Prospective Evaluation of CyberKnife® as Monotherapy or Boost Stereotactic Body Radiotherapy for Intermediate or High Risk Localized Prostate Cancer
Phase: NA
Conditions: Prostate Adenocarcinoma
Sponsor: Wake Forest University Health Sciences

 
 
 
 
 
PROSPECTIVE EVALUATION OF CYBERKNIFE® AS 
MONOTHERAPY OR BOOST STEREOTACTIC BODY 
RADIOTHERAPY FOR INTERMEDIATE OR HIGH RISK 
LOCALIZED PROSTATE CANCER: 
AN OBSERVATIONAL STUDY 
 
 
 
 
STUDY CHAIR 
 
Arica Hirsch, MD 
Advocate Lutheran General Hospital 
1700 Luther Lane, Suite 204 
Park Ridge, IL 60068 
 
 
STUDY CO- CHAIRS 
James Ruffer, M.D. 
Majid Mohiuddin, M.D. 
 
 
 
 
 
 
 
 
 
 
 
Version Date: May 16, 2019 

Page 2 of 36 
 
Protocol Signature Page 
 
 
 
PROSPECTIVE EVALUATION OF CYBERKNIFE® AS 
MONOTHERAPY OR BOOST STEREOTACTIC BODY 
RADIOTHERAPY FOR INTERMEDIATE OR HIGH RISK 
LOCALIZED PROSTATE CANCER 
 
I have read this protocol and agree to adhere to the requirements. I will provide copies of this protocol 
and all pertinent information to the study personnel under my supervision. I will discuss this material 
with them and ensure they are fully informed regarding the conduct of the study according to the 
protocol and in strict accordance with all applicable U.S. Food and Drug Administration (“FDA”) 
regulations and guidelines applicable to the Study, including without limitation the regulations set 
forth in Parts 50, 54, 56 and 812 of 21 C.F.R., and all other applicable federal, state, or local laws, 
guidelines, rules, and regulations of any type. 
 
 
 
 
Clinical Site 
 
 
 
Signature, Principal Investigator 
Date 
 
 
 
Printed Name, Principal Investigator 

Page 3 of 36 
 
CONTACT INFORMATION 
 
INDEX 
 
Schema, Eligibility Checklist 
 
1.0 
Background 
 
2.0 
Objectives 
 
3.0 
Device 
 
4.0 
Pretreatment Evaluation 
 
5.0 
Patient Selection & Eligibility 
 
6.0 
Registration Procedures 
 
7.0 
Pathology 
 
8.0 
Treatment 
 
9.0 
Patient Assessments & Toxicity 
 
10.0 
Data Collection 
 
11.0 
Statistical Considerations 
 
12.0 
Data Safety and Monitoring 
 
13.0 
Source of Subjects and Recruitment Procedures 
 
14.0 
Risk to Benefit Ratio 
 
15.0 
Costs and Payments 
 
16.0 
Appendices 
 
Appendix I: 
Patient consent 
Appendix II: Performance Status Scales 
Appendix III: Staging 
Appendix IV:  Data collection documents 
Appendix V: NCI common toxicity criteria/RTOG/EORTC 
Appendix VI:  AUA, EPIC, SHIM questionnaires 
 
17.0 
References 

PROSPECTIVE EVALUATION OF CYBERKNIFE STEREOTACTIC BODY RADIOTHERAPY FOR LOCALIZED PROSTATE CANCER 
SCHEMA 
ADENOCARCINOMA OF THE PROSTATE 
Clinical Stage T1b – T4, NX-0, MX-0 
Any Gleason score 
PSA < 50 
ECOG Performance Status 0-1 
No prior prostate radiation or other definitive therapy 
 
 
STRATIFICATION 
 
RISK GROUPS 
Intermediate 
Risk: 
CS T2b- 
c 
Gleason ≤ 6 & PSA ≤ 
10 
OR 
CS T1b-T2a, 
Gleason = 7 & PSA ≤ 10, OR 
Gleason ≤ 6 & PSA 11- 20 
High Risk: 
CS T3- 
4 
OR 
Gleason > 7 & PSA <50 
 
REGISTRATION 
(Physics Quality Assurance) 
 
Ultrasound & Fiducial Placement 
 
Planning CT and Fused MRI 
 
 
 
GROUP 1 
GROUP 2 
Short term (4-6 months) 
ADT1 
Short or Long term 
(6 months  - 3 years) 
ADT1 
1)  CyberKnife boost: 
21 Gy (7Gy x 3) 
1)  CyberKnife boost: 
21 Gy (7Gy x 3) 
2)  Prostate/SV IMRT 2 
45-50.4 Gy 
2)  Whole Pelvis IMRT 2 
45-50.4 Gy 
OR3 
Short term (4-6 months) ADT1 
CyberKnife SBRT 36.25Gy (7.25Gy x 5)
Required Sample Size: 40 
Required Sample Size:  32 
1) 
Androgen Deprivation Therapy is strongly recommended 
2) 
Intensity Modulated Radiation Therapy 
3) 
Per investigator decision and patient discussion, with consideration of age, performance status, medical co-morbidities, Gleason score and 
other disease features (Gleason score 4+3 vs. 3+4). Strong recommendation is made for consideration of combined modality therapy in 
intermediate risk and certainly “high intermediate” risk disease as defined by Gleason score 4+3 disease, more than 50% positive cores, 
and/or PSA velocity of more than 2ng/ml in the year preceding tissue diagnosis, given survival benefit of short term ADT per randomized 
data in intermediate risk disease. CK SBRT monotherapy would typically be appropriate only for low volume GS 3+4 disease with no 
other adverse features. 

 
 
ELIGIBILITY CHECKLIST 
  
(Y) 
Is there histologically proven prostate adenocarcinoma, biopsy 
within one year of enrollment? 
  
 
What is the Gleason Score? 
  
(T1b-4) 
What is the clinical T-stage? (AJCC 7th Edition) 
  
(Y) 
Is the patient clinical Nx or N0, and Mx or M0? 
  
(0-50) 
PSA evaluated 90 days prior to radiation therapy  or the most 
recent PSA evaluated prior to ADT, whichever is applicable 
  
(I, H) 
Does the patient fall into one of these risk groups (AJCC 6th 
Edition): 
-  Intermediate: CS T2b-c, Gleason <6, PSA ≤ 10, or 
CS T1b-T2a, and Gleason 7, PSA ≤ 10 ng/ml, or Gleason<6, PSA 
11-20 ng/ml 
-High: CS T3-4 or Gleason >7 and PSA<50 
  
(Y) 
Is the prostate volume ≤ 100 cc? 
  
(0-1) 
What is the ECOG performance status? 
  
(N) 
Has the patient undergone prostatectomy or cryotherapy of the 
prostate? 
  
(N) 
Has the patient had radiotherapy to the prostate or lower pelvis? 
  
(N) 
Is there implanted hardware near the planning target volume that 
would prohibit appropriate treatment planning or treatment 
delivery in the investigator’s opinion? 
  
(N) 
Has the patient  had chemotherapy for a malignancy in  the    last 5 
years? 
  
(N) 
Has the patient had an invasive malignancy (other than this 
prostate cancer, or basal or squamous skin cancers) in the last 5 
years? 
  
(n/a,Y) 
Has the patient’s androgen function been ablated during the past 2 
months? 

Page 6 of 35 
 
1. BACKGROUND 
1.1. During the prostate-specific antigen era, an ever-increasing percentage of men 
with prostatic adenocarcinoma have presented with clinically localized, , 
potentially curable disease. Conventional treatment options for these patients 
include laparoscopic or open radical prostatectomy, external beam radiation 
therapy, permanent source interstitial brachytherapy, and high dose rate (HDR) 
remote after loading brachytherapy, either as monotherapy, or in combination with 
external beam radiotherapy.1 
 
1.2. Although each of the treatment options is potentially curative in selected patients, 
each treatment option also has drawbacks. The post-operative recovery period may 
be substantial following radical prostatectomy; the period of urologic symptoms 
may be protracted and occasionally severe following permanent source 
brachytherapy; the scheduling duration is substantial for external beam 
radiotherapy and the discomfort of indwelling transperineal catheters is significant 
for HDR brachytherapy patients. Additionally, all local treatments carry a risk of 
negative long-term quality of life consequences, and occasionally, serious 
complications. 
 
