Androgen Deprivation and Localized Radiotherapy to Metastases in Patients With Oligometastatic Hormone - Sensitive Prostate Cancer
Phase: PHASE2
Conditions: PSA Level Greater Than Two, Stage IV Prostate Adenocarcinoma AJCC v7
Sponsor: City of Hope Medical Center

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CITY OF HOPE NATIONAL MEDICAL CENTER 
1500 E. DUARTE ROAD 
DUARTE, CA 91010 
DEPARTMENT OF MEDICAL ONCOLOGY AND THERAPEUTICS RESEARCH 
TITLE: Androgen Deprivation and Localized Radiotherapy to Metastases In Patients with Oligometastatic 
Hormone – Sensitive Prostate Cancer. 
CITY OF HOPE PROTOCOL NUMBER/VERSION: 
IRB # 05190 
VERSION: 09 
COH Amendment 01, Dated January 11, 2008  
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COH Amendment 02 (Addition of Sumanta Pal, MD as participating clinician) 
02
COH Amendment 03 (Protocol Dated 02/13/2012) 
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COH Amendment 04 (Title Page Dated 09/25/2013) 
04
COH Amendment 05 at Continuation (Title Page Dated 07/18/2017) 
05
COH Amendment 06 (Title Page Dated 10/27/2017) 
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COH Amendment 07 (Title Page Dated 12/06/2017) 
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COH Amendment 08 (Protocol dated 05/02/2019)                                                                    08 
COH Amendment 09 at Continuation (Title Page Dated 06/14/2019) 
09
SITE:
Prostate 
HISTOLOGY:
Adenocarcinoma 
STAGE:
IV
MODALITY:
TYPE:
PRINCIPAL INVESTIGATOR:
Cy Stein, M.D. 
COLLABORATING INVESTIGATOR: 
Jeffrey Wong, M.D.
PARTICIPATING CLINICIANS:
Medical Oncology: Warren Chow, M.D., Vincent Chung, 
M.D., Mihaela Cristea, M.D., Stephen Koehler, M.D., Dean 
Lim, M.D., Marianna Koczywas, M.D., Jana Portnow, M.D., 
Sumanta Pal, M.D.
Radiation Oncology:  Nayana Vora, M.D., Yi-Jen Chen, 
M.D., Savita Dandapani, M.D.   
PARTICIPATING STATISTICIAN: 
Paul Frankel, Ph.D. 
PARTICIPATING INSTITUTIONS: 
City of Hope National Medical Center 
City of Hope Medical Group, Pasadena, CA 

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Androgen Deprivation and Localized Radiotherapy to Metastases In Patients 
with Oligometastatic Hormone - Sensitive Prostate Cancer. 
 

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TABLE OF CONTENTS 
 
 
SCHEMA 
1.0 
OBJECTIVES ......................................................................................................................4 
2.0 
BACKGROUND AND HYPOTHESIS ..............................................................................4 
3.1 
ZOLADEX£ (GOSERELIN) ..............................................................................................7 
4.0 
STAGING CRITERIA .......................................................................................................10 
5.0 
ELIGIBILITY CRITERIA .................................................................................................12 
6.0 
TREATMENT PLAN ........................................................................................................13 
7.0     TOXICITIES MONITORED, DOSAGE MODIFICATIONS ..........................................16 
8.0 
STUDY PARAMETERS AND CALENDAR ..................................................................16 
9.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS ..............................17 
10.0     STATISTICAL CONSIDERATIONS ...............................................................................20 
11.0     REGISTRATION GUIDELINES ......................................................................................20 
12.0 
RECORDS TO BE KEPT, DATA COLLECTION AND SUBMISSION SCHEDULE 211 
13.0     MINORITIES AND WOMEN STATEMENT ..................................................................21 
14.0 
ETHICAL AND REGULATORY CONSIDERATIONS………………………………..21 
 
15.0    PATHOLOGY REVIEW ....................................................................................................21 
16.0 
DATA AND SAFETY MONITORING ............................................................................22 
 
 
APPENDICES (Appendices must be ordered as they appear in the document) 
A. Common Terminology Criteria for Adverse Events, v3 (CTCAE Publish date 12/12/03) 
 
 
 
 
 

