A Feasibility Study of Oral Hormonal Therapy and Radiation for Non-metastatic, Intermediate or High Risk Prostate Cancer in Men 70 and Older or With Medical Comorbidities
Phase: NA
Conditions: Prostate Cancer
Sponsor: University of Chicago

 
1
IRB# 10-625-A                                          PROTOCOL 
 
 
 
A feasibility study of oral hormonal therapy and radiation for non-metastatic, intermediate or 
high risk prostate cancer in men 70 and older or with medical comorbidities 
 
Coordinating Center: 
University of Chicago Medical Center 
 
Principal Investigator: 
Stanley Liauw, M.D. 
Department of Radiation and Cellular Oncology 
5758 S. Maryland Avenue MC 9006 
Chicago, IL 60637 
sliauw@radonc.uchicago.edu 
 
Co-Investigators: 
Department of Radiation and Cellular Oncology 
Daniel Haraf, M.D. 
Andrew Howard, M.D. 
Matthew Koshy, M.D. 
Department of Medicine 
Russell Szmulewitz, M.D 
Department of Medicine, Section of Geriatrics 
William Dale, M.D. 
Department of Urology 
Glenn Gerber, M.D 
 
 
 
Research and Nursing Personnel: 
Department of Radiation and Cellular Oncology 
Fauzia Arif, *** 
Denise Cloutier, R.N.  
 
Statistician: 
Department of Health Studies, Biostatistics Laboratory 
Theodore Karrison, Ph.D. 
 
 
 
Protocol version:  
 
12.15.2010 (Initial Submission) 
 
01.21.2011 (Amendment #1) 
 

 
2
07.19.11 (Amendment #2) 
 
10.20.2014 (Amendment #3) 
 
04.19.2017 (Amendment #4) 
 

 
3
SCHEMA 
 
 
 
 
Patient Population: (see section 3.0 for complete eligibility criteria) 
 Age ≥70 and/or Charlson Comorbidity Score ≥2  
 Biopsy proven prostate adenocarcinoma 
 No clinical or radiographic evidence of metastatic disease 
 By risk groupings, 2+ intermediate risk factors or 1+ high risk factor 
 Zubrod performance status ≤ 2 
 No history of androgen deprivation therapy (ADT) [GnRH agonist or antiandrogen] 
 No prior pelvic radiation 
 
Required Sample Size:  Minimum of 40 experimental subjects and 30 control subjects (total of 70).  
 
Study Center:  
University of Chicago Medical Center,. 
 
Concept and Rationale:  Randomized data support the addition of ADT to standard dose external beam 
radiation (RT) in men with non-metastatic, intermediate and high risk prostate cancer.  However, the role 
of medical castration with ADT is less certain when dose-escalated RT is administered.  In particular, the 
benefit of standard ADT remains unclear in older men and in those with medical comorbidites in whom 
the risks of therapy may be heightened.    Therefore, we propose to de-intensify standard ADT in this 
population, in favor of dual oral androgen manipulation with an antiandrogen and a 5-alpha reductase 
inhibitor (5AR).  We hypothesize that health-related quality of life (HRQOL) will be improved with the 
removal of the gonadotropin releasing hormone (GnRH) and that oncologic outcomes will not be 
compromised.  Dual oral androgen manipulation therapy will be delivered prior to and concurrent with 
dose-escalated radiation with the goal of maximizing its anti-tumoral effect. 
 
Primary Objective:  To test the hypothesis that health-related quality of life (HRQOL) of men over 70 
and/or with medical comorbidities treated with oral androgen manipulation and radiation (RT) will be 
improved compared to that of patients undergoing standard ADT and RT.   
 
Secondary Objectives:  To test the hypothesis that the oncologic outcomes of patients treated with dual 
oral androgen manipulation with RT will be comparable to the outcomes of patients undergoing standard 
ADT with RT.   
 
 
Study Design:  Single arm prospective, feasibility trial.  A synchronous control cohort receiving standard 
ADT will be followed for collection of data on HRQOL endpoints. 
 
Statistical Methods: 
Prostate adenocarcinoma with 
2+ intermediate risk  OR
1+ high risk feature
AND
Age 70 years or older AND/OR
Charlson Comorbidity Score 2+
2 months oral androgen 
manipulation                                   
(anti-androgen + 5AR inhibitor)
Dose-escalated External 
Beam Radiation + Oral 
Androgen Manipulation 
Continue 5AR inhibitor 
alone x 2 years

 
4
Patient reported data will be grouped into summary scores in each relevant quality of life domain 
(sexual, urinary, bowel, hormonal/vitality.  Quality of life and toxicity scores will be compared to 
those of patients in the synchronous control cohort receiving standard ADT with radiation.  
Univariate analysis of mean scores will be performed using a two sample t-test.  Scores will also be 
compared between trial patients and the control cohort while controlling for covariates using linear 
regression analysis. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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TABLE OF CONTENTS 
 
SCHEMA ................................................................................................................................................. 3 
1. 
OBJECTIVES ................................................................................................................................. 5 
1.1. 
Primary Objectives ................................................................................................................. 5 
1.2. 
Secondary Objectives ............................................................................................................. 5 
2. 
BACKGROUND ............................................................................................................................. 5 
2.1. 
Intermediate and High Risk Prostate Adenocarcinoma ..................................................... 5 
2.2. 
Rationale .................................................................................................................................. 6 
3. 
PATIENT SELECTION ................................................................................................................ 8 
3.1. 
Eligibility Criteria ................................................................................................................... 8 
3.2. 
Exclusion Criteria ................................................................................................................. 10 
3.3. 
Inclusion of Minorities and Women .................................................................................... 11 
4. 
TREATMENT PLAN ................................................................................................................... 11 
4.1. 
Dual Oral Androgen Manipulation ..................................................................................... 11 
4.2. 
Measuring Health-Related Quality of Life and Toxicity .................................................. 11 
4.3. 
Experimental Controls ......................................................................................................... 12 
4.4. 
General Concomitant Medication and Supportive Care Guidelines ............................... 12 
4.5. 
Duration of Therapy ............................................................................................................. 12 
4.6. 
Duration of Follow Up .......................................................................................................... 13 
4.7. 
Criteria for Removal from Study ........................................................................................ 13 
    4.8.      Registration Process 13 
5. 
RADIATION THERAPY GUIDELINES .................................................................................. 13 
5.1. 
Treatment Planning Procedures ......................................................................................... 13 
5.2. 
Dose Specifications: 3D Conformal Radiotherapy (3DCRT) or IMRT .......................... 13 
5.3. 
Suggested Critical Structure Dose Constraints ................................................................. 13 
5.4. 
Technical Factors .................................................................................................................. 14 
5.5. 
Treatment Planning/Target Volumes ................................................................................. 14 
5.6. 
Treatment Verification ......................................................................................................... 15 
6. 
RISKS AND BENEFITS .............................................................................................................. 15 
6.1. 
Adverse Events ...................................................................................................................... 15 
6.2. 
Reporting ............................................................................................................................... 16 
6.3. 
Data and Safety Monitoring ................................................................................................ 17 
7. 
STUDY CALENDAR ................................................................................................................... 17 
8. 
MEASUREMENT OF EFFECT ................................................................................................. 18 
9. 
STATISTICAL CONSIDERATIONS ........................................................................................ 18 
9.1. 
Study Design/Primary Endpoint ......................................................................................... 18 
9.2. 
Sample Size/Accrual Rate .................................................................................................... 18 
9.3. 
Analysis of Secondary Endpoints ........................................................................................ 19 
10. 
CONFIDENTIALITY .............................................................................................................. 19 
References .............................................................................................................................................. 20 
APPENDIX A: ...................................................................................................................................... 22 
APPENDIX B ........................................................................................................................................ 28 
APPENDIX C: ...................................................................................................................................... 32 
APPENDIX D: ...................................................................................................................................... 34 
 
 
 

 
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1. OBJECTIVES 
 
1.1. Primary Objectives  
The broad objective is to test the feasibility of delivering dual oral androgen manipulation with 
an antiandrogen and a 5-alpha reductase (5AR) inhibitor in conjunction with dose-escalated 
radiation (RT) in intermediate and high risk prostate cancer patients 70 years of age or older 
and/or with moderate to severe medical comorbidities.  The primary objective is to test the 
hypothesis that health-related quality of life (HRQOL) in patients treated with dual oral 
androgen manipulation will be improved compared to that of controls treated with standard 
androgen deprivation therapy (ADT) including a gonadotropin releasing hormone (GnRH) 
agonist +/- an antiandrogen.  
 
1.2.  Secondary Objectives 
The secondary objective is to test the hypothesis that oncologic outcomes including 
biochemical progression free survival, distant metastasis free survival, cause specific survival, 
and overall survival after treatment with dual oral androgen manipulation and dose escalated 
radiation will be comparable to the outcomes of patients treated with standard ADT.  
 
1.3.  Tertiary Objectives 
For select men who consent to a research biopsy, we would like to analyze the RNA expression 
of prostate cancers treated with hormonal therapy prior to radiation for prostate cancer. We 
would a comparison using tissue from the same patient, before any treatment (initial biopsy) 
and then after two  months of ADT (at the time of fiducial marker placement) to show how 
RNA expression changes in the tumor of the prostate with ADT. We would also compare 
differences in expression across the 2 cohorts of patients, treated with oral-only ADT and 
traditional injectable ADT. The hypothesis is that oral-only ADT would induce similar changes 
within the tumor, thus complementing the clinical outcome evaluation (primary and secondary 
objectives) with a mechanistic evaluation.  
 
