CyberKnife Dose Escalation for Unfavorable and High-risk Prostate Cancer
Phase: NA
Conditions: Prostate Cancer, Prostate Adenocarcinoma, Prostate Neoplasm
Sponsor: Crozer-Keystone Health System

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CLINICAL STUDY PROTOCOL 
 
Protocol Title: CyberKnife Dose Escalation Prostate Cancer Trial (CK-DESPOT) 
 
Hypothesis: Dose Escalated Stereotactic Body Radiation Therapy (DE-SBRT) is adequate 
for biochemical control of Unfavorable Intermediate and High Risk Prostate Cancer. 
 
 
Principal Investigator: Rachelle Lanciano, MD 
Sub-Investigator: John Lamond, MD 
Sub-Investigator: Anthony Ricco, MD  
Nurse: Dawn Stevenson, RN, BSN 
Research Nurse: Lorie Matson, RN, BS, CCRP 
 
 
Study Version 2.0: September 28, 2021 
Study Version 3.0:  June 4, 2022 

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INDEX 
 
1.0 
Introduction 
 
Schema 
 
Patient Eligibility 
Eligibility Checklist 
Other Patient Data 
2.0 
Objectives 
 
3.0 
Pre-treatment Evaluation 
 
4.0 
Radiation Therapy 
 
5.0 
Androgen Therapy 
 
6.0 
Patient Assessments 
 
7.0 
Clinical Endpoints 
 
8.0 
Statistical Considerations 
 
9.0 
References 
 
 
 
Appendix I 
- 
NCI Common Toxicity Criteria 
Appendix II 
- 
The Expanded Prostate Cancer Index Composite (EPIC) 
Appendix II 
I 
- 
EuroQol EQ-5D 

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1.0 
INTRODUCTION 
 
External Beam Radiation Therapy in the Management of Clinically Localized Prostate 
Cancer: Rationale for Dose Escalation 
 
Local tumor control with radiation is dose-dependent, following a sigmoid dose-response 
relationship. Results of early clinical applications of conventional external-beam radiation 
treatment (60–70 Gy in 2-Gy fractions) yielded 10-year disease-free survivals ranging from 
40%–70% prompting investigations of dose escalation (1-6). The randomized dose escalation 
trial performed at the M. D. Anderson Cancer Center compared 70 Gy to 78 Gy (7). As 
expected, the 78-Gy arm resulted in improved local control, but, at the price of increased rectal 
complications. Similar results have been obtained in other reported randomized trials (8-9). The 
risk of rectal bleeding appears to be dependent on both the radiation dose and the volume of the 
rectum subjected to high doses (10-12). 
 
It has become clear that increases in the total dose delivered to the prostate enhance local tumor 
control, offering a therapeutic benefit, as long as normal tissue tolerances are respected. 
Intensity modulated radiation therapy (IMRT) is considered a dosimetric improvement over 
3DCRT. Dosimetric comparisons of conventional treatment plans with IMRT plans have 
revealed that IMRT is capable of sparing adjacent normal tissues (13, 14). Use of IMRT for 
prostate cancer treatment allows for high levels of clinical and biochemical local control with 
lower complication rates as compared to conventional external-beam techniques (14, 15). 
 
Rational for Hypofractionation 
 
The optimal radiation schedule for the curative treatment of prostate cancer remains unknown. 
Prostate cancer patients receiving IMRT are typically treated 5 days per week for 8-9 weeks. 
This prolonged treatment time is inconvenient for many patients and increases treatment costs. 
Recent data suggest that large radiation fraction sizes are radio-biologically favorable over lower 
fraction sizes in prostate cancer radiotherapy (16). The sensitivity of a tumor or normal tissue to 
fraction size of radiation can be approximated by the alpha-beta ratio (α/β). Recently, Brenner 
and Hall (17) suggested that the α/β for prostate cancer is actually as low as 1.5. These results 
imply that the current radiation therapy paradigm for prostate cancer treatment might be 
fundamentally flawed, as high fraction sizes would be expected to damage tumor more readily. 
These findings are of considerable interest for prostate cancer treatment and could be exploited 
with high fraction-size radiation therapy. 
 