1.3. The use of hypofractionated CyberKnife® stereotactic therapeutic radiation as a 
modality of treatment for early-stage prostate cancer has also been described.2,3,4 
In contradistinction to traditional external beam radiotherapy, this method entails 
a therapeutic radiation process that uses a more precise targeting methodology, 
allowing a more focal treatment margin around the prostate. This more effectively 
limits the volume of adjacent tissue receiving high dose radiation, which in turn 
allows the delivery of a much shorter series of treatments, employing a much larger 
dose of radiation per treatment. When so applied, the radiation becomes tissue 
ablative within the high dose zone, and as such, may be described as a form of 
radiosurgery. 
 
1.4. Although limited experience has been gained to date, the radiosurgical approach 
for prostate cancer carries with it a number of potential advantages, including the 
possibility of lower morbidity due to the very small treatment margins, more rapid 
recovery from side effects due to the lack of a surgical resection or implanted 
radioactivity, convenience of a one week treatment course, and lack of 
transperineal HDR catheters with their attendant pain and hospital admission 
requirement. 
 
1.5. The main technical problem that prevents the application of radiosurgery for 
prostate cancer is that the prostate may move substantially, both between fractions 
(interfraction motion) and during the treatment itself (intrafraction motion), even 
if rigid body immobilization is applied, due to the effect of organ motion.5,6 This 
prostate motion effect necessarily leads to the application of a larger radiotherapy 
planning target volume to compensate, effectively rendering radiosurgery 
impossible by traditional radiotherapy or radiosurgical systems. 
1.6. The CyberKnife® is a unique noninvasive radiosurgical system, capable of 
treating any part of the body from any of approximately 1600 different  targeting 

Page 7 of 35 
 
angles, creating a highly conformal three-dimensional radiosurgical treatment 
volume, guided by orthogonal X-ray-based targeting feedback, and delivering 
radiation by a highly collimated, robotically controlled linear accelerator. The 
CyberKnife® system targets implanted fiducial markers with sub-millimeter initial 
set-up accuracy, and continuously updates the planning target volume by obtaining 
multiple intrafractional orthogonal X-ray-images, producing an automated robotic 
adjustment after each X-ray feedback step, resulting in a real-time target volume 
tracking process that maintains millimeter accuracy throughout the radiosurgical 
treatment.7 Thus, the CyberKnife® device allows a reproducible method of 
radiosurgical prostate treatment. 
 
1.7. There are also radiobiological data that suggest hypofractionated radiosurgical 
treatment may be advantageous for prostate cancer, as contemporary data suggest 
the α/β ratio for prostate cancer tissue may be as low as 1.5Gy.8 These values of 
α/β are comparable to, if not lower, than late-responding normal tissues.8 This 
means that in addition to causing effective cancer cellular ablation and tissue 
sparing due to of its physics attributes, a course of hypofractionated CyberKnife® 
prostate radiosurgery may also create a favorable therapeutic ratio by virtue of the 
radiobiologic sensitivity of prostate cancer itself to hypofractionation, effectively 
resulting in radiobiologic tumor dose escalation.8, 9 
 
1.8. From a dosimetry standpoint, CyberKnife® radiosurgery appears capable of 
producing a dose distribution comparable to that created by prostate HDR 
brachytherapy treatment, without the invasive transperineal catheters. As such, the 
CyberKnife® prostate radiosurgery dose fractionation schedule prescribed in this 
study is based upon prior published prostate HDR brachytherapy experience, 
which suggests efficacy and safety, with a long follow-up. Hypofractionation with 
brachytherapy using high-dose-rate (HDR)-brachytherapy has demonstrated 
excellent efficacy and toxicity profiles as both monotherapy and post-EBRT-boost 
for localized PCa10-21. The University of California San Francisco (UCSF) has 
recently reported its HDR-brachytherapy-boost experience in mostly intermediate 
to high risk disease, achieving five-year bNED rates of 93% with minimal toxicity. 
A randomized phase III trial has reported superior bNED rates with HDR- 
brachytherapy-boost over EBRT alone, and a recent systematic review of the 
world literature has concluded that the combination of EBRT and HDR- 
brachytherapy results in superior bNED and overall survival (OS) as compared to 
EBRT alone or EBRT plus permanent prostate seed implant (PPI)-boost. Others 
have also reported equivalent disease control and improved toxicity and quality of 
life (QOL) measures with HDR brachy-monotherapy as compared to PPI 
monotherapy. 
 
1.9. The radiosurgery volume in this study will be made to resemble prostate HDR 
brachytherapy therapeutic volume as closely as possible, with similar dose 
limitation objectives to adjacent tissues, including the rectum, bladder and urethra. 

Page 8 of 35 
 
1.10. As most patients with low and intermediate risk prostate cancers survive at least 
10 years after intervention, the morbidity associated with therapy for early stage 
prostate cancer is a crucial factor of patient outcome. 
 
1.11. Although traditional, physician-reported toxicity data are a useful component for 
evaluating treatment-related morbidity, it has been shown that patient-report data 
(collected via standardized questionnaires) are more sensitive than physician 
reports to the full severity and broad range of therapy effects on patient Health- 
Related Quality of Life (HRQOL), particularly among men with prostate cancer.25 
 
1.12. The feasibility of CyberKnife® for treating localized prostate cancer was first 
described by King at Stanford University. Their phase I protocol delivered 
36.25Gy in 5 fractions of 7.25Gy. In a recent report of acute and 18-month late 
toxicity in 26 “low-risk” patients, no patient experienced grade 3 or 4 acute or late 
toxicity, and only one patient experienced a grade 2 late morbidity (urethral 
stricture). Toxicity was less than that reported in MD Anderson’s external beam 
dose escalation trial. Mean PSA 18 months after treatment was 0.22ng/m25. 
Similar excellent results have also been reported by Jabbari et al. from the 
University of California for both CyberKnife® monotherapy and boost post whole 
pelvic radiation therapy3, and King and Freedman using the original Stanford 
fractionation of five fractions when used as monotherapy4. 
 
1.13. Another potential benefit of CyberKnife® radiosurgery relative to HDR 
brachytherapy is better preservation of potency, even if the radiation distribution 
is essentially identical between these modalities. This is so because needle trauma 
has been identified as a potentially significant contributory factor to erectile 
dysfunction with brachytherapy, including HDR-based monotherapy technique, 
presumably due to direct physical injury to the neurovascular bundle and/or bulb 
of the penis, particularly when greater than 13 needle insertions are performed.27 
By comparison, CyberKnife® radiosurgery is noninvasive, and so removes this 
particular erectile dysfunction risk factor. 
Table 1. 5-Year bDFS Outcomes for HDR-Monotherapy for Prostate Cancer 
 
HDR Details 
Institution 
#pts 
Median f/u yrs 
Phoenix 
ASTRO 
6–7.25 Gy x 6 CA Endocurie30 
117 
3.3 
97% 
9.5 Gy x 4 
Beaumont31 
95 
4.2 
98% 
7.5 Gy x 6 
Texas Tech32 
145 
5 
90% 
6.5 Gy x 6 
Gamma West – Fav.  (SLC)33 
209 
1.2 
96%* 
99%* 
Gamma West – Int. 33 
119 
1.2 
89%* 
89%* 
6 Gy x 8-9 
Osaka (Japan)34 
111 
2.25 
70%† 
Totals 
796 
2.4 
90% 
*3 year result; Projecting constant failure rate in this series to 5 years yields 98% 
and 82% ASTRO-definition PSA DFS for favorable and intermediate risk cases, 
respectively. †Predominantly unfavorable prognosis cases in this series; 5 year 
local control is 97%. 

