A Phase I and II Study of Stereotactic Body Radiation Therapy (SBRT) for Low and Intermediate Risk Prostate Cancer (SBRT Prostate)
Phase: PHASE1
Conditions: Prostate Cancer
Sponsor: University of Texas Southwestern Medical Center

Official Title: Phase I and II Study of Stereotactic Body Radiation Therapy (SBRT)  
 for Low and Intermediate Risk Prostate Cancer 
NCT Number: 00547339 
Document Date: 11/20/2013  
Version: 15 

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Phase I and II Study of Stereotactic Body Radiation Therapy (SBRT) 
 for Low and Intermediate Risk Prostate Cancer 
 
 
Organizing Institution: 
University of Texas Southwestern Medical Center, Dallas, TX 
 
Principal Investigator (P.I.): Robert Timmerman, M.D. 
 
 
 
 
 
 
 
Department of Radiation Oncology 
 
Co-Investigators: 
David Pistenmaa, M.D., Ph.D. 
 
Department of Radiation Oncology 
 
Yair Lotan, M.D. 
 
Department of Urology 
 
Michael Story, Ph.D. 
Department of Radiation Oncology 
 
Xian-Jin Xie, Ph.D. 
Biostatistics 
 
Affiliated Institutions: 
 
University of Minnesota, Minneapolis, MN 
 
Principal Investigator (P.I.): 
L. Chinsoo Cho, M.D. 
 
 
 
 
 
 
 
Department of Radiation Oncology 
 
 
University of Colorado, Aurora, CO 
 
Principal Investigator (P.I.): 
Bryan Kavanagh, M.D. 
 
 
 
 
 
 
 
Department of Radiation Oncology 
 
 
Prairie Lakes Hospital, Watertown, SD 
 
 
 
 
Principal Investigator (P.I.): 
Jeffrey Brindle, M.D. 
 
 
 
 
 
 
 
Department of Radiation Oncology 
 
 
MD Anderson Cancer Center Orlando, FL 
 
 
 
 
Principal Investigator (P.I.): 
Akash Nanda, M.D. 
 
 
 
 
 
 
 
Department of Radiation Oncology 
 
 
 
 
 
 
 
 
 

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Protocol Version History 
Version 1 
7/11/2006 
Version 2 
9/15/2006 
Version 3 
2/22/2007 
Version 4 
7/5/2007 
Version 5 
7/13/2007 
Version 6 
11/9/2007 
Version 7 
1/30/2008 
Version 8 
07/23/2008 
Version 9 
08/06/2008 
Version 10 
12/8/2008 
Version 11 
9/30/09 
Version 12 
10/13/09 
Version 13 
10/8/2010 
Version 14 
11/04/2011 
Version 15 
11/20/2013 

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INDEX 
 
 
Schema  
 
Eligibility Checklist  
 1.0 
Introduction 
 2.0 
Objectives 
 
 3.0 
Patient Selection  
 4.0 
Pretreatment Evaluations/Management 
 5.0 
Registration Procedures 
 6.0 
Radiation Therapy  
 7.0 
Drug Therapy 
 8.0 
Other Therapy 
 9.0 
Specimen Submission 
10.0 
Patient Assessments 
11.0 
Data Collection 
12.0 
Statistical Considerations 
13.0 
Data Safety Monitoring Plan  
 
References 
 
 
Appendix I  
- Study Parameters 
 
Appendix II 
- Performance Status Scoring 
 
Appendix III 
- Staging System 
 
Appendix IV 
- Gleason Classification 
 
Appendix V 
- On-Study AUA Symptom Score (PQ) 
 
Appendix VI 
- Expanded Prostate Cancer Index Composite (EPIC) 
 
Appendix VII 
- Risks to Subjects 
 
 
 
 
 

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Synopsis 
 
Schema 
 
 
Number of patients   = between 7-45 for phase I (depending on tolerance) 
 
 
 
= 50 for phase II 
 
Phase I 
Patients in each dose cohort will all be treated as a single group for dose escalation.  The 
starting dose for the dose escalation portion will be 9 Gy per fraction for 5 fractions (total dose 
= 45 Gy).  Subsequent cohorts of patients will receive an additional 0.5 Gy per treatment (total 
2.5 Gy per escalation) as follows: 
 
No. Fractions  
Dose per fraction (Gy) 
Total Dose (Gy) 
No. Patients 
 
 
5 
 
 
9 
 
 
 
45 
 
 
7-15 
 
 
5 
 
 
9.5 
 
 
 
47.5 
 
 
7-15 
 
 
5 
 
 
10 
 
 
 
50 
 
 
7-15 
 
 
  
Minimum waiting periods will be assigned between each dose cohort to observe toxicity.  The 
phase I portion of the study will be completed when dose limiting toxicity is reached or when a 
sufficiently high dose level (i.e.,10 Gy per fraction, 50 Gy total), is attained to consider the 
therapy likely to be efficacious.   
 
 
Phase II 
Additional patients will be treated at either the maximum tolerated dose (MTD) or at the 10 Gy 
per fraction dose level as determined from the Phase I portion of the study.  The phase II study 
will evaluate efficacy endpoints with larger patient numbers and continue to build the toxicity 
profile of this regimen following the phase I study. 
 
Eligibility 
Men who satisfy all of the following conditions will be eligible for this study: 
 
Willing and capable to provide informed consent 
 
Signed study specific informed consent form. 
 
PSA  ≤ 20 prior to hormone therapy (if given) for patients with Gleason 2-6. For those 
with Gleason score of 7.  PSA should be less than or equal to 15 ng/ml prior to 
hormonal therapy (if given). Thus, risk of pelvic lymph node involvement according to 
Roach formula would be under 20%. 
 
Gleason score ≤ 7  
 
Appropriate staging studies identifying as AJCC stage T1a, T1b, T1c, T2a, or T2b   
 
No direct evidence of regional or distant metastases after appropriate staging studies 
Eligible patient 
SBRT 
5 Fractions 
Immobilization using: 
1. Implanted 
fiducials, daily CT, 
or daily US 
imaging 
2. Daily enema 
3. Daily rectal tube 
Follow for 
toxicity and 
PSA control 

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 
Histologic confirmation of cancer by biopsy 
 
Adenocarcinoma of the prostate 
 
Age ≥ 18 
 
Zubrod Performance Status 0-2 
 
Up to 9 months of previous hormonal therapy is allowed (but not required) 
 
AUA score must be ≤ 15 (alpha blockers allowed) 
 
CT or Ultrasound-based volume estimation of prostate gland ≤ 60 grams 
 
Agreement to use effective contraceptive methods such as condom/diaphragm and 
spermicidal foam, intrauterine device, or prescription birth control pills. 
 
Ineligibility 
Women are not eligible for this study.  Men with one or more of the following conditions also are 
ineligible for this study: 
 
Positive lymph nodes or metastatic disease from prostate cancer 
 
Prior invasive malignancy unless disease free for a minimum of 3 years (carcinoma in 
situ of the breast, oral cavity, or cervix, or non-melanomatous skin cancer are all 
permissible) 
 
T2c, T3, or T4 tumors 
 
Previous pelvic radiotherapy 
 
Previous surgery or chemotherapy for prostate cancer 
 
Previous transuretheral resection of the prostate (TURP) or cryotherapy to the prostate 
 
Previous hormonal therapy given for more than 9 months prior to therapy  
 
Concomitant antineoplastic therapy (including surgery, cryotherapy, conventionally 
fractionated radiotherapy, and chemotherapy) while on this protocol. 
 
History of Crohn’s Disease or Ulcerative Colitis. 
 
Previous significant obstructive symptoms; AUA score must be ≤ 15 (alpha blockers 
allowed) 
 
Significant psychiatric illness 
 
Men of reproductive potential may not participate unless they agree to use an effective 
contraceptive method. 
 
Ultrasound or CT estimate of prostate volume > 60 grams  
 
Severe, active co-morbidity as defined in section 3.17. 
 

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Phase I and II Study of Stereotactic Body Radiation Therapy (SBRT) 
 for Low and Intermediate Risk Prostate Cancer 
 
ELIGIBILITY CHECKLIST 
 
Case #                     
 
 
(page 1 of 2) 
 
______________ (Y)  
1. Prostate adenocarcinoma histologically confirmed by biopsy? 
 
 
 
 
 
 
 
2. What is the TNM-Stage?  
______________ (T1a, T1b, T1c, T2a, OR T2b) 
                             (N0) 
______________ (M0) 
 
______________ (≤ PSA)3. What is/was the serum Prostate-Serum Antigen (PSA) prior to any 
hormonal therapy (if given)? (PSA ≤ 20 ng/ml for Gleason 2-6 and 
≤ 15 ng/ml for Gleason 7) 
 
______________ (≤ 7) 4. What is the Gleason score from the prostate biopsy? 
 
______________ (N) 
5. Does the patient have history of significant inflammatory colitis 
(e.g., Crohn’s Disease or Ulcerative colitis)?  
 
______________ (≥ 18) 6. How old is the patient (in years)?  
 
______________ (0-2) 7. What is the patient’s Zubrod performance status? 
 
______________ (Y) 
8. Has the patient agreed to use an effective method of contraception 
if able to have children?  
 
______________ (Y) 
9. Have the required pretreatment evaluations and staging studies 
been obtained? 
 
______________ (Y/N) 10. Has the patient had prior hormonal therapy? 
______________ (N) 
 
If yes, was more than 9 months of therapy given prior to study 
entry? 
 
______________ (N)  11. Any prior chemotherapy or surgery for prostate cancer? 
 
______________ (N)  12. Any prior radiotherapy to the pelvis?  
 
______________ (N) 
13. Are other concomitant cancer therapies planned including 
surgery, cryotherapy, chemotherapy, or conventionally 
fractionated radiotherapy? 
 
______________ (N)  14. Has the patient undergone previous transurethral resection of the 
prostate (TURP) or cryotherapy to the prostate? 

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______________ (Y/N)  15. Has the patient had a previous cancer (carcinoma in situ of the 
breast, oral cavity, or cervix, or non-melanomatous skin cancer 
are all permissible)? 
______________ (Y)  
If yes, has the patient been disease free for > 3 years? 
 
______________ (Y)  
16. Is the patient’s AUA score ≤ 15? 
 
______________ (N)   17. Is the patient’s ultrasound or CT estimate of the prostate volume 
> 60 grams? 
 
______________ (N)   18. Severe, active co-morbidity as defined in section 3.17. 
 
______________  (Y) 
19.  Has the patient signed the protocol consent?  
 
______________   (N)     20. In the past 6 months, has the  
 
 
 
 
 
  
  
patient been treated with potent immunosuppressive drugs? 
 
 
 
 
Completed by 
 
 
 
 
 
Date  
 
 
 
 

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1.0 
INTRODUCTION 
1.1      Localized Prostate Cancer  
 
There were 232,000 new cases of prostate cancer diagnosed in the United States in 
2005 and 30,000 deaths [1].  Among males, prostate carcinoma was the 2nd leading 
cause of cancer mortality behind lung cancer and ahead of colo-rectal cancer.  The 
incidence of early stage prostate cancer rose dramatically in the US with the onset of 
widespread use of prostate-specific antigen (PSA) blood test screening.  Levels 
have continued to increase but more slowly in men younger than 65, but have 
leveled off in men older than 65 since 1995.  Death rates have remained level or 
decreasing since the mid 1990s, presumably from earlier detection with PSA 
screening.  The main risk factors are age, ethnicity, and family history.  Up to 70% of 
all prostate cancers are diagnosed in men greater than 65 years old which impacts 
therapy options as a result of competing co-morbidities.  Men of African decent have 
the highest incidence of prostate cancer while men in North American have higher 
incidence than men in Asia and South America.  Familial disposition may account for 
5-10 percent of prostate cancers.  Early detection of the disease appears to account 
for improvements seen in the US cause-specific mortality rate.  The American 
Cancer Society recommends annual screening PSA testing and digital rectal 
examination (DRE) in all men starting at age 50 (starting at age 45 in high risk men) 
in order to allow diagnosis of cancer while still organ confined.  With this approach, 
overall 5-year survival has improved from 67% in 1974 to nearly 100% in 2000; 
however, cancer specific survival continues to decline after five years due to the long 
natural history and lack of cancer control in many men.   
  
 
Radiotherapy options for organ confined prostate cancer have included protracted 
radiation in the form of external beam delivered over 7-10 weeks of daily therapy 
(including 2-D, 3-D conformal, and intensity modulated radiation therapy or IMRT)  
[2-4] and also permanent brachytherapy seed implantation using iodine or palladium 
[5-7].  Treatments have also been delivered using shorter overall treatment times.  
These include hypofractionated external beam treatments and high dose rate (HDR) 
brachytherapy implants [8-11].  In addition to being more convenient for patients with 
fewer trips to the treatment facilities, these treatment options completed over a 
shorter period have unique long term effects in both tumor and normal tissues.  
Depending on the relative differences between tumor response and normal tissue 
injury, the timing in which radiotherapy is delivered may have significant impact on 
the therapeutic ratio (benefit/toxicity).  A commonly used mathematical model used 
to describe these effects has been the “linear-quadratic” model proposed by Douglas 
and Fowler [12].  In this model, the log survival vs. dose relationship is modeled by 
an arithmetic power series truncated to the linear and quadratic terms.  The linear 
coefficient in this progression is commonly called “alpha” while the quadratic 
coefficient is called “beta.”  It has also been proposed that the linear term described 
by alpha corresponds to the more infrequent effect of double strand breaks within 
tissue DNA caused by radiation which disable the clonagenicity of the cell with little 
chance of repair.  In turn, the beta term reflects the consequence of more than one 
single strand break in close enough proximity on the DNA to disable the cell.  These 
single strand breaks occur much more frequently than double strand breaks, but 
they may be more readily repaired unless they happen so frequently that repair 
mechanisms become overwhelmed such as might occur with large dose per fraction 
radiation.  Hence, at low dose per fraction, alpha events dominate the cellular 
response while at large dose per fraction, beta events become more important.  