Stereotactic Body Radiation Therapy In the Management of Prostate Cancer 
 
The term stereotactic refers to precise positioning which safely allows higher radiation doses per 
fraction and fewer fractions (hypofractionation) than conventional RT. Multiple single 
institution experiences suggest high biochemical control rates with acceptable toxicity (18-24). 

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These series suggest that clinically significant late Grade 3 toxicities are infrequent and lower or 
similar to rates observed in series of IMRT patients. Early quality of life data indicate that 
treatment is well tolerated with acceptable declines in patient reported urinary, bowel and sexual 
function (25). Recent updates have confirmed a 5-10 year biochemical disease-free survival in 
excess of 90% and local control greater than 98% (26-28). The use of SBRT has accelerated in 
the last few years largely due to early efficacy and safety data and high degree of penetration of 
IMRT techniques in the radiation oncology community. As such, the learning curve associated 
with SBRT compared to IMRT is not as steep. A survey of 500 radiation oncologists in 2010 
found that approximately 64% had reported using SBRT in their practice for some type of cancer 
(29). Second, the number of SBRT-capable radiation platforms has expanded significantly since 
the introduction of CyberKnife SBRT in 1999. Additionally, cost is also significantly less for 
SBRT compared to IMRT or proton therapy and this has become increasingly important with 
scarce healthcare dollars (30). 
 
Clinical Experience with Hypofractionation for Unfavorable Clinically Localized Prostate 
Cancer 
 
Large radiation fraction sizes have been clinically utilized in the treatment of unfavorable 
prostate cancer for many years. HDR brachytherapy as a boost to external-beam radiotherapy 
(EBRT) has shown promise in this regard (31-36). Initial trials combined external beam 
radiation therapy (36-50.4 Gy) with high dose rate (HDR) brachytherapy (2-4 fractions of 3-11.5 
Gy). HDR brachytherapy was employed to escalate the dose to gross disease within the prostate 
and seminal vesicles. HDR brachytherapy allows greater flexibility in dose delivery which 
provides for intraprostatic dose escalation and optimization of periprostatic doses. Supplemental 
EBRT was designed to treat the prostate and seminal vesicles with a margin to encompass 
adjacent microscopic disease. Draw backs relate to associated hospitalization with the patient 
confined to bed and remaining supine for 24–48 hours to accommodate treatment. Even so, 
catheter migration between treatments is common and must be corrected (36-38). 
 
Similarly, recent long term data from the ASCEND-RT trial utilizing LDR brachytherapy boost 
in similar fashion showed a dramatic 21% improvement in biochemical control at 9 years 
favoring LDR brachytherapy boost compared to conventional dose escalated EBRT although no 
corresponding benefit was identified in overall survival, incidence of bone metastases or prostate 
cancer specific mortality (39). Unfortunately, the incidence of late grade 3 or higher urinary 
toxicity was increased 3-fold (18 vs 6%) in the LDR brachytherapy arm compared to the EBRT 
arm. Given the associated toxicity and resources with brachytherapy boosts, recent research has 
focused on utilizing prostate SBRT to deliver escalated doses similar to HDR or LDR 
brachytherapy since SBRT is well tolerated and non-invasive (42-43). 
 