Page 9 of 35 
 
Based on the data provided in the reports summarized above, and adding a PSA 
DFS degradation factor to the Gamma West series to compensate for their short 
median follow-up, the average calculated 5 year HDR monotherapy ASTRO-based 
PSA DFS is 98% for favorable prognosis, 82% for intermediate prognosis and 59% 
for unfavorable prognosis cases. There are too few Phoenix-based PSA DFS results 
to project a meaningful Phoenix-based HDR monotherapy PSA DFS efficacy 
result. 
It is anticipated that the case mix in this study will be approximately 75% 
intermediate, and 25% high risk prognosis cases, leading to a predicted 5 year PSA DFS 
rate of 85%-90% for intermediate risk patients, and 75%-80% for high risk patients 
based on HDR brachytherapy boost trial. Table 2. Toxicity review for HDR- 
Monotherapy for Prostate Cancer 
>= Gd 3 toxicity 
HDR Details 
Institution 
# pts 
Median f/u 
Total (%) 
GI (%) 
GU (%) 
6–7.25Gy x 6 
CA Endocurie30 
117 
3.3 
3 
0 
3 
9.5Gy x 4 
Beaumont31 
95 
4.2 
8 
0 
8 
7.5Gy x 6 
Texas Tech32 
145 
5 
5 – 8* 
1 
4 – 7* 
6.5Gy x 6 
Gamma West (SLC)33 
328 
1.2 
1 
0 
1 
6Gy  x 8-9 
Osaka (Japan)34 
111 
2.25 
7 
1 
6 
Totals 
796 
2.4 
6 
0 -1 
5 
*3% acute and 4% chronic grade 3 GU toxicity – It is unclear to what degree acute 
and chronic grade 3 GU toxicity populations overlap in this study. 
 
To confirm our hypothesis that CyberKnife® radiosurgery may be made to resemble 
a “noninvasive HDR dosimetry delivery system,” in addition to simply creating 
equivalent dosimetry, it is necessary to show clinical equivalence both in terms of 
efficacy and toxicity. Due to short median follow-up, the incidence of >= grade 3 
late toxicity is likely underestimated. We project that the incidence of late toxicity 
will increase by approximately 50% when all data reach 5 years maturity, yielding 
a projected cumulative 5 year HDR monotherapy grade 3 toxicity incidence of 9% 
(7-8% GU; 1-2% GI). In this study, biochemical disease-free survival (ASTRO and 
Phoenix definition), freedom from local recurrence, freedom from distant relapse, 
clinical disease-free survival, disease-specific survival and overall survival will be 
recorded. The incidence of grade 3 or higher toxicity and the effect of CyberKnife® 
radiosurgery on bladder, bowel, and sexual function will be followed and monitored 
using standardized, patient self-administered questionnaires28 and compared with 
results published in peer-reviewed literature for other prostate cancer therapeutic 
modalities.29 
 
2. OBJECTIVES 
PRIMARY OBJECTIVES: 
• Document the efficacy of the CyberKnife® procedure, where efficacy is 
defined by biochemical Disease-Free Survival (bDFS), using Phoenix and 
ASTRO definitions, at 5 years. 

Page 10 of 35 
 
• Compare the CyberKnife® Stereotactic Radiosurgery System bDFS rate to 
published HDR monotherapy bDFS rates reported in the literature. 
 
SECONDARY OBJECTIVES: 
• Measure rates of acute and late grade 3-5 gastrointestinal and genitourinary 
toxicity observed during the five years following CyberKnife® Stereotactic 
Radiosurgery System for prostate cancer. Acute toxicity will be defined as 
occurring within 90 days from completion of treatment. Late toxicity will be 
defined as occurring more than 90 days from completion of treatment. It is 
graded based upon Common Terminology Criteria for Adverse Events 
(CTCAE), v3.0 and RTOG/ECOG definitions (see appendix 5). 
• Measure rates of local failure, distant failure, clinical disease-free survival, 
disease-specific survival, and overall survival 
• Examine Quality of Life (QOL) in generic and organ-specific domains 
 
3. DEVICE 
Accuray, Inc. (Sunnyvale, CA), received FDA clearance in July 1999 to provide 
treatment planning and image guided stereotactic radiosurgery and precision 
radiotherapy for lesions, tumors and conditions of the brain, base of skull and 
cervico-thoracic spine, head and neck using the CyberKnife®. On August 10, 2001, 
Accuray, Inc. received 510(k) FDA clearance (510(k) number K011024) to provide 
treatment planning and image-guided stereotactic radiosurgery and precision 
radiotherapy for lesions, tumors, and conditions anywhere in the body when radiation 
treatment is indicated. 
 
4. PRETREATMENT EVALUATION 
4.1. Complete history and physical exam 
4.2. DRE findings from urologist or radiation oncologist 
4.3. Assessment of performance status 
4.4. Histological evaluation of prostate biopsy with assignment of Gleason score 
4.5. Evaluation of the pelvic lymph nodes with CT or MRI is optional 
4.6. Serum PSA. Laboratory evaluation must be done within 90 days prior to 
treatment 
4.7. CBC, platelets, serum BUN and creatinine 
4.8. The prostate volume may be obtained by prior transrectal ultrasound. A CT or 
MRI-based prostate volume measurement will also be acceptable (specify which 
modality). 
4.9. Patient questionnaires (see Appendix VI). 
4.9.1. AUA questionnaire 
4.9.2. EPIC-26 questionnaire 
4.9.3. SHIM questionnaire 
 
5. PATIENT SELECTION & ELIGIBILITY 
5.1. Patient must be ≥ 18 years of age. 

Page 11 of 35 
 
5.2. Histologically proven prostate adenocarcinoma 
5.2.1. Gleason score 2-10 (reviewed by reference lab) 
5.2.2. Biopsy within one year of date of registration 
5.3. 
Clinical stage T1b-T4, N0-Nx, M0-Mx (AJCC 7th Edition) 
5.3.1. T-stage and N-stage determined by physical exam and available 
imaging studies (ultrasound, CT, and/or MRI; see section 4.5) 
5.3.2. M-stage determined by physical exam, CT or MRI. Bone scan not 
required unless clinical findings suggest possible osseous metastases. 
5.4. 
PSA ≤ 50 ng/ml, CBC, platelets, BUN, creatinine prior to treatment 
5.5. 
Patients belonging in one of the following risk groups: 
5.5.1. Intermediate: CS T2b-c and Gleason <6 and PSA ≤ 10, or CS T1b- 
T2b, and Gleason 7 and PSA ≤ 10 ng/ml, or Gleason <6 and PSA 11-20 
ng/ml 
5.5.2. High: CS T3-4, Gleason score >7and PSA<50 
5.6. 
Prostate volume: ≤ 100 cc 
5.6.1. Determined using: volume = π/6 x length x height x width 
5.6.2. Measurement from MRI, CT or ultrasound prior to registration. 
5.7. 
ECOG performance status 0-1 
5.8. 
No prior prostatectomy or cryotherapy of the prostate 
5.9. 
No prior radiotherapy to the prostate or lower pelvis 
5.10. 
No implanted hardware or other material that would prohibit appropriate 
treatment planning or treatment delivery, in the investigator’s opinion. 
5.11. 
No chemotherapy for a malignancy in the last 5 years. 
5.12. 
No history of an invasive malignancy (other than this prostate cancer, or 
basal or squamous skin cancers) in the last 5 years. 
5.13. 
Completion of patient questionnaires in section 4.7. 
5.14. 
Consent signed. 
 