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SCHEMA 
Start 
36 (+2 weeks) weeks 
Androgen Deprivation Treatment 
(may start treatment before consenting to study) 
(may join study at any point of 36 weeks of treatment or at the end of 
treatment if PSA has normalized) 
 
 
 
 
 
 
 
PSA Normalizes 
Start Radiation to all known sites of disease  
(if joining study after start of Androgen Deprivation Treatment, may start  
Radiation at the same time, if PSA normalized) 
(may join study after completion of 36 weeks of treatment and receive Radiation if Serum  
Testosterone remains at castrated levels) 
 
 
 
 
 
 
 
 
 
End Androgen Deprivation Treatment when a total of 36 weeks of  
Treatment has been received 
 
 
 
 
 
 
 
 
 
 
Follow until PSA Relapse 
Off Study 
Restart Androgen Deprivation Treatment 
Long term followup of patients: PSA, Local Control of stage IV disease, PFS, OS, site and number 
of new metastases, systemic treatments, long term toxicity. 

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1.0 
OBJECTIVES 
1) To evaluate time to PSA relapse in patients with oligometastatic (≤ 5 lesions) hormone –
sensitive prostate cancer treated with 36 weeks of androgen deprivation and localized 
radiotherapy to all known tumor sites.  
2) To assess the Prostate-Specific Antigen (PSA) and objective response rate to treatment with 
36 weeks of androgen deprivation and localized radiotherapy in patients with 
oligometastatic hormone-sensitive prostate cancer. 
3) To assess the toxicity of 36 weeks of androgen deprivation and localized radiotherapy to 
oligometastases in patients with oligometastatic hormone-sensitive prostate cancer. 
4) In appropriate situations evaluate the feasibility and toxicities of using helical tomotherapy 
image-guided IMRT to treat oligometastatic sites. 
5) Long term follow-up of patients: PSA, Local Control of stage IV disease, PFS, OS, site and 
number of new metastases, systemic treatments, long term toxicity. 
            
2.0 
BACKGROUND AND HYPOTHESIS 
2.1 
Metastatic prostate cancer and cancer metastases: 
Carcinoma of the prostate remains a significant health problem in the United States, with 
230,000 new cases and 30,000 deaths estimated in 2004 (1). Despite progress in early 
detection thanks to the widespread use of serum Prostate Specific Antigen (PSA) about 15% 
of patients present with metastatic disease at diagnosis and 30% of patients suffer relapse to 
regional lymph nodes or distant organs despite local therapy.  
 
Historically several hypotheses based on clinical evidence attempted to explain mechanisms 
of metastatic tumor cell spread. Halsted suggested that tumors spread in an orderly manner 
initially spreading to regional lymph nodes and then centrifugally to distant organs (2).  In 
contrast the “systemic hypothesis” most clearly articulated by Fisher proposed two principal 
types of cancer: those that cannot metastasize and those that have metastasized widely 
before clinical detection (3).  In an attempt to reconcile clinical and laboratory features in a 
unified hypothesis, the “spectrum” model has been proposed (4). This theory accepts that 
some tumors spread widely before clinical detectability while others never metastasize, but 
for the majority of cancers, metastatic capacity evolves during the clinical phase of tumor 
growth. During the evolutionary process there may be a stage, termed “oligometastases”, 
when metastases are limited in number and location because metastatic capacity has not 
fully evolved (5). 
 
With a few exceptions such as testis cancer and some hematologic malignancies, the 
treatment of metastatic cancer by hormonal or cytotoxic agents is rarely curative and in 
many instances ineffective. In this context an important question is whether in the natural 
history of metastatic spread there is a time when metastases are limited in number and/or in 
destination organs and therefore treatment with systemic agents augmented by regional 
treatments may be effective. Examples of this include resection of lung metastases from 
sarcoma, liver metastases from colorectal cancer and isolated resection of breast metastases 
(6,7,8).  Despite their limitations hormone therapy and chemotherapy have been effective in 
eradicating subclinical deposits when used as an adjuvant to local therapy. But all too often 

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the tumor recurs in a few locations, the likely consequence of the large number of tumor 
cells at these sites or limited drug availability at the site. These remaining oligometastases 
then may serve as a nidus for further dissemination.  
 