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These events occur, at different rates and proportions, in both tumor and normal 
tissues exposed to radiation. 
It has been commonplace to describe tissue response properties of various tissues 
toward radiation by their alpha to beta ratio.  The alpha and beta values may be 
measured in vitro by exposing cell cultures to varying doses and schedules of 
radiation.  Normal tissues, more capable of repairing radiation injury, typically have a 
lower alpha/beta ratio in the order of 2-3.  Common cancers of the lung, cervix and 
head and neck are quoted to have alpha/beta ratios in the 10 range.  For such 
tumors, exploitation of the differences between normal tissue and tumor response 
has led radiation oncologists to use more protracted courses of radiation using small 
daily doses to high total cumulative doses (so-called conventional fractionation, e.g., 
2 Gy per fraction to a total dose of 70-76 Gy).  Prostate cancer cell lines have been 
difficult to grow in tissue culture and therefore there has been less direct evidence of 
the alpha/beta ratio.  It was generally assumed to be similar to epithelial 
malignancies of the gastrointestinal and bronchopulmonary tract leading to the 
conventional dose fractionation schedules used in clinical practice or the low dose 
rate implants used in permanent prostate seed brachytherapy.  More recent 
evidence, however, has implied that the alpha/beta ratio for prostate cancer may be 
much lower than expected.  In fact, using outcome data of patients treated with 
different dose fractionation schemes (in vivo), it has been suggested that the 
alpha/beta ratio for prostate cancer may be as low as 1.5-3 which is perhaps even 
lower than the surrounding normal tissues.  If this were true, there would be no 
advantage to protracted radiotherapy schedules.  This realization has led to several 
investigations of much shortened radiotherapy schedules.  Of course, the shortest 
radiotherapy schedules of all have been SBRT treatment schedules which is the 
impetus for this protocol. 
 
Several investigators at a variety of institutions have investigated using modestly 
larger dose per fraction treatment schemes as compared to conventional 
fractionated radiotherapy [references].  For example, in a mature prospective 
experience reported by Livsey and colleagues from England, 50 Gy total in 3.13 Gy 
fractions produced PSA control rates comparable to published reports using 70 Gy 
with 2 Gy fractions [13-14].  In addition, they found the treatment carried out with 3-D 
conformal techniques was well tolerated.  That same group is carrying on the 
research using 3 Gy per fraction, 60 Gy total dose, and intensity modulated radiation 
therapy (IMRT) techniques in an effort to improve PSA control rates [11].  In the US, 
Kupelian and colleagues used 2.5 Gy per fraction and published mature results to 70 
Gy total dose in 5.5 weeks [10].  Their patients also had good PSA control rates and 
acceptable rates of toxicity, especially if the volume rectum getting 70 Gy is limited to 
10 cc.  Similar investigations are now being planned or carried out for larger groups 
of patients in cooperative group trials.   Altogether, these trials show that the 
treatment can be delivered much more quickly and conveniently using 
hypofractionation without compromising PSA control or toxicity so long as careful 
technique is respected. 
     
1.2 
Stereotactic Body Radiation Therapy (SBRT) 
 
‘Stereotactic radiosurgery’ generally refers to a procedure design to treat deep-
seated brain tumors or abnormalities, and is commonly performed on a specialized 
machine, such as the Gamma Knife.  This procedure involves immobilizing the 
patient (cranial halo), affixing a stable 3-D coordinate system (fiducial box and head 

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frame), performing high resolution imaging (CT or MRI), registering the images to the 
coordinate system using a computer, virtually simulating delivery of very focal and 
conformal dose profiles of radiation with steep dose gradients toward normal tissue, 
and finally carrying out the treatment with sub-millimeter accuracy.  Typically very 
high doses of radiation (15-40 Gy) are given in a single treatment with this 
technique.  Any adjacent normal tissues that receive this dose may be significantly 
damaged, thus the requirement for very conformal treatments with rapid dose fall-off.  
An alternate strategy has been to divide total radiation dose into two or three 
fractions, still with fairly large dose per fraction (6-10 Gy), attempting to decrease 
adjacent normal tissue toxicity.  These fractionated techniques are referred to as 
‘stereotactic radiotherapy,’ and are carried out with hope that surrounding normal 
tissue will tolerate the treatment as a result of relatively more successful sublethal 
damage repair as compared to tumor. 
 
Translation of the stereotactic radiosurgery and radiotherapy concepts to 
extracranial sites has not been straightforward [15-17].  With brain treatments, the 
skull serves as an excellent surface to rigidly couple the immobilization frame using 
stainless steel pins under local anesthesia.  Once the skull is immobilized, targets 
within the skull are likewise immobilized in that there is very little movement of 
intracranial structures outside of fluid waves around the ventricles.  Such is not the 
case for extracranial sites.  Inherent motion, such as the heart beating, lungs 
expanding and emptying, and bowels churning, results in movement of potential 
targets.  In addition, the external surface anatomy does not have structures 
amenable to rigid fixation to a frame.  In 1994, Lax, et al, from the Karolinska 
Hospital in Sweden reported on the development and testing of an extracranial 
frame that incorporated a fiducial stereotactic coordinate system along its side 
panels [18].  The system used vacuum pillows to make contact with three sides of 
the patient (maximizing surface area of contact) and correlation of external 
anatomical reference points on the sternum and calf for immobilization.  To decrease 
respiratory excursion, an abdominal press was employed forcing the patient to 
perform relatively more chest wall rather than diaphragmatic breathing.  A formal 
verification of reproducibility study was carried out, and target motion was reduced to 
within 0.5 cm in the axial plane and 1.0 cm in the caudal/cephalad plane.  With this 
degree of accuracy (compared to 0.05 cm target position accuracy for the Gamma 
Knife), stereotactic radiosurgery could not be performed; however, they did set up a 
program treating patients with extracranial stereotactic radiotherapy. 
 
Stereotactic body radiation therapy (SBRT) is a new therapeutic paradigm for 
treating localized tumors outside of the central nervous system and involves 
delivering very high doses of focused radiation using unique beam arrangements 
and special immobilization equipment [19].  As already demonstrated in lung and 
liver cancers, these treatments offer hope for improved local control of cancers that 
may translate into gains in survival especially for smaller early stage lesions.  SBRT 
employs daily treatment doses dramatically higher than typical for conventionally 
fractionated radiation therapy (CFRT).  In turn, it is incorrect to assume that SBRT 
radiobiology is similar to historical CFRT.  Indeed, a unique biology of radiation 
response for very large dose per fraction treatments is being appreciated both in 
terms of tumor control as well as normal tissue consequences translating into unique 
clinical outcomes.  For example, local control with CFRT in early stage lung cancer 
is consistently reported below 50% while several series using SBRT show local 
control around 90% [20-21].  

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SBRT has been defined by the American College of Radiology (ACR) and American 
Society of Therapeutic Radiology and Oncology (ASTRO) to involve the use of very 
large dose per fraction [22].  Indeed, dose per fraction of 8 Gy minimum would 
obviously make SBRT very different from even the more abbreviated 
hypofractionation schemes described above.  Typically, only 1-5 fractions are used 
for SBRT depending on the tolerance of adjacent or intervening normal tissues.  
Linear structures (like the spinal cord) and tubular structures (like the bowels) are 
commonly called “serially functioning tissues” akin to series electrical circuits 
because their function is disrupted if there is a defect anywhere along their pathways 
[23-24].  It has been shown that serial functioning tissues are less tolerant to SBRT 
than so-called “parallel functioning tissues” like the peripheral lung and liver.  In 
response, typically more fractions are employed (e.g., five fractions rather than one) 
when serially functioning tissue cannot be avoided.  In the case of treating prostate 
cancer, the rectum is an adjacent serially functioning tissue while the urethra is an 
intervening serially functioning tissue traversing the very center of the prostate 
target. 
  
     
1.3 
Current Protocol 
 
Prostate cancer has several good treatment options for organ confined disease such 
as surgery and conventional radiation.  In addition, some men with indolent disease 
are appropriately treated with watchful waiting.  However, all of the established 
treatments continue to fail in a portion of patients via tumor recurrence.  
Furthermore, current treatments are often unpalatable for many patients because 
they are either too invasive or too inconvenient.  It has also been shown recently that 
many prostate cancers may be better controlled using large dose per fraction 
treatments such as might be delivered by stereotactic body radiation therapy 
(SBRT). While large dose per fraction treatments are facilitated by new generation 
radiation delivery equipment, technology cannot independently overcome normal 
tissue consequences to tubular organs adjacent or within targets (e.g., the urethra 
and rectum for prostate cancer).  As such, careful prospective clinical trials must be 
designed that appropriately bridge the information learned from laboratory testing, 
historical clinical experience, and the clinical experience with SBRT from other sites 
in order to test this new therapy for prostate cancer.  This is an important problem, 
since localized prostate continues to recur despite current treatments and more 
effective, less toxic and more convenient treatments are necessary. 
 
As the SBRT therapy is strictly local, we will select for patients with prostate cancer 
locally confined to the prostate gland.  As such, we will select eligibility criteria 
sanctioned in the past by the Radiation Therapy Oncology Group to predict  
reasonably low risks of both extraprostatic capsular extension and seminal vesicle 
invasion.  We will apply the Roach formula to limit eligibility to patients with under a 
20% risk of pelvic lymph node involvement.  Some patient eligible for this trial may 
have a somewhat higher risk of extraprostatic spread (e.g., T2b, Gleason 7 or 
PSA>10) and it will be allowed to use pre-treatment hormonal therapy in such 
patients at the investigator’s discretion.  Hormonal therapy may also be used to 
shrink prostates that are massively enlarged.  As the primary toxicity will likely be 
mucosal damage, we will avoid enrolling patients with pre-existing mucosal 
dysfunction (including those with previous radiation, TURP, very large prostate 
glands, and inflammatory bowel disease).  In this way, patients will be uniformly 

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selected in a fashion that would identify patients likely to receive benefit from the 
therapy. 
 
As the most efficacious SBRT dose for treatment of the prostate has not been 
prospectively identified, we will start with a careful phase I dose escalation toxicity 
study.  Patients enrolled at each dose level will undergo routine evaluations to 
identify potential toxicities.  Adequate waiting periods will be respected to insure 
dose escalation does not proceed prior to observing toxicity.  When the MTD is 
determined or the dose reaches a significantly high level expected to be both 
tumoricidal and able to control PSA by the investigators, subsequently enrolled 
patients will be accrued into the phase II portion.  In the phase II portion, further 
patients will be accrued to confirm toxicity data on a larger scale, and attempt to 
characterize whether there is enough beneficial effect in this population to warrant 
further clinical testing. 
 
We will use a treatment regimen carried out in 5 total fractions.  This would be a 
more tolerant regimen than our 3 fraction regimens published in liver and lung 
cancer [25-26] and may lessen the toxicity to serial functioning tissues in close 
approximation to the prostate (rectum and urethra). Given there will be only 5 
treatments, daily enemas, rectal tubes, and even urethral catheters for simulation 
are all feasible undertakings that may help optimize the therapy.   
 
It is predicted that the dose limiting toxicity from this treatment will likely relate to 
urethral dysfunction (e.g., ulceration, bleeding, pain, narrowing and frank stricture) 
and rectal damage (ulceration, bleeding, chronic inflammation, and pain).  Since the 
radiotherapy target for radiotherapy of the prostate is the entire gland, the urethra 
will by definition be situated toward the center of the target thereby receiving the 
target margin dose at a minimum.  In fact, the urethra may receive even a higher 
dose than the minimum target dose owing to the fact that SBRT dosimetry 
commonly includes a 10-30 percent higher central dose within the target.  While 
wedges and other methods of modulation (including IMRT) may be used to steer this 
higher dose away from the visualized urethra, these techniques will have limited 
ability to protect the urethra.  The prostatic urethra will likely be significantly 
damaged which may limit dose escalation.  If it has the ability to heal by second 
intention as it has been shown to do after other severe insults such as transurethral 
resection without forming a diffuse untreatable stricture, the treatment may still be 
feasible.  Certainly if mucosal clonagens can migrate from the bulbous urethra and 
bladder to “rescue” the prostatic urethra after SBRT, care will be taken to spare dose 
to those structures [24].  In regard to the rectum, the treatments will be carried out 
with a rectal tube to separate much of the circumference of the rectal wall from the 
prostate target.  This rectal tube must be positioned appropriately above the anus 
and extend superiorly to above the prostate to be effective.  In addition, the rectum 
should be evacuated of feces to avoid confounding the geometry prior to each 
treatment.  If the dose to the rectum is tightly confined to the anterior wall next to the 
target, it is hoped that the ulcer likely to be produced will heal by recruitment of 
clonagens and blood supply from the lateral and posterior walls.  Indeed, a 
precedent for assuming such a process exists with the reported treatment of small 
rectal cancers using an endorectal orthovoltage tube by Papillon and colleagues 
[27].  In that experience, doses as high as 150 Gy were given in as few as 4 
fractions which undoubtedly resulted in ulceration at the point of treatment but still no 

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reported long term untoward toxicity owing to the extremely localized high dose 
dosimetry.   
 
1.4 
Who Would Benefit from this Treatment? 
 
As noted above, there are several quite good but not perfect treatments for organ 
confined prostate cancer that have significant follow-up and published experience as 
well as an option for watchful waiting.  Still, there are populations that might find the 
invasiveness of surgery and brachytherapy implants less ideal and the 
inconvenience of IMRT and 3-D conformal therapy impractical.  General anesthesia 
is inappropriate for some patients due to significant co-morbid conditions.  We 
believe a very abbreviated, non-invasive, outpatient treatment would be considered 
a favorable option in particular to the underserved populations of men living in more 
remote areas including farmers, ranchers, and those in rural communities.  
Furthermore, if the concept of prostate cancer having a very low alpha to beta ratio 
discussed previously is confirmed, this treatment using SBRT may in fact be a better 
option for some men with prostate cancer. 
 
