reason 
before any study treatment is given.  On-study material and the End of Active 
Treatment/Cancel Notification Form must be submitted.  No further data 
submission is necessary. 
 
13.4 
A patient is deemed a major violation, if protocol requirements regarding 
treatment are severely violated such that evaluability for primary end point is 
questionable.  All data up until the point of confirmation of a major violation must 
be submitted.  The patient will continue the active monitoring phase and the 
event-monitoring phase of the study.  The patient may continue treatment off-
protocol at the discretion of the physician as long as there are no safety concerns, 
and the patient was properly registered.   
 
13.5  When the patient develops a biochemical recurrence only, he will continue on the 
protocol test schedule until further medical management is implemented at the 
discretion of his physician. 
 
13.6 
When the patient develops a local, regional, or distant recurrence, he will go off 
study with no further scheduled follow-up tests. 
 
14.0 
Body Fluid Biospecimens   
 Not applicable 
 
 
15.0 
Drug Information 
 Not applicable 
 
16.0  Statistical Considerations and Methodology  
 
16.1    Overview:  This Phase II study will utilize a one-stage binomial design to assess 
the rate of late grade 3 or higher GI and GU toxicities associated with a 
hypofractionation proton beam therapy regimen for prostate cancer.   
 
16.1.1 Endpoint:   The primary endpoint of this trial is the proportion of patients 
who experience a late grade 3 or higher GI or GU toxicity.  Toxicity will 
be defined as an adverse event possibly, probably, or definitely related to 
proton beam therapy.   A late GI or GU toxicity will be defined as a GI or 
GU toxicity that occurs between 3 months and 2 years from the 
completion of proton beam therapy.   All patients meeting the eligibility 
criteria who have signed a consent form and have begun treatment will be 
evaluable for late toxicity, with the exception of patients determined to be 
a major violation. 

 
28  
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16.2  Statistical Design: 
 
16.2.1 Decision Rule: It is hypothesized that ≤ 5% of patients will encounter a 
late grade 3 or higher GI or GU toxicity between 3 months and 2 years 
from the completion of proton beam therapy. The proposed treatment 
strategy would be considered ineffective in this population if ≥15% of 
patients experiences a late grade 3 or higher GI or GU toxicity.  
Subsequent studies with the proposed treatment strategy may be 
considered in this patient population if ≤5% of patients experiences a late 
grade 3 or higher GI or GU toxicity.  The following one-stage binomial 
design uses 51 evaluable patients to test the null hypothesis that the rate of 
late grade 3 or higher GI or GU toxicity is ≥15%. 
 
16.2.1.1  Final Decision Rule:  Enter 51 evaluable patients into the study. 
If 5 or more patients experience late grade 3 or higher GI or GU 
toxicity in the first 51 evaluable patients, we will consider this 
regimen ineffective in this patient population. If 4 or more fewer 
are patients in the first 51 evaluable patients experience late 
grade 3 or higher GI or GU toxicity, we may recommend further 
testing of this regimen in subsequent studies in this population. 
 
16.2.1.2  Over Accrual: If more than the target number of patients are 
accrued, the additional patients will not be used to evaluate the 
stopping rule or used in any decision making process.  Analyses 
involving over accrued patients are discussed in Section 16.3.4. 
 
16.2.2 Sample Size:  This study is expected to require a maximum of 51 
evaluable patients. We anticipate accruing 5 additional patients to account 
for ineligibility, cancellation, major treatment violation, or other reasons. 
Therefore, this study is expected to accrue a maximum of 56 patients 
overall. 
 
16.2.3 Accrual Rate and Study Duration:  The anticipated accrual rate is 
approximately 3-4 patients per month. Therefore, the accrual period for 
this phase II study is expected to be approximately 1.5 years. The final 
analysis can begin as soon as the last patient has been observed for 2 
years, or at approximately 3.5 years after the study opens to accrual. 
 
16.2.4 Assuming that the number of late grade 3 or higher GI or GU toxicities is 
binomially distributed, with a significance level of 10%, the probability of 
declaring that the regimen warrants further studies (i.e., statistical power) 
under various toxicity proportions can be tabulated as a function of the 
true toxicity proportion as shown in the table below. 
 