Since testosterone is the main growth and survival factor for prostate cancer most patients 
will respond initially to ablation of gonadal androgen production through surgical (bilateral 
orchiectomy) or medical (luteinizing hormone-releasing hormone [LHRH] agonist therapy) 
approaches (9). Combined androgen blockade is achieved by the addition of an androgen 
receptor blocker and confers small survival advantage over castration alone (10). Triple 
hormone therapy involves the use of LHRH agonist, antiandrogen agent and 5 alpha 
reductase inhibitor finasteride (Proscar®) that prevents conversion of testosterone to more 
potent dihydrotestosterone (DHT) (11).  Unfortunately, eventually all patients will develop 
progressive disease despite continued androgen suppression, with a median time to 
progression of 14 to 30 months (12).  
 
There are many mechanisms responsible for the development of resistance to androgen 
deprivation. They include amplification of androgen receptors, increased sensitivity of 
androgen receptors, mutations of androgen receptors that allow activation by non-androgenic 
ligands and activation of alternative survival pathways (13).  There are several approaches 
that are proposed to circumvent or delay the development of androgen independence, but 
none of them have been proven clinically. Intermittent androgen deprivation has been shown 
to delay the development of hormone-refractory disease in preclinical models (14,15).  
Intermittent hormonal therapy usually consists of initial androgen deprivation for 6-12 
months followed by an off - therapy interval until time of relapse (6-15 months). When PSA 
values meet threshold criteria (usually pre-treatment levels) treatment is re-started. Most of 
the initial responders (57-100 %) respond to re-treatment. This cyclic treatment continues 
until the development of hormone-refractory disease. While off-treatment, many patients 
experience improvement in their libidos, erections, hot flushes and energy (16).    
Unfortunately once resistance to hormone-refractory occurs, prognosis is dismal. This so-
called “hormone- refractory prostate cancer” (HRPC) or “androgen - independent prostate 
cancer” is characterized by virulent biologic and clinical behavior with median survival of 
18 months despite treatment with chemotherapy (17,18,19).  
 
Metastatic prostate cancer is a heterogeneous disease and patients with ≤ than 5 lesions have 
better survival than patients with > 5 metastatic lesions (20).  It is more likely that patients 
with limited number of metastases will benefit from local therapy and the patients with         
≤ than 5 metastases will be the focus of this study. 
 
We hypothesize that it is possible and safe to treat patients with prostate cancer 
oligometastases with androgen deprivation and localized radiotherapy and that aggressive 
treatment of oligometastases early in the course of disease when disease is still sensitive to 
hormone manipulation will improve treatment outcomes of patients with metastatic prostate 
cancer.      
  
2.2       Helical tomotherapy 
Rapid advances in computer and medical imaging technologies have resulted in the ability to 
deliver radiotherapy with greater precision and conformality.  External beam radiotherapy 

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has traditionally relied on radiologic imaging to direct therapy to appropriate anatomic 
regions.  The integration of CT imaging into radiation treatment planning, allows for a three 
dimensional view of each patient’s tumor relative to dose-limiting adjacent normal organs, 
allowing for customized beam shaping, beam orientation and dose conformality.  The use of 
3D conformal radiotherapy allows for further escalation of dose, which has resulted in 
higher tumor control, while maintaining risks and side effects at acceptable levels.  
 
Intensity modulated radiation therapy (IMRT) has opened a new era in radiation oncology.  
By delivering therapy from multiple directions using multiple segmented or modulated 
beamlets, one can now sculpt radiation doses to fit the unique shape of each patient’s tumor, 
optimizing radiation delivery to complex volumes and regions of the body.  Some compare 
IMRT to “painting” radiation with a finer brush, where more precise, conformal and 
sophisticated dose patterns are now possible.  This has also resulted in a greater degree of 
conformal dose avoidance of adjacent normal organs.  Dose escalation is now possible with 
IMRT, which was not possible with technology just a decade ago.  For example, radiation 
doses for prostate cancer, which have been limited to approximately 7000 cGy with 
conventional technologies, are now >8000 cGy using IMRT.  As a result, a significant 
improvement in tumor control and a reduction in bladder and rectal toxicities have been 
reported (21). 
 