6. REGISTRATION PROCEDURES 
 
6.1. PHYSICS QUALITY ASSURANCE shall at a minimum include: 
6.1.1. ABSOLUTE DOSIMETRY: Must document CyberKnife® absolute 
calibration in water according to AAPM TG51. Site must also document 
that, within the last year, photon beam output has been verified by the 
Radiological Physics Center (RPC). 
6.1.2. DAILY QA: must provide documentation that, for the prior month, the 
following has been performed daily: 
6.1.2.1.1. 
At least 3000 MUs delivered daily for machine warm-up (per 
Accuray) 
6.1.2.1.2. 
Temperature and atmospheric pressure recorded, output 
calibration performed, and new output factor recorded. 
6.1.2.1.3. 
Position of laser at perch position verified to be within 1mm of 
floor reference point. 
6.1.3. MONTHLY QA: must provide documentation that the following monthly 
QA is being performed: 
6.1.3.1.1. 
Beam output in phantom verified as +/- 1% of specified output 

Page 12 of 35 
 
6.1.3.1.2. 
Beam energy constancy verified by ion chamber measurements 
at two depths in phantom, using 60mm collimator and 80cm SAD. 
Ratio should be within +/- 2% of the output ratio determined from 
TPR tables. 
6.1.3.1.3. 
Beam symmetry measured by water scanning system or by 
radiographic (XV) or gafchromic (EBT or MD55) film. Beam 
symmetry should not exceed +/- 2% using area method. 
6.1.3.1.4. 
Fiducial tracking end-to-end tests using ball-cube phantom. 
Maximum tracking radial error should be <0.95mm, with left- 
right, ant-post, and inf-sup errors not exceeding 0.8mm. 
6.1.3.1.5. 
Laser – radiation field congruence measured using XV or EBT 
film in phantom under standard conditions (SAD = 80cm, 5mm 
build-up material and 60mm collimator), with laser center marked 
by a pin. Displacement, evaluated using imaging software or 
graph paper, should not exceed 1mm. 
6.1.4. Daily and monthly QA as described above may be recorded in the 
CyberKnife® Robotic Radiosurgery System QA Log Book, or in other 
documents, and should continue throughout the enrollment period. 
 
6.2. PATIENT REGISTRATION: Patients may be registered only after all eligibility 
criteria are met: see Eligibility Checklist above, and Inclusion Criteria and 
Exclusion Criteria CRFs (Case Report Forms). After the patient signs the Consent 
Form the patient is enrolled in the study, and scheduled for treatment. The pre- 
treatment CRFs are then filled out by the investigator and/or research associate. 
This data is retained in the patient’s chart located in the research office. The date 
of registration may be the date the consent was signed. Fiducials must be placed 
within 60 days, and the first fraction of radiosurgery must be administered within 
90 days of registration. 
 
7. PATHOLOGY 
7.1. Pathology procedures will be conducted in accordance with institutional policy. 
7.2. Pathology Evaluation: Slides/blocks from the pre-treatment diagnostic prostatic 
biopsy will be reviewed by signing pathologist to confirm the diagnosis and 
Gleason score. Other histopathologic features, including extent of tumor in the 
biopsies, the number of biopsies positive and perineural invasion, shall be 
recorded. 
7.3. Central Review: encouraged but not required. 
 
8. TREATMENT:  CYBERKNIFE® RADIOSURGERY 
 
8.1. Intermediate risk patients will be treated with either: CyberKnife® SBRT boost  
of 21 Gy (7 Gy X 3) followed by prostate/SV IMRT 45-50.4 Gy (treatment 
planning and delivery per current standards of care); or CyberKnife® SBRT 
monotherapy 36.35Gy (7.27Gy x 5). Short term Androgen Deprivation Therapy 
(4-6 months per standards of care) is strongly recommended for all intermediate 
risk patients. 

Page 13 of 35 
 
High risk patients will be treated with CyberKnife® boost of 21 Gy (7 Gy X 3) 
followed by whole pelvis IMRT 45-50.4 Gy (treatment planning and delivery per 
current standards of care). Short or long term ADT (6 months up to 3 years per 
current standards of care) is strongly recommended for high risk patients. 
 
Standards of care are based on National Comprehensive Cancer Network 
guidelines. Per investigator decision and patient discussion, the appropriate 
treatment plan will be determined for each patient based on their risk group 
outlined by these guidelines. Patient age, performance status, medical co- 
morbidities, Gleason score and other disease features (Gleason score 4+3 vs. 3+4) 
will be taken into consideration. Strong recommendation is made for 
consideration of combined modality therapy for patients with : Gleason score 4+3 
disease, more than 50% positive cores, and/or PSA velocity of more than 2ng/ml 
in the year preceding tissue diagnosis, given survival benefit of short term ADT. 
CyberKnife® SBRT monotherapy would typically be appropriate only for low 
volume GS 3+4 disease with no other adverse features. 
 
8.2. FIDUCIAL PLACEMENT: All patients will have fiducial seeds measuring 3-5 
mm placed in the prostate prior to treatment planning. A minimum of three fiducial 
seeds will be placed under transrectal ultrasound guidance, using either 
transperineal or transrectal approach, with local anesthesia and/or sedation as 
required. The use of linked fiducials is encouraged, since they may migrate less 
than individually placed fiducials. The physician will place seeds such that they 
are visible (and not superimposed) on CyberKnife® orthogonal imaging, are not 
collinear, and ideally are separated by 2 cm or more. Fiducials will be placed as 
an outpatient procedure. Local anesthetic injection, oral or intravenous sedating 
medication, oral or intravenous pain medication and prophylactic antibiotics may 
be given at the discretion of the investigator to maximize the safety and comfort 
of fiducial placement. At least three seeds must be usable for tracking during 
treatment. If an interim analysis shows unacceptable fiducial migration with a 
specific technique or type of fiducial, further use of this technique or type of 
fiducial may be prohibited by the Principal Investigator.  SpaceOAR Hydrogel 
can be used per physician discretion.  SpaceOAR Hydrogel reduces rectal injury 
in men receiving prostate cancer radiation therapy (RT) by acting as a spacer – 
pushing the rectum away from the prostate. 
 
SpaceOAR hydrogel is an option for men who undergo radiation treatment for 
prostate cancer. It acts as a spacer providing space between the rectum and the 
prostate, making it much less likely that the rectum is exposed to radiation. It is 
injected into place prior to the start of radiation treatment. Patients may be 
awake or asleep under general anesthesia for the procedure. SpaceOAR 
hydrogel is minimally invasive, remains stable during radiation therapy and then 
is gradually absorbed by the body after radiation therapy has been completed. 
 
8.3. TREATMENT PLANNING IMAGING: 
8.3.1. To allow fiducial stabilization and resolution of swelling, planning studies 
will be imaged >= 7 days after fiducial placement. Alpha Cradle or a similar 
immobilization device will be used as needed. 
8.3.2. CT scans will be taken for treatment planning. CT slices will be 1 – 1.5mm, 

Page 14 of 35 
 
with 250-512 slices taken centered at the prostate. The imaging sets will be 
downloaded to the CyberKnife® treatment planning system to develop the 
radiosurgery treatment plan. 
8.3.3. If not medically contraindicated, all patients will undergo MRI imaging to 
determine the anatomical borders of the prostate. This study will be fused to 
the treatment planning CT. No endorectal coil allowed. 
8.3.4. URETHRAL IDENTIFICATION: 
The planning CT and MRI scans will be done with a Foley catheter in 
place to define the natural course of the urethra through the CTV.  To 
improve comfort and minimize inconvenience to the patient, if possible, 
CT and MRI planning studies will be done consecutively. 
8.3.5. Prior to treatment planning imaging, the patient will follow the 
bowel/urinary preparation procedures used for treatment (see section 8.4.2). 
8.4. CYBERKNIFE®  TREATMENT PLANNING: 
8.4.1. TREATMENT PLANNING PROCEDURES: Inverse planning using the 
CyberKnife® planning system will be employed. The treatment plan used for 
each treatment will be based on an analysis of the volumetric dose including 
dose-volume histogram (DVH) analyses of the PTV and critical normal 
structures. Any beams entering through a hip prosthesis on their way to the 
planning target volume shall be turned off. Number of paths and beams used 
for each patient will vary and will be determined by the selected individual 
treatment plan. A priority will be placed on reducing overall treatment time, 
number of non-zero beams and total monitor units without compromising the 
dosimetric limits listed in section 8.3.4. All plans are expected to require no 
more than 2 hours per treatment, no more than 300 non-zero beams and no 
more than 95,000 monitor units for all fractions. 
8.4.2. QUALITY ASSURANCE 
8.4.2.1. BENCHMARK (DRY RUN) CASE REVIEW: A treatment plan shall 
be developed, and the plan reviewed by the PI and Physics Chair; 
completion of a satisfactory plan is required prior to patient enrollment. 
8.4.3. EVALUATED STRUCTURES: 
8.4.3.1. CTV: The Clinical Treatment Volume (CTV) 
8.4.3.1.1. 
The CTV is the pre-registered MRI defined prostate volume, 
unless MRI-based imaging is medically contraindicated or judged 
inaccurate by the investigator (see section 8.3.3.1.2.), in which case 
the CT may be used to define the CTV. Additionally, at the 
discretion of the investigator, some or all of the adjacent seminal 
vesicle volume may be included in the CTV for any of the following 
reasons: prostate base involvement by any criteria, perineural 
invasion, or equivocal MRI evidence of seminal vesicle invasion in 
a patient with no other clinical or pathological evidence for seminal 
vesicle invasion, and/or intermediate or high risk disease. 
8.4.3.2. PTV: The prescription dose shall be delivered to the Planning Tumor 
Volume (PTV). 
8.4.3.2.1. 
The PTV is an enlargement of the CTV. The CTV should be 
expanded to include a 2-5 mm margin at the proximal, distal, 
anterior, lateral and generally less in the posterior aspects of the 
CTV. Posteriorly, where the CTV abuts the rectum, there will be 
no margin. 