If the true late toxicity rate is… 
0.20 
0.15 
0.10 
0.05 

 
29  
MC1651 
 
 
 
 
Then the probability of declaring 
that the regimen is promising and 
warrants further study is… 
 
0.02 
0.10 
0.41 
0.89 
 
16.2.5 Other considerations:  Adverse events, quality/duration of response, and 
patterns of treatment failure observed in this study, as well as scientific 
discoveries or changes in standard care will be taken into account in any 
decision to terminate the study 
 
16.3 
Analysis Plan  
 
16.3.1 Primary Outcome Analyses: 
 
16.3.1.1 Definition:   The primary endpoint of this trial is the proportion of 
patients who experience a late grade 3 or higher GI or GU toxicity. 
Toxicity will be defined as an adverse event possibly, probably, or 
definitely related to proton beam therapy. A late GI or GU toxicity 
will be defined as a GI or GU toxicity that occurs between 3 
months and 2 years from the completion of proton beam therapy.   
All patients meeting the eligibility criteria who have signed a 
consent form and have begun treatment will be evaluable for late 
toxicity, with the exception of patients determined to be a major 
violation.    
 
16.3.1.2 Estimation:   The proportion of grade 3 or higher GI or GU 
toxicities will be estimated by the number of patients with a late 
grade 3 or higher GI or GU toxicity divided by the total number of 
evaluable patients. Exact binomial 95% confidence intervals for 
the toxicity proportion will be calculated.    
 
16.3.2 Secondary Outcome Analyses:    
 
16.3.2.1  Disease-free survival is defined as the time from registration until 
the time of the first occurrence of biochemical failure (Section 
11.2.1), local recurrence, regional recurrence, distant metastases, 
or death due to any cause.  The distribution of disease-free 
survival will be estimated using the method of Kaplan-Meier.  
The disease-free survival rate will be estimated at 2 years and 5 
years. 
 
16.3.2.2 Disease-specific survival is defined as the time from registration 
until the date of death due to prostate cancer (Section 11.2.6). The 
distribution of disease-specific survival will be estimated using 
the method of Kaplan-Meier. The disease-specific survival rate 
will be estimated at 2 years and 5 years. 
 

 
30  
MC1651 
 
 
 
 
16.3.2.3 Overall survival is defined as the time from registration until the 
death due to any cause (Section 11.2.7).  The distribution of 
overall survival will be estimated using the method of Kaplan-
Meier. The overall survival rate will be estimated at 2 years and 5 
years. 
 
16.3.2.4 An acute adverse event is defined as an adverse event that occurs 
any time between registration and 3 months after the completion of 
proton beam therapy.  The rate of  ≥ grade 3 GI or GU acute 
adverse events will be estimated by the number of patients with a ≥ 
grade 3 GI or GU acute adverse event divided by the total number 
of evaluable patients.  Exact binomial 95% confidence intervals for 
the true rate of ≥ grade 3 GI or GU acute adverse events will be 
calculated. 
 
16.3.2.5 A late adverse event is defined as an  adverse event that occurs 
any time between 3 months and 2 years after completion of proton 
beam therapy.   The rate of  ≥ grade 2 GI or GU late adverse events 
will be estimated by the number of patients with a ≥ grade 2 GI or 
GU late adverse event divided by the total number of evaluable 
patients.  Exact binomial 95% confidence intervals for the true rate 
of ≥ grade 2 GI or GU late adverse events will be calculated. 
 
16.3.2.6 Adverse Events:  All eligible patients that have initiated treatment 
will be considered evaluable for assessing adverse event rate(s).  
The maximum grade for each type of adverse event will be 
recorded for each patient, and frequency tables will be reviewed to 
determine patterns.  Additionally, the relationship of the adverse 
event(s) to the study treatment will be taken into consideration.  
Acute and late adverse events (as defined in sections 16.3.2.2 and 
16.3.2.3) will be summarized separately. 
 