Helical tomotherapy (HT) represents the next major advance in external beam radiotherapy 
delivery systems. HT is an FDA approved radiation therapy delivery device, which is a 
marriage of spiral CT and IMRT technology.  Specifically, a 6 MV linear accelerator is 
mounted on a CT ring gantry and rotates around the patient as the patient translates through 
the ring.  The treatment fan beam is segmented using a 64-leaf collimator.  Each leaf casts a 
0.6 mm width shadow at 85 cm isocenter distance with the fan beam, which varies in width 
from 0.5 to 5 cm.  The minimum voxel or beamlet size is therefore 5 x 6 mm.  By rapid 
opening and closing of leaves as a function of gantry angle while the patient slides through 
the ring, helical tomotherapy provides unprecedented ability to sculpt radiation doses to 
complex shaped tumor regions while simultaneously avoiding dose to normal organs 
(22,23,24).  
 
Evaluating HT treatment plans for prostate cancer demonstrated rapid drop-off of dose 
around the target (prostate gland) in all directions resulting in excellent sparing of rectum, 
bladder and femoral heads superior to prior IMRT techniques (25). It is predicted that for 
select patients with lung cancer, tumor doses as high as 16,000 cGy will be achievable while 
maintaining normal lung doses (and therefore risks) at comparable levels as with 
conventional delivery methods, which are limited to doses of 6,000 cGy to the tumor in most 
patients. 
 
In addition, an array of detectors mounted on the same rotating gantry and positioned 
directly opposed to the beam source, gives the HT delivery system two unique capabilities 
not found on any other delivery systems.  First, these detectors allow for the generation of 
megavoltage CT (MVCT) images using the 6 MV beam.  Resolution and contrast of MVCT 
is more than adequate to easily distinguish tissue planes and organ boundaries.  This allows 
the HT system to automatically align beam orientation to anatomic external landmarks and 
internal organs in 3 dimensions prior to each daily session, vastly improving the precision of 

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radiation delivery.  Second, these same arrays can be used to monitor output of the beam as 
it exits through the patient, providing an additional level of dose verification.  It is 
anticipated that future software and hardware modifications will allow for this type of 
“adaptive radiotherapy” to occur in real time, constantly modulating beam output to account 
for minute-by-minute variations in tumor and organ motion. 
 
The advent of HT brings for the first time to the clinic the potential to deliver highly 
conforming dose distributions to large complex target shapes.  For example, with HT 
shaping the dose to the entire pleural surface, while sparing lung parenchyma is now 
possible for patients with mesothelioma. 
 
3.0   
DRUG INFORMATION: 
 
3.1 
Zoladex£ (Goserelin)  
 
Description:  Zoladex is an LHRH analog with substitutions for the L-amino acid Glycine 
in positions 6 and 10.  These substitutions produce an analog with 50-100 times the potency 
and longer duration of action then naturally occurring peptide when assessed in acute animal 
tests.   
 
Supply:  Zoladex£ is commercially available as either 3.6 mg (one month) or 10.8 mg 
(three month) pellet for subcutaneous injection.  
 
Storage:  The Zoladex£ 3.6 mg depot is supplied with 16-gauge needle, and the Zoladex£ 
10.8 mg depot is supplied with a 14-gauge needle. The unit is sterile and comes in a sealed, 
light-and moisture-proof package. The pack should be stored at room temperature. Before 
being opened, each package must be inspected for damage in which case the syringe must 
not be used.  Being sterile, the syringe should be removed from its package only by the 
physician/nurse immediately before use. 
 
Administration:  If requested by the patient, a local anesthetic, i.e., 0.2 to 0.5 ml of 1% 
lidocaine hydrochloride may be given intradermally. Zoladex£ will be injected 
subcutaneously using an aseptic technique. Insert the needle to its full length, pull it back 1 
cm, then inject. The manufacturer recommends inserting the needle into the subcutaneous fat 
then changing the direction of the needle so it parallels the abdominal wall before inserting 
the needle to its full length. This will create a little pocket for the Zoladex£ plug so that it 
doses not extend when the needle is withdrawn. After checking to ensure that the depot has 
been discharged, the used syringe will be discarded in a safe manner. One can ensure that the 
depot has been discharged by ensuring that the tip of the plunger is visible within the tip of 
the needle. The tear off portion of the depot package label will be removed and affixed to the 
patient's permanent record.  
 