Radiation Dose Selection 
 
In this protocol, CK-SBRT will be used to target the microscopic and gross disease in the 
prostate, seminal vesicles. An escalated dose of 40Gy in 5 fractions will be delivered to the entire 
target volume while any nodules visible within the prostate gland on endorectal MRI will receive 
50Gy in 5 fractions. The linear quadratic formula was used to calculate equivalent doses and 
three assumptions were made: 1) Sublethal damage is completely repaired between fractions, 2) 

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No repair of sublethal damage occurs during a given fraction, and 3) No repopulation occurs 
during the treatment course (i.e., there is no time factor). Data analysis from grouped prostate 
hypofractionation trials (1) suggests that an EQD2 of > 80 Gy may be required to achieve long 
term biochemical disease free survival in the 96-98% range. In this protocol, this dose will be 
achieved by five SBRT treatments (Minimum EQD2 108.6 Gy calculated 3 mm from the prostate 
border). The feasibility and safety of DE-SBRT for treating localized prostate cancer has been 
shown in two recently completed prospective trials (44). These studies confirm that DE-SBRT is 
technically feasible and reproducible with acceptable toxicity similar to or lower than patients 
receiving DE-IMRT. 
 
Evaluating Quality of Life After the Treatment of Prostate Cancer. 
 
The treatment alternatives for clinically localized prostate cancer provide similar local control 
and survival (46). Quality of life (QOL) outcomes are thus an important factor in selecting 
treatment (47). Several studies have demonstrated that radiation treatment for prostate cancer can 
adversely affect urinary, bowel and sexual function (25, 26). The severity and duration of these 
toxicities varies among patients. The expanded prostate cancer index composite (EPIC) has been 
developed as a disease specific, patient-administered instrument to measure quality of life in men 
with prostate cancer (48). Thus, acceptance of a novel regimen for treatment of unfavorable-risk 
prostate cancer patients must not only be effective and have minimal impact on short- and long- 
term quality of life, but it must also be cost effective (30,49). Quality-Adjusted Life Years 
(QALYs) are well-established for measurement of cost-effectiveness for many different types of 
diseases, and can be calculated through use of clinical quality of life measurements, such as the 
EuroQol EQ-5D (50). These tools will be utilized for longitudinal QOL assessments for the 
duration this study. 
 
The Philadelphia CyberKnife Experience 
 
The Philadelphia CyberKnife center is a highly specialized radiation oncology facility within the 
Crozer Keystone Health System with a sole focus on stereotactic radiation therapy services and 
delivery. As one of the early adopters and pioneers of SBRT techniques, our expertise and 
experience is on par with nationally renowned academic centers and our physicians serve on 
national committees and lead multi-institution prospective trials. Our published experience with 
CyberKnife prostate SBRT has shown favorable biochemical control compared to IMRT cohorts 
with low toxicity rates (51, 52). We have also compared prostate SBRT to IMRT using a large 
national database showing no detriment to SRBT compared to IMRT (53, 54). We will leverage 
our experience, expertise and national standing to conduct this pivotal prospective study. 
 
Updated Clinical Experience for SBRT 
 
Since initiation of the current trial two important randomized studies have been published which 
support the current trial structure and importance.  Focal boost to the intraprostatic MRI 
documented tumor has been studied in a recently completed randomized Phase III trial for 
external beam radiotherapy with standard IMRT 77Gy/35 fractions (2.2Gy per fraction) vs same 
dose to the prostate with integrated focal boost up to 95Gy (2.7Gy per fraction).  The recently 
completed trial published January 2021coined the FLAME trial revealed an improvement of 
biochemical disease free survival for patients with intermediate and high risk prostate cancer 

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with integrated boost without impacting toxicity and quality of life. (56)  More importantly, a 
phase III trial (HYPO-RT-PC) of 1200 men with intermediate to high risk prostate cancer found 
ultra-hypofractionation 42.7Gy/7fx to be non-inferior to conventional fractionation 78Gy/39fx 
with late toxicity similar in both treatment arms. (57)  The National Comprehensive Cancer 
Network (NCCN) version 4.2022 defines SBRT as an acceptable standard radiation treatment 
option for unfavorable, high and very high risk prostate cancer using 5 fractions with dose of 
36.25-40Gy, www.nccn.org.  Therefore, the experimental aspect of this research is the 
additional boost to MRI defined nodule with dose painting. 
 