16.3.3  Correlative Analyses 
 
16.3.3.1 Patients will complete the Expanded Prostate Cancer Index 
Composite short form (EPIC-26) questionnaire at baseline and at 
the specified post-treatment time points as shown Section 4.0.   
Subdomains for urinary, bowel, and sexual function will be 
evaluted at each time point and summarized descriptively.  
Changes across time will be evaluated to assess patient function 
and quality of life after study treatment. 
 
16.3.4 Over Accrual: If more than the target number of patients are accrued, the 
additional patients will not be used to evaluate the stopping rule or used in 
any decision making processes; however, they will be included in final 
endpoint estimates and confidence intervals. 

 
31  
MC1651 
 
 
 
 
 
16.4 
Data & Safety Monitoring: 
 
16.4.1 The principle investigator(s) and the study statistician will review the 
study at least twice a year to identify accrual, adverse event, and any 
endpoint problems that might be developing. The Mayo Clinic Radiation 
Oncology Data Safety Monitoring Board (DSMB) is responsible for 
reviewing accrual and safety data for this trial at least once a year, based 
on reports provided by the statistical office. 
 
16.4.2 Adverse Event Stopping Rules:   The stopping rules specified below are 
based on the knowledge available at study development.  We note that the 
Adverse Event Stopping Rule may be adjusted at any time during the 
conduct of the trial and in consideration of newly acquired information 
regarding the adverse event profile of the treatment(s) under investigation.  
The study team may choose to suspend accrual if there are unexpected 
adverse event profiles that have not crossed the specified rule below. 
 
Accrual will be temporarily suspended, if at any time we observe events 
considered at least possibly related to study treatment (i.e. an adverse 
event with attribute specified as  “possible,” “probable,” or “definite”) that 
satisfy one of the following: 
 
• If 4 or more patients in the first 20 treated patients experience a grade 
3 or higher GI or GU adverse event at least possibly related to 
treatment at any time and after 3 months following completion of the 
protocol treatment 
 
• After the first 20 patients have been treated: if ≥ 20% of all patients 
experience a grade 3 or higher GI or GU adverse event at least 
possibly related to treatment at any time after 3 months following the 
completion of protocol treatment. 
 
In addition, we will review grade 4 and 5 adverse events deemed 
“unrelated” or “unlikely to be related”, to verify their attribution and to 
monitor the emergence of a previously unrecognized treatment-related 
adverse event. 
 
16.6   Results Reporting on ClinicalTrials.gov: At study activation, this study will be 
registered within the “ClincialTrails.gov” website. The Primary and Secondary 
Endpoints along with other required information for this study will be reported on 
ClinicalTrials.gov. For purposes of timing of the Results Reporting, the initial 
estimated completion date for the Primary Endpoint of this study is 3.5 years after 
the study opens to accrual. The definition of “Primary Endpoint Completion 
Date” (PECD) for this study is at the time the last patient registered has been 
followed for at least 2 years. 

 
32  
MC1651 
 
 
 
 
 
16.7 
Inclusion of Minorities 
 
16.7.1 This study will be available to all eligible patients, regardless of raceor 
ethnic origin. 
 
16.7.2 There is no information currently available regarding differential effects of 
this regimen in subsets defined by race, or ethnicity, and there is no reason 
to expect such differences to exist. Therefore, although the planned 
analysis will, as always, look for differences in treatment effect based on 
racial groupings, the sample size is not increased in order to provide 
additional power for subset analyses. 
 
16.7.3 The geographical region served by Mayo Clinic Cancer Center has a 
population which includes approximately 3% minorities.  Based on 
prior Mayo Clinic Cancer Center studies involving similar disease 
sites, we expect about 3-5% of patients will be classified as 
minorities by race and 100% of patients will be men. Expected sizes 
of racial by gender subsets are shown in the following table: 
 
Accrual Estimates by Gender/Ethnicity/Race  
 
Ethnic Category 
Sex/Gender 
Females 
Males 
Unknown 
Total 
Hispanic or Latino 
0 
2 
0 
2 
Not Hispanic or Latino 
0 
54 
0 
54 
Ethnic Category: Total of all subjects* 
0 
56 
0 
56 
Racial Category 
 