Page 15 of 35 
 
 
8.4.3.3. NORMAL  TISSUES:  CONTOURING  REQUIRED:  The structures 
listed below will be contoured and evaluated with DVH analysis. Bowel 
peristalsis and bladder filling change the size and location of normal 
structures. If the CT and MRI show normal tissues in different locations 
immediately adjacent  (i.e.,  within < 2cm)  the prostate, the   contoured 

Page 16 of 35 
 
structure shall be a larger composite of both image sets. Grid size should 
be sufficiently large to include the entire structure. 
8.4.3.3.1. 
RECTUM: defined as a solid organ (not the wall), extending 
from 1.5 cm superior to 1.5 cm inferior to PTV. 
8.4.3.3.2. 
BLADDER, defined as a solid structure including the bladder 
wall and lumen. 
8.4.3.3.3. 
URETHRA: To be defined on CT more so than MRI. Approval 
by the Radiation Oncologist is required. 
8.4.3.3.4. 
PENILE BULB: Will be defined only if a co-registered MRI is 
used in the planning process. The penile bulb is defined as the 
portion of the bulbous 
spongiosum  that  lies  inferior to the 
urogenital diaphragm. 
8.4.3.3.5. 
SIGMOID COLON OR OTHER BOWEL lying within 2 cm of 
the PTV should be contoured. 
8.4.3.3.6. 
PENIS AND TESTICLES: The region of the penis and testicles 
shall be contoured with enough margin to allow for day-to-day 
changes in their positioning. 
 
8.4.4. DOSE SPECIFICATIONS: All specified doses are for the entire treatment 
course. All volume percentages are rounded to the nearest tenth of a percent 
for consistency, i.e. a volume of 0.02% shall be recorded as 0.0%. 
 
8.4.4.1. The PRESCRIPTION DOSE of 36.25Gy in 5 fractions for 
monotherapy or 21Gy in 3 fractions for boost will be delivered in <10 
days, with > 95% of the PTV encompassed within the prescription 
isodose volume. Maximum PTV dose 130% prescription dose. 
8.4.4.2. CONFORMALITY INDEX FOR NORMAL TISSUES:  The ratio 
of the prescription isodose volume to the PTV will be >1.0 and <1.5. 
Minor variation:  < 0.99 or >1.51 – 2.0 
8.4.4.3. DOSE OBJECTIVES: The following table outlines the target and 
normal tissue objectives: 
 
Organ 
Constraint 
21Gy in 3Fx 
36.25Gy in 5 Fx 
PTV 
Dose Normalization 
70 - 80% 
70 - 80% 
PTV 
Dose min 95% 
>= 21 Gy 
>= 36.25 Gy 
PTV 
Dose Max 
26.25 - 30 Gy 
45.31 - 51.79 Gy 
Prostate 
Dose Min to 100% 
>= 21 Gy 
>= 36.25 Gy 
Rectum 
Dose Max to 1 cc 
<= 22.05 Gy 
<= 38.06 Gy 
Rectum 
3 cc 
<= 19.95 Gy 
<= 34.4 Gy 
Rectum 
10% 
<= 18.9 Gy 
<= 32.625 Gy 
Rectum 
20% 
<= 16.8 Gy 
<= 29 Gy 
Rectum 
50% 
<= 10.5 Gy 
<= 18.125 Gy 

Page 17 of 35 
 
Bladder 
Dose Max to 1 cc 
<= 22.05 Gy 
<= 38.06 Gy 
Bladder 
10% 
<= 18.9 Gy 
<= 32.625 Gy 
Bladder 
50% 
<= 10.5 Gy 
<= 18.125 Gy 
Penile Bulb 
Dose Max to 1 cc 
<= 21 Gy 
<= 36.25 Gy 
Penile Bulb 
3 cc 
<=  11.34 Gy 
<=  20 Gy 
Femoral Heads 
Dose Max to 1 cc 
<=  17.01 Gy 
<=  30 Gy 
Femoral Heads 
10 cc 
<=  11.34 Gy 
<=  20 Gy 
Urethra 
Dose Max to 0.03 cc 
<=  22.5 Gy 
<=  38.78 Gy 
Bowel 
20 cc 
<=  24 Gy 
<=  25 Gy 
Penis/Testicles 
1 cc 
as low as possible 
as low as possible 
8.4.4.4.  
 
8.5. CYBERKNIFE®  TREATMENT DELIVERY 
8.5.1. The prescribed PTV dose shall be given using the CyberKnife® 
8.5.2. Bowel/bladder preparation: 
8.5.2.1. The rectum will be emptied of its contents by use of one or more 
Fleets enemas prior to the planning CT and MRI scans. 
8.5.2.2. To improve comfort and minimize inconvenience to the patient, if 
possible, the CT and MRI planning studies will be done consecutively. 
8.5.3. Treatment should be completed within 7 days. 
8.5.4. At least three fiducials should be identified for each treatment. If fewer than 
three fiducials can be tracked, then additional fiducials will be placed, and the 
patient replanned. Every effort will be made to treat using rotational 
corrections. The treatment system will be set to record rotations on the 
treatment printout. On a given treatment, if rotational corrections are not 
possible, treatment may continue, with rotational deltas recorded, as long as 
these remain below 2 degrees. For subsequent treatments, diet changes or 
additional bowel preparations will be made, and/or rectal tube placed, and 
treatment shall be attempted using rotational corrections. If treatment 
proceeds without rotational corrections, the therapist shall inform the 
attending radiation oncologist, and record the duration of treatment performed 
without rotations. 
8.5.5. On the day of the CyberKnife® treatment, the patient will be taken into the 
CyberKnife® system treatment room, set up in their respective 
immobilization devices and positioned on the CyberKnife® couch. X-rays 
will be taken with the CyberKnife® system to ensure that the tumor is aligned 
in a manner consistent with the position in which the treatment plan CT image 
was taken. Target movement is expected to require imaging every 1-3 nodes, 
per the discretion of the attending physician, and in no situation should 
imaging occur less frequently than every 5 nodes. Fiducial locations in the 
images will be extracted and compared to the fiducial locations in the CT 
scans to estimate target movements. The following planning and treatment 
information shall  be  recorded for  every plan and  fraction delivered: set-up 

Page 18 of 35 
 
time required, number of nodes treated, number of nodes treated with 
rotational corrections, number of nodes imaged, and total treatment time. This 
data will be collected onto Case Report Forms. 
8.5.6. All planned nodes will be treated whenever possible. If treatment must be 
terminated prematurely on fractions 1-3, compensate as follows. If 2/3 or more 
of all non-zero nodes were treated, then the untreated nodes plus the full 
next fraction should be treated on the next treatment day (this should 
introduce an error of < 5% in BED delivered). If less than 2/3 of the non-
zero nodes were treated, then the untreated portion of this fraction (only) 
will be made up for on the following day. The subsequent fraction shall be 
delivered on the next treatment day. If treatment must be terminated 
prematurely on the fourth fraction, and 90% of the non-zero nodes were 
treated, then no further treatment shall be given (this should introduce an 
error of < 5% for total BED delivered). If fewer than 90% of the non-zero 
nodes were treated, then the deficit shall be delivered on the following 
treatment day. All such variations shall be recorded. 
 