Defining Unfavorable Risk Prostate Carcinoma 
 
For this study, 3 sub-classifications of unfavorable risk prostate carcinoma will be defined. 
 
1. Unfavorable Intermediate Risk Carcinoma: Any patients with intermediate risk prostate 
cancer not meeting favorable risk classification. 
a. Gleason score 4+3=7 
b. Gleason score 3+4=7 with more than 50% of cores positive 
c. Gleason Score 3+4=7 and PSA 10-20 ng/ml 
d. Gleason Score 3+4=7 and >T2a 
 
2. High Risk Prostate Cancer: 
a. T3a (ECE only) or 
b. Gleason score 8 or 
c. PSA >20 ng/ml 
 
3. Very High Risk Prostate Cancer: 
a. T3b or 
b. Gleason Score 9-10 or 
c. PSA >20 ng/ml 
 
STUDY SCHEMA 
 
1. 
Registration 
 
2. 
Endorectal/Multi parametric MRI and Staging Studies 
 
3. 
Ultrasound with fiducial and SPACE OAR placement 
 
4. 
Planning CT and MRI 
 
5. 
SBRT treatment to the prostate and proximal seminal vesicles (4000 cGy in 5 treatments) 
 
 
 
 
 

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PATIENT ELIGIBILITY 
 
Histologically confirmed adenocarcinoma of the prostate diagnosed within 360 days of 
enrollment. 
 
PSA documented within 90 days prior to registration. 
Clinical staging completed within 90 days of registration. 
No Nodal or Distant Metastases documented on CT or MRI of the pelvis and bone scan (PSMA  
PET/CT may be substituted for bone scan). 
 Unfavorable Risk Prostate Carcinoma as Described is documented. 
No prior pelvic radiotherapy. 
No prior TURP. 
Prostate volume < 100 cc 
AUA score < 20 
 
No recent (within 5 years) or concurrent cancers other than non-melanoma skin cancers. 
 
Patient must have no medical or psychiatric illnesses that would interfere with treatment or 
follow-up. 
 
No implanted hardware adjacent to the prostate that would prohibit appropriate treatment 
planning and treatment delivery is allowed. 
 
Patient must speak and comprehend the English language to complete questionnaires. 
 
Patient’s with very high risk prostate cancer must be seen in consultation by medical oncology as per NCCN 
guidelines version 4.2022 for consideration for abiraterone or docetaxel following radiation.  
 
 
 
 
 
 
 
 
 
 
 
 
 

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ELIGIBILITY CHECKLIST 
 
 
  
(Y) 
1. Is there histologically confirmed adenocarcinoma of the prostate within 
360 days of enrollment? 
 
2. What is the Gleason score? 
 
 
3. What is the T stage? 
 
 
(N0 or Nx) 
4. What is the N stage? 
 
 
(M0 or Mx) 
5. What is the M stage? 
 
 
(ng/ml) 
6. What is the PSA (< 90 days prior to registration)? 
 
 
(N) 
7. Has the patient had prior pelvic radiation? 
 
 
(N) 
8. Has the patient had a TURP? 
 
 
(< 100 cc) 
9. Is the prostate volume < 100 cc? 
 
 
(N) 
10. Has the patient had previous (within the last 5 years) or concurrent 
cancer other than basal cell or squamous cell skin cancer? 
 
(N) 
11. Are there any major medical or psychiatric illnesses which would 
prevent the completion of treatment or interfere with follow-up? 
 
(Y) 
12. Has the patient signed a study-specific consent form? 
 
 
(AUA < 20) 
13. Is the patient’s AUA score < 20? 
 
 
_______(N) 
14. Does the patient have implanted hardware adjacent to the prostate  
that would prohibit appropriate treatment planning and treatment delivery?

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2.0 
OBJECTIVES 
 
This is a phase II study designed to prospectively evaluate the efficacy and safety of DE 
CK-SBRT for unfavorable risk prostate cancer in a community setting. 
 