American Indian or Alaskan Native 
0 
0 
0 
0 
Asian 
0 
0 
0 
0 
Black or African American 
0 
2 
0 
2 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
0 
White 
0 
54 
0 
54 
Racial Category: Total of all subjects* 
0 
56 
0 
56 
 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rico, South or 
Central American, or other Spanish culture or origin, regardless of race. The 
term “Spanish origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 

 
33  
MC1651 
 
 
 
 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the 
original peoples of North, Central, or South America, and who maintains tribal 
affiliations or community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, 
China, India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, 
Thailand, and Vietnam. (Note: Individuals from the Philippine Islands have 
been recorded as Pacific Islanders in previous data collection strategies.)  
Black or African American – a person having origins in any of the black racial 
groups of Africa.  Terms such as “Haitian” or “Negro” can be used in addition 
to “Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of 
the original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the 
Middle East, or North Africa. 
 
17.0  
Pathology Considerations/Tissue Biospecimens   
 
 
Not Applicable 
 
18.0 
Records and Data Collection Procedures   
 
18.1 
Submission Timetable 
 
Initial Material(s) 
CRF 
Baseline 
(Compliance with Test Schedule Section 4.0) 
 
Demographics 
 
 
                          2 weeks after registration 
 
 
*6 months from accrual 
Patient Eligibility 
On-Study 
Adverse Events-Baseline 
PSA and Testosterone Values 
Prostate Radiotherapy Questionnaires 
Androgen Deprivation Treatment  
 
 
 
Test Schedule Material(s)  
CRF 
 
Active-Monitoring Phase2 
(Compliance with Test Schedule Section 4.0) 
Event-Monitoring Phase3 
(Compliance with Test 
Schedule Section 4.0) 

 
34  
MC1651 
 
 
 
 
On-Study 
At each 
evaluation 
during 
treatment 
At end of 
treatment 
Post-RT: 3, 6, 12, 18, 
and 24 months  
(Active Monitoring) 
Post-RT: 30, 36, 42, 48, 
and 60 months 
(Event Monitor) 
Adverse Event: Solicited 
Form 
X 
X 
X 
X 
X 
Adverse Events Other 
X 
X1 
X1 
X1 
X1 
Radiation Treatment  
 
 
X 
 
 
Androgen Deprivation 
Treatment  
X 
X4 
X4 
X4 
X4 
End of Active Treatment 
 
 
X 
 
 
PSA and Testosterone 
Values 
 
X 
 
X5 
X5 
Adverse Events: Post 
Radiation Treatment  
 
 
 
X 
X 
Post Radiation Patient 
Status/Assessment  
 
 
 
X 
X6 
Prostate Radiotherapy 
Questionnaires 
 
 
 
X 
X 
Consent Withdrawal form 
 
X1 
X1 
X1 
X1 
Lost to Follow-up 
 
X1 
X1 
X1 
X1 
1. When applicable 
2. Post RT (Active monitoring phase): 3 months (+/- 1 months), 6 months (+/- 1 months), 
12 months (+/- 1 months), 18 months (+/- 1 months), and 24 months (+/- 1 months) post 
RT.  
3. Post RT (Event-monitoring phase): 30 months (+/- 1 months), 36 months (+/- 1 months), 
42 months (+/- 1 months), 48 months (+/- 1 months), 54 months (+/- 1 months), and 60 
months (+/- 1 months) post RT.  
4. Coordinator will look to see if patient received Androgen Deprivation Therapy since the 
previous reporting period.  If there was no change, indicate on form.  
5. Testosterone is collected at post-RT month 12, 24, 36, 48, and 60 months post RT.  
However, if one was completed it should be entered into the CRF.  Therefore, the form 
will populate at each visit, and if it wasn’t completed because it was not required, 
indicate “not completed” on form.  
6. History, physical exam, and ECOG are not required during Event Monitoring Phase. 
 
18.2 
Data Handling and Record Keeping 
 
18.2.1 Confidentiality 
Information about study subjects will be kept confidential and managed 
according to the requirements of the Health Insurance Portability and 
Accountability Act of 1996 (HIPAA).  Those regulations require a signed 
subject authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from 
subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use 
of their PHI.  