 
2. BACKGROUND 
 
2.1. Intermediate and High Risk Prostate Adenocarcinoma 
 
Prostate cancer is the most common non-dermatologic malignancy and the second leading 
cause of cancer-related death in men in the United States.  In 2010, an estimated 217,730 men 
will be diagnosed with prostate cancer, and 32,050 will die of their disease.[1]  Prostate cancer 
is predominately a disease affecting older men, with 75% of cases diagnosed in men aged 65 
and older.[2]  Despite a trend toward earlier stage at diagnosis with the widespread use of 
prostate specific antigen (PSA) screening, a significant percentage of patients are diagnosed 
with advanced disease.  In an analysis of over 10,800 men with prostate cancer diagnosed 
between 1990 and 2007, over 50% of patients entering the cohort between 2004 and 2007 were 
diagnosed with intermediate or high risk prostate cancer. [3]   
 
Multiple treatment options exists for intermediate and high risk prostate cancer ranging from 
active surveillance to aggressive combined modality therapy with surgery and/or radiation with 
or without androgen deprivation therapy (ADT).  Treatment decisions involve consideration of 
disease features including clinical T stage, PSA, and Gleason score.  In addition, the therapeutic 
approach should take into account comorbidities, quality of life concerns, and patient 
preferences.   

 
7
 
Therapeutic decision-making can be particularly complicated in men with a limited life 
expectancy.  In these cases, weighing the oncologic benefits of treatment against the possibility 
of toxicity related to a given therapy is clouded by competing risks of mortality related to 
comorbid illnesses and aging.   The majority of patients with intermediate or high risk disease 
will undergo definitive therapy including either surgery or radiation, but advanced age and 
comorbidities are known to influence the choice of primary treatment.  In one series of over 
11,000 patients, 4% of those over age 75 underwent surgery as primary therapy compared to 
60% of patients under the age of 75. [4]   Patients who are elderly or who have multiple 
medical illnesses are more likely to receive external beam radiation than younger, healthier 
men.[5]   
 
 
2.2. Rationale 
 
Extensive evidence from randomized trials demonstrates a benefit in PSA control, cause-
specific, and in some cases, overall survival, with the addition of ADT to radiation in men with 
both intermediate [6, 7] and high risk prostate cancer [8-10].   In these randomized trials, 
radiation was delivered to doses on the order of 66-70 Gy.  With improvements in techniques 
for radiation delivery, doses can now be safely escalated upwards of 80 Gy with significant 
improvements in disease control.  Multiple randomized trials have demonstrated absolute 
improvements in 5-year biochemical control in all risk groups by 10 to 20% with doses in the 
range of 74-80 Gy.[11-15]   Dose escalated radiation has therefore become standard practice in 
patients receiving radiation alone; however, the role of dose escalated radiation in combination 
with ADT in patients with intermediate and high risk disease has not been fully elucidated.  
This is, in large part, the rationale for the ongoing Radiation Therapy Oncology Group 0815 
trial which randomizes patients with intermediate risk prostate cancer to 79.2 Gy of radiation 
with or without Leuprolide and Bicalutamide. 
 
 
While the benefits of ADT have been well-established in randomized trials, so have the 
toxicities; androgen blockade with a GnRH agonist has well-known potential adverse effects 
including sexual dysfunction (loss of libido, impotence), decreased bone mineral density, hot 
flashes, hematologic toxicity (anemia), fatigue, hyperglycemia, hypercholesterolemia, 
hypertension, anxiety, depression, breast tenderness, and pain.   For complete androgen 
blockage, GnRH agonists are commonly given in conjunction with a nonsteroidal antiandrogen 
(e.g. bicalutamide). However, the side effects of ADT are, for the most part, driven by the 
GnRH agonist component of treatment, which induces a castrate state.  In a randomized 
comparison of bicalutamide monotherapy versus leuprolide monotherapy for nonmetastatic 
prostate cancer, bicalutamide monotherapy increased bone mineral density and resulted in less 
fatigue, sexual dysfunction, fat accumulation, and vasomotor flushing than leuprolide 
monotherapy. [16]  
 
Due to the significant toxicities associated with ADT, and the uncertain benefit in the setting of 
dose escalation, the role of ADT in the elderly and in patients with significant comorbidities is 
particularly unclear.  Some question the role of further testosterone suppression in elderly men 
in whom up to 80% meet the criteria for hypogonadism before treatment.[17]  Furthermore, the 
elderly may have heightened sensitivity to the adverse effects of ADT resulting in more severe 
quality of life detriment than in younger patients.  In a randomized trial from Harvard showing 
an overall survival benefit with the addition of short-term ADT to radiation in intermediate and 
high risk patients, a post-randomization analysis revealed a significant interaction between 

 
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comorbidity score and the effect of ADT on survival.  In patients with moderate or severe 
comorbidities, the survival benefit to adding ADT to radiation was lost. [18]  The lack of 
benefit to ADT seen in some groups may in part be due to hastening of cardiovascular disease, 
and thus death due to causes other than prostate cancer.   Furthermore, given the long natural 
history of prostate cancer, the beneficial effects of ADT may be masked by competing causes 
of mortality in aging and unhealthy populations who are unlikely to benefit from aggressive 
therapy.   
 
However, there is some clinical evidence in support of the use of ADT even in the elderly or 
those with significant comorbidities.  A reanalysis of the Radiation Therapy Oncology Group 
(RTOG) 85-31 trial comparing ADT until progression versus no ADT in patients treated with 
radiation for high risk non-bulky disease, there was no impact of hormonal therapy on the risk 
of cardiovascular mortality.[19]  In the Harvard randomized study of radiation with or without 
short term ADT, of 206 patients enrolled, there were 78 with mild or no comorbidity who were 
over the age of 72.  Among the 70% of these men who were healthy, all cause mortality at 8 
years was 16% in those treated with ADT plus radiation compared to 41% in those receiving 
radiation alone.[20]  More investigation is warranted to clarify the risks and benefits of ADT in 
addition to radiation in patients with medical comorbidities and advanced age in order to 
improve patient selection. 
 
One alternative to medical castration with a GnRH agonist is nonsteroidal antiandrogen 
monotherapy.  Due to the aforementioned toxicity profiles, bicalutamide monotherapy has been 
studied in the setting of locally advanced, node positive, recurrent, and metastatic prostate 
cancer as an alternative to gonadal suppression.  A multicenter randomized trial comparing 
bicalutamide monotherapy to medical or surgical castration in patients with locally advanced or 
metastatic disease revealed no difference in disease progression or overall survival with a 
median 6.5 years follow-up in the group without metastases.  In addition, measures of sexual 
interest, physical capacity, and bone mineral density were significantly higher in the 
bicalutamide arm.[21]  In contrast, gynecomastia and breast pain were more common in the 
group treated with bicalutamide alone.   
 
The Bicalutamide Early Prostate Cancer Program is the largest study of bicalutamide 
monotherapy as an adjuvant to standard treatment in patients with localized or locally advanced 
prostate cancer.  The study was comprised of 3 parallel trials: one in North America (trial 23), 
one in Mexico, South Africa, Australia, and Europe (trial 24), and one in Scandinavia (trial 25).  
The trials randomized over 8,000 patients to placebo or bicalutamide (150 mg QD) following 
the standard therapy of choice including watchful waiting (in trials 24 and 25 only), radical 
prostatatectomy, or radiation.  In 1,370 patients who underwent radiation (median dose 64 Gy) 
with a median follow-up of over 7 years, patients randomized to bicalutamide after radiation 
had prolonged biochemical and objective progression free survival compared to those receiving 
placebo (HR 0.61 and HR 0.75, respectively).  Furthermore, patients treated with bicalutamide 
with locally advanced disease (T3-T4 or N1 M0) had superior overall survival to those 
receiving placebo (HR 0.65).[22]  This overall survival benefit is in line with the 23% 
reduction in overall deaths seen in RTOG 85-31 which randomized patients with locally 
advanced, non-bulky disease to radiation followed by goserelin or radiation alone.[23] 
 
Another class of testosterone modulators, 5-alpha reductase (5AR) inhibitors, blocks the 
intraprostatic conversion of testosterone to its more potent form, dihydrotestosterone.  In 
addition, 5AR inhibitors down-regulate androgen receptor expression and may decrease the rate 
of subsequent androgen independent prostate cancers. [24]  Dutasteride and finasteride are 

 
9
effective in the treatment of benign prostatic hyperplasia and male pattern baldness, and they 
are generally well tolerated because serum testosterone levels are maintained.  The Prostate 
Cancer Prevention Trial (PCPT) compared finasteride to placebo in men at high risk for 
prostate cancer; men randomized to finasteride had a 25% reduction in the incidence of prostate 
cancer.[25]  A similar effect was noted in a randomized study testing dutasteride to placebo for 
the prevention of prostate cancer in men at high risk; the relative risk reduction with the use of 
dutasteride was 23% for the incidence of prostate cancer over 4-years.[26]  As monotherapy for 
either localized or advanced prostate cancer, 5AR inhibitors may have some effect on 
progression of disease, however no studies have confirmed an effect on survival. [27-29]   
 
Several phase II trials have investigated 5AR inhibitors in combination with antiandrogens with 
promising findings.  A CALGB study investigated the role of finasteride plus flutamide in 101 
patients with rising PSA after definitive surgery or radiation therapy.  In 98.6% of patients, 
PSA was reduced 80% below baseline.  Approximately 2/3 of patients achieved undetectable 
PSA levels, and amongst this group, only one patient progressed with a median of 16 months 
follow up. [30]  In sequential phase II studies at Walter Reed Army Medical Center, patients 
with rising PSA after definitive treatment received either combined flutamide and finasteride or 
flutamide monotherapy.  In comparing the two cohorts, those receiving combined therapy had 
greater PSA decreases and lower nadir values.  On multivariable analysis, patients on combined 
therapy were less likely to progress (HR 0.21).  There was no difference in the frequency of 
side effects between the two arms. [31]  In the setting of metastatic prostate cancer, a UK 
randomized trial compared goserelin plus flutamide versus goserelin plus finasteride versus 
flutamide plus finasteride.  The PSA value at 24 weeks decreased 97-99% from baseline and 
was no different between the 3 groups, although the group that was spared from goserelin 
therapy appreciated less sexual toxicity. [32]  
 