Hypothesis 
 
1. Dose Escalated Stereotactic Body Radiation Therapy is adequate for biochemical control of 
Unfavorable Intermediate and High Risk Prostate Cancer. 
 
Primary Objective 
 
1. To assess efficacy endpoints: Biochemical disease-free survival (bDFS) assessed using 
the Phoenix definition (55), duration of local control, distant failure and site of distant 
failure, disease-free survival, disease-specific survival and overall survival. 
 
Secondary Objectives 
 
1. To estimate the proportion of patients who develop late (> six months) grade 3-5 
gastrointestinal and genitourinary toxicity observed following SBRT for prostate cancer. 
 
2. To evaluate Quality of life (QOL) using standardized instruments. 

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3.0 
PRETREATMENT EVALUATION 
 
Evaluations Required for Eligibility: 
1. 
Complete history & physical examination 
 
2. 
Assessment of performance status 
 
3. 
Serum PSA (<90 days prior to registration) 
 
4. 
Pathologic confirmation of adenocarcinoma of the prostate 
 
5. 
Bone scan (PSMA PET can be substituted for bone scan) 
 
6. 
Ultrasound of prostate, MRI or CT of pelvis 
7. 
Endorectal/Multi parametric MRI 
 
8. 
Patient questionnaires (see appendix VI). 
1 
Expanded Prostate Cancer Index Composite (EPIC)-26 questionnaire 
EuroQol EQ-5D-5L

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4.0 
RADIATION THERAPY 
 
DE-SBRT will be delivered using the CyberKnife robotic radiosurgery system. Patients 
will be treated with five SBRT treatments (8 Gy per fraction to the PTV, and 9-10 Gy per fraction 
to any nodules identified on endorectal MRI) over 7-10 days. 
 
1 
MARKER/SPACE OAR PLACEMENT 
 
All patients will have fiducial markers placed in the prostate prior to treatment planning. 
At least three fiducial markers or electromagnetic transponders will be placed under transrectal 
ultrasound guidance, using either transperineal or transrectal approach, with local anesthesia 
and/or sedation as required. At least three markers must be usable for tracking during treatment. 
Space OAR hydrogel is a spacer providing space between the rectum and the prostate, making it 
much less likely that the rectum is exposed to high dose radiation must be utilized in all patients 
undergoing treatment. 
 
2 
TREATMENT PLANNING IMAGING AND CONTOURING STRUCTURES 
 
To allow marker stabilization and resolution of swelling, planning studies will be imaged 
> 7 days after placement. Immobilization devices will be used as needed. CT scans will be taken 
for treatment planning. Planning MRI images will be obtained simultaneously with CT images 
and are utilized for treatment planning. 
 
The structures listed below will be contoured on the CT scan and evaluated with DVH 
analysis. Bowel peristalsis and bladder filling change the size and location of normal structures. 
For treatment plans utilizing MRI, if the CT and MRI show normal tissues in different locations 
immediately adjacent the prostate, the contoured structure shall be a larger composite of both 
image sets. 
 
1. Rectum: For this study, the rectum is defined as the solid structure, including the lumen 
and rectal wall, extending from the level of the ischial tuberosity to the sigmoid flexure. 
 
2. Bladder: For this study, the bladder is defined as a solid structure including the bladder 
wall and lumen. 
 
3. Femoral heads: For this study, the femoral heads are defined as the femoral head and neck. 
 
4. Sigmoid colon or other bowel: Bowel lying within 2 cm of the PTV should be contoured. 
For non-isocentric treatment plans, distal hot spots need to be avoided. 
 
5. Prostatic urethra: For this study, the prostatic urethra is defined as the lumen-mucosal 
interface, extending from bladder neck to the membranous urethra. 

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6. Membranous urethra: For this study, the membranous urethra is defined as the lumen- 
mucosal interface, extending from the prostatic apex to the penile bulb. 
 