1.5 
Starting Dose for the Phase I Study 
 
There has been experience published or presented to indicate the appropriate 
starting dose for the phase I study.  Direct evidence of tolerance by a similar 
treatment strategy has been presented by Madsen and colleagues from Virginia 
Mason University where 33.5 Gy in 5 fractions of 6.7 Gy were delivered using SBRT 
in men with early stage prostate cancer [28].  That dose was tolerated without grade 
III or higher toxicity, but had rather poor PSA control [personal communication, Berit 
Madsen, M.D., 5/05).  Although not using SBRT techniques, Collins and colleagues 
used a 6 fraction regimen to 36 Gy at 6 Gy per fraction with more conventional 
external beam delivery techniques which again was well tolerated [29-30].  A similar 
but more invasive treatment approach to SBRT is the high dose rate (HDR) implant 
experience which gives large dose per fraction treatments on a daily basis through 
implanted brachytherapy catheters.  Indeed the heterogeneous target dosimetry is 
similar in many ways to SBRT.  While HDR has mostly been used as a boost 
treatment after conventional external beam treatment, there is institutional data from 
Martinez and colleagues using HDR as monotherapy.  That group at the William 
Beaumont Hospital used a 4 fraction regimen of 9.5 Gy to a total dose of 38 Gy and 
published an acceptable toxicity profile in treated patients [31-32].  Grills, et al. 
reported an update of these results of HDR monotherapy for the management of 65 
patients with T1a-T2b, and total Gleason Score 7 or less.  The preliminary 
biochemical PSA control rate was 98% at 3 years and it was similar to their 
experience with standard 103Pd low dose rate brachytherapy [40].  In a similar 
experience using HDR, Yashioka and colleagues from Japan used higher total 
doses up to 48-50 Gy in 6 Gy fractions as monotherapy for localized prostate cancer 
without untoward toxicity [33-34].  Considering all of these experiences as basis for 
dose selection, we will use a starting dose of 9 Gy per fraction and deliver a total of 5 
fractions to a total dose of 45 Gy.  Subsequent dose levels will require a modest 
dose per fraction escalation of 0.5 Gy (e.g., 9 Gy to 9.5 Gy to 10 Gy per fraction, 
etc).  We hope to reach as high of biologically potent dose as possible without 
exceeding tolerance (i.e., a 2 Gy equivalent dose of at least 100 Gy) that would be 
delivered in around 2 weeks rather than 10-12 weeks as would be required with 
conventional fractionation. 

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2.0 
 OBJECTIVES 
2.1 
In phase I, to the primary objective is to escalate the dose of stereotactic radiotherapy 
to a tumorcidal dose without exceeding the maximum tolerated dose in patients with 
organ confined prostate cancer. 
 
2.2 
In phase I, a secondary objective is to determine the dose-limiting toxicity (if the 
maximum tolerated dose is reached). 
 
2.3 
In phase II, the primary objective is to determine the late severe grade 3-5 GU and GI 
toxicity from 270-540 days (i.e., 9-18 months) from the start of the protocol treatment. It 
is graded based on CTCAE v3.0.    
 
2.4 
In phase II, secondary objectives will be to determine the 2 year biochemical (PSA) 
control (freedom from PSA failure), disease free and overall survival, local control, 
freedom from distant metastases, and the incidence of high grade adverse events of 
any type from the therapy in the treated patients in order to determine if the therapy 
is promising enough for further clinical investigation. 
 
3.0 
PATIENT SELECTION  
3.1  
All patients must be willing and capable to provide informed consent to            
           participate in the protocol. 
 
3.2  
Eligible patients must have appropriate staging studies identifying them as AJCC 
stage T1 (a, b, or c) or T2 (a and b only) adenocarcinoma of the prostate gland. The 
patient should not have direct evidence of regional or distant metastases after 
appropriate staging studies.  Histologic confirmation of cancer will be required by 
biopsy. 
 
3.3 
The patient’s Zubrod performance status must be 0-2 
 
3.4 
The Gleason score should be less than or equal to 7 
 
3.5 
The serum PSA should be less than or equal to 20 ng/ml prior to starting hormonal 
therapy (if given) for patients with Gleason score 2-6.  For patients with Gleason 
score of 7, PSA should be less than or equal to 15 ng/ml prior to starting hormonal 
therapy (if given).  As such, the risk of pelvic lymph node involvement according to 
the Roach formula would be under 20%.  
 
3.6 
Eligible patients should not have had previous pelvic radiotherapy or have had 
chemotherapy or surgery for prostate cancer.  Hormonal therapy given for up to 9 
months prior to SBRT is allowed as a neoadjuvant therapy or to downsize the 
prostate gland. 
 
3.7 
There must be no plans for the patient to receive other concomitant or post 
treatment adjuvant antineoplastic therapy while on this protocol including surgery, 
cryotherapy, conventionally fractionated radiotherapy, hormonal therapy, or 
chemotherapy given as part of the treatment of prostate cancer. 
 
3.8 
Patients should not have undergone previous transurethral resection of the prostate 
(TURP) or cryotherapy to the prostate. 

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3.9 
Patients must be past their 18th birthday at time of registration. 
 
3.10 
Patients with history of inflammatory colitis (including Crohn’s Disease and 
Ulcerative colitis) are not eligible. 
 
3.11 
Patients may have used prior hormonal therapy, but it should be limited to no more 
than 9 months or therapy prior to enrollment. 
 
3.12 
Patients should not have significant urinary obstructive symptoms; AUA score must 
be ≤ 15 (alpha blockers allowed). 
 
3.13 
The ultrasound or CT based volume estimation of the patient’s prostate gland should 
not be greater than 60 grams. 
3.14 
Patients should not have a history of significant psychiatric illness. 
 
3.15 
Men of reproductive potential may not participate unless they agreed that they or 
their partner use an effective contraceptive method such as condom/diaphragm and 
spermacidal foam, intrauterine device (IUD), or prescription birth control pills. 
 
3.16 
Prior invasive malignancy (except non-melanomatous skin cancer) unless disease 
free for a minimum of 3 years (e.g., carcinoma in situ of the breast, oral cavity, or 
cervix are all permissible). 
 
3.17 
Severe, active co-morbidity, defined as follows: 
3.17.1 
Unstable angina and/or congestive heart failure requiring hospitalization within 
the last 6 months. 
3.17.2 
Transmural myocardial infarction within the last 6 months. 
3.17.3 
Acute bacterial or fungal infection requiring intravenous antibiotics at the time of 
registration. 
3.17.4 
Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness 
requiring hospitalization or precluding study therapy within 30 days before 
registration. 
3.17.5 
Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; 
note, however, that laboratory tests for liver function and coagulation parameters 
are not required for entry into this protocol. 
3.17.6 
Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC 
definition; note, however, that HIV testing is not required for entry into this 
protocol. The need to exclude patients with AIDS from this protocol is necessary 
because the treatments involved in this protocol may be significantly 
immunosuppressive.  Protocol-specific requirements may also exclude immuno-
compromised patients. 
3.17.7 
History of treatment with potent immunosuppressive drugs for such conditions 
as post organ transplant, severe rheumatoid arthritis, etc. within the past 6 
months. 
 
4.0 
PRETREATMENT EVALUATIONS/MANAGEMENT  
Note: This section lists baseline evaluations needed before the initiation of protocol 
treatment that do not affect eligibility.   
4.1 
 Required Evaluations/Management 

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4.1.1 
History and physical examination to include digital rectal examination of the 
prostate, determination of AUA score, and completion of EPIC prostate quality of 
life questionnaire. 
4.1.2 
Zubrod performance status (Appendix II). 
4.1.3 
Lymph node evaluation performed within 90 days prior to registration by either CT 
or MRI (lymph node dissection is acceptable but not required). 
4.1.4 
Prostate Specific Antigen (PSA) prior to treatment (prior to hormonal therapy, if 
given). 
4.1.5 
See Section 11.1; note that failure to perform one or more of these tests may result 
in assessment of a protocol violation.  
 
4.2 
Highly Recommended Evaluations/Management 
Cystoscopy, if advised by the urologist, may be performed to check for urethral 
damage including strictures, bladder pathology, or a large median prostate lobe.  
Anosocopic exam with initial and follow up exams. 
 
5.0 
REGISTRATION PROCEDURES 
5.1.1 Preregistration Requirements for diagnostic pathology review 
There are no requirements for central review of pathology used for initial diagnosis. 
5.1.2 Pre-Registration Requirements for SBRT Treatment Approach 
In order to utilize SBRT in this protocol, the institution must have met technology 
requirements and have provided a description of techniques, methods, training, 
and experience showing competency to the study PIs.  
5.2 
Registration 
5.2.1 
Fax Registration 
Prior to registration, participating investigators and institutions should review the 
eligibility checklist and confirm eligibility. Patients can be registered only after 
eligibility criteria are met.  To register a patient, the site should fax the Enrollment 
Form to the Project Manager (fax #: 214-648-5923).  A unique, participant ID 
number will then be assigned.  
5.3 
Accreditation 
5.3.1 
Institutional Processes 
Prior to treating patients on protocol, the institution’s specific methods for 
immobilization (e.g., frame vs. frameless), targeting, dose construction, daily 
verification of accuracy, ongoing assessment of accuracy and Quality Assurance 
policies must be described to and approved by the study PI and other approved 
institutional PIs.  The primary purpose of accreditation will be to insure that dose is 
delivered to the targets and avoiding normal tissues according to protocol criteria.  
This accreditation may be assessed by written documentation, conference calls, or 
direct observation via site visits.  Additional data may be required of institutions to 
verify that techniques are performing as intended. 
  
6.0 
RADIATION THERAPY 
6.1 
Dose Specifications 
6.1.1 
Stereotactic Targeting and Treatment 
The term “stereotactic” for the purposes of this protocol implies the targeting, 
planning, and directing of therapy using beams of radiation along any trajectory in 
3-D space guided by one or several fiducials of known 3-D coordinates.  This 
differs from conventional radiation therapy in which therapy is directed toward skin 
marks or bony landmarks and assumed to correlate to the actual tumor target 
based on a historical simulation.  It should be understood that Stereotactic Body 

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Radiation Therapy (SBRT) has become a treatment that is well beyond just 
stereotactic targeting.   Indeed SBRT is mostly about ablative range dose per 
fraction, accounting properly for errors including motion, careful construction of 
dosimetry that compacts high dose into the tumor and not normal tissues, and 
extra careful treatment conduct.  This protocol will require treatments to be 
conducted with the use of a fixed 3-D coordinate system defined by fiducials.  The 
coordinate system defined by the fiducials should be directly related to the 
radiation producing device (e.g., couch and gantry) in a reproducible and secure 
fashion.   Capability should exist to define the position of targets within the patient 
according to this same 3-D coordinate system.  As such, the patient is set up for 
each treatment with the intention of directing the radiation toward an isocenter or 
target according to the known 3-D coordinates as determined in the process of 
treatment planning.  The nature of the fiducials themselves may include radio-
opaque markers or rods placed at known locations in a frame or fixed structure 
adjacent to the patient as well as use of the tumor itself as a fiducial (e.g. acquiring 
tomographic views of the tumor simultaneously with the treatment).  Metallic 
“seeds” or markers placed within the tumor will be allowed so long as they are not 
prone to migration movement.   
6.1.2 
Dose Fractionation 
Patients will receive 5 fractions of radiation.  A minimum of 36 hours and a 
maximum of 8 days should separate each treatment.  No more than 3 fractions will 
be delivered per week (7 consecutive days).  Total dose will depend on the phase 
of the study (see schema). 
6.1.3 
Premedications 
Unless contraindicated, it is recommended that all patients receive corticosteroid 
premedication (e.g. Decadron 4 mg p.o. in a single dose, or equivalent) 15-60 
minutes prior to each of the five treatments for the intended purpose of modulating 
immediate acute inflammatory effects. It is strongly recommended that all patients 
be treated prophylactically with drugs intended to avoid urinary retention 
associated with SBRT.  This class of drugs include alpha blockers (e.g., tamsulosin 
aka Flomax, doxazosin aka Cardura, terazosin aka Hytrin, etc) and 5-alpha 
reductase inhibitors (e.g., finasteride aka Proscar, dutasteride aka Avodart, etc), or 
drugs with similar intended effect.  It is recommended to start the therapy at least 
one day prior o the first SBRT treatment and continue for 3 months post finishing 
all SBRT therapy.  The drugs should be taken at standard doses for obstructive 
indications, and contraindications to these drugs should be respected.  Analgesic 
premedication, such as Tylenol 650 mg 30 minutes prior to therapy and as needed 
every 6 hours, to avoid general discomfort during long treatment durations also is 
recommended when appropriate.   
6.1.4 
Supportive medicines 
Consider Tamsulosin (e.g., Flomax) during treatment period to reduce urinary 
symptoms.  Consider using 5-alpha reductase inhibitor like Finasteride (e.g. 
Proscar) to relieve potential obstructive issues.  For both drugs, standard doses 
will be utilized as needed unless contraindicated. Also consider 1 tablespoon of 
Milk of Magnesia, taken the night before simulation/treatment (Note: Inform patient 
that this will cause diarrhea). Fleet’s enema should be taken 2 hrs, before 
simulation/treatment. An antibiotic (Bactrim or similar) may be prescribed to 
alleviate UTI if necessary.  This should be taken at standard doses as needed. 
6.2 
Technical Factors 
6.2.1 
Physical Factors 