Toxicity:  During routine screening of Zoladex£, no significant pharmacological activity 
was apparent in the cardiovascular, respiratory, central nervous, renal, metabolic, 
coagulation or gastric systems.  However, the following can occur: vasomotor, hot flashes, 
edema, gynecomastia, bone pain, thrombosis, decreased bone mineral density, lethargy, 

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dizziness, insomnia, anorexia, nausea, upper respiratory tract infection, rash, sweating, 
COPD, congestive heart failure, and GI disturbances. Please refer to the Package Insert for 
further information.  Studies have shown that serum levels of testosterone can be reduced 
and maintained within the castrate range resulting in objective evidence of tumor regression. 
Other than the occasional transient worsening of cancer symptoms tumor flare due to an 
initial temporary rise in testosterone serum levels on initiating therapy, no significant 
toxicity apart from that attributed to castration has been reported. In general, allergic 
reactions have been extremely uncommon with Zoladex£ therapy. There have been isolated 
reports of urethral obstruction, urticaria, or spinal cord compression. 
 
3.2.  
Leupron£ (leuprolide acetate implant) 
 
Description:  Leuprolide acetate is a synthetic nonapeptide analog of naturally occurring 
gonadotropin-releasing hormone (GnRH or LH-RH). The analog possesses greater potency 
than the natural hormone. Leuprolide acetate, an LH-RH agonist, acts as a potent inhibitor of 
gonadotropin secretion when given continuously and in therapeutic doses.  Animal and 
human studies indicate that following an initial stimulation, chronic administration of 
leuprolide acetate results in suppression of ovarian and testicular steroidogenesis. This effect 
is reversible upon discontinuation of drug therapy. Administration of leuprolide acetate has 
resulted in inhibition of the growth of certain hormone dependent tumors (prostatic tumors 
in Noble and Dunning male rats and DMBA-induced mammary tumors in female rats) as 
well as atrophy of the reproductive organs. In humans, administration of leuprolide acetate 
results in an initial increase in circulating levels of luteinizing hormone (LH) and follicle 
stimulating hormone (FSH), leading to a transient increase in levels of the gonadal steroids 
(testosterone and dihydrotestosterone in males, and estrone and estradiol in premenopausal 
females.  However, continuous administration of leuprolide acetate results in decreased 
levels of LH and FSH. In males, testosterone is reduced to castrate levels. In premenopausal 
females, estrogens are reduced to postmenopausal levels. These decreases occur within two 
to four weeks after initiation of treatment, and castrate levels of testosterone in prostatic 
cancer patients have been demonstrated for more than five years. 
 
Supply:  Leuprolide is commercially available as either 7.5 mg (one month), 22.5 mg (three 
month), or 30 mg (four month) depots for intramuscular injection. Each kit contains a vial of 
sterile lyophilized microspheres, which is leuprolide incorporated in a biodegradable 
polymer of polylactic acid. Any formulation may be used. 
 
Storage:  The vial of leuprolide and the ampule of diluent may be stored at room 
temperature. Product does not contain preservative; discard if not used immediately. 
 
Administration:  As with other drugs administered by injection, the injection site should be 
varied periodically. 
 
Toxicity:  In the majority of patients, testosterone levels increased above baseline during the 
first week, declining thereafter to baseline levels or below by the end of the second week of 
treatment. The most common side effect of Leuprolide is hypertension, depression, 
insomnia, headache, dizziness, nervousness, impotence, decreased libido, anorexia, nausea 
and vomiting, myalgia, neuromuscular disorders, dyspnea, anemia, skin reactions, asthenia, 

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and injection site reactions. Please refer to the Package Insert for further information. 
Potential exacerbations of signs and symptoms during the first few weeks of treatment is a 
concern in patients with vertebral metastases and/or urinary obstruction or hematuria which, 
if aggravated, may lead to neurological problems such as temporary weakness and/or 
paresthesia of the lower limbs or worsening of urinary symptoms. 
 