7. Penile Bulb: For this study, the penile bulb is defined as the portion of the bulbous 
spongiosum that lies inferior to the urogenital diaphragm. 
 
8. Bladder Neck: For this study, the bladder neck is defined as the most proximal portion of 
the bladder extending from the prostate base and urethral junction. 
 
 
3 
SBRT: 
 
SBRT delivery: 
 
The protocol requires image guidance via radio-opaque fiducial markers or 
electromagnetic transponders implanted in the prostate. At least three fiducial markers must be 
identified for each treatment. If fewer than three can be tracked, then additional fiducial markers 
will be placed, and the patient re-planned. Live fiducial tracking is required. No rectal balloons 
are allowed. 
 
Dose specifications: 
 
Patients will receive five SBRT treatments of 8 Gy each. The total dose will be 40 Gy. The five 
treatments will be completed in 7-10. A minimum of 20 hours should elapse between 
treatments. The total duration of treatments should take no longer than 10 days. 
 
Target Volumes: 
 
Gross Tumor Volume (GTV): The GTV shall include the prostate and any gross extension. 2cm 
of the SV will be contoured separately. Malignant Nodules identified on MRI will be contoured 
separately. 
 
Planning Tumor Volume (PTV): The prescription dose (8 Gy) shall be delivered to the PTV. The 
PTV shall equal the CTV expanded 3 mm in all other directions. Any malignant nodules 
identified on endorectal/Multi parametric MRI will be prescribed an integrated boost of 10Gy 
per fraction while respecting all dose constraints. (9 Gy per fraction will be considered an 
acceptable variation if dose constraints cannot be met.) The PTV-SV will receive 7.25 Gy per 
fraction. 
 
SBRT Dose Specifications: 
 
PTV: The prescription dose of 40 Gy shall be the dose to the PTV: Per protocol, the volume of 
the PTV receiving 40 Gy (V40 Gy) shall be at least 95%. The PTV-SV will be treated to 36.25 
Gy and the PTV-SV receiving 36.25 Gy shall be at least 95%. 

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Rectum: Per protocol, the volume of the rectum receiving 36 Gy (V36 Gy) shall be < 1cc. The 
rectal dose-volume histogram (DVH) constraints are < 50% rectal volume receiving 50% of the 
prescribed dose, < 20% receiving 80% of the dose, < 10% receiving 90% of the dose, and < 5% 
receiving 100% of the dose 
 
Bladder: Per protocol, the volume of the bladder receiving 40Gy (V40 Gy) shall be < 5 cc. 
Although not required, the bladder dose-volume histogram (DVH) goals are < 40% bladder 
volume receiving 50% of the prescribed dose, < 10% receiving 100% of the dose. 
 
Bladder Neck: Per protocol, the maximum dose (0.03 cc) to the bladder neck should be ≤ 40 Gy. 
 
Sigmoid colon and other bowel: Per protocol, the volume of the sigmoid colon and other bowel 
receiving 36 Gy (V36Gy) shall be < 1cc. 
 
Prostatic urethra: Per protocol, the maximum dose (0.03 cc) to the prostatic urethra should be < 
43 Gy. 
 
Membranous urethra: Per protocol, the maximum dose (0.03 cc) to the membranous urethra 
should be < 43 Gy. 
 
Penile bulb: Per protocol, the volume of the penile bulb receiving 35 Gy (V35Gy) shall be < 
50%. Minor variations: V35Gy ≥ 50%, but < 75%. Major variations: V35Gy > 50%. 
 
5.0 
ANDROGEN SUPPRESSION 
 
Androgen suppression (ADT) consists of LHRH agonist for a total of 6 months for 
unfavorable intermediate risk patients and 18 months for high and very high-risk patients. The 
choice of LHRH agonist is at the discretion of the treating physician.   ADT should proceed 
initiation of SBRT however there is no minimum interval of ADT prior to initiation of SBRT 
which is patient/physician defined but should not exceed 6 months. 
 