9. PATIENT ASSESSMENTS AND TOXICITY 
Assessment 
Pre- 
entry 
Follow-up 
(# of months from last radiation therapy treatment) 
1 
3 
6 
12 
18 
24 
30 
36 
48 
60 
History 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam (DRE) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG Performance Scale 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prostate Biopsy & Gleason score 
X 
PSA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prostate volume assessment 
X 
CBC, platelets 
X 
BUN, creatinine 
X 
Toxicity evaluation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AUA score 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EPIC-26 Questionnaire 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SHIM Questionnaire 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Follow up evaluations may be performed +/- 30 days 
 
9.1. EVALUATION DURING TREATMENT & FOLLOWING TREATMENT 
9.1.1. PRE-ENTRY ASSESSMENT: see section 4.7. 
9.1.2. Stereotactic radiosurgery is an outpatient procedure. Patient 
management immediately after the procedure will follow routine 
patient care guidelines as determined by the physician.  Subjects 
will be provided instructions on who to call with specific contact 
information, in the event they experience any untoward effects 
following treatment. In the event a subject experiences any 
untoward effects following CyberKnife® treatment, information 
specific to the patient’s condition and symptoms, treatment 
intervention required, and hospital stay and course will be 
recorded for purposes of clinical evaluation. 
9.1.3. ASSESSMENTS FOLLOWING TREATMENT: At 1 month 
following last radiation treatment, patients will be assessed for 

Page 19 of 35 
 
acute toxicity, and will fill out AUA form, EPIC-26 and SHIM. 
At month 3, every 6 months from year 1-3 (months 6, 12, 18 and 
24, 30 and 36) and at year 4 and 5, AUA, EPIC-26 and SHIM 
will be administered, and an H&P with DRE and toxicity 
evaluation will be completed. Examination and studies may be 
done at outside facility. 
9.1.4. Recommended: at the time of biochemical failure, or when 
the patient develops signs of symptoms suggesting metastatic 
disease, it is at the physician’s discretion to perform a 
prostate biopsy or imaging studies. 
9.2. CRITERIA FOR TOXICITY 
9.2.1. ACUTE AND LATE TOXICITY 
9.2.2. Side effects will be assessed using the NCI Common 
Toxicity Criteria version 3.0 (see appendix V). 
9.3. QUALITY OF LIFE ASSESSMENTS 
9.3.1. EXPANDED PROSTATE CANCER INDEX COMPOSITE 
(EPIC)-26: is a validated comprehensive instrument developed to 
assess patient function and bother after prostate cancer treatment. 
It was developed by an expert panel of urological oncologists, 
radiation oncologists (including those with brachytherapy 
expertise), survey researchers, and prostate cancer nurses, to 
address symptoms related to radical prostatectomy, external beam 
radiotherapy, prostate brachytherapy, and hormonal symptoms. See 
appendix VI. 
9.3.2. AMERICAN UROLOGICAL ASSOCIATION (AUA) SYMPTOM 
INDEX: Also known as the International Prostate Symptom Score (IPSS), 
this widely used index assesses urinary symptom bother.  See appendix VI. 
9.3.3. SEXUAL HEALTH INVENTORY FOR MEN (SHIM): is a widely used, 
internationally validated and sensitive instrument for assessing erectile 
dysfunctioni. 
 
9.4. CRITERIA FOR DISEASE CONTROL: intervals will be measured from 
enrollment date. 
9.4.1. BIOCHEMICIAL DISEASE-FREE SURVIVAL (bDFS): is measured as 
time to PSA failure. While earlier reports of prostate cancer patients treated 
with radiotherapy have used the ASTRO consensus definition (ACD) of 
PSA failure, recent studiesii,iii,iv have suggested the “nadir+2” definition is a 
more sensitive and specific definition of biochemical failure. Indeed, a 
recent expert panel met in Phoenixv and developed a consensus 
recommendation using the latter definition. So that comparisons can be 
made with earlier literature, both definitions shall be used: 
9.4.1.1. Phoenix definition: failure occurs when the PSA is ≥ 2 ng/ml more 
than the lowest PSA measurement before the current one, with no 
backdating. Administration of salvage therapy (hormones, surgery, 
etc…) will be considered failure. 
9.4.1.2. Strict ASTRO Consensus Definition (ACD): failure is defined as three 
consecutive rises in post-treatment PSA, measured at the specified 
follow-up intervals. If three consecutive PSA rises occur during the 

Page 20 of 35 
 
first 2 years after treatment, followed by a non-hormonal induced PSA 
decline, this will not be considered a failure. Administration of salvage 
therapy (hormones, surgery, etc…) will be considered failure. Failure 
date is the midpoint between the dates of the last non-rising PSA and 
the first PSA rise. 
9.4.2. CRITERIA FOR LOCAL FAILURE: 
Clinical evidence of local progression or recurrence: Clinical failure includes 
a palpable abnormality that has increased in size, failure of regression of a 
palpable abnormality by 2 years after treatment, or redevelopment of a 
prostate abnormality after complete response. Patients with a prostate 
abnormality compatible with local recurrence or a PSA failure shall undergo 
a prostate biopsy. A histologic criterion for local failure is a positive prostate 
biopsy more than 2 years after treatment. Patients with a normal exam and 
no evidence of PSA failure shall be considered controlled locally. Patients 
with clinical failure and no biopsy are considered local failures. If a patient 
is locally controlled at the time of orchiectomy or androgen ablation, he is 
censored and considered “not evaluable” for further local control. 
9.4.3. CRITERIA FOR NONLOCAL FAILURE 
9.4.3.1. DISTANT FAILURE (includes regional failure): documented if 
clinical, bone scan, CT or other imaging study shows metastatic 
disease. Biochemical failure with a negative prostate biopsy shall be 
considered distant only failure. Biopsy of metastatic site required if 
radiographic or clinical findings are equivocal. Type of metastatic 
failure (distant and/or regional) shall be recorded if known. Prostate 
biopsy recommended at this time. 
9.4.3.2. DISEASE-FREE SURVIVAL: for any measure of disease, 
including PE, PSA, bone scan, CT/MRI and biopsy, or death. 
9.4.3.3. DISEASE-SPECIFIC SURVIVAL: for any of the following: 
9.4.3.3.1. 
Death due to prostate cancer. 
9.4.3.3.2. 
Death due to other causes, with active malignancy (defined by 
clinical or biochemical evidence of progression). If a patient 
suffered a previous relapse, but has inactive disease, this is not 
considered a disease-specific death. 
9.4.3.3.3. 
Death due to complications of treatment. 
9.4.3.4. OVERALL SURVIVAL: Survival duration will be measured from 
the date of study entry to the date of death from any cause 
 
10. DATA COLLECTION 
See appendix IV for Case Report Forms & patient questionnaires. 
 
11. STATISTICAL CONSIDERATIONS 
11.1. 
DATA ANALYSIS AND SAMPLE SIZE CALCULATION 
 
Response rates with 95% confidence intervals and one-sample Kaplan-Meier analysis 
will be performed to show 5 year disease free survival and overall survival for patients 
treated with CyberKnife® SBRT monotherapy and patients treated with whole pelvis 
IMRT and ADT per current standards of care, followed by CyberKnife® SBRT boost. 
 

Page 21 of 35 
 
In treatment groups, toxicity, rates of local failure, distant failure, clinical disease-free 
survival, disease-specific survival, and overall survival; quality of life (QOL) in generic 
and organ-specific domains will be reported descriptively for the samples. In addition 
descriptive statistics will be provided comparing the CyberKnife® Stereotactic 
Radiosurgery System bDFS rate to published HDR monotherapy bDFS rates reported in 
the literature for each group. 
 
Investigators expect that overall, patients treated with CyberKnife® SBRT 
monotherapy will have a 5 year PSA DFS rate of 80% ± 0.15 (total width = .30) using a 
confidence level of 95%, a required sample size of 32 subjects is necessary. 
 