Dual oral androgen manipulation has not been formally investigated as definitive treatment for 
untreated prostate cancer, nor as a concurrent therapy with radiation.  The proposed study will 
investigate the role of dual oral androgen manipulation overlapping with radiation as an 
alternative to a GnRH agonist.  We hypothesize that the proposed treatment will result in less 
quality of life decline than standard therapy.  In this study, we aim to demonstrate the 
feasibility of administering radiation therapy with oral hormonal therapy to a population of 
prostate cancer patients of advanced age or with comorbidities and to demonstrate the 
feasibility of evaluating a number of quality of life endpoints. After some preliminary data are 
established, we anticipate moving forward with a larger phase II study design, testing radiation 
therapy with oral only versus standard hormonal therapy, with a primary endpoint of quality of 
life.  Disease outcome would be an important secondary endpoint; we also theorize that dual 
oral androgen manipulation will impart some anti-tumoral effect or radiosensitization, thus 
resulting in acceptable oncologic outcomes. The data from this larger randomized phase II 
study could then potentially contribute towards a phase III, cooperative group, randomized 
study testing for a quality of life benefit, or for non-inferiority regarding efficacy of therapy. 
 
3. PATIENT SELECTION 
3.1. Eligibility Criteria 
 
3.1.1. Age ≥ 70 years 
                                
        AND/OR 
 
Charlson comorbidity index score ≥ 2 (see Appendix C)  

 
10
(Prostate cancer diagnosis does not contribute to total score) 
 
3.1.2. Pathologically (histologically) proven diagnosis of prostatic adenocarcinoma. 
 
3.1.3. Intermediate or high risk for recurrence according to the following criteria: 
 
Two or more of the following intermediate risk features for recurrence  
 Gleason Score = 7  
 PSA 10-20 ng/ml 
 Clinical Stage T2b-T2c  
 Percent positive biopsy cores ≥50% 
                                          
OR 
 
One or more of the following high risk features for recurrence 
 Gleason Score 8-10 
 PSA >20 ng/ml 
 Clinical Stage T3a-T4 
 
3.1.4. Clinically negative lymph nodes as established by imaging (pelvic +/- abdominal CT or 
MRI), nodal sampling, or dissection, except as noted immediately below: 
 
 
Patients with intermediate risk factors only do not require abdominopelvic imaging, 
but these studies may be obtained at the discretion of the treating physician.  
 
For men with any high risk feature (psa > 20, gleason score >8, or clinical stage T3), a 
pelvic CT or MRI, are required. It is recommended that the duration between these scans 
and study registration be less than 60 days, but if the time period is >60 days and the 
opinion of the clinician is that repeat studies would offer limited benefit, then these studies 
do not need to be repeated. A lymph node will be considered radiographically positive 
if it is >1.5cm in size, occurs within the expected distribution for prostate cancer 
metastasis (i.e. internal iliac or obturator fossa), and is without classic benign 
features (i.e. fatty hilum). Patients with lymph nodes equivocal or questionable by 
imaging are eligible for inclusion in this study.  
3.1.5. No evidence of bone metastases (M0) on bone scan. 
• 
Patients with intermediate risk factors only do not require a bone scan, but these 
studies may be obtained at the discretion of the treating physician.  
• 
Patients with any high risk factors are required to undergo a bone scan. It is 
recommended that the duration between these scans and study registration be less 
than 60 days, but if the time period is >60 days and the opinion of the clinician is 
that repeat studies would offer limited benefit, then these studies do not need to be 
repeated. 
• 
Equivocal bone scan findings are allowed if additional imaging (e.g. plain film x-
rays, or CT) does not confirmmetastasis. 
 
3.1.6. History/physical examination (to include, at a minimum, digital rectal examination of 
the prostate and examination of the skeletal system and abdomen, and formal comorbidity 
assessment via the Charlson Comorbidity Index within 60 days prior to registration. 
 
3.1.7. Zubrod Performance Status 0-2 

 
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3.1.8. Age ≥ 18 
 
3.1.9. Baseline serum PSA value performed with an FDA-approved assay (e.g., Abbott, 
Hybritech) within 60 days prior to registration 
 
3.1.10.  Baseline serum testosterone obtained within 60 days prior to registration 
 
3.1.11. Study entry PSA and serum testosterone must not be obtained during the following time 
frames: (1) 10-day period following prostate biopsy; (2) following initiation of oral 
androgen manipulation; (3) within 30 days after discontinuation of finasteride or 
dutasteride 
 
3.1.12. CBC/differential obtained within 60 days prior to registration with adequate bone 
marrow function defined as follows: 
 
 Absolute neutrophil count (ANC) ≥ 1,800 cells/mm3 
 Platelets ≥ 100,000 cells/mm3 
 Hemoglobin ≥ 8.0 g/dl (Note: The use of transfusion or other intervention to 
achieve Hgb ≥8.0 g/dl is acceptable.) 
 
3.1.13. Patient must be able to provide study-specific informed consent prior to study entry. 
 
3.1.14. Liver function parameters as follows: 
 
 Total Bilirubin ≤2 x institutional upper limit of normal 
 AST (SGOT) or ALT (SGPT) ≤2 x institutional upper limit normal 
 
3.2. Exclusion Criteria 
 
 
3.2.1. Prior radical surgery (prostatectomy), high-intensity focused ultrasound (HIFU) or 
cryosurgery for prostate cancer 
 
3.2.2. Prior hormonal therapy, such as LHRH agonists (e.g., goserelin, leuprolide), 
antiandrogens (e.g., flutamide, bicalutamide), estrogens (e.g., DES), or bilateral 
orchiectomy 
 
3.2.3. Use of 5-alpha reductase inhibitors (finasteride, dutasteride) specifically prescribed for 
the treatment of prostate cancer. 
 
3.2.4. Prior or concurrent cytotoxic chemotherapy for prostate cancer; prior chemotherapy for 
a different cancer is permitted. 
 
3.2.5. Prior radiation, including brachytherapy, to the region of the prostate that would result 
in overlap of RT fields. 
 
3.2.6. Active lupus or scleroderma 
 

 
12
3.2.7. Severe, active co-morbidity, including but not limited to:  
 
3.2.7.1.Unstable angina within the last 6 months without subsequent corrective 
cardiovascular procedure. 
3.2.7.2.Acute bacterial or fungal infection requiring intravenous antibiotics at the time of 
registration. 
 
3.2.7.3.  Hepatic insufficieny with AST, ALT, or Bilirubin > 2 x upper limit of normal, 
clinical jaundice, and/or coagulation defects 
 
3.2.7.4. Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC 
definition; note, however, that HIV testing is not required for entry into this protocol. 
Patients who are HIV seropositive but do not meet criteria for diagnosis of AIDS are 
eligible for study participation. 
 
3.3. Inclusion of Minorities and Women 
 
All races and ethnic groups are eligible for this trial.  Women are not eligible as the natural 
history and epidemiology of prostate cancer is such that only men develop the disease.   
 
4. TREATMENT PLAN 
 
4.1. Dual Oral Androgen Manipulation 
 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential risks 
are described in Section 6. 
 
After study enrollment, patients will initiate dual oral androgen manipulation therapy consisting of 
an androgen receptor blocker and a 5AR inhibitor according to the following dose and route 
schedules: 
 
 Bicalutamide 50 mg PO daily 
 Dutasteride 0.5 mg PO daily (recommended) or Finasteride  5 mg PO daily  
 
During week 6-8 of oral androgen manipulation therapy, patients will undergo CT simulation for 
radiation planning.  After 8 weeks of hormonal therapy, patients will begin dose escalated radiation 
with concurrent androgen manipulation for approximately 7-8 weeks, Monday through Friday.  
Details regarding planning and administration of RT are described in Section 5.   
 
Following completion of radiation, having completed 4 total months of dual androgen 
manipulation, patients will discontinue Bicalutamide.  All patients will continue taking the 5AR 
inhibitor as monotherapy for 2 years after completion of radiation for a total of 2 years, 4 months 
of treatment. 
 
4.2. Measuring Health-Related Quality of Life and Toxicity 
Patient-reported outcome measures will include a modified version of the Expanded Prostate 
Cancer Index Composite (EPIC-26) which has been validated as an alternative to the complete 
questionnaire (EPIC-50).[33]  The questionnaire will include all EPIC-26 items as well as 
additional items in the hormonal/vitality domain drawn from the full length EPIC-50.  General 

 
13
health-related quality of life, including fatigue, will be assessed with the PROMIS v1.0 Global 
short form and the EQ-5D visual scale for quality of life. All items will be consolidated into 2 
questionnaires.  The first questionnaire is the standard questionnaire administered to all patients 
with prostate cancer in the department of radiation oncology (see Appendix A).  A supplemental 
four page questionnaire will be administered to all patients on trial and to all consenting control 
patients at baseline (see Appendix B).  Both questionnaires will again be administered at 1-2 
months after initiation of hormonal treatment (before RT), at 3-4 months (during RT), and at 6 
months after initiation of study therapy. Questionnaires will be completed in writing by the patient. 
Questionnaires at 12, 18, and 24 months after completion of radiation therapy will not be required, 
although any collected data over this time frame will be recorded and available for analysis. 
 