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Only photon (x-ray) beams produced by linear accelerators, betatrons, or microtron 
accelerators with photon energies 6-21 MV will be allowed.  Cobalt-60 and charged 
particle beams (including electrons, protons, and heavier ions) are not allowed.  
6.2.1 
Dose Verification at Treatment 
Personal dosimeter measurements (e.g. diode, TLD, etc.) may be obtained for 
surface dose verification for accessible beams as per institutional preference.  This 
information is not required by the protocol. 
6.3 
Localization, Simulation, and Immobilization 
6.3.1 
Patient Positioning 
Patients will be positioned supine in a stable position capable of allowing accurate 
reproducibility of the target position from treatment to treatment.  Positions 
uncomfortable for the patient should be avoided so as to prevent uncontrolled 
movement during treatments.  A variety of immobilization systems may be utilized 
including stereotactic frames that surround the patient on three sides and large 
rigid pillows (conforming to patients external contours) with reference to the 
stereotactic coordinate system (see Section 6.1).  All positioning systems must be 
validated and accredited by the Study Committee (Principal Investigator and 
Institutional PIs) prior to enrolling or treating patients on this trial.  Patient 
immobilization must be reliable enough to insure that the Gross Tumor Volume 
(GTV) does not deviate beyond the confines of the Planning Treatment Volume 
(PTV) as defined in Section 6.4 with any significant probability (i.e., < 5%). 
6.3.2 
Inhibition of Effects of Internal Organ Motion 
Special considerations must be made to account for the effect of internal organ 
motion (i.e., breathing, etc.) on target positioning and reproducibility.  In some 
cases, the intrafractional tumor motion is small and no special maneuvers are 
required to achieve motion limits as defined in section 6.4 (this may be true for 
many cases of prostate cancer).  Treating in the prone position will accentuate 
internal organ motion problems related to breathing and should be avoided unless 
special measures are taken to account for this motion.  When accounting for 
intrafractional motion, acceptable maneuvers including reliable abdominal 
compression, accelerator beam gating with the respiratory cycle, and active 
breath-holding techniques. Internal organ inhibition maneuvers must be reliable 
enough to insure that the Gross Tumor Volume (GTV) does not deviate beyond the 
confines of the Planning Treatment Volume (PTV) as defined in Section 6.4 with 
any significant probability (i.e., < 5%).  Assessment of this motion will be left to the 
institution and may included identifying the position of radio-opaque seeds 
implanted into the prostate prior to each treatment.  This type of interfractional 
motion analysis with correction is only required by protocol just prior to each 
separate treatment.  Intrafraction assessment during the course of each treatment 
(dynamic and adaptive maneuvers) is allowed and encouraged especially if 
treatment times are long. 
6.3.3 
Localization and treatment maneuvers 
A more direct method of localization of the prostate gland than conventional 
treatment (i.e., one that uses skin and boney landmarks solely as a surrogate to 
the prostate position) must be used in this protocol.  Acceptable methods would 
include daily ultrasound or placing a radio-opaque seed or marker that can be 
visualized and triangulated using dual  imaging or markers that emit a signal that 
can me used to detect position electronically all placed prior to simulation and 
planning.  Also, it would be acceptable to perform computed tomography such as 
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identify the tumor target directly.  Image quality should be good enough to identify 
the prostate borders. 
 
In addition to the identification of the prostate in the preceding paragraph, the 
rectum should also be identified and reliably repositioned with a large (e.g., around 
60 cc) rectal tube.  Prior to positioning at least 30 minutes and no more than 2 
hours before each treatment, patients should undergo an effective bowel 
evacuation.  Typically, this will involve 1-2 fleet’s enemas.  This maneuver is to 
clear the rectum of stool and significant gas accumulation.  Just prior to 
relocalization and treatment, a rectal tube filled with air should be introduced into 
the rectum to both visualize the rectum and separate the anterior and posterior 
walls.  The rectal balloon and implementation plan must be approved by the PI 
prior to use. 
 
Isocenter port localization films (anterior/posterior and lateral) should be obtained 
at each treatment on the treatment unit (or patients should undergo a tomographic 
imaging study utilizing the linear accelerator couch, if available) immediately before 
treatment to ensure proper alignment of the geometric center (i.e., isocenter) of the 
simulated fields.   Verification CT scans and portal films may be taken at the 
discretion of the participating institution, but are not required for protocol 
participation. 
6.4 
Treatment Planning/Target Volumes 
6.4.1 
Image Acquisition 
Computed Tomography (CT) will be the primary image platform for targeting and 
treatment planning.  The planning CT scans must allow simultaneous view of the 
patient anatomy and fiducial system for stereotactic targeting.  Treatment planning 
images should be performed in the treatment position using all aids/maneuvers 
described above including urethral tube, bladder contrast, urethrogram, and rectal 
balloon after bowel evacuation with enemas.  The treatment planning scans must 
use a small caliber radio-opaque urethral catheter to allow visualization of the 
prostatic urethra as it will be a high dose spillage avoidance structure for treatment 
planning as indicated in section 6.4.2 below. Axial acquisitions with gantry 0 
degrees will be required with spacing ≤ 3.0 mm between scans.  Images will be 
transferred to the treatment planning computers via direct lines, disc, or tape. 
 
Image fusion with other imaging modalities such as MRI that might be useful in 
delineating the target and normal tissues is encouraged. 
 
The entire prostate without the seminal vesicles will constitute the CTV target for 
this protocol.  It is not required to identify a GTV within the prostate, but if 
institutions have special techniques to identify the gross tumor, such as MRI with 
high tesla strength, it is encouraged to collect the contours.  CTV target volume 
(entire prostate gland) will be outlined by an appropriately trained physician.  The 
target will generally be drawn using CT soft tissue windows.  An additional 0.3-0.5 
cm in the axial plane and 0.5-1.0 cm in the longitudinal plane (cranio-caudal) will 
be added to the GTV to constitute the planning treatment volume (PTV) depending 
on the institution’s accuracy and treating physician’s preference. 
6.4.2 
Dosimetry 
Three-dimensional coplanar or non-coplanar 3-D beam, arc rotation, or Intensity 
Modulated Radiotherapy (IMRT) beam arrangements will be custom designed for 
each case to deliver highly conformal prescription dose distributions.  Non-

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opposing, non-coplanar beams are preferable.  Typically, 10-15 beams of radiation 
will be used with roughly equal weighting.  Generally, more beams are used for 
larger lesion sizes.  When static beams are used, a minimum of 10 non-opposing 
beams should be used.  For arc rotation techniques, a minimum of 300 degrees 
(cumulative for all beams) should be utilized.  For this protocol, the isocenter is 
defined as the common point of gantry and couch rotation for the treatment unit. 
Field aperture size and shape should correspond nearly identically to the projection 
of the PTV along a beam’s eye view (i.e. no additional “margin” for dose build up at 
the edges of the blocks or MLC jaws beyond the PTV).  As such, prescription lines 
covering the PTV will typically be the 60-90% line (rather than 95-100%); however, 
higher isodoses (hotspots) must be manipulated to occur within the target and not 
in adjacent normal tissue.  The isocenter in stereotactic coordinates will be 
determined from system fiducials (or directly from the tumor) and translated to the 
treatment record. 
 
The treatment dose plan will be made up of multiple static beams or arcs as 
described above.  The plan should be normalized to a defined point corresponding 
closely to the center of mass of the PTV (COMPTV).  Typically, this point will be the 
isocenter of the beam rotation; however, it is not a protocol requirement for this 
point to be the isocenter.  Regardless, the point identified as COMPTV must have 
defined stereotactic coordinates and receive 100% of the normalized dose.  
Because the beam apertures coincide nearly directly with the edge of the PTV 
(little or no added margin), the external border of the PTV will be covered by a 
lower isodose surface than usually used in conventional radiotherapy planning, 
typically around 80% but ranging from 60-90%.  The prescription dose in five 
fractions will be delivered to the margin of the PTV and fulfill the requirements 
below.  As such, a “hot spot” will exist within the PTV centrally at the COMPTV with 
a magnitude of the prescription dose times the reciprocal of the chosen 
prescription isodose line (i.e., 60-90%). 
 
For purposes of dose planning and calculation of monitor units for actual treatment, 
all tissues within the body should be modeled in the planning system as to their 
electron density.  Proper heterogeneity correction algorithms should be approved 
by the PI. 
  
Successful treatment planning will require accomplishment of all of the following 
criteria:   
1) 
Normalization  
The treatment plan should be normalized such that 100% corresponds to the 
center of mass of the PTV (COMPTV).  This point will typically also correspond 
(but is not required to correspond) to the isocenter of the treatment beams.  
2) 
Prescription Isodose Surface Coverage 
The prescription isodose surface will be chosen such that 95% of the target 
volume (PTV) is conformally covered by the prescription isodose surface and 
99% of the target volume (PTV) receives a minimum of 90% of the 
prescription dose. 
3) 
Target Dose Heterogeneity 
The prescription isodose surface selected in number 2 (above) must be ≥ 
60% of the dose at the center of mass of the PTV (COMPTV) and ≤ 90% of the 
dose at the center of mass of the PTV (COMPTV). The COMPTV corresponds to 
the normalization point (100%) of the plan as noted in 1) above. 

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4) 
High Dose Spillage 
a)  Location 
Any dose greater than 105% of the prescription dose should occur 
primarily within the PTV itself and not within the normal tissues outside 
of the PTV.  Therefore, the cumulative volume of all tissue outside of 
the PTV receiving a dose greater than 105% of prescription dose 
should be no more than 15% of the PTV volume.  However, if 
possible, attempts should be made to avoid higher than the 
prescription isodose to the prostatic urethra within the prostate.  
Ideally, these hot spots will be manipulated to occur within the 
peripheral zones of the prostate.  IMRT and other techniques will be 
encouraged to accomplish this goal.  
b)  Volume 
Conformality of PTV coverage will be judged such that the ratio of the 
volume of the prescription isodose meeting criteria 1) through 4) to the 
volume of the PTV is ideally less than 1.3.  
 
5) 
Respect all critical organ dose-volume limits listed in Section 6.5.1 below. 
6) 
Urethral “hot spot” avoidance.  It is recommended that efforts be made by the 
use of compensation or intensity modulation to avoid excessive dose to the 
urethra.  The prostatic urethra should be identified as an avoidance structure 
such that dose beyond the prescription dose ideally does not fall on this 
structure.  As an example, if the treatment dose covering the PTV 
corresponds to the 80% isodose line for a given patient, hot spots of 20% 
higher dose will exist within the prostate.  The intensity modulation techniques 
should be employed to distribute these hot spots away from the prostatic 
urethra and more into the peripheral zones of the prostate.  Part of the 
rationale for daily image guidance on this protocol is to carry out this intention 
of avoiding a “hot spot” to the urethra in practice during treatment as depicted 
on the treatment plan. 
 
6.5 
Critical Structures 
6.5.1 
Critical Organ Dose-Volume Limits 
The following table lists maximum dose limits to a point or volume within several 
critical organs.  These are absolute limits, and treatment delivery that exceeds 
these limits will constitute a major protocol violation (See Section 5.7).  The dose is 
listed as total over 5 fractions and per fraction.   
 
These limits were formulated with the approval of the study committee using 
known tolerance data, radiobiological conversion models, norms used in current 
practice at academic centers.  Participating centers are encouraged to observe 
prudent treatment planning principles in avoiding unnecessary radiation exposure 
to critical normal structures irrespective of these limits.   
 
In order to verify each of these limits, the organs must be contoured such that 
appropriate dose volume histograms can be generated.  Instruction for the 
contouring of these organs will follow below. 
 
Organ 
Volume 
Dose (cGy) 
Spinal Cord 
Maximum point  dose 
 22 Gy (4.4 Gy per fraction) 
Less than 8 cc 
20 Gy (4 Gy per fraction) 

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Cauda Equina 
Maximum point  dose 
27.5 Gy (5.5 Gy per fraction) 
Less than 10 cc 
25 Gy (5 Gy per fraction) 
Sacral Plexus 
Maximum point  dose 
30 Gy (6 Gy per fraction) 
Less than 10 cc 
27.5 Gy (5.5 Gy per fraction) 
Peri-prostatic Anterior 
rectal wall 
Maximum point  dose 
 No more than 105% of the 
prescription dose 
Peri-prostatic Lateral 
rectal walls 
Maximum point  dose 
 No more than 100% of the 
prescription dose 
Less than 3 cc 
cumulative (both 
sides) 
No more than 90% of the 
prescription dose 
Peri-prostatic 
Posterior rectal wall 
and anus 
Maximum point  dose 
 No more than 45% of the 
prescription dose 
Rectum superior to 
prostate 
Maximum point dose 
30 Gy (6 Gy per fraction) 
Less than 10 cc 
25 Gy (5 Gy per fraction) 
Small intestine 
Maximum point  dose 
29 Gy (5.8 Gy per fraction) 
Less than 10 cc 
19.5 Gy (3.9 Gy per fraction) 
Prostatic urethra  
Maximum point  dose 
No more than 105% of 
prescription dose 
Bladder 
Maximum point  dose 
 No more than 105% of 
prescription dose 
Less than 10 cc 
18.3 Gy (3.65 Gy per fraction) 
Penile bulb 
Maximum point  dose 
No more than 100% of 
prescription dose 
Less than 3 cc 
30 Gy (6 Gy per fraction) 
Femoral heads 
Less than 10 cc 
cumulative (both 
sides) 
30 Gy (6  Gy per fraction) 
Skin within fold (e.g., 
the gluteal fold) 
Maximum point  dose 
20 Gy (4 Gy per fraction) 
Skin not within fold 
Maximum point  dose 
27.3 Gy (5.45 Gy per fraction) 
Seminal Vesicles 
No dose constraint 
Collect dose statistics for 
documentation only 
 