 
35  
MC1651 
 
 
 
 
In the event that a subject revokes authorization to collect or use PHI, the 
investigator, by regulation, retains the ability to use all information 
collected prior to the revocation of subject authorization.  For subjects that 
have revoked authorization to collect or use PHI, attempts should be made 
to obtain permission to collect at least vital status (long term survival 
status that the subject is alive) at the end of their scheduled study period. 
 
18.2.2 Source Documents 
Source data is all information, original records of clinical findings, 
observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  Source data are contained in 
source documents.  Examples of these original documents, and data 
records include: hospital records, clinical and office charts, laboratory 
notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, 
subject files, and records kept at the pharmacy, at the laboratories, and at 
medico-technical departments involved in the clinical trial. Source 
documents are kept in a secure location that is locked and requires 
approved access.  
 
18.3.3 Case Report Forms  
The study case report form (CRF) is the primary data collection 
instrument for the study.  All data requested on the CRF must be recorded.  
All missing data must be explained.  If a space on the CRF is left blank 
because the procedure was not done or the question was not asked, write 
“N/D”.  If the item is not applicable to the individual case, write “N/A”.  
All entries should be printed legibly in black ink.  If any entry error has 
been made, to correct such an error, draw a single straight line through the 
incorrect entry and enter the correct data above it.  All such changes must 
be initialed and dated.  Do not erase or use “white-out” for errors.  For 
clarification of illegible or uncertain entries, print the clarification above 
the item, then initial and date it.  If the reason for the correction is not 
clear or needs additional explanation, neatly include the details to justify 
the correction.  
 
 
 
18.3.4 Records Retention 
The investigator will maintain records and essential documents related to 
the conduct of the study.  These will include subject case histories and 
regulatory documents. 
 
The investigator will retain the specified records and reports for; 
1. As outlined in the Mayo Clinic Research Policy Manual –“Retention 
of and Access to Research Data Policy” 
  
19.0  
Study Finances 

 
36  
MC1651 
 
 
 
 
 
 
19.1 
Costs charged to patient:  routine clinical care 
 
19.2 
Tests to be research funded: None. All tests and treatments performed in the study are 
part of routine clinical care. 
 
19.3 
Other budget concerns: The Mayo Clinic Radiation Oncology Unit will cover costs 
related to administrating the study including a clinical research associate. 
 
20.0 
Publication Plan 
The principal investigators hold primary responsibility for publication of the results of this study 
and approval from the principal investigators must be obtained before any information can be 
used or passed on to a third party.   
 
 
21.0 
References 
 
1. 
Wang, J.Z., M. Guerrero, and X.A. Li, How low is the alpha/beta ratio for prostate cancer? 
International journal of radiation oncology, biology, physics, 2003. 55(1): p. 194-203. 
2. 
Brenner, D.J., et al., Direct evidence that prostate tumors show high sensitivity to fractionation 
(low alpha/beta ratio), similar to late-responding normal tissue. International journal of radiation 
oncology, biology, physics, 2002. 52(1): p. 6-13. 
3. 
King, C.R. and J.F. Fowler, A simple analytic derivation suggests that prostate cancer alpha/beta 
ratio is low. International journal of radiation oncology, biology, physics, 2001. 51(1): p. 213-4. 
4. 
Fowler, J., R. Chappell, and M. Ritter, Is alpha/beta for prostate tumors really low? International 
journal of radiation oncology, biology, physics, 2001. 50(4): p. 1021-31. 
5. 
Vargas, C., et al., Dose-volume comparison of proton therapy and intensity-modulated 
radiotherapy for prostate cancer. International journal of radiation oncology, biology, physics, 
2008. 70(3): p. 744-51. 
6. 
Nihei, K., et al., Multi-institutional Phase II study of proton beam therapy for organ-confined 
prostate cancer focusing on the incidence of late rectal toxicities. International journal of 
radiation oncology, biology, physics, 2011. 81(2): p. 390-6. 
7. 
Slater, J.D., et al., Proton therapy for prostate cancer: the initial Loma Linda University 
experience. International journal of radiation oncology, biology, physics, 2004. 59(2): p. 348-52. 
8. 
Mendenhall, N.P., et al., Five-year outcomes from 3 prospective trials of image-guided proton 
therapy for prostate cancer. International journal of radiation oncology, biology, physics, 2014. 
88(3): p. 596-602. 
9. 
Zietman, A.L., et al., Randomized Trial Comparing Conventional-Dose With High-Dose 
Conformal Radiation Therapy in Early-Stage Adenocarcinoma of the Prostate: Long-Term 
Results From Proton Radiation Oncology Group/American College of Radiology 95-09. Journal 
of Clinical Oncology, 2010. 28(7): p. 1106-1111. 
10. 
Hoppe, B.S., et al., Comparative effectiveness study of patient-reported outcomes after proton 
therapy or intensity-modulated radiotherapy for prostate cancer. Cancer, 2014. 120(7): p. 1076-
82. 
11. 
Hall, E. and G. A.J., Time, Dose, and Fractionated in Radiotherapy, in Radiobiology for the 
Radiologist2006, Lippincott Williams & Wilkins: Philadelphia. p. 378-397. 
12. 
Cheung, P.C., et al., Concomitant Hypofractionated IMRT Boost for High-Risk Prostate Cancer: 
5 Year Results. International journal of radiation oncology, biology, physics, 2013. 87(2): p. 
S106. 