The evaluation period of acute radiation-related toxicity will be defined by the period from the start 
of radiation to three months following the completion of radiation.  Toxicity will be graded 
according to Radiation Therapy Oncology Group (RTOG) acute toxicity scale (see Appendix D).  
Toxicity will be recorded on a weekly basis during radiation treatment and at the first follow up 
visit.  Chronic toxicities will also be graded according to the RTOG toxicity scale and will be 
recorded at each point of clinical contact beyond the third month after completion of radiation.  
 
 
4.3. Experimental Controls 
 
Patients who meet eligibility criteria of the study but who do not enroll on the trial who receive 
standard ADT with radiation will be approached for participation in the parallel data collection 
study.  These patients will serve as the control group with which to compare HRQOL outcomes of 
patients treated on trial.  Patients consenting to enrollment on the parallel data collection study will 
receive standard of care treatment, follow-up, imaging, and laboratory studies not subject to the 
plan described in this protocol.  Health information may be recorded from the electronic medical 
record.  Patients on the data collection study will be asked to complete the same supplemental four-
page questionnaire (see Appendix B) as those on trial at baseline, 1-2 months after initiation of 
standard ADT (before RT), and at 6 months.  Completion of the supplemental questionnaire will 
not be required at 12 18, and 24 months after initiation of radiation, however any collected data 
over this time frame will be recorded and available for analysis.   In addition, all controls will 
complete the six-page questionnaire which is standard practice for all patients treated in the 
department of radiation oncology according to usual practice. 
 
 
4.4. General Concomitant Medication and Supportive Care Guidelines 
 
Development of painful mastitis and gynecomastia are potential side effects of antiandrogen 
therapy in the absence of gonadal suppression.  There is no restriction towards the use of radiation 
for the prophylaxis or treatment of breast tenderness or gynecomastia.  Patients should not receive 
Tamoxifen or other estrogen modulating therapy during treatment on the trial given concern for 
unknown effects on the hormonal milieu.  Treatment with breast radiation to breast tissue should be 
clearly documented for each patient in whom it is employed.  If prophylactic or therapeutic 
intervention is sought, a dose of 12 Gy in 3 fractions using en face electrons is preferred.  
 
4.5. Duration of Therapy 
 
Duration of dual oral androgen manipulation will be 4 months in all patients.  The duration of 5AR 
inhibitor use will be 2 years, 4 months.  Radiation therapy should be delivered over the course of 7-

 
14
8 weeks (Monday through Friday) beginning after the initial 8 weeks of oral androgen 
manipulation.  Treatment delays should be avoided unless: 
 Intercurrent illness prevents further administration of treatment 
 There are unacceptable adverse event(s) 
 The patient decides to withdraw from the study, or 
 General or specific changes in the patient’s condition render the patient unacceptable for 
further treatment in the judgment of the investigator. 
 
The use of continued treatment with 5AR beyond 2 years, 4 months is at the discretion of the 
treating physician. 
 
4.6. Duration of Follow Up 
Patients will be followed on protocol through the completion of therapy (2 years after completion 
of radiation therapy). Beyond this time point, further data collection will be at the discretion of the 
treating physician. It is encouraged to continue follow-up every six months until 5 years after 
completion of radiation therapy, and monitor serum PSA over each of these visits, according to 
standard practice.  
 
4.7. Criteria for Removal from Study 
Patients will be removed from the study when any of the criteria listed in Section 4.5 applies.  The 
reason for study removal and the date the patient was removed must be documented in the Case 
Report Form. 
 
4.8 Registration Procedures 
 Guidelines for the Lead  (University of Chicago):  
All patients should be registered by the responsible Clinical Research Associate and or 
Research Nurse in the Velos Database after consent and prior to the start of treatment. The 
appropriate eligibility criteria in 3.1 should be confirmed prior to registration. 
 
 
4.9 Tissue Collection 
For patients consenting to tissue collection portion of the study, the first block of FFPE tissue will be 
taken from the left over samples of Prostate biopsy done at initial diagnosis. If the patient has more 
than one diagnostic biopsy then tissue will be taken from the most recent biopsy sample. 
 
A research biopsy will be collected at the time of intra-prostatic fiducial marker placement, after the 
initial 2 months of hormonal therapy. The marker placement is considered standard of care therapy, 
using a transrectal ultrasound probe (similar to the approach for a prostate biopsy). The biopsy would 
include patients in both treatment and control group. If the patient has had prior MRI, these images can 
be fused to the ultrasound using software (UroNav) which will increase the yield of the biopsy for 
tumor. The tissue collected will be stored at HRTC. 
 
The following tables outline the requirements for tissue banking. Tissue will be collected and stored 
for batched future analysis. 
 
Biospecimen Type 
Collection time point 
Number of samples 

 
15
A paraffin embedded tissue 
block of primary prostate 
cancer taken at initial 
diagnostic biopsy (left over 
sample) 
Pretreatment, before 
starting any hormonal 
therapy 
1 block 
2 cores of paraffin 
embedded tissue of tumor  
After 2 months of 
hormonal therapy at the 
time of fiducial marker 
placement , for 
consenting patients 
2 blocks of FFPE 
 
Tumor biopsy for molecular analysis will be conducted. Either fresh tissue or archived paraffin 
embedded specimens will be used for analysis. RNA from tumor samples will be isolated using 
standard techniques. We would like to 1) analyze intra-patient differences in RNA expression at initial 
biopsy specimen and after two months of hormonal therapy, and 2) compare the inter-patient 
differences in RNA expression in the oral ADT cohort versus the traditional injectable ADT cohort to 
test the hypothesis that oral-only ADT results in a similar RNA expression profile to traditional 
therapy.  
 
5. RADIATION THERAPY GUIDELINES 
 
5.1. Treatment Planning Procedures 
5.1.1. Placement of fiducial markers in the prostate gland (e.g. gold markers) for image 
guidance is recommended but not required. 
 
5.1.2. Simulation will be CT-based in all cases. The use of urethral contrast at the time of 
simulation is recommended but not required. Patients will be positioned supine on a flat 
tabletop with a customized thermoplastic immobilization cast or a molded foam cradle for 
stabilization and setup reproducibility.  
 
5.2. Dose Specifications: 3D Conformal Radiotherapy (3DCRT) or IMRT 
The prostate and seminal vesicles will be treated to a dose of 50-50.4 Gy in 1.8-2 Gy fractions 
prescribed to the PTV1.  Subsequently, the prostate and any additional gross disease will be treated 
to a cumulative total dose of 75.6-79.2 Gy in 1.8-2 Gy fractions prescribed to the PTV2.  The 
PTV2 prescription dose may be reduced to 72 Gy at the discretion of the treating radiation 
oncologist only if it is felt that critical structure dose constraints cannot be met for that particular 
case at a prescription dose of 75.6-79.2 Gy.   All attempts should be made to deliver the dose with 
the heterogeneity constraints and adherence to the critical structure parameters listed below in 
Table 1. If 3DCRT is used, more relaxed rectal and bladder constraints are acceptable, but the 
rectal V70Gy must be ≤20% in all cases. 
 
 
 
5.3. Suggested Critical Structure Dose Constraints        
Table 1.                            
Target or Tissue 
(priority) 
Parameter  
Target 
 
PTV (++++) 
V100% (%)  
≥ 95% 
 
V95% (%) 
≥ 98% 
 
V105%* 
≤ 10% 

 
16
 
V110%* 
≤ 5% 
 
Max dose to 
voxel 
≤ 115% 
Rectum (+++) 
V70Gy (%) 
≤ 10% 
 
V65Gy (%) 
≤ 20%  
 
V40Gy (%) 
≤ 40%  
Bladder (++) 
V70Gy 
≤ 15% 
 
V65Gy  
≤ 30%  
 
V40Gy (%) 
≤ 60%  
Femoral heads (+) 
V50Gy (%) 
≤ 10%  
Penile bulb (++) 
V50Gy  
≤ 50%  
 
 
5.4. Technical Factors 
 
RT will be delivered with megavoltage equipment at energies ≥6 MV.   
 
5.5. Treatment Planning/Target Volumes 
 
The definition of volumes will be in accordance with the ICRU Report #50: Prescribing, Recording, 
and Reporting Photon Beam Therapy. 
 
5.5.1. The recommended CTV1 includes the entire prostate gland and the proximal 2 cm of 
the seminal vesicles.  In general, it is recommended that patients with intermediate risk 
disease and no evidence of seminal vesicle involvement should have at least the proximal 
1.0 cm of seminal vesicles included in the target volume.  The entire seminal vesicles 
should be included for any patients who have prostate cancer involving any portion of the 
seminal vesicles.  
   
5.5.2. The CTV2 is defined by the physician as the entire prostate gland. If there is seminal 
vesicle involvement, it is recommended to include the entire seminal vesicles . If the rectal 
V70Gy ≤20% cannot be met, then the uninvolved portion of the seminal vesicle may be 
excluded from the final CTV2 volume.  
 
5.5.3. The Planning Target Volume (PTV1) will provide a margin around the CTV1 to 
compensate for the variability of treatment set up and internal organ motion. A range of 5-
10 mm around the CTV1 is required to define the PTV1. Superior and inferior margins 
(capping) should be 5-10 mm depending on the thickness and spacing of the planning CT 
scan. Careful consideration should be made when defining the 5-10 mm margin in 3 
dimensions. 
 
5.5.4. The Planning Target Volume (PTV2) will provide a margin around the CTV2 to 
compensate for the variability of treatment set up and internal organ motion. A range of 5-
10 mm around the CTV2 is required to define each respective PTV. Superior and inferior 
margins (capping) should be 5-10 mm depending on the thickness and spacing of the 
planning CT scan. Careful consideration should be made when defining the 5-10 mm 
margin in 3 dimensions. 
 

 
17
5.5.5. The ICRU Reference Points are to be located in the central part of the PTV and, 
secondly, on or near the central axis of the beams. Typically these points should be 
located on the beam axes or at the intersection of the beam axes. 
 