6.5.2 
Contouring of Normal Tissue Structures 
6.5.2.1 
Spinal Cord 
The spinal cord will be contoured as one structure based on the bony limits of 
the spinal canal.  The spinal cord should be contoured anywhere it is visualized 
in the treatment plan (typically superior to L2). 
6.5.2.2 
Cauda Equina 
The cauda equina will be contoured as one structure based on the bony limits of 
the spinal canal.  The cauda equina should be contoured starting superiorly at 
the bottom of the spinal cord (typically around L2 and terminal at the inferior 
extent of the thecal sac (typically at S3). 
6.5.2.3 
Sacral Plexus 
The left and right sacral plexus will be contoured collectively as one structure.  
The location of the sacral plexus will be approximated by contouring the space 
defined medially by the sacral foramina from S1-S3 including contouring within 
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cm lateral to the sacral foramina, and anteriorly about 3-5 mm from the posterior 
limits of the countour. 
6.5.2.4 
Peri-prostatic Rectal wall 
The circumference of the rectum adjacent to the prostate will be divided into 4 
equal quadrants (anterior, left lateral, right lateral, and posterior).  Assigning 0 
degrees at the most anterior aspect of the rectum at the mid sagittal plane, the 
dividing lines between each quadrant will occur at 45, 135, 225, and 315 
degrees.  The right and left lateral walls will be combined into a single structure.  
Only the rectal wall will be included in these contours, not the contents of the 
lumen.  Patients will be treated with a rectal balloon filling the lumen which 
should therefore not be included in the contours. 
6.5.2.4.1 
Anterior Peri-prostatic Rectal Wall 
Starting inferiorly just above the anal sphincter, the anterior quadrant of the 
rectal wall (from 315 to 45 degrees) should be contoured (absent the lumen) 
up to 1 cm above the superior extent of the prostate. 
6.5.2.4.2 
Lateral Peri-prostatic Rectal Wall 
Starting inferiorly just above the anal sphincter, the lateral quadrant of the 
rectal wall (from 45 to 135 degrees and also from 225 to 315 degrees) should 
be contoured (absent the lumen) up to 1 cm above the superior extent of the 
prostate.  These two structures should be combined as a single structure for 
purposes of dose volume analyses. 
6.5.2.4.3 
Posterior Peri-prostatic Rectal Wall 
Starting inferiorly just above the anal sphincter, the posterior quadrant of the 
rectal wall (from 135 to 225 degrees) should be contoured (absent the lumen) 
up to 1 cm above the superior extent of the prostate. 
6.5.2.5 
Rectum Superior to Prostate 
Starting inferiorly at the superior extent of the Peri-prostatic Rectal Wall 
described above, the entire wall and lumen of the rectum should be contoured 
up to the level of the sacral promontory. 
6.5.2.6 
Small Intestine 
The small intestines should be contoured as a conglomerate of all bowel loops 
within each CT cut starting at the first appearance of small intestine in the pelvis 
and extending superiorly up to the level of the sacral promontory within each cut. 
6.5.2.7 
Prostatic Urethra 
The prostatic urethra will be identified by the urethral catheter plus 1-2 mm of tissue 
radially into the prostate.  The inferior aspect of the prostatic urethra coincides with 
the apex of the prostate (urethrograms may be helpful in identifying the apex).  The 
superior aspect of the prostatic urethra coincides with the base of the prostate at the 
bladder inlet.   
6.5.2.8 
Bladder 
The bladder should be contoured in its entirety absent its contents.  As such, 
only the wall of the bladder is included in the dose volume analysis.  The bladder 
wall may be approximated by contouring the outer outline of the entire bladder 
and subtracting this volume from the same volume minus 0.5 cm in all directions 
(to define the inner surface of the bladder). 
6.5.2.9 
Penile Bulb 
The penile bulb will be contoured starting superiorly at the inferior aspect of the 
pelvic diaphragm (urethral sphincter) and extending inferiorly and anteriorly up 
to 3 cm. 
6.5.2.10 
Femoral heads 
The femoral heads will be contoured bilaterally as one structure. 

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6.5.2.11 
Skin 
The skin will constitute the external contour minus 5 mm.  The skin within folds, 
especially in the gluteal folds as the skin surfaces make contact, will be 
contoured as a separate structure. 
6.5.2.12 
Seminal vesicles 
The seminal vesicles should be contoured right and left as one structure.  There 
is no protocol dose constraint for these structures, but they will be contoured to 
collect dose deposition data. 
6.5.2.13     Anus 
 
       Anus will be contoured as one structure starting just inferior to rectum.  
6.6 
Documentation Requirements 
6.6.1 
In general, treatment interruptions should be avoided by preventative medical 
measures and nutritional, psychological, and emotional counseling.  Treatment 
breaks, including indications, must be clearly documented on the treatment 
record. 
 
6.7 
Compliance Criteria 
6.7.1 
Accreditation Compliance 
All criteria listed in Section 5 must be completed to the satisfaction of the study 
committee in order to be accredited.  Upon completion of the criteria, a letter will 
be sent to institutions’ PIs informing them of accreditation for the study. No 
institution will be allowed to enroll patients without accreditation. 
6.7.2 
Dosimetry Compliance 
Section 6 describes appropriate conduct for treatment planning dosimetry. 
Criteria for both major and minor deviations are provided in the table in Section 
6.4.  In addition to the criteria in section 6.4, the table in Section 6.5 lists dose 
volume limits for specific organs and structures.  Exceeding these limits by more 
than 2.5% constitutes a minor protocol violation.  Exceeding these limits by 
more than 5% constitutes a major protocol violation. 
6.7.3 
Treatment Delivery Compliance 
Set-up films will be compared to digitally reconstructed radiographs from the 
same beam’s eye view.  Deviations of less than 0.5 cm will be considered 
compliant.  Deviations from 0.5-0.75 cm will be considered minor protocol 
deviations.  Deviations greater than those listed as minor will be considered 
major protocol deviations. 
 
6.8 
R.T. Quality Assurance Reviews 
Dr. Timmerman, along with a medical physicist, will perform an RT Quality 
Assurance Review after complete data for the first 20 cases enrolled has been 
received at the University of Texas Southwestern. They will perform the next review 
after complete data for the next and subsequent 20 cases enrolled has been 
received at the University of Texas Southwestern. The final cases will be reviewed 
within 3 months after this study has reached the target accrual or as soon as 
complete data for all cases enrolled has been received, whichever occurs first. 
 
6.9 
Radiation Adverse Events 
6.9.1 
Gastro-intestinal  
Monitored treatment related toxicity associated with gastrointestinal function will 
include colitis, dehydration, diarrhea, enteritis, fistula, nausea, vomiting, 
obstruction, proctitis, fecal incontinence, stricture/stenosis, hemorrhage, and 

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ulcer.  The consequences of gastro-intestinal toxicity should all be graded 
according to the Common Terminology Criteria For Adverse Events (CTCAE). 
6.9.2 
Renal/Genitourinary/Sexual/Reproductive 
Monitored treatment related toxicity associated with renal and genito-urinary 
function will include cystitis, fistula, urinary incontinence, urinary obstruction, 
stricture/stenosis, hemorrhage, and urinary retention.  Monitored treatment 
related toxicity associated with sexual and reproductive function will include 
erectile dysfunction and ejaculatory dysfunction.  The consequences of 
renal/genitourinary/sexual and reproductive toxicity should all be graded 
according to the Common Terminology Criteria For Adverse Events (CTCAE).  
In addition, patients will fill out the AUA scoring sheets reflecting basic urinary 
function at regular intervals according to the study calendar in Appendix VI. 
6.9.3 
Neurology 
Monitored treatment related toxicity associated with neurology function will 
include myelitis, motor and sensory neuropathy, plexopathy, and pain.  The 
consequences of neurology toxicity should all be graded according to the 
Common Terminology Criteria For Adverse Events (CTCAE). 
6.9.4 
Constitutional Symptoms 
Monitored treatment related toxicity associated with constitutional function will 
include fatigue, fever, and weight loss.  The consequences of constitutional 
toxicity should all be graded according to the Common Terminology Criteria For 
Adverse Events (CTCAE). 
6.9.5 
Skin 
 
Monitored treatment related toxicity associated with skin function will include 
fibrosis, rash (desquamation), ulceration, and telangiectasia.  The 
consequences of skin toxicity should all be graded according to the Common 
Terminology Criteria For Adverse Events (CTCAE). 
6.9.6 
Quality of Life and Other Toxicities 
 
Other treatment related toxicity attributed to the therapy will be captured, 
recorded and the consequences of should all be graded according to the 
Common Terminology Criteria For Adverse Events (CTCAE).  Quality of life 
after prostate cancer treatment will be assess using the Expanded Prostate 
Cancer Index Composite (EPIC) formalism [41].  Validation and description of 
this scale can be found at the website:  
http://roadrunner.cancer.med.umich.edu/epic/epicmain.html 
 
6.10 
Serious Adverse Event Reporting  
6.10.1 
ERGO 
Electronic Research Grant Organizer (ERGO) constitutes a mechanism for 
reporting serious adverse events to the UTSW IRB for reporting purposes.   
 
Any adverse event equivalent to CTCAE V.3 grade 3, 4, or 5 or which precipitates 
hospitalization or prolongs an existing hospitalization must be reported regardless 
of designation (expected or unexpected) along with the attribution. This includes all 
deaths that occur within 30 days after the patient was discontinued from the study 
regardless of attribution AND any events that occur beyond 30 days and are 
considered probably related to treatment. 
 
Participating sub-sites must file an SAE report (the CRF plus information 
describing the event, the grade, and the attribution) within 48 hours of the 
investigator’s awareness of the occurrence of the event.  

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26 
 
 
Attribution of an event can be categorized as:  
 
Not Related 
 
Possibly Related 
 
Likely Related 
 
Adverse events (below grade 3) do not need to be submitted immediately.  Rather, 
they should be documented in the Adverse Events CRF along with a brief 
description of the event, grade, and attribution). 
 
All SAE reports should be made via FAX transmission to: 
 
Department of Radiation Oncology 
Clinical Research Office 
The University of Texas Southwestern Medical Center 
Attention:  Jean Wu, Project Manager 
FAX #: 214-648-5923 
 
 
7.0 
DRUG THERAPY  
Not applicable to this trial. 
 
8.0 
OTHER THERAPY 
8.1 
Permitted Supportive Therapy 
All supportive therapy for optimal medical care will be given during the study period 
at the discretion of the attending physician(s) within the parameters of the protocol 
and documented on each site’s source documents as concomitant medication. 
8.1.1 
Obstructive flow medicines (alpha blockers) 5 alpha reductase inhibitors) 
8.1.2 
Antiemetics 
8.1.3 
Anticoagulants 
8.1.4 
Antidiarrheals 
8.1.5 
Analgesics 
8.1.6 
Hematopoietic Growth Factors 
8.1.7 
Herbal products 
8.1.8 
Nutritional supplementation 
 
9.0 
SPECIMEN SUBMISSION 
9.1 
Specimen Investigational Nature  
Initially serum will be collected in order to build proteomic profiles of treatment 
response, however, with time there may be other analytical methodologies that are 
not yet devised.  Blood cells will be processed and RNA and DNA collected.  
Ultimately, gene expression and genotyping will be performed and correlated with 
treatment outcome or normal tissue response. 
9.2 
Specimen Collection for Translational Research 
 
 Serum will be collected and frozen for subsequent analysis for patients who 
choose to participate  
9.3 
Whole blood will be drawn [20 ml per collection timepoint: 10 ml from red top and 
10 ml from lavender top tubes] using standard procedure in order to collect 
lymphocytes as well as plasma serum.  Blood will be processed using standard 
procedure immediately after it is collected and then stored at -70 to -80 degrees C. 
The samples will be kept indefinitely or until exhausted.    

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27 
 
9.3.1 
Collection Timepoints 
 
1. Within 1 week prior to the first treatment (baseline) 
 
2. Immediately after the first treatment 
3. Immediately before the second treatment (approximately 48-72 hours after the 
first treatment) 
4. Immediately after the fifth treatment 
5. 6 months after completing the fifth treatment 
9.3.2 
A Pathology Report from the pretreatment core biopsy describing the original 
tumor specimen is required. The patient’s name and/or other identifying 
information should be removed from the report. The surgical pathology numbers 
and information must NOT be removed from the report. 
9.3.3 
For serum collection, the following materials must be provided:  the date of 
collection of the serum, timepoint of blood collection, type of sample, the protocol 
number, and the patient’s study specific study-ID number. 
9.3.4 
Submit materials for Translational Research to: 
Michael Story, Ph.D. 
UT Southwestern Medical Center at Dallas 
5323 Harry Hines Blvd, Dallas, Texas 75390 
(214) 648-5557 
Michael.Story@utsouthwestern.edu 
9.4 
Confidentiality/Storage  
9.4.1 
Upon receipt, the specimen is labeled with the protocol number and the patient’s 
assigned study-identification number only. The database only includes the 
following information: the number of specimens received, the date the specimens 
were received, documentation of material sent to a qualified investigator, type of 
material sent, and the date the specimens were sent to the investigator. No clinical 
information is kept in the database. 
9.4.2 
Specimens for translational research will be stored for an indefinite period of time 
(or until exhausted) and may be used for future studies. If at any time the patient 
withdraws consent to store and use specimens, the material will be returned to the 
institution that submitted it. 
9.4.3 
Specimen will be stored at the UT Southwestern Medical Center Division of 
Molecular Radiation Biology laboratories (NC 7.206) and the UT Southwestern 
Tissue Repository.  
 
10.0 
PATIENT ASSESSMENTS 
10.1 
Study Parameters: See Appendix II. 
10.2  Follow-up Schedule 
10.2.1  Initial follow-up visit at 1.5 months from the end of treatment. 
10.2.2  After initial follow-up visit, follow-up will be done at 3, 6, 9, and 12 months post 
therapy. 
10.2.3  Then every six months until three years post treatment. 
10.2.4  Then annually for years 3-10. 
10.2.5  A bone scan will be performed on any patient who presents with complaints of 
bone pain that cannot be attributed to any intercurrent disease. Discretionary plain 
films may be needed to evaluate lesions seen on bone scan to confirm the 
diagnosis of metastatic disease. 
 
10.3  
Criteria for Toxicity 
10.3.1  All acute and late adverse events from protocol radiation therapy will be reported 
and scored for severity using the NCI Common Terminology Criteria for Adverse 

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Events (CTCAE) version 3.0. A copy of the CTCAE v3.0 can be downloaded from 
the CTEP home page (http://ctep.info.nih.gov). 
 
Please note that this study will not be using separate toxicity scales for 
acute and late radiation adverse events. 
 
10.4  
Measurement of Response 
10.4.1  Although not required, it is encouraged that prostate tumor dimensions in 
centimeters or grams be recorded on the data collection forms for the follow up 
evaluations.  PSA levels should be obtained per study calendar. 
10.4.2  After study entry, disease evaluations will be made and recorded using the 
following criteria: 
10.4.2.1 No Evidence of Disease (NED): No clinical evidence of disease on digital rectal 
examination and no PSA failure. 
10.4.2.2 Equivocal Disease (ED): This rating will be assigned under the following 
circumstances: 
1) If abnormalities are present on the prostate digital rectal examination but are 
thought to be abnormal due to treatment and felt not to represent tumor. 
2) If clinical evidence of residual tumor is present but this has regressed from a 
previous examination (initial registration). 
3) PSA 2.1 - 4 ng/mL.  Rebiopsy is required, before starting hormone therapy, in 
any patient with PSA failure but with negative bone scan and CT scans. If the 
biopsy is negative, then they will be scored as NED. 
10.4.2.3 Progressive Disease (PD): Progressive disease will be declared if one or more of 
the following criteria are met: 
1) Clinical evidence in the prostate gland of disease progression or recurrence. 
2) Clinical or radiographic evidence of tumor recurrence within the pelvic 
lymphatics or soft tissue beneath the bifurcation of the common iliac arteries, 
3) Clinical or radiographic evidence of hematogenous (osseous, hepatic, etc.) 
and/or extrapelvic lymphatic of soft tissue relapse. 
 