Investigators expect that overall, patients treated with whole pelvis IMRT and ADT per 
current standards of care, followed by CyberKnife® SBRT boost will have a 5 year PSA 
DFS rate of 70% ± 0.15 (total width = .30) using a confidence level of 95%, a required 
sample size of 40 subjects is necessary. 
 
It is expected that up to 150 subjects will be enrolled at this site. 
 
12  RISK TO BENEFIT RATIO 
 
12.1The determination of entry into the clinical evaluation will be made independent 
of the decision to treat with stereotactic radiosurgery. The radiation oncologist 
and/or medical team performing the procedure will discuss the potential risks 
associated with stereotactic radiosurgery and the potential benefits of control of 
disease progression, despite the limited clinical experience. 
 
12.1 Risks: 
12.1.1. Risk classifications assigned below are based on currently available 
literature on treating prostate cancer with radiation therapy in a manner 
comparable to the radiosurgery planned for this protocol. The protocol for 
this clinical evaluation was designed to assure that the benefits and 
knowledge collected for stereotactic radiosurgery of malignant prostate 
tumors outweigh the potential risks to the subjects. 
 
12.1.2. Risks to patients in this study include all those risks currently associated 
with fiducial placement as well as the risks of localizing and delivering 
radiation to the prostate environment.  The safety of the CyberKnife® 
system in treating intracranial tumors has been well documented.  Risks of 
the procedure for this clinical study along with the methods to minimize the 
risk are described below. The radiation risks presented are categorized 
according to version 2.0 of the National Cancer Institute’s Common Toxicity 
Criteria. Likely effects are listed as those side effects which occur in more 
than 20% of patients. Less likely effects occur in 20% or less of patients 
treated.  Rare but serious effects occur in less than 3% of patients. 
 
12.1Risks Associated with External Radiation Therapy: 
12.1.3. All patients treated under this protocol will be provided with specific 
instructions and contact information, in the event any patient develops side 

Page 22 of 35 
 
effects. Many of these side effects go away shortly after radiation therapy is 
stopped, but in some cases side effects can be long-lasting or permanent. 
The following includes risks associated with external beam radiation therapy 
to the prostate and surrounding pelvis. 
 
Temporary fatigue (Likely): self-limited side effect. 
 
Temporary frequent or loose stools (likely): see notes 1 & 3. Diet changes or 
Imodium will be prescribed if necessary. 
 
Temporary urinary frequency, irritation, or reduced stream (Likely): see notes 
1,2,3. Alpha blocker, antispasmodic, anti-inflammatory or other appropriate 
symptomatic medicines will be prescribed if necessary. 
 
Temporary redness, tanning, or hair loss of skin in the treatment area (less 
likely): see note 1. Topical preparations will be prescribed, if necessary. 
 
Permanent urinary “bother”, e.g. need to urinate urgently or frequently (less 
likely): see notes 1,2,3. Chronic alpha blocker or other medical therapy may be 
required. 
 
Permanent bowel “bother”, e.g. need to move bowels urgently or frequently (less 
likely): see notes 1,2,3. Addition of “bulk” (e.g. Metamucil) to diet, or Imodium, 
may be required. 
 
Rectal bleeding (rare, but serious): see notes 1,2,3. Hydrocortisone suppositories 
or enemas may be required; blood transfusions, photocoagulation, topical 
chemical coagulation, hyperbaric oxygen treatments. In extremely rare cases, 
colostomy may be necessary. 
 
Urinary obstruction which could require catheter placement (Rare): see notes 
2,3. Foley catheter, intermittent straight catheterization, or suprapubic catheter 
may be required. 
 
Urethral scarring, which could impair urine stream, and could require surgery to 
repair (Rare, but serious): see notes 2,3. Cystoscopy, trans-urethra incision, 
and/or dilation may be required. 
 
Leakage of small amounts of urine, which could require wearing pads in 
underwear (less likely): see notes 2,3. 
 
Permanent inability to control urine, which could require a catheter, penile 
clamp, or surgery to repair (rare, but serious): see notes 2,3. 
 
Urinary bleeding (rare, but serious): see notes 1,2,3: cystoscopy or 
electrocoagulation may be required. In extremely rare cases major surgery such as 
urinary diversion could be required. 
 

Page 23 of 35 
 
Prostate, bladder, urethra, or rectal pain (rare): see notes 1,2,3. May require 
treatment with antibiotics, surgery (either open or cystoscopic), analgesics, or 
other medications placed in the bladder, urethra, or rectum. 
 
Impotence (Less likely, but serious): see notes 1,2. May require treatment will 
medications (e.g. Viagra, Muse, etc…), other erectile aids (e.g. penile pump), or 
surgery (implantable penile prosthesis). 
 
Reduction in ejaculate volume (likely), which could reduce fertility: This 
condition is highly likely following treatment since the target includes structures 
which contribute to semen. 
 
Pain with ejaculation, or change in the sensation of orgasm (less likely): see note 
2,3. May require analgesics. 
 
Rectal or urethral ulceration, or fistula, which could result in colostomy and/or 
ileostomy (rare, but serious): see notes 1,2,3. Could also require antibiotics, 
suprapubic or Foley catheter, liquid diet, hypobaric oxygen treatments, 
medications or other surgeries. 
 
Reproductive Risks:  No fertility issues pertinent to this patient population 
 
Note 1: because the CyberKnife® treats the prostate with over 100 beams coming 
from many directions, radiation dose is concentrated on the prostate. Compared 
with other external beam radiation devices, less radiation dose is given to the 
surrounding normal tissues, such as the rectum and bladder. In addition, 
throughout treatment, CyberKnife® frequently images the prostate and corrects 
for movement of the patient or the prostate. This allows physicians to treat a 
smaller region around the prostate compared to other commonly used externally 
generated radiation methods. This minimizes radiation exposure to surrounding 
normal structures. The design characteristics of the CyberKnife® thus 
intrinsically minimize the risk for side effects or adverse effects. 
 
Note 2: the radiation tolerance of the normal tissues surrounding the target has 
been carefully considered, and likely acceptable tolerances have been calculated. 
These normal tissue constraints are listed in section 8.3.2. DVH analyses will be 
performed as specified, to insure adherence to these constraints, thus minimizing 
risk. 
 
Note 3: the large dose per fraction delivered with CyberKnife® takes advantage 
of the low α/β ratio of prostate cancer relative to the surrounding normal 
structures. The hypofractionation scheme this reduces the risk of side effects or 
adverse effects. 
 
12.2. 
Risks Associated with Fiducial Placement: 
Infection (rare): In the event that a patient experiences infection as a result of 
fiducial placement, antibiotic treatment will be prescribed. 
 

Page 24 of 35 
 
12.2 Minimization of Risk: 
Stringent inclusion/exclusion criteria have been incorporated into this protocol to 
assure that any subject who may be at increased risk from an adverse event is not 
enrolled into this clinical study. Subjects will be observed post procedure to 
assure that any acute adverse effects are detected in a timely manner so that 
proper medical treatment can be initiated. Subjects also will be provided with 
instructions as to whom to contact along with contact telephone numbers, in the 
event they experience any complications. 
 
12.3 Potential Benefits: 
Although previously confined to intracranial treatment, SRS is gaining 
recognition in the medical community as an alternative to external beam radiation 
therapy in other parts of the body. Use of the CyberKnife® system may provide 
the following benefits: 
 
• Minimally invasive procedure performed on an outpatient basis 
• Lengthen interval to tumor progression 
• Improved survival 
• Decreased genitourinary, rectal and gastrointestinal toxicities 
compared with conventional radiation therapy and radical 
prostatectomy 
• Decreased toxicities to sexual function compared to other types of 
radiation therapy and radical prostatectomy 
 
12.4 Early Termination: 
Subjects may withdraw or be discontinued by the investigator from the clinical 
evaluation at any time; however, they may be requested to continue with their 
follow-up PSA tests and exams five years following their last SRS treatment. 
 