5.5.6. Normal Critical Structures to be defined on the treatment planning CT scan will include 
the following: bladder (the outer bladder wall), rectum (from its origin at the rectosigmoid 
flexure to the inferior-most extent of the ischial tuberosities), bilateral femora (to the level 
of ischial tuberosity), penile bulb, and skin. Any small bowel within the primary beam 
aperture should be defined as well. All structures will be contoured in their entirety as 
solid organs. 
 
5.5.7. A dose reduction to 72 Gy minimum PTV dose is permitted if the above constraints 
cannot be met at the planned dose level of 78 Gy. Of note, the penile bulb constraint is to 
be regarded as a suggested guideline, and adherence to this should not, in any way, result 
in compromised coverage of the dose delivery to the target volume. 
 
 
5.6. Treatment Verification 
5.6.1. First day port films or orthogonal pair portal images must be obtained. Thereafter, 
weekly verification films or images of orthogonal isocenter views (anterior to posterior 
and lateral projection) are required. The use of daily image guided therapy (using fiducial 
markers or transabdominal ultrasound) is highly recommended. 
 
5.6.2. For IMRT the intensity profiles of each beam must be independently verified and 
compared to the planned field intensity. Portal films are not required for IMRT but 
orthogonal verification films are required, just as for 3DCRT. These images are to be 
archived by the institution for later review if requested by the study chair. 
 
 
6. RISKS AND BENEFITS 
 
The study will be fully explained to the subjects emphasizing the potential risks and benefits of their 
participation: the potential loss of their confidentially with regards to their prostate cancer, the closer 
monitoring of their progress due to both research and medical staff working on their case, and the 
altruistic aspect of helping men in the future with prostate cancer.  No monetary gain will be offered to 
the subjects and they will be informed that that their decision will have no impact on the quality of care 
they will receive. The primary investigator will answer any and all questions in full. Subjects will be 
given a copy of the consent for their own records and will be given instructions as to how to withdraw 
from the study if they change their mind.  
 
Medication and radiation side effects will be discussed with all patients.  Adverse events will be 
monitored and reported. 
 
6.1. Adverse Events 
 
6.1.1. Dutasteride: 
Side effects of dutasteride may include serum testosterone increase, thyroid-stimulating 
hormone increased, impotence, libido decreased, ejaculation disorders (≤1%), gynecomastia, 
breast tenderness or pain, hypersensitivity (pruritus, rash, urticaria, swelling face/lips, 

 
18
angioedema), dizziness, edema, diminished urinary flow, hepatic impairment.  Pregnant women 
or women trying to conceive should not handle the product. 
6.1.2. Finasteride 
Side effects of finasteride may include, impotence, decreased libido, neuromuscular or skeletal 
weakness, postural hypotension, edema, dizziness, somnolence, ejaculation disturbances, 
gyncomastia, dyspnea, rhinitis, hypersensitivity (pruritus, rash, urticaria, swelling face/lips), 
breast tenderness, testicular pain, and diminished urinary flow.   Women should not handle 
finasteride as its active ingredient is absorbed through skin; pregnant women should not handle 
finasteride as it may negatively impact fetal development. 
 
6.1.3. Antiandrogen (Bicalutamide) 
Side effects of antiandrogen therapy may include gynecomastia, breast tenderness or pain, 
hepatotoxicity (including rare cases of fatal hepatitis), inhibition of spermatogenesis, hot 
flashes, gastrointestinal disorders, diarrhea, nausea, weakness, pruritus, decreased libido, 
erectile dysfunction, and rash.  Bicalutamide should be discontinued if ALT rises above two 
times the upper limit of normal or the patient develops jaundice.  
 
 
6.1.4. Radiation 
Radiation side effects are limited to the area involved in the treatment field.  Acute and late 
toxicity related to radiation therapy may include fatigue, skin erythema, diarrhea or loose 
stools, damage to the bowel or rectum (including stricture or obstruction, bleed, fistula 
formation, or perforation), radiation enteritis, dysuria, hematuria, increased urinary frequency, 
urethral stricture, urinary incontinence, decreased sexual function, and impotence. 
 
6.2. Reporting 
All life threatening Grade 4 or fatal toxicities (grade 5) must be reported immediately and 
evaluated. 
 University of Chicago Reporting Guidelines: 
o If the reaction requires reporting, the Research Nurse or MD reports the adverse 
reaction to the Cancer Clinical Trials Office (CCTO) at 773-702-5149 by the end of 
the business day when he/she becomes aware of the event.  Events occurring after 
business hours will be reported to the CCTO by 12 pm (noon) the next business day. 
o The following information is required when calling in the event: 
 Caller’s Name and Telephone Number 
 Patient Initials 
 Patient Medical Record Number 
 IRB Protocol Number 
 PI of Study 
 Attending Physician 
 Date of Event 
 Description of Event (including grade of even and attribution of the even and 
if the event required hospitalization). 
 
o Email is sent to the research nurse, attending physician, and PI of the study 
informing them that adverse reaction notification has been received 
o The University of Chicago’s IRB Serious Adverse Event Form must be sent to the 
CCTO within 5 calendar days of event occurrence.  The UC IRB Serious Adverse 
Event for is available on line at http://ors.bsd.uchicago.edu/HS/newirbforms.  This 

 
19
form must be typed.  Once the forms are completed, the original is forward to the 
study PI to review and sign.  The signed report is delivered to the QA Coordinator.  
A weekly report of delinquent or pending documents will be forwarded to the 
applicable person who reported the event.  All delinquent reporting (great than 10 
days from the even occurrence) must include documentation of reason fro 
delinquency and may require implementation of an action plan. 
o Once the appropriate AE documents have been received, the CCTO forwards these 
to the IRB.  A copy will be forward to the appropriate Research Nurse. 
 
 
 
6.3. Data and Safety Monitoring 
A weekly meeting in the department of radiation oncology will be held for data and safety 
monitoring of patients enrolled at the University of Chicago site.   
 
The primary endpoint, HRQOL, will be formally evaluated at 6 months.   
 
Stopping rules include excessive failures defined by biochemical failure in > 70% of patients at 2 
years or excessive toxicity defined as >15% of patients with acute or late Grade 3+ toxicity.   
 
7. STUDY CALENDAR 
Baseline evaluations (including performance status, history and physical, scans) are to be conducted 
within 60 days prior to the start of protocol therapy.  
 
Baseline 
Month 2 
(pre-RT) 
Month 3-4 
(during RT) 
Month 6 
(2 mos 
post-
RT) 
Month 10 
(6 mos 
post-RT) 
Month 16 
(12 mos 
post-RT) 
Month 22 
(18 mos 
post-RT) 
Month 28 
(24 mos p
RT) 
Inclusion/ 
exclusion 
X 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
Path confirms 
cancer 
X 
 
 
 
 
 
 
 
History and 
Physical 
X 
X 
X** 
X 
X 
X 
X 
X 
Vital Signs, weight 
X 
 
X** 
X 
X 
X 
X 
X 
Zubrod 
Performance status 
and Charlson index 
X 
 
 
 
 
 
 
 
Document Current 
Medicines  
X 
X 
X** 
X 
X 
X 
X 
X 
CT Ab/Pelvis OR 
MRI* 
X 
 
 
 
 
 
 
 
Bone Scan * 
X 
 
 
 
 
 
 
 
Tumor tissue 
collection 
X 
X 
 
 
 
 
 
 
CBC with 
differential and 
CMP 
X 
X 
X# 
X 
 
X 
 
X 
Toxicity 
Assessment 
 
 
X** 
X 
X 
X 
X 
X 
Patient Outcome 
Questionnaire 
X 
X 
 
X 
X 
X≠ 
X≠ 
X≠ 
PSA  
X 
X 
 
X 
X 
X 
X 
X 

 
20
Total, serum 
Testosterone 
X 
X 
 
 
 
X 
 
X 
^ This evaluation will occur at the planning stage before radiation therapy has begun (e.g. fiducial 
marker placement or simulation) 
*  See Section 3 for requirements/exceptions  ** Weekly during radiation treatment 
# These labs will be drawn in the last week of radiation therapy 
≠ Optional 
Note that the protocol allows for 1 month of flexibility to meet any follow-up appointment time (e.g. 
the month 6 visit may occur at month 5 or month 7.) 
Beyond month 10, follow-up is recommended but not required. All data collected between month 10 
and month 28 will be registered under this study so that longer term quality of life data (beyond the 
primary endpoint of 6 months) may be analyzed. 
 
 
8. MEASUREMENT OF EFFECT 
Disease Control 
Although disease control is not the primary endpoint of this trial, patients will be assessed by 
standard criteria for disease response with serum PSA and clinical examinations.  For the purposes 
of this study, patients should undergo serum PSA and testosterone testing at baseline, 2 months (at 
start of RT), and every three to six months until completion of androgen manipulation at 2 years, 4 
months according to the study calendar.  After completion of study treatment, it is recommended 
that PSA should be drawn every 6 months until 5 years post-treatment.  Clinical exams should be 
performed on a regular basis at the discretion of the treating physician, but a least biannually 
during the course of therapy and at least annually thereafter.  Screening for distant metastases will 
be based on clinical information and is at the discretion of the treating physician.   
 
 
9. STATISTICAL CONSIDERATIONS 
9.1. Study Design/Primary Endpoint 
The study is designed as a feasibility study to determine quality of life endpoints for men treated 
with oral androgen deprivation therapy in conjunction with dose-escalated radiation.  Data gathered 
from this preliminary cohort will aid in defining the expected range of quality of life changes as to 
facilitate a subsequent Phase II randomized comparison of oral therapy with standard ADT.   
 