10.5 
Other Response Parameters 
10.5.1  Disease-Free Interval: The disease-free interval will be measured from the date of 
accession to the date of documentation of progression or until the date of death 
(from other causes). 
10.5.2 
Time to Biochemical Failure: The RTOG-ASTRO definition (also known as the 
Phoenix definition) of PSA failure will be used. Thus, when the PSA rises by more than 
2 ng/ml above the lowest level (nadir) achieved after treatment, biochemical failure has 
occurred and the date of the failure is recorded at the time the nadir plus 2 ng/ml level 
is reached. 
10.5.3  Time to Local Progression: The time to progression will be measured from the date 
of study entry to the date of documented local progression as determined by 
clinical exam. 
10.5.4  Time to Distant Failure: The time to distant failure will be measured from the date 
of study entry to the date of documented regional nodal recurrence or distant 
disease relapse. Patients with evidence of biochemical failure, but a negative 
prostate biopsy, will be considered as distant failure only. 
10.5.5  Overall Survival: The survival time will be measured from the date of accession to 
the date of death. All patients will be followed for survival. Every effort should be 
made to document the cause of death. 

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10.5.6  Disease-Specific Survival Disease-specific survival will be measured from the date 
of study entry to the date of death due to prostate cancer. The following will be 
considered as failure events in assessing disease specific survival: 
Death certified as due to prostatic cancer. 
Death from other causes with active malignancy (clinical or biochemical 
progression). 
Death due to complications of treatment, irrespective of the status of 
malignancy. 
Death from other causes with previously documented relapse (either clinical or 
biochemical) but inactive at the time of death will not be considered in 
disease-specific survival, but will be analyzed separately. 
10.5.7 Responsibilities of the Medical Monitor: 
The medical monitor is required to review all unanticipated problems involving risk to 
subjects or others, serious adverse events and all subject deaths associated with the 
protocol and provide an unbiased written report of the event.  At a minimum, the 
medical monitor must comment on the outcomes of the event or problem and in case 
of a serious adverse event or death, comment on the relationship to participation in 
the study.  The medical monitor must also indicate whether he/she concurs with the 
details of the report provided by the principal investigator.  Reports for events 
determined by either the investigator or medical monitor to be possibly or definitely 
related to participation and reports of events resulting in death must be promptly 
forwarded to the USAMRMC ORP HRPO. 
 
11.0 
DATA COLLECTION 
Data should be submitted to: 
Department of Radiation Oncology 
Clinical Research Office 
The University of Texas Southwestern Medical Center 
Attention:  Jean Wu, Project Manager 
5801 Forest Park Road 
Dallas, Texas  75390-9183 
FAX #: 214-648-5923 
 
Patients will be identified only by initials (first middle last) and a unique study ID number 
assigned to each study participant; if there is no middle initial, a hyphen will be used (first-
last). Last names with apostrophes will be identified by the first letter of the last name. 
Participating sub-sites must remove or black-out identifiers from source documentation that 
is sent to UTSW.   
 
11.1 
Summary of Data Submission 
 
 
Item 
Due 
Demographics 
Within 2 weeks of study entry 
Eligibility and Entry Characteristics including 
baseline H&P and PSA 
Within 2 weeks of study entry 
Pathology Report  
Within 2 weeks of study entry 
AUA and EPIC baseline forms 
Within 2 weeks of study entry 
 
 
SBRT dosimetry information 
Within 1 week after completion of SBRT 
 
 
Follow-up H&P data including PSA 
After last SBRT treatment, post SBRT follow-up at 
1.5, 3, 6, 9, 12 months, then every 6 months to 3 
years; then annually for years 3-10  

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30 
 
 
 
AUA and EPIC post treatment forms 
After last SBRT treatment, post SBRT follow-up at 
1.5, 3, 12, and 18 months 
 
 
 
 
 Adverse Event assessment 
After each SBRT treatment, then post SBRT 
follow-up at 1.5, 3, 6, 9, and 12 months, then 
every 6 months to 3 years; then annually for years 
3-10  
 
13.0 
STATISTICAL CONSIDERATIONS 
 
13.1 Phase I Study Endpoints 
13.1.1 Primary Endpoint 
The primary endpoint of the phase I portion is to either reach the maximum tolerated 
dose (MTD) or a dose of 50 Gy total (whichever comes first) by escalating the dose of 
SBRT toward the tumorcidal dose of 50 Gy total.  Patients will be treated in cohorts of 
seven to fifteen,..  Toxicity will be graded using the NCI Common Toxicity Criteria for 
Adverse Events (CTCAE) v. 3.0.  A dose- limiting toxicity (DLT) is any treatment-
related grade 3, 4, or 5 toxicity in the following categories (specific conditions listed 
in section 6.9):  gastrointestinal, renal, genito-urinary, sexual- reproductive, or 
neurological.  A DLT will also include any treatment-related grade 4 or 5 toxicity 
related in the following categories (specific conditions listed in section 6.9):  
constitutional symptoms.  In addition, any other grade 4 or 5 toxicity attributed to the 
therapy constitutes DLT.  All reported DLTs will be verified by study chair, data 
monitoring committee, and independent review before final determination that a DLT 
has in fact occurred.   Doses will be escalated an additional 0.5 Gy per treatment for 
5 treatments (total 2.5 Gy per increment).  The phase I portion of the study will be 
completed when either of the following events occur:  1) the MTD for a cohort is 
reached or 2) when the highest protocol dose level is treated and tolerated (10 Gy 
per fraction, total 50 Gy) where we consider the therapy likely to be tumorcidal per 
determination of the investigators. 
13.1.2 Phase I Dose Escalation 
The phase I study is designed to end if the rate of DLTs within 90 days from the start 
of treatment is 33% or higher.  For each dose level cohorts, a total of seven to fifteen 
patients will be enrolled.  If zero out of the first seven with 90 day follow-up, two or 
fewer out of the first nine with 90 day follow-up, three or fewer out of the first twelve 
with 90 day follow-up, or four or fewer out of the first fifteen of patients with 90 day 
follow-up experience a DLT as defined above, then the dose will escalate to the next 
dose level.  If three or more of the first nine patients, four or more of the first twelve, 
or five or more of the first fifteen patients experience a DLT, then the MTD will be 
considered to have been exceeded.  The MTD will be defined as the immediately 
previous lower dose level tolerated.  The probability that at least two of nine patients 
will experience a DLT when the true rate of acute DLTs is 33% is 0.80; that is, the 
probability of making the correct decision if the true DLT rate is at least 33% is 0.80.   
 
The sample size of the phase I component of this study will not exceed 45 
patients. 
 
13.1.3 Phase I Waiting Periods 
Dose escalation on the phase I portion of this study should not occur until a sufficient 
waiting period has occurred after patients have been treated.  A period of 90 days 
must pass in order to assess toxicity.  If 90 days have transpired without DLT in each 

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of the first seven (7) patients enrolled to a specific dose level, then dose escalation 
to the next level may proceed.  Patients will continue to be enrolled to  each dose 
level (up to a maximum of 15 patients) with ongoing assessment of those reaching 
90 day follow-up so long as either criteria for defining the MTD (section 13.1.2) or 
criteria for further dose escalation is not reached.  If fifteen patients are enrolled to a 
given dose level yet criteria for adequate follow-up are not reached in a 
representative sample of patients (section 13.1.2), further enrollment to the protocol 
will be suspended until adequate follow-up is reached.  
 
13.2 Phase II Study Endpoints 
Patients will be treated at either the MTD or highest dose from the phase I study. 
13.2.1 Primary Endpoint 
Late severe GU and GI toxicity is defined as grade 3-5 GU and GI toxicity occurring 
between 270-540 days (i.e., 9-18 months) from the start of the protocol treatment. It is 
graded based on CTCAE v3.0.  Grade 3-5 GU or GI toxicity that originally occurred prior 
to 270 days from start of protocol treatment will only be considered late severe GU or GI 
toxicity if it persists at a severity grade of 3-5 based on CTCAE v3.0 after 270 days. 
13.2.2  Secondary Endpoints 
• Acute severe GU and GI toxicity is defined as grade 3-5 toxicity occurring prior to 270 
days from the start of protocol treatment. It is graded based on CTCAE v3.0. 
• Non GU and GI toxicity. 
• Biochemical failure RTOG-ASTRO definition (also known as Phoenix definition) - Thus, 
when the PSA rises by more than 2 ng/ml above the lowest level (nadir) achieved after 
treatment,, biochemical failure has occurred and the date of the failure is recorded at the 
time the nadir plus 2 ng/ml level is reached.  
• Overall survival 
• Disease-specific survival 
• Clinical progression including local/regional and distant relapse 
 
13.3 Sample Size 
13.3.1 Overview: The primary goal of this study is to estimate the rate of late grade 3-5 
genitourinary and gastrointestinal toxicity following treatment with stereotactic body 
radiation therapy.  For purposes of this phase II study, late toxicity will be defined as 
toxicity occurring 270-540 days (i.e., 9-18 months) from the start of radiotherapy. It is 
graded based on CTCAE v 3.0. 
13.3.2 Sample Size Derivation: The phase II component of this study is designed to test 
whether late GU/GI toxicity at 270-540 days from the start of treatment following the 
protocol treatment is above 10%. The sample size is determined so that the probability 
of rejecting the treatment because of excessive late toxicity is 90% if the true late toxicity 
rate is 23% or higher. Assuming an exponential distribution for time from the end of the 
acute period (270 days from the start of protocol treatment) to the occurrence of late 
toxicity, the hazard rate for the expected 10% toxicity rate and the unacceptable 23% 
toxicity rate is 0.006/month and 0.015/month, respectively. Following the asymptotic 
property of the observed hazard and using Z-test for the logarithm of the hazard ratio 
[35-36], we require 12 cases with severe late GU/GI toxicity. Thus, 47 patients are 
required to be accrued within three to four years and be followed for 270 days after the 
acute period (i.e., a total of 540 days) to have a statistical power of 90% with a one-sided 
significance level of 0.05. Considering 5% ineligible cases and lack-of-data cases, the 
sample size of the phase II component of this study is 50 patients.  Patients treated in 
phase I at the dose level ultimately used in phase II will be included in the phase II 
analysis as part of the 50 patient trial. 
 

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The sample size of the phase II component of this study will not exceed 50 
patients. 
 
13.4 Patient Accrual and Study Duration 
13.4.1 It is expected that it will take approximately three to five years to complete the study. The 
analysis for late toxicity will be carried out after each patient has had at least 270 days 
(i.e., 9 months) of follow-up from the end of the acute period, a total of 540 days (i.e., 18 
months) of follow-up. For the secondary endpoint of biochemical failure, an additional 18 
months of follow-up are needed to estimate the 3-year failure rate. Study-related data 
will be stored for 5 years after termination of the study when accrual is no longer taking 
place and all patients have discontinued follow-up procedures. Blood drawn for 
translation research will be kept indefinitely or until exhausted. 
 
13.5 Analysis Plan 
 
Interim Reports: Interim reports will be prepared every six months until the results of the 
study are published.  In general, the interim reports will contain information about patient 
accrual rate with projected completion dates of the trial, status of QA review and 
compliance rate of treatment per protocol, and the frequencies and severity of toxicity. 
13.5.2 The Analysis of Severe Late GU/GI Toxicity: This analysis will be carried out when each 
patient has had at least 270 days (i.e., 9 months) of follow-up after the end of the acute 
period, a total of 540 days (i.e., 18 months) of follow-up. The time to the occurrence of 
severe late GU/GI toxicity is defined as the time interval from start of protocol treatment 
to the date of onset of grade 3-5 GU/GI toxicity.   The time analysis for recording severe 
late GU/GI toxicity for this protocol will be limited to 540 days from start of protocol 
therapy.  If no such toxicity is observed before the time of the analysis, the patient will be 
censored at the time of the analysis. The hazard rate will be estimated by the life table 
approach with a time span of 18 months. The one-sided Z-test will be used to test the 
significance of the difference between the logarithm of the observed hazard rate and the 
logarithm of the hypothesized hazard rate of 0.006/month with variance equal to the 
reciprocal of the number of cases with late toxicity observed. Because of the lead time of 
9 months for the acute period, the 18-month late toxicity will be estimated by the 9-
month toxicity rate using the cumulative incidence approach [37] to the defined time to 
severe late GU/GI toxicity. 
13.5.3 Estimation of Secondary Endpoints Related to the Efficacy: Cumulative incidence 
approach [37] will be used to estimate the failure rate for biochemical, disease-specific, 
local-regional and distant failures. Kaplan-Meier method [38] will used to estimate the 
overall survival rate. 
 
13.6 
Gender and Minorities 
 
Projected Minority Inclusion 
 
Gender 
Ethnic Category 
Females 
Males 
Total 
Hispanic or Latino 
NA 
14 
14 
Not Hispanic or Latino 
NA 
83 
83 
Ethnic Category: Total of all subjects* 
NA 
97 
97 
 
Gender 
Racial Category 
Females 
Males 
Total 
American Indian or Alaskan Native 
NA 
2 
2 
Asian 
NA 
6 
6 
Black or African American 
NA 
16 
16 
Native Hawaiian or other Pacific Islander 
NA 
2 
2 

Version 15 
 
33 
 
 
Gender 
Ethnic Category 
Females 
Males 
Total 
White 
NA 
57 
57 
Racial Category: Total of all subjects* 
NA 
97 
97 
 
NA = Not Applicable 
 
14.0 
DATA SAFETY MONITORING PLAN 
 
14.1 Data Safety Monitoring Committee and Institutional IRB reporting 
 
A data safety monitoring committee including radiation oncologists not participating in this 
trial will be formed to review toxicity endpoints and efficacy data. In the phase I component, 
the data safety monitoring committee will review and verify all reported DLTs. In particular, 
this committee will scrutinize the grading of adverse events and the attribution to therapy 
previously assigned by the investigators.  This panel will have access to basic patient 
information so as to have the ability to critically review toxicity events.  This study will use 
this committee to perform ongoing safety assessment at regular defined intervals defined in 
the statistics section of this protocol.  Unexpected toxicities occurring between defined 
interim analyses points will be reported to the treating center’s IRB and also to the 
University of Texas Southwestern IRB. 
 