Risks of Androgen Suppression 
 
ADT has several reported adverse and serious adverse reactions that have been reported in 
patients with advance prostate cancer who received Orgovyx (ADT oral use tablets). The 
most common adverse reactions hot flush, musculoskeletal pain (including arthralgia, back 
pain, pain in extremity, musculoskeletal pain, myalgia, bone pain, neck pain, arthritis, 
musculoskeletal stiffness, non-cardiac chest pain, musculoskeletal chest pain, spinal pain, 
and musculoskeletal discomfort), fatigue, diarrhea, and constipation. 
 
Serious adverse reactions occurred in 12% of patients who received ADT. Serious adverse 
reactions in ≥ 0.5% of patients included myocardial infarction (0.8%), acute kidney injury 
(0.6%), arrhythmia (0.6%), hemorrhage (0.6%), and urinary tract infection (0.5%). Fatal 
adverse reactions occurred in 0.8% of patients receiving ADT including metastatic lung 
cancer (0.3%), myocardial infarction (0.3%), and acute kidney injury (0.2%). Fatal and non- 
fatal myocardial infarction and stroke were reported in 2.7% of patients receiving Orgovyx. 

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6.0 
PATIENT ASSESSMENTS 
 
Assessment 
Pre-entry 
Follow-up interval: months post therapy 
1 
3 
6 
12 
18 
24 
36-60 
History (SHIM, AUA) 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam (DRE) 
X 
X 
X 
X 
X 
X 
X 
ECOG Performance Scale 
X 
X 
X 
X 
X 
X 
X 
Prostate Biopsy 
X 
PSA 
X 
X 
X 
X 
X 
X 
X 
Prostate volume assessment 
X 
Bone scan 
X 
Pelvic imaging 
X 
Toxicity evaluation (AUA) 
X 
X 
X 
X 
X 
X 
X 
X 
EPIC-26 Questionnaire 
X 
X 
X 
X 
X 
EuroQol EQ-5D-5L 
X 
X 
X 
X 
X 
Assessment schedule: Quality of life measurements will take place per the table, then annually 
through 5 years post-treatment. 
 
7.0 
CLINICAL ENDPOINTS: 
 
Patients will have toxicity evaluation weekly during treatment. At 1 month following 
treatment, patients will be assessed for acute toxicity. At 6, 12, 18, and 24 month intervals (and 
every year thereafter, through year 5- 10, if investigators opt to continue past year 5), patients 
will be seen and evaluated, including a history, physical exam, performance status, PSA, toxicity 
evaluation. In addition, at 6 months, 12 months and annually thereafter, EPIC-26 will be 
administered. Examination and studies may be done at outside facility. Prostate biopsy, bone 
scan (PSMA PET/CT may be substituted for bone scan) and pelvic MRI will be performed at 
time of biochemical or clinical failure. 
 
Criteria for toxicity: 
 
Acute side effects (<=90 days of treatment start) and late side effects (> 90 days of 
treatment start) will be assessed using the NCI Common Toxicity Criteria version 4.0 (see 
appendix V). 
 
Criteria for disease control: 
 
1. Biochemical disease free survival (bDFS): 
a. Phoenix definition (55): 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 will be considered failure. 
 
2. Duration of local control: 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. Histologic criteria 
for local failure is a positive prostate biopsy more than 2 years after treatment. Patients 

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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. 
 
3. 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. 
 
4. Disease-free survival: for any measure of disease, including PE, PSA, bone scan, 
CT/MRI and biopsy, or death. 
 
5. Disease-specific survival: for any of the following: Death due to prostate cancer. 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. Death due to complications of treatment. 
 