The primary endpoint is HRQOL at 6 months after initiation of therapy; at this time point, 
symptoms and side effects are expected to stabilize. In a large study of HRQOL in patients treated 
with standard ADT, scores at 6 months were comparable to those at 24 months in all domains.[34]  
Analysis at the six month time point will allow an early evaluation of what is expected to persist 
during longer term follow-up.  HRQOL will be summarized using a score reflecting reported 
symptoms in sexual, hormone/vitality, fatigue, and global quality of life domains.  A composite 
score inclusive of each of these domains except for breast tenderness and gynecomastia will also be 
analyzed; assessments of breast tenderness and gynecomastia will be excluded from this summary 
score as it is expected that some patients may receive additional therapies directed at reducing this 
side effect which may confound the analysis.  Incidence of breast symptoms and signs will be 
recorded and reported separately from the other HRQOL endpoints.  Mean scores in each quality of 
life domain will be calculated and confidence intervals will be derived. 
 
Quality of life and toxicity scores will be compared to those of patients in the synchronous control 
cohort receiving standard ADT with radiation.  Univariate analysis of mean scores (continuous 

 
21
variables) will be performed using a two sample t-test.  Scores will also be compared between trial 
patients and the control cohort while controlling for covariates using linear regression analysis. 
 
9.2. Sample Size/Accrual Rate 
Success will be defined as a decline in hormonal/vitality domain score by no more than 30% from 
baseline.  The required rate of success is p=0.6.  A minimum sample size of n=40 experimental 
subjects will provide a 95% confidence interval width of + 15%.  We anticipate that approximately 
30 patients will be entered into the control group.  In total, we plan to accrue 70 patients. 
The expected accrual rate for patients in the experimental group is 2 per month at each 
participating site.  The expected accual rate for patients in the control group is 1 to 2 per month.   
We will collect tumor tissue only for the 14 patients who will be enrolled on the study. 8 in the 
treatment arm and 6 in the control arm. 
 
 
9.3. Analysis of Secondary Endpoints 
As secondary endpoints, the study will investigate oncologic outcomes of the prescribed protocol 
therapy including biochemical progression-free survival, distant metastasis-free survival, cause 
specific survival, and overall survival.  Kaplan-Meier curves will be generated for each endpoint.  
Findings will be compared to a synchronous cohort of controls.   
 
Biochemical progression free survival will be defined to be the time from the start of therapy with 
oral androgen manipulation until PSA failure occurs as defined by the Phoenix definition of a rise 
to 2 ng/ml above the nadir PSA value.  The relative hazard for a PSA failure in patients on protocol 
therapy compared to those in the control cohort will be calculated using the proportional hazards 
regression model of Cox, but formal statistical conclusions will not be drawn from this analysis. 
 
Hematologic effects of dual oral androgen manipulation will be assessed using hemoglobin levels 
from scheduled CBC’s.  Changes in mean hemoglobin between baseline and various time points 
throughout treatment will be assessed.  Univariate analysis of mean scores will be performed using 
a two sample t-test. 
 
 
10. CONFIDENTIALITY 
 
Study records that identify patients will be kept confidential.  Study records will contain patients’ 
name, address, and medical history number, and will be available to the study doctor, research nurse, 
and data coordinator.  Data collected in this study will be maintained on a password protected 
computer that only the principal investigator, co-investigators, research nurse, and data coordinator 
will be able to access.  Study records will be secured in locked offices in the Department of Radiation 
and Cellular Oncology.  Neither patient names nor other personally identifying information will be 
used in any publication resulting from the research study. 
 
 

 
22
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Peeters, S.T., et al., Dose-response in radiotherapy for localized prostate cancer: results of the 
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Dearnaley, D.P., et al., The early toxicity of escalated versus standard dose conformal 
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Beckendorf, V., et al., The GETUG 70 Gy vs. 80 Gy randomized trial for localized prostate 
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Smith, M.R., et al., Bicalutamide monotherapy versus leuprolide monotherapy for prostate 
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Efstathiou, J.A., et al., Cardiovascular mortality after androgen deprivation therapy for locally 
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Nguyen, P.L., et al., Survival following radiation and androgen suppression therapy for 
prostate cancer in healthy older men: implications for screening recommendations. Int J Radiat 
Oncol Biol Phys, 2010. 76(2): p. 337-41. 
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Iversen, P., et al., Bicalutamide monotherapy compared with castration in patients with 
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See, W.A. and C.J. Tyrrell, The addition of bicalutamide 150 mg to radiotherapy significantly 
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Andriole, G.L., et al., Effect of dutasteride on the risk of prostate cancer. N Engl J Med, 2010. 
362(13): p. 1192-202. 
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Andriole, G., et al., Treatment with finasteride following radical prostatectomy for prostate 
cancer. Urology, 1995. 45(3): p. 491-7. 
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Presti, J.C., Jr., et al., Multicenter, randomized, double-blind, placebo controlled study to 
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30. 
Picus J, H.S., Hussain A, Philips G, Kaplan E, et al, Efficacy of peripheral androgen blockade 
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Banez, L.L., et al., Combined low-dose flutamide plus finasteride vs low-dose flutamide 
monotherapy for recurrent prostate cancer: a comparative analysis of two phase II trials with a 
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32. 
Kirby, R., et al., Finasteride in association with either flutamide or goserelin as combination 
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33. 
Szymanski, K.M., et al., Development and Validation of an Abbreviated Version of the 
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24
APPENDIX A: 
 
 
DEPARTMENT OF RADIATION AND CELLULAR ONCOLOGY  
DIVISION OF THE BIOLOGICAL SCIENCES AND  
THE PRITZKER SCHOOL OF MEDICINE  
 
This questionnaire is designed to measure Quality of Life issues in patients with Prostate Cancer. To help us get the 
most accurate measurement, it is important that you answer all questions honestly and completely. Please note that 
there are 2 sides on each page. 
 
Remember, as with all medical records, information contained with this survey will remain strictly confidential.  
 
 
Name : ___________________________ 
 
Today’s Date:  Month ______ Day___ Year _____ 
 
 
 
The following questions are about your general health.  
 
List any health problems, including diagnosis of any other cancers, that have required new therapy (such as medicines 
or procedures) or hospitalization since your last visit:  
 
 
 
 
 
 
 
List the date of any recent colonoscopy (examination of the colon using a camera):   __________ 
List the date of any recent cystoscopy (examination of the bladder using a camera): __________ 
 
 
Include the names, addresses, and phone/fax numbers of any physicians who are actively involved with your medical 
care. We will send documentation of your clinic visit to any physicians listed here.  
 
 
 
 
 
 
Physician use only 
 
  Grade     Comment 
 
 
 
GI 
 
 
 
GU 
 
 
 
Sexual 
 
 
 
Other 
 
 

 
25
The following questions are about your urinary function.  
 
1. Over the past 4 weeks, how often have you leaked urine? 
More than once a day……………………… 1 
About once a day………………………….. 2 
More than once a week……………………. 3 
 
(Circle one number) 
About once a week....…………………....... 4 
Rarely or never …………………………… 5 
 
2. Which of the following best describes your urinary control during the last 4 weeks? 
No urinary control whatsoever…………….. 1 
Frequent dribbling…………………………. 2 
 
(Circle one number) 
Occasional dribbling………………………. 3 
Total control……………………………….. 4 
 
3. How many pads or adult diapers per day did you usually use to control leakage during the last 4 weeks? 
None……………………………………….. 0 
1 pad per day………………………………. 1 
2 pads per day……………………………… 2 
 
(Circle one number) 
3 or more pads per day…………………….. 3 
 
 
4. How big a problem, if any, has each of the following been for you during the last 4 weeks? 
 
(Circle one number on each line) 
 
  
 
 
 
 
No 
         Very Small 
  Small  
Moderate 
   Big 
  
 
 
 
        Problem  
Problem 
Problem 
Problem 
Problem 
a. Dripping or leaking urine …….      0                           1                      2                     3                      4 
b. Pain or burning on urination …     0                           1                      2                     3                      4 
c. Bleeding with urination ………      0                           1                      2                     3                      4 
d. Weak urine steam 
     or incomplete emptying ……..    
0                           1                      2                     3                      4 
e. Waking up to urinate ………… 
0 
 
     1 
 
     2 
 
    3 
 
    4 
f. Need to urinate frequently 
    during the day ………………..      0                           1                      2                     3                      4 
 
5. Overall, how big a problem has your urinary function been for you during the last 4 weeks? 
No problem………………………………… 1 
Very small problem………………………... 2 
Small problem……………………………… 3 
 
(Circle one number) 
Moderate problem………………………….. 4 
Big problem………………………............... 5 
 
 
 
 
6. International Prostate Symptom Score (IPSS). The following questions are about symptoms during the last 4 
weeks. 

 
26
 
 
 
Not at 
all 
 
Less than 
1 time in 5 
Less than 
half the 
time 
 
About half 
the time 
More 
than half 
the time 
 
Almost 
always 
 
Your 
score 
a. Incomplete emptying 
How often have you had a sensation of 
not emptying your bladder completely 
after you finish urinating? 
 
0 
 
1 
 
2 
 
3 
 
4 
 
5 
 
b. Frequency 
How often have you had to urinate 
again less than two hours after you 
finish urinating? 
 
0 
 
1 
 
2 
 
3 
 
4 
 
5 
 
c. Intermittency 
How often have you found you 
stopped and started again several 
times when you urinated? 
 
0 
 
1 
 
2 
 
3 
 
4 
 
5 
 
d. Urgency 
How often have you found it difficult 
to postpone urination? 
 
0 
 
1 
 
2 
 
3 
 
4 
 
5 
 
e. Weak stream 
How often have you had a weak 
urinary stream? 
 
0 
 
1 
 
2 
 
3 
 
4 
 
5 
 
f. Straining  
How often have you had to push or 
strain to begin urinating? 
 