3.3 Casodex£ (bicalutamide) 
 
Description:  Casodex bicalutamide is a nonsteroidal antiandrogen, which has no 
androgenic or progestational properties. The chemical name is propanamide, 
N-[4-cyano-3(trifluoromethyl)phenyl]- 3- [(4fluorophenyl)sulphonyl]- 2- hydroxy- 2methyl, 
(+,-). Casodex is a racemic mixture with the antiandrogen activity residing exclusively in the 
(-) or (R) enantiomer. Casodex 50 mg has the status of an approved new drug. Casodex has a 
long half-life compatible with once-daily dosing. Casodex is well tolerated and has good 
response rates in phase 11 trials (Kennealey and Furr, 1991, Tyrrell 1994). 
 
Supply:  Casodex is commercially available as a 50 mg tablet. 
 
Storage:  Casodex should be stored in a dry place at room temperature between 69o-77oF. 
 
Administration:  Casodex is administered orally at a dose of one 50 mg tablet per day. 
Administration will be suspended only if there is an apparent or suspected reaction to the 
drug.  
 
Toxicity:  In animal experiments, birth defects (abnormal genitalia, hypospadias) were 
found in male offspring from female animals dosed with Casodex during pregnancy. 
Although offspring from male animals dosed with Casodex did not show any birth defects, 
patients enrolled in this trial are advised to neither cause pregnancy nor to donate sperm 
while receiving protocol therapy or during the first 3 months after cessation of therapy. The 
use of barrier contraceptives is advised.   
 
The most frequent adverse events reported among subjects receiving bicalutamide therapy 
are breast tenderness, breast swelling, and hot flashes. Adverse events not directly related to 
the pharmacological properties of bicalutamide were infrequent. Nonpharmacological 
adverse events, reported in the trial using bicalutamide 50 mg as monotherapy include 
asthenia, pelvic pain, peripheral edema, pruritus, rash, constipation, impotence, dyspnea, 
nausea, hypertension, dizziness, paresthesia, insomnia, sweating, diarrhea, increased liver 
enzyme tests, nocturia, hematuria, UTI hyperglycemia, weight loss, anemia, and chest pain 
(Kaisary 1994). There has been no observed change in cardiac parameters during long-term 
administration of bicalutamide 50 mg daily. 
 
When bicalutamide 50 mg was given in combination with an LHRH analogue, the LHRH 
analogue adverse event profile predominated with a high incidence of hot flashes (53%) and 
relatively low incidences of gynecomastia (4.7%) and breast pain (3.2%). 
 
 

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4.0    
STAGING CRITERIA 
STAGE  SUB-
STAGE  DEFINITION  
T1  
   
Clinically unapparent tumor, not detected by DRE nor 
visible by imaging  
   
T1a  
Incidental histologic finding; <5% of tissue resected 
during TURP  
   
T1b  
Incidental histologic finding; >5% of tissue resected 
during TURP  
   
T1c  
Tumor identified by needle biopsy due to elevated PSA  
T2  
   
Confined within the prostate (detectable by DRE)  
   
T2a  
Tumor involves half of the 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 the prostate capsule but has not 
spread to other organs  
   
T3a  
Extracapsular extension  
   
T3b  
Tumor invades seminal vesicle(s) 
T4  
   
Tumor is fixed or invades adjacent structures other than 
seminal vesicles  
   
T4a  
Tumor invades bladder neck and/or external sphincter 
and/or rectum  
   
T4b  
Tumor invades levator muscles and/or is fixed to pelvic 
wall  
 
 
 
 
 
 
 
 
 

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STAGE  SUB-
STAGE  DEFINITION  
Node 
(N)  
   
Regional lymph nodes  
   
N0  
No lymph nodes metastasis  
   
N1  
Metastasis in single lymph node <2 cm in greatest 
dimension  
   
N2  
Metastasis in single lymph node >2cm but <5 cm in 
greatest dimension, or multiple lymph nodes, none >5 
cm  
   
N3  
Metastasis in lymph node >5 cm in greatest dimension  
 
STAGE  
SUB-
STAGE  DEFINITION  
Metastasis     
Systemic spread  
   
M0  
No distant metastasis  
   
M1a  
Non-regional lymph node metastasis  
   
M1b  
Bone metastasis 
     1) Axial skeleton only 
     2) Extending also to peripheral skeleton   
   