6. Overall survival: for death from any cause. 
 
Quality of Life/Health Outcomes instruments (See Appendix VI): 
 
1. Disease-specific quality of life: The 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, survey researchers, and prostate cancer 
nurses, to address symptoms related to radical prostatectomy, radiotherapy, and hormonal 
symptoms. 
 
Quality-Adjusted Life Years (QALY): EuroQol EQ-5D-5L is a validated instrument which 
provides a single index value for a patient’s overall health status (otherwise known as “utility”). 
It is widely used in cancer clinical trials (56, 57). Five of the items are scored on a 3-point Likert 
scale (mobility, ability for self-care, ability to perform usual activities, pain/discomfort, anxiety 
depression), and one item assesses a patient’s overall health state on a visual analog scale 
ranging from 0 (worse imaginable state) to 100 (best imaginable). 
 
 
8. STATISTICAL CONSIDERATIONS: 
Endpoints: 
Primary Endpoint 
 
1. Toxicity will be assessed using the NCI Common Toxicity Criteria version 4.0. 

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Secondary Endpoints 
 
1. Biochemical disease-free survival (bDFS) will be defined as the time in months from 
completion of SBRT to biochemical failure. Patients who are free from biochemical 
failure on the date of closing follow-up will be censored on that date. The Phoenix 
definition will be used to assess biochemical failure as described in Section 10. 
 
2. Duration of local control will be defined as the time in months from SBRT completion 
to local failure. 
 
3. Distant failure (includes regional failure) will be defined as the time in months from 
SBRT completion to distant failure. 
 
4. Disease-free survival will be defined as the time in months from the date that the patient 
is determined to be free of disease to the date of known disease recurrence for any 
measure of disease. Patients who are alive and free from disease recurrence on the date of 
closing follow-up will be censored on that date. 
 
5. Disease-specific survival will be defined as the time in months from completion of 
SBRT to death due to prostate cancer, other causes with active malignancy, or 
complications from treatment. Patients who are alive or dead with disease relapse but 
with inactive disease on the date of closing will be censored on that date. 
 
6. Overall survival will be defined as the time in months from SBRT completion until 
death. Patients who are alive on the date of closing will be censored on that date. 
 
7. Quality of life 
 
 
 
Study Design: 
 
The target sample size is 100 patients for this Phase II study. Allowing for a 15% 
ineligibility rate, the total sample size is 115 patients. Accrual is anticipated to be completed 
within 5 years of institutional IRB approval. This Phase II trial will provide information to guide 
future Phase III studies. Sample size determination is based on the late toxicity endpoint. A 
single-stage Fleming design will be used to test the null hypothesis that the late unacceptable 
radiation toxicity probability at 2 years p is < 0.05 versus the alternative hypothesis that toxicity 
probability at 2 years is > 0.15. Unacceptable toxicity will be defined as grade 3 or higher 
toxicity. If 10 or fewer patients experience late radiation toxicities at 2 years, the null hypothesis 
will not be rejected and then the regimen will be considered for a phase III study. If at least 10 
patients experience late radiation toxicities at 2 years, the null hypothesis will be rejected. This 
design has a power of 89% and a type I error rate of 0.10. 

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Analysis Plan 
 
1. Number and percentage of subjects for each toxicity will be summarized overall by body 
system and by onset time (acute: ≤90 days of treatment start and late: >90 days of 
treatment start). The tabulation will also be separated by toxicities of Grade 3 and above. 
Future studies incorporating DE-SBRT would be worthwhile if the rate of grade 3 
GU/GI toxicity was ≤ 10%. 
 
2. Biochemical disease-free survival, disease-free survival, disease-specific and overall 
survival curves will be calculated and presented by the methods of Kaplan and Meier. 
 
3. The proportion of patients with local and distant failure will be reported with a 95% 
binomial confidence interval. 
 
4. General health related and disease specific quality of life measurements will be 
summarized over time. Graphical displays will be created for each patient’s trajectory 
over time and also summarized using the average for all patients. 
 
 
 
 
 
 
 
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