0 
 
1 
 
2 
 
3 
 
4 
 
5 
 
 
None 
1 time 
2 times 
3 times 
4 times 
≥5 
times 
 
g. Nocturia 
How many times did you most 
typically get up to urinate each 
night from the time you went to 
bed at night to the time you got up 
the next morning? 
 
 
0 
 
 
1 
 
 
2 
 
 
3 
 
 
4 
 
 
5 
 
 
 
 
 
 
 
 
 
 
 
 
TOTAL IPSS SCORE: 
 
 
 
 
 
 
 
 
 
Quality of life: If you were to spend 
the rest of your life with your 
urinary condition just the way it is 
now, how would you feel about 
that? 
 
 
Delighted 
 
 
Pleased 
 
Mostly 
satisfied 
 
 
Mixed 
 
Mostly 
dissatisfied 
 
 
Unhappy 
 
 
Terrible 
0 
1 
2 
3 
4 
5 
6 
  
 
 

 
27
The following questions are about your bowel function.  
 
7. How often have you had rectal urgency (felt like you had to pass stool, but did not) during the last 4 weeks? 
More than once a day ……………………… 1 
About once a day ……….............................. 2 
More than once a week ……………………. 3 
 
(Circle one number) 
About once a week …………........................ 4 
Rarely or never …………………………….. 5 
 
8. How often have you had stools that were loose or liquid (no form, watery, mushy) during the last 4 weeks? 
Never………………………………………. 1 
Rarely………................................................. 2 
About half the time……………………….... 3 
 
(Circle one number) 
Usually…………........................................... 4 
Always……………………………………... 5 
 
9. How often have you had bloody stools during the last 4 weeks? 
Never………………………………………. 1 
Rarely………................................................. 2 
About half the time……………………….... 3 
 
(Circle one number) 
Usually…………........................................... 4 
Always……………………………………... 5 
 
10. How big a problem, if any, has each of the following been for you? (Circle one number on each line) 
 
                                                No 
         Very Small 
  Small  
Moderate 
   Big 
 
 
 
        Problem  
Problem 
Problem 
Problem 
Problem 
 
a. Urgency to have a 
bowel movement ……….. 0                           1                       2                      3                    4 
b. Increased frequency 
of bowel movements ……  0                           1                       2                      3                    4 
c. Watery bowel movements. 0 
 
      1  
       2  
       3  
     4 
d. Losing control of  
your stools ………...........  0 
                  1                       2                      3                    4 
d.   Bloody stools …………..  0 
 
      1                       2                      3                    4 
e. Abdominal/Pelvic 
Rectal pain ……………..  0                           1                       2                      3                    4 
 
 
 
11. Overall, how big a problem have your bowel habits been for you during the last 4 weeks? 
No Problem………………………………… 1 
Very Small Problem……….......................... 2 
Small Problem……………………………... 3 
 
(Circle one number) 
Moderate Problem…………......................... 4 
Big Problem………………………………... 5 
 
 
The following questions are about your sexual function.  

 
28
12. How would you rate each of the following during the last 4 weeks? (Circle one number on each line) 
Very 
Poor/ 
 
 
 
Very 
 
 
 
None 
Poor 
Fair 
Good 
Good 
a. Your level of sexual desire?  
                            1          2         3            4          5 
b. Your ability to have an erection?                                1          2         3            4          5 
c. Your ability to reach orgasm (climax)?                      1          2         3            4          5 
 
13. How would you describe the usual QUALITY of your erections WITHOUT assistance of medicines or  
devices during the last 4 weeks? 
 
None at all……………………………………………………………….. 1 
 
Not firm enough for any sexual activity………………………………… 2  
 
 
Firm enough for masturbation and foreplay only……………………….. 3     (Circle one number) 
 
Firm enough for intercourse…………………………………………….. 4 
 
14. How would you describe the usual QUALITY of your erections (WITH assistance of medicines or  
devices if needed) during the last 4 weeks? 
 
None at all……………………………………………………………….. 1 
 
Not firm enough for any sexual activity………………………………… 2  
 
 
Firm enough for masturbation and foreplay only……………………….. 3     (Circle one number) 
 
Firm enough for intercourse…………………………………………….. 4 
 
15. Regarding the use of any medications or devices to aid or improve erections: 
 
Have 
NOT 
tried it 
Tried it, but 
was NOT 
HELPFUL 
It HELPED, 
but I am NOT 
using it NOW 
It HELPED, 
and I use it 
sometimes 
It HELPED, 
and I use it 
always 
a. Viagra or other pill  
(name if not viagra): __________ 
    Dose used: _______________ 
1 
2 
3 
4 
5 
b. Vacuum erection device (such as 
erect-aid) 
1 
2 
3 
4 
5 
c. Muse (intra-urethral alprostadil 
suppository) 
1 
2 
3 
4 
5 
d. Penile injection therapy (such as 
caverject) 
1 
2 
3 
4 
5 
e. Other (if not listed): ___________ 
1 
2 
3 
4 
5 
 
16. How would you describe the FREQUENCY of your erections during the last 4 weeks? 
I NEVER had an erection when I wanted one…………………………... 1 
I had an erection LESS THAN HALF the time I wanted one…………... 2 
I had an erection ABOUT HALF the time I wanted one………………... 3    (Circle one number) 
I had an erection MORE THAN HALF the time I wanted one…………. 4 
I had an erection WHENEVER I wanted one…………………………… 5 
 
 
17. During the last 4 weeks, how often did you have sexual intercourse? 
Not at all ………………………………………………………… 1 
Less than once a week ………....................................................... 2 
About once a week ……………………….... …………………… 3    (Circle one number) 
Several times a week …………..................................................... 4 
Daily …………………………………………………………….. 5 
 

 
29
 
18. Overall, how would you rate your ability to function sexually during the last 4 weeks? 
 
Very poor…………………………………………… 1 
 
Poor…………………………………………………. 2 
 
Fair………………………………………………….. 3 
(Circle one number) 
 
Good………………………………………………… 4 
 
Very good…………………………………………… 5 
 
19. Overall, how big a problem has your sexual function or lack of sexual function been for you 
        during the last 4 weeks? 
 
No Problem…………………………………………. 1 
 
Very small problem…………………………………. 2 
 
Small problem………………………………………. 3 
(Circle one number) 
 
Moderate problem…………………………………... 4 
 
Big problem………………………………………..... 5 
 
20. Sexual Health Inventory for Men (SHIM). Answer the following questions, including the use of medications or 
devices if you use them. 
 
a. How do you rate your confidence that you could get and keep an erection? 
 
 
Very low 
1 
Low 
2 
Moderate 
3 
High 
4 
Very high 
5 
 
b. When you had erections with sexual stimulation, how often were your erections hard enough for 
penetration (entering your partner)? 
 
No sexual 
activity 
 
0 
Almost never or 
never 
 
1 
A few times  
(much less than 
half the time) 
2 
Sometimes  
(half the time) 
 
3 
Most times 
(much more than 
half the time) 
4 
Almost always  
or always 
 
5 
 
c. During sexual intercourse, how often were you able to maintain your erection after you had penetrated 
(entered) your partner? 
 
Did not attempt 
intercourse 
 
0 
Almost never or 
never 
 
1 
A few times  
(much less than 
half the time) 
2 
Sometimes  
(half the time) 
 
3 
Most times 
(much more than 
half the time) 
4 
Almost always  
or always 
 
5 
 
d. During sexual intercourse, how difficult was it to maintain your erection to completion of intercourse? 
 
Did not attempt 
intercourse 
0 
Extremely  
difficult 
1 
Very difficult 
 
2 
Difficult 
 
3 
Slightly difficult 
 
4 
Not difficult 
 
5 
 
e. When you attempted sexual intercourse, how often was it satisfactory for you? 
 
Did not attempt 
intercourse 
 
0 
Almost never or 
never 
 
1 
A few times  
(much less than 
half the time) 
2 
Sometimes  
(half the time) 
 
3 
Most times 
(much more than 
half the time) 
4 
Almost always  
or always 
 
5 
 
 
 
TOTAL SHIM SCORE: 
 

APPENDIX B 
 
 
DEPARTMENT OF RADIATION AND CELLULAR ONCOLOGY  
DIVISION OF THE BIOLOGICAL SCIENCES AND  
THE PRITZKER SCHOOL OF MEDICINE  
 
This questionnaire is a supplement to the standard of care questionnaire used for all patients treated for 
prostate cancer in our department.  These questions are aimed at further describing your general state of 
well being, under the study IRB:____: “A Phase II study of oral hormonal therapy and radiation therapy 
for non-metastatic, intermediate or high risk prostate cancer in men with advanced age or medical 
comorbidity.” 
 
Please note that there are 2 sides on each page.   
 
 
 
To help people say how good or bad a health state is,  
we have drawn a scale (rather like a thermometer) on 
which the best state you can imagine is marked by 100 
and the worst state you can imagin is marked by 0. 
 
We would like you to indicate in this scale how good or 
bad is your own health today, in your opinion.  Please do 
this by drawing an “X” on the line at whichever point on 
the scale indicates how good or bad your current health is. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physician use only: 
Baseline      
Pre-ADT     Pre-RT      2 mos post-RT         6 mos post-RT     12 mos post-RT     18 mos post-RT    24 mos post-RT                                      
STUDY VISIT: 
(circle month) 
    0 
         2 
                   3-4  
                    10 
              16 
                22 
          28 
 

 
31
 
 
The following questions are about your energy and overall well being.  
 