14.2 Early Stopping for Toxicity 
 
In phase I, stopping for toxicity will be related to dose limiting toxicity as described in the 
statistical section.  Early stopping of the phase II portion of this protocol will be based on 
unacceptable toxicity, defined as grade 3 - 5 toxicity related to the following organ systems:  
gastrointestinal, renal, genitor-urinary, sexual, reproductive, neurological, blood, bone 
marrow, or constitutional symptoms OR any other grade 4 or 5 toxicity attributed to the 
therapy occurring in 30% or more of treated patients.  If a single patient has more than one 
unacceptable toxicity, they will only be counted as one unacceptable toxicity for this 
analysis.   
 
Three interim analyses of toxicity are planned after 25% (12 patients), 50% (24 patients), 
and 75% (36 patients) of the total number of evaluable patients to be accrued in phase II.  
These interim analyses will be done after patients have finished their toxicity assessment 
periods for each group (i.e., 90 days of post therapy follow-up). 
 
The following early stopping rules reject the null hypothesis that the toxicity rate is less than or 
equal to 10% in favor of the alternative hypothesis that the toxicity rate is at least 30% with an 
overall Type I error rate of no more than 0.055: 
 
6 or more cases of unacceptable toxicities out of the first 12 evaluable patients, or 
7 or more cases of unacceptable toxicities out of the first 24 evaluable patients, or 
8 or more cases of unacceptable toxicities out of the first 36 evaluable patients. 
 
The final analysis will test the same null hypothesis using the rejection rule of 10 or more 
patients with unacceptable toxicities out of the total sample of 47 evaluable patients. This will 
insure an overall significance level of 0.05 for the final conclusion. If more than 47 of the 50 
accrued patients are evaluable, then the first 47 evaluable patients will be used for this analysis. 
 
If the number of unacceptable toxicities observed demonstrate via the monitoring rules 
above that the  treatment-related unacceptable toxicity rate is 30% or more, consideration 

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will be initiated for stopping the study.  In this case, the study chair, study PIs, and 
statistician will review the toxicity data along with the Data Safety Monitoring Committee and 
make appropriate recommendations about continuing the study.   Additionally, the 
treatment-related unacceptable toxicity rate will continued to be monitored during the five 
year follow-up period.  If the unacceptable toxicity rate exceeds 30% at any time during the 
five year follow-up period, the study chair, study PIs, and statistician will review the toxicity 
data along with the Data Safety Monitoring Committee and make appropriate 
recommendations about reporting the information.  
 
14.3 Reporting Requirements and Responsibilities of the Organizing PI to the USAMRMC, 
ORP, and HRPO: 
 
The protocol will be conducted in accordance with the protocol submitted to and approved 
by the USAMRMC ORP HRPO and will not be initiated until written notification of approval 
of the research project is issued by the USAMRMC ORP HRPO. 
 
Accurate and complete study records will be maintained and made available to 
representatives of the U.S. Army Medical Research and Materiel Command as a part of 
their responsibility to protect human subjects in research.  Research records will be stored 
in a confidential manner so as to protect the confidentiality of subject information. 
 
All unanticipated problems involving risk to subjects or others, serious adverse events 
related to participation in the study and subject deaths related to participation in the study 
should be promptly reported by phone (301-619-2165), by email 
(hsrrb@det.amedd.army.mil), or by facsimile (301-619-7803) to the USAMRMC, Office of 
Research Protections, Human Research Protection Office.  A complete written report will 
follow the initial notification.  In addition to the methods above, the complete report will be 
sent to the U.S. Army Medical Research and Materiel Command, ATTN: MCMR-ZB-PH, 
504 Scott Street, Fort Detrick, Maryland 21702-5012. 
 
Any deviation to the protocol that may have an effect on the safety or rights of the subject or 
the integrity of the study must be reported to the USAMRMC ORP HRPO as soon as the 
deviation is identified. 
 
Major modifications to the research protocol and any modifications that could potentially 
increase risk to subjects must be submitted to the USAMRMC ORP HRPO for approval 
prior to implementation.  All other amendments will be submitted with the continuing review 
report to the USAMRMC ORP HRPO for acceptance. 
 
A copy of the approved continuing review report and the local IRB approval notification will 
be submitted to the USAMRMC ORP HRPO as soon as these documents become 
available.  A copy of the approved final study report and local IRB approval notification will 
be submitted to the USAMRMC ORP HRPO as soon as these documents become 
available. 
 
The knowledge of any pending compliance inspection/visit by the FDA, OHRP, or other 
government agency concerning clinical investigation or research, the issuance of Inspection 
Reports, FDA Form 483, warning letters or actions taken by any Regulatory Agencies 
including legal or medical actions and any instances of serious or continuing noncompliance 
with the regulations or requirements will be reported immediately to USAMRMC ORP 
HRPO. 

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36 
 
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3. Michalski JM, Winter K, Purdy JA, Parliament M, Wong H, Perez CA, Roach M, 
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 Radiation therapy dose escalation for prostate cancer: a rationale for IMRT. 
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Int J Radiat Oncol Biol Phys. 2005 Dec 1;63(5):1463-8. 
11. Mott JH, Livsey JE, Logue JP.  Development of a simultaneous boost IMRT class solution for a 
hypofractionated prostate cancer protocol.  Br J Radiol. 2004 May;77(917):377-86. 
12. Douglas, BG, and Fowler, JF:  The effects of multiple small doses of x-rays on skin reactions in the 
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13. Livsey JE, Cowan RA, Wylie JP, Swindell R, Read G, Khoo VS, Logue JP.  Hypofractionated conformal 
radiotherapy in carcinoma of the prostate: five-year 
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14. Amer AM, Mott J, Mackay RI, Williams PC, Livsey J, Logue JP, Hendry JH.  Prediction of the benefits 
from dose-escalated hypofractionated intensity-modulated radiotherapy for prostate cancer.  Int J Radiat 
Oncol Biol Phys. 2003 May 1;56(1):199-207. 
15. Blomgren H, Lax I, Naslund I, et al: Stereotactic high dose fraction radiation therapy of 
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16. Blomgren, H, Lax, I, Goranson, H, et al:  Radiosurgery for tumors in the body:  clinical experience using 
a new method.  J Radiosurgery 1998; 1(1): 63-74. 
17. Uematsu, M, Shioda, A, Suda, A, et al:  Computed tomography-guided frameless stereotactic 
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18. Lax I, Blomgren H, Naslund I, et al:  Stereotactic radiotherapy of malignancies in the abdomen. 
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19. Kavanagh, B., Timmerman, R.D., editors, Stereotactic Body Radiation Therapy,  Lippincott, Williams, 

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and Wilkins, Baltimore, MD, 2005. 
20. Timmerman R, Papiez L, McGarry R, Likes L, DesRosiers C, Frost S, Williams M.  Extracranial 
stereotactic radioablation: results of a phase I study in medically inoperable stage I non-small cell lung 
cancer.  Chest. 2003 Nov;124(5):1946-55. 
21. Wulf J, Haedinger U, Oppitz U, Thiele W, Mueller G, Flentje M.   Stereotactic radiotherapy for primary 
lung cancer and pulmonary metastases: a noninvasive treatment  approach in medically inoperable 
patients.  Int J Radiat Oncol Biol Phys. 2004 Sep 1;60(1):186-96. 
22. Potters L, Steinberg M, Rose C, Timmerman R, Ryu S, Hevezi JM, Welsh J, 
Mehta M, Larson DA, Janjan NA; American Society for Therapeutic Radiology and Oncology; American 
College of Radiology. American Society for Therapeutic Radiology and Oncology and American College 
of Radiology practice guideline for the performance of stereotactic body radiation therapy.  Int J Radiat 
Oncol Biol Phys. 2004 Nov 15;60(4):1026-32. 
23. Wolbarst, AB, Chin, LM, Svensson, GK:  Optimization of radiation therapy:  integral-response of a 
model biological system.  Int J Radiat Oncol Biol Phys 1982; 8:1761-1769. 
24. Yeas, RJ, Kalend, A:  Local stem cell depletion model for radiation myelitis.  Int J Radiat Oncol Biol 
Phys 1988; 14:1247-1259. 
25. Schefter, TE, Kavanagh, BD, Timmerman, RD, Cardenes, HR, Baron, A, Gaspar, LE, “A phase I trial of 
stereotactic body radiation therapy (SBRT) for liver metastases,” Int J Radiat Oncol Biol Phys 
62(5):1371-1378, 2005. 
26. McGarry, RC, Papiez, L, Williams, M, Whitford, T, Timmerman, RD, “Stereotactic body radiation therapy 
of early stage non-small cell lung cancer:  Phase I study,” Int J Radiat Oncol Biol Phys 63(4):1010-5, 
2005. 
27. Papillon J.  Intracavitary irradiation of early rectal cancer for cure. A series of 186 
cases. 1975.  Dis Colon Rectum. 1994 Jan;37(1):88-94. 
28. Madsen BL, Hsi RA, Pham HT, Presser J, Esagui L, Corman J, Myers L, Jones D.  Intrafractional 
stability of the prostate using a stereotactic radiotherapy technique. 
Int J Radiat Oncol Biol Phys. 2003 Dec 1;57(5):1285-91. 
29. Collins CD, Lloyd-Davies RW, Swan AV.  Radical external beam radiotherapy for localised carcinoma of 
the prostate using a hypofractionation technique. 
Clin Oncol (R Coll Radiol). 1991 May;3(3):127-32. 
30. Lloyd-Davies RW, Collins CD, Swan AV.   Carcinoma of prostate treated by radical external beam 
radiotherapy using hypofractionation. Twenty-two years' experience (1962-1984).  Urology. 1990 
Aug;36(2):107-11.  
31. Grills IS, Martinez AA, Hollander M, Huang R, Goldman K, Chen PY, Gustafson 
GS.  High dose rate brachytherapy as prostate cancer monotherapy reduces toxicity 
compared to low dose rate palladium seeds.  J Urol. 2004 Mar;171(3):1098-104. 
32. Martinez AA, Pataki I, Edmundson G, Sebastian E, Brabbins D, Gustafson G.  Phase II prospective 
study of the use of conformal high-dose-rate brachytherapy as monotherapy for the treatment of 
favorable stage prostate cancer: a feasibility report.  Int J Radiat Oncol Biol Phys. 2001 Jan 1;49(1):61-
9.  
33. Yoshioka Y, Nose T, Yoshida K, Oh RJ, Yamada Y, Tanaka E, Yamazaki H, Inoue 
T, Inoue T.  High-dose-rate brachytherapy as monotherapy for localized prostate cancer: aretrospective 
analysis with special focus on tolerance and chronic toxicity. 
Int J Radiat Oncol Biol Phys. 2003 May 1;56(1):213-20. 
34. Yoshioka Y, Nose T, Yoshida K, Inoue T, Yamazaki H, Tanaka E, Shiomi H, Imai 
A, Nakamura S, Shimamoto S, Inoue T.  High-dose-rate interstitial brachytherapy as a monotherapy for 
localized prostate cancer: treatment description and preliminary results of a phase I/II clinical trial.  Int J 
Radiat Oncol Biol Phys. 2000 Oct 1;48(3):675-81. 
35. Schoenfeld D The Asymptotic Properties of Nonparametric-Tests For Comparing Survival Distributions 
(1981) Biometrika, 68: 316-19   . 
36. Schoenfeld & Richter Nomograms For Calculating The Number Of Patients Needed For A Clinical-Trial 
With Survival As An Endpoint (1982) Biometrics, 68: 316-19. 
37. Gray RJ: A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann 
Stat. 16:1141-1154, 1988. 

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38. Kaplan EL and Meier P: Nonparameteric estimation from incomplete observations. J. Amer. Statist. 
Assoc. 53:457-481, 1958. 
39. Fleming T. One-sample multiple testing procedure for phase II clinical trials. Biometrics. 38:143-151, 
1982. 
40. Grills IS, Martinez AA, Hollander M, et al: High dose rate brachytherapy as prostate cancer 
monotherapy reduces toxicity compared to low dose rate palladium seeds. J Urol 171:1098-104, 2004 
41. Wei J, Dunn R, Litwin M, Sandler H, and Sanda M. "Development and Validation of the Expanded 
Prostate Cancer Index Composite (EPIC) for Comprehensive Assessment of Health-Related Quality of 
Life in Men with Prostate Cancer", Urology. 56: 899-905, 2000. 

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39 
 
APPENDIX I 
STUDY PARAMETER TABLE 
 
 
Pre-Treatment 
During 
Treatment 
Follow-Up (months after therapy) 
 
Within 
180 days 
of study 
entry 
Within 90 
days of 
study 
entry 
Within 
30 days 
of study 
entry 
With each 
treatment 
1.5  3 
6 
9 
12 
18 
24 
30 
36 
42 
48 
54 
Prostate Biopsy 
with Gleason 
Score for 
Diagnosis 
Xe  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PSA 
 
 
Xa 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
History/physical 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight  
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Performance 
Status 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CT or MRI of 
pelvis 
 
X 
 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
AUA Symptom 
index 
 
 
X 
 
X 
X 
 
 
X 
X 
 
 
 
 
 
 
EPIC 
Questionnaire 
 
 
X 
 
X 
X 
 
 
X 
X 
 
 
 
 
 
 
BUN, creatinine, 
CBC, & platelets 
 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Draw for 
Translational 
Research  
 
 
X f 
Xg 
 
 
X 
 
 
 
 
 
 
 
 
 
Informed consent 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor response 
evaluation 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Bone scanD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event 
evaluation 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
aBaseline PSA should be recorded as pre-hormonal level if taking hormones even if >30 days prior to entry. 
bCT or MRI prior to each treatment may include conebeam CT, orthogonal imaging of seeds or daily ultrasound 
localization is acceptable alternative to daily CT or MRI. 
cFor reference but not eligibility 
dAt time of PSA failure or suspected progression 
eRepeat prostate biopsy for patients with biopsy >180 days from study entry is not required unless the PSA taken 
at within 30 days of study entry is greater than the PSA taken at the time of biopsy by more than 5 ng/ml. 
f1 week prior to first treatment 
gImmediately after first treatment, immediately before second treatment, immediately after fifth treatment. 