 
37  
MC1651 
 
 
 
 
13. 
Quon, H., et al., Hypofractionated concomitant intensity-modulated radiotherapy boost for high-
risk prostate cancer: late toxicity. International journal of radiation oncology, biology, physics, 
2012. 82(2): p. 898-905. 
14. 
Pollack, A., et al., Randomized trial of hypofractionated external-beam radiotherapy for prostate 
cancer. Journal of clinical oncology : official journal of the American Society of Clinical 
Oncology, 2013. 31(31): p. 3860-8. 
15. 
Arcangeli, S., et al., Updated results and patterns of failure in a randomized hypofractionation 
trial for high-risk prostate cancer. International journal of radiation oncology, biology, physics, 
2012. 84(5): p. 1172-8. 
16. 
Arcangeli, G., et al., Acute and late toxicity in a randomized trial of conventional versus 
hypofractionated three-dimensional conformal radiotherapy for prostate cancer. International 
journal of radiation oncology, biology, physics, 2011. 79(4): p. 1013-21. 
17. 
Schallenkamp, J.M., et al., Prostate position relative to pelvic bony anatomy based on 
intraprostatic gold markers and electronic portal imaging. International journal of radiation 
oncology, biology, physics, 2005. 63(3): p. 800-11. 
18. 
Hsu, A., et al., A study of image-guided intensity-modulated radiotherapy with fiducials for 
localized prostate cancer including pelvic lymph nodes. International journal of radiation 
oncology, biology, physics, 2007. 68(3): p. 898-902. 
19. 
Adamczyk, M., et al., Dosimetric consequences of prostate-based couch shifts on the precision of 
dose delivery during simultaneous IMRT irradiation of the prostate, seminal vesicles and pelvic 
lymph nodes. Physica medica : PM : an international journal devoted to the applications of 
physics to medicine and biology : official journal of the Italian Association of Biomedical 
Physics, 2014. 30(2): p. 228-33. 
 
 
 

 
38  
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Appendix I 
 
Zubrod Performance Scale  
 
0 
Asymptomatic and fully active 
 
1 
Symptomatic; fully ambulatory; restricted in physically strenuous activity 
 
2 
Symptomatic; ambulatory; capable of self-care; more than 50% of waking hours are spent out of  
 
bed 
 
3 
Symptomatic; limited self-care; spends more than 50% of time in bed, but not bedridden 
 
4 
Completely disabled; no self-care; bedridden 
 

 
39  
MC1651 
 
 
 
 
Appendix II 
 
International Index of Erectile Function Questionnaire (IIEF)  
 
Please circle the appropriate response option to indicate how you were feeling over the past month (4 weeks). 
                                                   
 1:  
During the past month or so, how often were you able to get an erection during sexual activity? 
            