 
2.   Over the last 4 weeks, how often have you experienced hot flashes? 
 
 More than once a day……………………………….1 
 About once a day……………………………………2 
 More than once a week……………………………...3 
(Circle one number) 
 About once a week…………………………………..4 
 Rarely or never………………………………………5 
 
3.    How often have you had breast tenderness during the last 4 weeks? 
More than once a day………………………….……..1 
About once a day……………………………………..2 
More than once a week……………………………….3 
(Circle one number) 
About once a week………………………………...…4 
Rarely or never……………………………………….5 
 
4.   During the last 4 weeks, how often have you felt depressed? 
More than once a day…………………………………1 
About once a day……………………………………...2 
More than once a week………………………………..3 
(Circle one number) 
About once a week……………………………………4 
Rarely or never………………………………………..5 
 
 
5.   During the last 4 weeks, how often have you felt a lack of energy? 
More than once a day…………………………………1 
About once a day……………………………………...2 
More than once a week………………………………..3 
(Circle one number) 
About once a week……………………………………4 
Rarely or never………………………………………..5 
 
 
 
6.   How much change in your weight have you experienced during the last 4 weeks, if any? 
Gained 10 pounds or more…………………………......1 
Gained less than 10 pounds…………………………....2 
No change in weight…………………………………...3 
(Circle one number) 
Lost less than 10 pounds……………………………….4 
Lost 10 pounds or more………………………………...5 
 
 
 
 
 

 
32
 
 
 
 
7.  How big a problem during the last 4 weeks, if any, has each of the following been for you? 
 
                                                    No          Very Small 
  Small  
Moderate 
   Big 
 
 
 
              Problem 
Problem 
Problem 
Problem           Problem 
a. Hot flashes……….……….. ... 0                     1                       2                      3                      4  
 
b. Breast tenderness/ 
   enlargement…………………...0                      1                      2                       3                     4                                         
 
c. Feeling Depressed………….....0                     1                      2                       3                     4 
 
d. Lack of energy………………..0  
     1 
 
      2                    3                     4  
 
e. Change in body weight ………0  
     1                       2                       3                     4 
 
 
 
8.   Overall, how big a problem has hormonal therapy been for you during the last 4 weeks? 
 
 
No Problem…………………………………………...1 
 
Very small problem…………………………………..2 
 
Small problem………………………………………..3 
(Circle one number) 
 
Moderate problem…………………………………....4 
 
Big problem………………………………………......5 
 
 
 
9.  Please respond to each by circling one number per row. 
 
 
 
 
 
 
        Excellent      Very Good       Good 
    Fair   
   Poor 
a. In general, would you say  
your health is:………….,……………............1 
           2 
          3 
      4                     5 
 
b. In general, would you say your 
quality of life is: ……….………………….....1                    2 
          3 
      4                      5 
 
c. In general, how would you rate  
your physical health? :………………………..1                    2 
           3 
       4                     5 
 
d. In general, how would you rate 
your mental health, including your 
mood and your ability to think? ……………..1                    2 
           3 
       4                     5 
 
 

 
33
 
Excellent 
      Very Good         Good 
    Fair   
   Poor 
e.   In general, how would you rate  
your satisfaction with your social  
activities and relationships? …………………..1                    2 
           3 
       4                      5 
 
f.    In general, please rate how well you  
carry out your usual social activities and 
roles (This includes activities at home, at 
work and in your community, and  
responsibilities as a parent, child, spouse, 
employee, friend, etc.) ……………….………..1                   2 
           3 
       4                       5 
 
 
 
10.  To what extent are you able to carry out your everyday physical activities such as walking, climbing stairs, 
carrying groceries, or moving a chair?  
 
Never………………………………………….….....1 
 
Rarely…………………………………………..….. 2 
 
Sometimes…………..………………………….….. 3 
(Circle one number) 
 
Often……………………………………………..... 4 
 
Always ………………………………………..........5 
 
11.  In the past 7 days, how often have you been bothered by emotional problems such as feeling anxious, 
depressed or irritable? 
 
Not at All…………………………………………....1 
 
A Little……………………………………………...2 
 
Moderately…………..……………………………...3 
(Circle one number) 
 
Mostly……………………………………………....4 
 
Completely ………………………………………....5 
 
12.  In the past 7 days, how would you rate your fatigue on average? 
 
None………………………………………………....1 
 
Mild…..…………………………………………...…2 
 
Moderate……………..………………………….......3 
(Circle one number) 
 
Severe..……………………………………………....4 
 
Very Severe ………………………………………....5 
 
 
 
 
Signature__________________________________________   
 
Date___/____/_______ 
 
 
 

 
34
APPENDIX C: 
 
 
Charlson Comorbidity Index: 
 
Comorbidity should be recorded according to the defined criteria in the original publication of 
Charlson, et al. 
 
Myocardial infarct: Includes patients with one or more definite or probable myocardial 
infarctions; these patients have been hospitalized and had electrocardiographic and/or enzyme 
changes.  Patients with electrocardiographic changes alone were no designated as having had an 
infarction.  
Congestive heart failure: Includes patients who have had exertional or paroxysmal nocturnal 
dyspnea and who have responded symptomatically (or on physical examination) to digitalis, 
diuretics, or afterload reducing agents.  It does not included patients who are on medication but 
have had no symptomatic response and no evidence of improvement of physical signs. 
Peripheral vascular disease: Includes patients with intermittent claudication or those who had a 
bypass for arterial insufficiency and those with gangrene or acute arterial insufficiency and those 
with an untreated thoracic or abdominal aneurysm. (6 cm or more). 
Hypertension: Includes patents with diastolic pressure over 100 mmHg and those with 
controlled hypertension on medications. 
Chronic Pulmonary Disease: Moderate pulmonary disease is Dyspneic with slight activity, 
with or without treatment and those who are dyspneic with moderate activity despite treatment.  
Severe pulmonary disease includes patients who are dyspneic at rest, despite treatment, those 
who require constant oxygen, those with CO2 retention and those with a paseline P02 <50 
mmHg. 
Cerebrovascular disease: Includes patients with a history of a cerbrovascular accident with 
minor or no residua and transient ischemic attacks 
Dementia: Includes patients with chronic cognitive deficit. 
Renal Disease: Moderate renal disease includes patients with serum creatinine of >3 mg/dl.  
Severe renal disease includes patients on dialysis those who had a transplant and those with 
uremia 
Liver disease: Severe liver disease consists of patients with cirrhosis, portal hypertension, and a 
history of variceal bleeding.  Moderate liver disease consists of cirrhosis with portal hypertension 
and without bleeding. 
Lymphoma includes patients with Hodgkins, lymphosarcoma, waldenstroms 
macroglobulinemia, myeloma, and other lymphomas. 
Leukemia includes patients with acute and chronic myelogenous leukemia, acute and chronic 
lymphocytic leukemia, and polycythemia vera. 
Tumor consists of patients with solid tumors without documented metastases but initially treated 
in the last 5 years including breast, colon, lung, and other tumors.  Does not include the diagnosis 
under study (prostate cancer). 
 
 
 
 

 
35
 
 
 
Charlson, M.E., et al., A new method of classifying prognostic comorbidity in 
longitudinal studies: development and validation. J Chronic Dis, 1987. 40(5): p. 373-83. 
 
Hall, W.H., et al., An electronic application for rapidly calculating Charlson comorbidity 
score. BMC Cancer, 2004. 4: p. 94. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
36
 
 
 
 
APPENDIX D: 
 
RTOG Toxicity Scale 
GU Toxicity 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Acute 
RTOG 
Frequency of urination 
or nocturia twice 
pretreatment habit/ 
dysuria, urgency not 
requiring medication 
Frequency of urination 
or nocturia which is 
less frequent than 
every hour. Dysuria, 
urgency, bladder 
spasm requiring local 
anesthetic (e.g., 
Pyridium) 
Frequency with 
urgency and nocturia 
hourly or more 
frequently/ dysuria, 
pelvis pain or bladder 
spasm requiring 
regular, frequent 
narcotic/gross 
hematuria with/ 
without clot passage 
Hematuria requiring 
transfusion/ acute 
bladder obstruction not 
secondary to clot 
passage, ulceration or 
necrosis 
Late RTOG 
BLADDER 
Slight epithelial 
atrophy Minor 
telangiectasia 
(microscopic 
hematuria)  
Moderate frequency 
Generalized 
telangiectasia 
Intermittent 
macroscopic 
hematuria 
Severe frequency and 
dysuria 
Severe generalized 
telangiectasia (often 
with petechiae) 
Frequent hematuria 
Reduction in bladder 
capacity (<150 cc) 
Necrosis/ Contracted 
bladder (capacity <100 
cc) 
Severe hemorrhagic 
cystitis 
 
 
 
GI Toxicity 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Acute RTOG 
Increased frequency 
or change in quality 
of bowel habits not 
requiring medication/ 
rectal discomfort not 
requiring analgesics  
Diarrhea requiring 
parasympatholytic 
drugs (e.g.Lomotil)/ 
mucous discharge not 
necessitating sanitary 
pads/ rectal or 
abdominal pain 
requiring analgesics  
Diarrhea requiring 
parenteral support/ 
severe mucous or 
blood discharge 
necessitating sanitary 
pags/abdominal 
distention (flat plate 
radiograph 
demonstrates 
distended bowel 
loops)  
Acute or subacute 
obstructionfistula or 
perforation; GI 
bleeding requiring 
transfusion; 
abdominal pain or 
tenesmus requiring 
tube decompression 
or bowel diversion  
Late RTOG 
SMALL/LARGE 
INTESTINE 
Mild diarrhea 
Mild cramping 
Bowel movement 5 
times daily 
Slight rectal 
discharge or bleeding 
Moderate diarrhea 
and colic 
Bowel movement >5 
times daily 
Excessive rectal 
mucus or intermittent 
bleeding 
Obstruction or 
bleeding 
requiring surgery 
Necrosis/ Perforation 
Fistula