12. COSTS AND PAYMENTS 
12.1. 
Research Study Costs: 
Screening and clinical assessment of the patient prior to the procedure will be no 
different than what typically occurs prior to conventional radiation therapy. 
Therefore, a patient’s insurance will be billed for all tests and imaging associated 
with this evaluation. The cost of the procedure itself will be billed to the patient’s 
insurance company under an appropriate code. This will include all operative, 
facility-based and hospital-based charges. Follow-up assessment also is no 
different than what typically occurs following a conventional radiotherapy and 
treatment for this population of patients.  Therefore, the patient’s insurance will 
be billed for all tests and imaging associated with the follow-up visits. 
 
13. Research Study Payments: 
There will be no financial reimbursement to the patient for participation in this 
evaluation. 

Page 25 of 35 
 
14. APPENDICES 
Appendix I: Sample Patient Consent Form 
 
Appendix II:  Performance Status Scales 
ECOG PERFORMANCE SCALE 
0 Fully active, able to carry on all predisease activities without restriction (Karnofsky 90-100). 
1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature. For example, light housework, office work (Karnofsky 70-80). 
2 Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more 
than 50% of waking hours (Karnofsky 50-60). 
3 Capable of only limited self-care, confined to bed or chair 50% or more of waking hours (Karnofsky 30- 
40). 
4 Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair (Karnofsky 10-20). 
 
Appendix III: AJCC STAGING SYSTEM, 7TH EDITION, PROSTATE 
Primary Tumor, Clinical (T) 
TX Primary tumor cannot be assessed 
T0 No evidence of primary tumor 
T1 Clinically inapparent tumor not palpable or visible by imaging 
T1a Tumor incidental histologic finding in 5% or less of tissue resected 
T1b Tumor incidental histologic finding in more than 5% of tissue resected 
T1c Tumor identified by needle biopsy (e.g., because of elevated PSA) 
T2 Tumor confined with prostate* 
T2a Tumor involves less than ½ of one lobe 
T2b Tumors involves greater than ½ of one lobe but < 2 lobes 
T2c Tumor involves both lobes 
T3 Tumor extends through prostate capsule** 
T3a Extracapsular extension (unilateral or bilateral) 
T3b Tumor involves the seminal vesicle(s) 
T4 Tumor is fixed or invades adjacent structures other than the seminal vesicles: bladder neck, external 
sphincter, rectum, levator muscles and/ or pelvic  wall 
*Note: Tumor found in one or both lobes by needle biopsy, but not palpable or reliably visible by imaging, 
is classified as T1c 
**Note: Invasion into the prostatic apex or into (but not beyond) the prostatic capsule is not classified as 
T3, but as T2. 
 
Regional Lymph Nodes (N) 
Clinical 
NX Regional lymph nodes cannot be assessed 
N0 No regional lymph node metastasis 
N1 Metastasis in regional lymph node or nodes 
Pathologic 
pNX Regional nodes not sampled 
pN0 No positive regional nodes 
pN1 Metastases in regional node(s) 
Distant Metastasis (M)* 
MX Presence of distant metastasis cannot be assessed (not evaluated by any modality) 
M0 No distant metastasis 
M1 Distant metastasis 
M1a Nonregional lymph node(s) 
M1b Bone(s) 
M1c Other site(s) with or without bone disease 
*Note: When more than one site of metastasis is present, the most advanced category is used; pM1c is most 
advanced. 

Page 26 of 35 
 
Appendix IV:   Data Collection Documents 
 
Appendix V:  NCI Common toxicity criteria/RTOG/EORTC: 
Refer to: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf 
 
 
Appendix VI: AUA, EPIC, SHIM Questionnaires 

Page 27 of 35 
 
American Urological Association (AUA) symptom index: was developed to help men 
determine how bothersome their urinary symptoms are and to check the effectiveness of 
treatment.vi This questionnaire has also been adopted worldwide and is known as the 
International Prostate Symptom Score (IPSS). It is sometimes seen with a Quality of Life 
Scale at the end of the questionnaire. 
 
Name:  
 
Today’s date:  
_ 
 
(Circle one number on each line) 
Almost 
never 
Less 
than 
1 time 
in 5 
Less 
than 
half the 
time 
About 
half the 
time 
More 
than 
half 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 
Over the past month or so, how often 
have you had to urinate again less than 
two hours after you finished urinating? 
0 
1 
2 
3 
4 
5 
Over 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 
Over the past month or so, how often 
have you found it difficult to postpone 
urination? 
0 
1 
2 
3 
4 
5 
Over the past month or so, how often 
have you had a weak urinary stream? 
0 
1 
2 
3 
4 
5 
Over the past month or so, how often 
have you had to push or strain to begin 
urination? 
0 
1 
2 
3 
4 
5 
None 
1 time 
2 times 
3 times 
4 times 
5 or 
more 
time
s
Over the past month, how many times 
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 
1 
2 
3 
4 
5 

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Page 29 of 35 
 
 

Page 30 of 35 
 
 

Page 31 of 35 
 
 
 

Page 32 of 35 
 
SEXUAL HEALTH INVENTORY FOR MEN (SHIM) 
PATIENT NAME:_ 
TODAY’S DATE:  
 
PATIENT INSTRUCTIONS 
Sexual health is an important part of an individual's overall physical and emotional well-being. 
Erectile dysfunction, also known as impotence, is one type of very common medical condition 
affecting sexual health. Fortunately, there are many different treatment options for erectile 
dysfunction. This questionnaire is designed to help you and your doctor identify if you may be 
experiencing erectile dysfunction. If you are, you may choose to discuss treatment options with 
your doctor. 
Each question has several possible responses. Circle the number of the response that best 
describes your own situation. Please be sure that you select one and only one response for each 
question. 
 
OVER THE PAST 6 MONTHS: 
 
1. How do you rate 
your confidence 
that you could get 
and keep an 
erection? 
VERY LOW 
LOW 
MODERATE 
HIGH 
VERY HIGH 
1 
2 
3 
4 
5 
2. When you had 
erections with 
sexual stimulation, 
how often were 
your erections hard 
enough for 
penetration 
(entering your 
partner)? 
NO SEXUAL 
ACTIVITY 
ALMOST 
NEVER OR 
NEVER 
A FEW TIMES 
(MUCH LESS 
THAN HALF 
THE TIME) 
SOMETIMES 
(ABOUT HALF 
THE TIME) 
MOST TIMES 
(MUCH MORE 
THAN, HALF 
THE TIME) 
ALMOST 
ALWAYS OR 
ALWAYS 
0 
1 
2 
3 
4 
5 
3. During sexual 
intercourse, how 
often were you able 
to maintain your 
erection after you 
had penetrated 
(entered) your 
partner? 
DID NOT 
ATTEMPT 
INTERCOURSE 
ALMOST 
NEVER OR 
NEVER 
A FEW TIMES 
(MUCH LESS 
THAN HALF 
THE TIME) 
SOMETIMES 
(ABOUT HALF 
THE TIME) 
MOST TIMES 
(MUCH MORE 
THAN, HALF 
THE TIME) 
ALMOST 
ALWAYS OR 
ALWAYS 
0 
1 
2 
3 
4 
5 
4. During sexual 
intercourse, how 
difficult was it to 
maintain your 
erection to 
completion of 
intercourse? 
DID NOT 
ATTEMPT 
INTERCOURSE 
EXTREMELY 
DIFFICULT 
VERY 
DIFFICULT 
DIFFICULT 
SLIGHTLY 
DIFFICULT 
NOT 
DIFFICULT 
0 
1 
2 
3 
4 
5 
5. When you 
attempted sexual 
intercourse, how 
often was it 
satisfactory for 
you? 
DID NOT 
ATTEMPT 
INTERCOURSE 
ALMOST 
NEVER OR 
NEVER 
A FEW TIMES 
(MUCH LESS 
THAN HALF 
THE TIME) 
SOMETIMES 
(ABOUT HALF 
THE TIME) 
MOST TIMES 
(MUCH MORE 
THAN, HALF 
THE TIME) 
ALMOST 
ALWAYS OR 
ALWAYS 
0 
1 
2 
3 
4 
5 
 
Add the numbers corresponding to questions 1-5. 
TOTAL: 
 

Page 33 of 35 
 
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23. 
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