0 = No sexual activity 
           
1 = Almost never/never 
          
2 = A few times (much less than half the time) 
  
3 = Sometimes (about half the time) 
4 = Most times (much more than half the time) 
           
5 = Almost always/always  
 
 
            
2:  
During the past month or so, when you had erections with sexual stimulation, how often were your 
erections hard enough for penetration? 
 
0 = No sexual activity 
1 = Almost never/never 
2 = A few times (much less than half the time) 
3 = Sometimes (about half the time) 
4 = Most times (much more than half the time) 
5 = Almost always/always 
 
3:  
During the past month or so, when you attempted sexual intercourse, how often were you able to penetrate 
(enter) your partner? 
                                                   
0 = Did not attempt intercourse 
1 = Almost never/never 
2 = A few times (much less than half the time) 
3 = Sometimes (about half the time) 
4 = Most times (much more than half the time) 
5 = Almost always/always 
 
4:  
During the past month or so, during sexual intercourse, how often were you able to maintain your erection 
after you had penetrated (entered) your partner? 
 
  
0 = Did not attempt intercourse 
1 = Almost never/never 
2 = A few times (much less than half the time) 
3 = Sometimes (about half the time) 
4 = Most times (much more than half the time) 
5 = Almost always/always 
 
5:  
During the past month or so. during sexual intercourse, how difficult was it to maintain your erection to 
completion of intercourse? 
 
0 = Did not attempt intercourse 
1 = Extremely difficult 
2 = Very difficult 
   
3 = Difficult 
4 = Slightly difficult 
5 = Not difficult 
 
 6:  
During the past month or so, how many times have you attempted sexual intercourse? 

 
40  
MC1651 
 
 
 
 
 
0 = No attempts 
1 = One to two attempts 
2 = Three to four attempts 
3 = Five to six attempts 
4 = Seven to ten attempts 
5 = Eleven + attempts 
 
 

 
41  
MC1651 
 
 
 
 
 
Appendix III 
 
American Urological Association Symptom Index 
 
Please circle the appropriate response option to indicate how you were feeling over the past month (4 weeks). 
 
1:  
Over the past month or so, how often have you had a sensation of emptying your bladder completely after 
 
you finished urinating? 
 
 
 
0= Not at all 
          
1 = Less than one time in five 
 
2 = Less than half the time 
3= About half the time 
           
4 = More than half the time 
 
5 = Almost always 
 
2:  
Over the past month or so, how often have you had to urinate again, less than two hours after you finished 
 
urinating? 
 
 
 
0= Not at all 
          
1 = Less than one time in five 
 
2 = Less than half the time 
3= About half the time 
           
4 = More than half the time 
 
5 = Almost always 
 
3:  
Over the past month or so, how often have you found you stopped and stated again several times when you 
 
urinated? 
 
 
 
0= Not at all 
          
1 = Less than one time in five 
 
2 = Less than half the time 
3= About half the time 
           
4 = More than half the time 
 
5 = Almost always 
 
4:  
Over the past month or so, how often do you find it difficult to postpone urination? 
 
 
 
0= Not at all 
          
1 = Less than one time in five 
 
2 = Less than half the time 
3= About half the time 
           
4 = More than half the time 
 
5 = Almost always 
 
5:  
Over the past month or so, how often have you had a weak urinary stream? 
 
 
 
0= Not at all 
          
1 = Less than one time in five 
 
2 = Less than half the time 
3= About half the time 
           
4 = More than half the time 
 
5 = Almost always 
 
6:  
Over the past month or so, how often have you had to push or strain to begin urination? 

 
42  
MC1651 
 
 
 
 
 
 
 
0= Not at all 
          
1 = Less than one time in five 
 
2 = Less than half the time 
3= About half the time 
           
4 = More than half the time 
 
5 = Almost always 
 
 
 
 
7:  
Over the past month or so, how often did you most typically get up at night to urinate? 
 
 
 
0= Not at all 
          
1 = Once every 8 hours 
 
2 = Once every 4 hours 
3= Once every 3 hours 
           
4 = Once every 2 hours 
 
5 = At least once every hour