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APPENDIX II 
 
ZUBROD 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 
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 self-care. Totally confined to bed or 
(Karnofsky 10-20). 
 
5 
Death (Karnofsky 0). 
 
 
 
KARNOFSKY PERFORMANCE SCALE 
100 
Normal; no complaints; no evidence of disease 
 
90 
Able to carry on normal activity; minor signs or symptoms of disease 
 
80 
Normal activity with effort; some sign or symptoms of disease 
 
70 
Cares for self; unable to carry on normal activity or do active work 
 
60 
Requires occasional assistance, but is able to care for most personal 
needs 
 
50 
Requires considerable assistance and frequent medical care 
 
40 
Disabled; requires special care and assistance 
 
30 
Severely disabled; hospitalization is indicated, although death not 
imminent 
 
20 
Very sick; hospitalization necessary; active support treatment is necessary 
 
10 
Moribund; fatal processes progressing rapidly 
 
0 
Dead 
 

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2 
 
APPENDIX III 
 
AJCC STAGING SYSTEM 
PROSTATE, 6th Edition 
 
DEFINITION OF TNM 
 
Primary Tumor, Clinical (T) 
TX  
 
Primary tumor cannot be assessed 
 
T0  
 
No evidence of primary tumor 
 
T1  
 
Clinically inapparent tumor neither 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 one-half of one lobe or less 
 
 
T2b  
Tumor involves more than one-half of one lobe but not both 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 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 classified not as T3, but 
as T2. 
 
Regional Lymph Nodes (N) 
NX  
Regional lymph nodes cannot be assessed 
N0  
No regional lymph node metastasis 
N1  
Metastasis in regional lymph node(s) 
 
Primary Tumor, Pathologic (pT) 
pT2*  
Organ confined 
 
pT2a  Unilateral, involving one-half of one lobe or less 
 
pT2b  Unilateral, involving more than one-half of one lobe but not both lobes 
 
pT2c  
Bilateral disease 
pT3  
Extraprostatic extension 
 
pT3a  Extraprostatic extension** 
 
pT3b  Seminal vesicle invasion 
 
pT4  
Invasion of bladder, rectum 
*Note: There is no pathologic T1 classification 
**Note: Positive surgical margin should be indicated by an R1 descriptor (residual microscopic 
disease).

Version 15 
 
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APPENDIX IV (continued) 
 
AJCC STAGING SYSTEM 
PROSTATE, 6th Edition 
 
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. 
 
Histopathologic Grade (G) 
GX  
 
Grade cannot be assessed 
G1  
 
Well-differentiated (slight anaplasia [Gleason 2-4]) 
G2  
 
Moderately differentiated (moderate anaplasia [Gleason 5-6]) 
G3-4  
 
Poorly undifferentiated or undifferentiated (marked anaplasia [Gleason 7-10]) 
 
Stage Grouping 
Stage I   
 
T1a  
 
 
N0  
 
 
M0  
 
 
G1 
 
Stage II  
 
T1a  
 
 
N0  
 
 
M0  
 
 
G2, G3-4 
 
 
 
T1b  
 
 
N0  
 
 
M0  
 
 
Any G 
 
 
 
T1c  
 
 
N0  
 
 
M0  
 
 
Any G 
 
 
 
T1  
 
 
N0  
 
 
M0  
 
 
Any G 
 
 
 
T2  
 
 
N0  
 
 
M0  
 
 
Any G 
 
Stage III  
 
T3  
 
 
N0  
 
 
M0  
 
 
Any G 
 
Stage IV  
 
T4  
 
 
N0  
 
 
M0  
 
 
Any G 
 
 
 
Any T   
 
N1  
 
 
M0  
 
 
Any G 
 
 
 
Any T   
 
Any N   
 
M1  
 
 
Any G 
 

Version 15 
 
4 
 
APPENDIX V 
 
GLEASON CLASSIFICATION 
 
Histologic patterns of adenocarcinoma of the prostate 
 
Pattern 
Margins 
Tumor Areas 
Gland 
Pattern 
Gland 
Size 
Gland 
Distribution 
Stromal 
Invasion 
1 
Well defined 
Single, separate, 
round 
Medium 
Closely 
packed 
Minimal, 
expansile 
2 
Less definite 
Single, separate rounded but 
more variable 
Medium 
Spaced up to 
one gland 
diameter, 
average 
Mild, in larger 
stromal planes 
 
3 
Poorly defined 
Single, separate 
more irregular 
Small, 
medium, 
or large 
Spaced more 
than one 
gland 
diameter, 
rarely packed 
Moderate, in 
larger or 
smaller stromal 
planes 
or 
3 
Poorly defined 
Rounded masses of 
cribriform or papillary 
epithelium 
Medium 
or large 
Rounded 
masses with 
smooth sharp 
edges 
Expansile 
masses 
4 
Ragged, 
infiltrating 
Fused glandular 
masses or "hypernephroid" 
Small 
Fused in 
ragged 
masses 
Marked, 
through smaller 
planes 
5 
Ragged, 
infiltrating 
Almost absent, few tiny 
glands or signet ring 
Small 
Ragged 
anaplastic 
masses of 
epithelium 
Severe 
between 
stromal fibers 
or destructive 
or 
5 
Poorly defined 
Few small lumina in rounded 
masses of solid epithelium 
central necrosis 
Small 
Rounded 
masses and 
cords with 
smooth sharp 
edges 
Expansile 
masses 
 
The Gleason Classification is a system of histologic grading based on over-all pattern of tumor growth at 
relatively low-magnification (40 to 100x). Five patterns of growth are recognized and numbered in order of 
increasing malignancy. Because of histologic variation in the tumor, two patterns are recorded for each case, 
a primary or predominate pattern and a secondary or lesser pattern. 
 
The Gleason Score is the sum of the primary and secondary pattern, If only one pattern is present, the 
primary 
and secondary pattern receive the same designation. 
 
(Primary = 2, Secondary = 1, Gleason = 3) 
(Primary = 2. Secondary = 2, Gleason = 4) 
 
1. Gleason, D.F. et al: Prediction of prognosis for prostatic carcinoma by combined histologic grading and 
clinical staging. J Urol 111:58, 1974. 

Version 15 
 
5 
 
APPENDIX VI 
 
ON-STUDY AUA SYMPTOM SCORE (PQ) 
 
PATIENT NAME _____________________________ 
CASE # ________________ 
 
INSTITUTION NAME __________________________ 
TOTAL SCORE __________ 
 
PLEASE FILL OUT THIS SHORT QUESTIONNAIRE TO HELP US FIND OUT MORE ABOUT ANY 
URINARY PROBLEMS YOU MIGHT HAVE. CIRCLE A NUMBER IN EACH COLUMN THAT BEST 
DESCRIBES YOUR SITUATION. YOU MUST ANSWER ALL QUESTIONS. 
 
Not at all 
Less 
than one 
time in 
five  
Less than  
half the 
time  
About 
half  
the time  
More 
than  
Half the 
time  
Almost  
always  
1. 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  
2. 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  
3. 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  
4. How often do you find it 
difficult to postpone urination?  
0  
1  
2  
3  
4  
5  
5. Over the past month or so, 
how often have you had a 
weak urinary stream?  
0  
1  
2  
3  
4  
5  
6. Over the past month or so, 
how often have you had to 
push or strain to begin 
urination?  
0  
1  
2  
3  
4  
5  
Not at all 
Once 
every 8 
hours 
Once 
every 4 
hours 
Once 
every 3 
hours 
Once 
every  
2 hours 
At least 
once 
every 
hour  
7. Over the past month or so, 
how often did you most 
typically get up at night to 
urinate?  
0  
1  
2  
3  
4  
5  
 
Total per column 
 
 
        ________   ________   ________   ________   ________ 
 
 
 
_________________________________________ 
 
_______________________________  
Patient Signature  
 
Date This Form was Completed  

Version 15 
 
6 
 
APPENDIX VII 
 
EXPANDED PROSTATE CANCER INDEX COMPOSITE (EPIC) 
 
Quality of life after prostate cancer treatment will be assessed using the Expanded Prostate 
Cancer Index Composite (EPIC) formalism [41].  Validation and description of this scale can be 
found at the website:  http://roadrunner.cancer.med.umich.edu/epic/epicmain.html 
 
The actual forms used for this assessment can also be downloaded on a PDF file from this 
website.  We will use the standard form for this protocol. 
 
 
 
 
Appendix VIII 
 
Risks to Subjects 
 
Procedure 
Risks 
Measures to Minimize Risks 
 
History and physical 
exam (H&P), digital rectal 
exam (DRE), PSA test at 
study entry and 1.5, 3, 6, 9,  
and 12 months post-
treatment, then every 6 
months for 5 years; annually 
for years 5-10) 
 
Blood draws (at all study 
timepoints) 
 
Zubrod Performance status 
evaluation; AUA 
Questionnaire – to measure 
urinary symptoms; EPIC 
Questionnaire – to assess 
quality of life after prostate 
cancer treatment 
 
Metallic marker implantation 
into prostate (once prior to 
treatment) 
 
Self-administered Fleet’s 
enema (1 or 2 prior to 
screening visit and each 
treatment) 
  
Discovery of previously unknown 
condition/progression of prostate 
cancer 
 
 
 
 
 
Discomfort, bleeding, bruising, 
dizziness, fainting, infection 
 
Discomfort, psychological stress 
of answering personal questions 
 
 
 
 
 
 
Discomfort, bleeding, bruising, 
dizziness, fainting, infection 
 
 
Discomfort 
 
 
 
 
 
Will be performed by MD and/or nurse 
practitioner with oncology experience.  
 
 
 
 
 
 
Blood will be drawn by an experienced 
phlebotomist. 
 
Subjects informed that they may refuse to 
answer, take a break, or discontinue 
participation at any time  
 
 
 
 
 
An experienced professional will perform 
this procedure.  
 
 
Detailed instructions will be provided. 
 
 
 
 

Version 15 
 
7 
 
 
Insertion of urethral catheter 
(at treatment planning) 
 
 
 
 
 
Insertion of rectal balloon (at 
treatment planning and prior 
to each treatment) 
 
 
 
Stereotactic body radiation 
therapy (5 treatments) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Very likely:  Pain or discomfort 
during insertion; Less likely, but 
serious: Bleeding from the 
urethra or bladder, urethral 
irritation with urge to urinate 
frequently, urinary tract infection  
 
Very likely:  Pain or discomfort 
during insertion; Less likely, but 
serious: Bleeding from the 
rectum, rectal irritation with urge 
for frequent bowel movements 
 
Dermatologic:  
Very likely:  Skin redness or 
tanning, rash, itching, peeling, 
temporary hair loss in treatment 
area 
 
Gastrointestinal. 
Very likely: Nausea, diarrhea, 
abdominal cramps, rectal 
irritation with frequent urge to 
have a bowel movement, bowel 
movements with mucus; 
Less likely:  Incontinence; 
Less likely but serious:  Injury to 
bowel, rectal bleeding, intestinal 
obstruction 
 
Genitourinary. 
Very likely:  Bladder irritation 
with frequent urge to urinate, 
burning on urination, injury to 
urethra slowly causing a 
narrowing (may need surgical 
correction); 
Less likely:  Incontinence; 
Less likely but serious:  
Injury to bladder, urethra or 
other tissues in pelvis or 
abdomen; urinary obstruction 
 
Sexual/Reproductive.  
Very likely:  Impotence (may be 
irreversible); 
Less likely: Ejaculatory 
dysfunction (may be 
irreversible), sterility 
 
Teratogenic:  possible harm to 
an unborn child   
Every effort will be made to minimize 
discomfort. Antibiotics will be prescribed 
as necessary.  The urethra may be 
numbed with local anesthesia, and the 
thinnest catheter possible will be used. 
 
 
Performed by an experienced physician, 
nurse, or technician. 
 
 
 
 
Referral to a dermatologist if necessary. 
 
 
 
 
 
Premedication with corticosteroid 
suggested; insertion of rectal balloon 
 
 
 
 
 
 
 
 
 
Recommended premedication with 
corticosteroid, alpha blocker, 5 alpha 
reductase inhibitor; imaging guidance 
prior to each treatment suggested; care 
taken to minimize dose to bulbous urethra 
and bladder; wedges or other modulation 
methods to steer higher dose away from 
prostatic urethra 
 
 
 
 
 
Restriction of dose on penile bulb. 
 
 
 
 
 
 
Use of contraception required for 
participation; need for immediate 

Version 15 
 
8 
 
 
 
 
 
 
 
 
 
FAX transmittal of case report 
forms (CRFs) to primary site 
 
Unforeseen risks 
 
 
 
Constitutional:   
Very likely:  fatigue 
 
 
General discomfort from lengthy 
(60 – 90 minutes) procedure 
 
Loss of privacy 
 
 
 
 
 
E.g., unpredictable interaction 
between SBRT and concomitant 
medications            
reporting of causing a pregnancy stressed 
 
Participants will be educated and asked 
to inform study personnel if encounter 
symptoms. 
 
Premedication with analgesic 
recommended. 
 
Sensitive patient information will be 
blacked-out.  CRFs will only be identified 
by subject initials and unique, study 
identification number before fax 
transmittal. 
 
Strong encouragement to report any 
difficulties and keep researchers aware of 
any change in medications