M1c  
Metastasis at other sites  
 
STAGE  
SUB-
STAGE  DEFINITION  
Histopathologic     
Differentiation  
   
GX  
Grade cannot be assessed  
   
G1  
Well differentiated (slight anaplasia)  
   
G2  
Moderately differentiated (moderate anaplasia)  
   
G3  
Poorly differentiated or undifferentiated 
(marked  
              

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STAGE GROUPING: 
 
 
Gleason 
I 
T1a 
N0 
M0 
G1 
II 
T1a 
N0 
M0 
G2, 3-4 
 
T1b 
N0 
M0 
Any G 
 
T1c 
N0 
M0 
Any G 
 
T1 
N0 
M0 
Any G 
 
T2 
N0 
M0 
Any G 
III 
T3 
N0 
M0 
Any G 
IV 
T4 
N0 
M0 
Any G 
 
Any T 
N1or N2 or N3 
M0 
Any G 
 
Any T 
Any N 
M1a or M1b or M1c Any G 
 
                  
5.0  ELIGIBILITY CRITERIA 
5.1 Inclusion Criteria 
5.1.1 Patients with histologically proven diagnosis of adenocarcinoma of the 
prostate stage N1, N2, N3, M1a, M1b, M1c with d 5 metastatic lesions. If the 
diagnosis of metastasis in the lymph node is based solely on imaging CT scan 
or MRI, the longitudinal diameter of the lymph node has to be t 2.0 cm. If 
the lymph node is positive on PET or Prostascint scan, the longitudinal 
diameter of the lymph node on CT scan or MRI has to be t 1.5 cm. 
5.1.2 Patients who have measurable disease must have had X-rays, scans or 
physical examination used for tumor measurement completed within 28 days 
prior to registration. Patients must have non-measurable disease assessed 
within 42 days prior to registration.  
5.1.3 Patients must have had documented PSA level of > 2 prior to onset of 
androgen deprivation. 
5.1.4 Patients might have received up to 36 weeks of adjuvant androgen 
deprivation therapy and up to 36 weeks of androgen deprivation therapy for 
metastatic disease prior to enrollment to this study. Patients may be on 
androgen deprivation for metastatic disease at the time of enrollment to the 
protocol.  Adjuvant therapy must have been completed at least 2 years before 

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androgen deprivation for metastatic disease and patients must remain 
hormone sensitive.   
5.1.5 Prior radiation therapy for metastatic disease is not allowed. 
5.1.6 Prior chemotherapy for metastatic disease is not allowed. Prior neoadjuvant 
and adjuvant chemotherapy is allowed. Patients must have recovered from all 
acute side-effects related to previous systemic therapy. 
5.1.7 Patients are allowed to receive one prior systemic non-chemotherapeutic 
treatment (i.e. immunotherapy, receptor tyrosine kinase inhibitor, 
antiangiogenic agent, differentiating agent) for recurrent or metastatic 
disease. Patients must have recovered from all acute side-effects related to 
previous systemic therapy. 
5.1.8 Use of bisphosphonates is allowed at the discretion of treating physician 
5.1.9 Patients must be at least 18 years of age. 
5.1.10 Patient must be capable of understanding the nature of the trial and must give 
written informed consent. 
5.1.11 Patients must have a WHO Performance status of 0, 1, or 2. 
5.2 Exclusion Criteria 
5.2.1 Patients with unstable or severe intercurrent medical conditions or active, 
uncontrolled infection. 
5.2.2 Patients with history of orchiectomy.  
5.2.3 Patients undergoing therapy with other investigational agents. Patients must 
have recovered from all acute effects of previously administered 
investigational agents and sufficient time must have elapsed since last 
administration to ensure the drug interactions not occur during this study. 
5.2.4 Patients with a history of brain metastases or who currently have treated or 
untreated brain metastases. 
5.2.5 Patients who have demonstrated refractoriness to hormone therapy with 
LHRH agonist.  Refractoriness is defined as occurrence of one of the 
following while on therapy with LHRH agonist: Increase in PSA by 25% 
over baseline (to at least > 2 ng/ml) on two consecutive PSA measurements, 
20% increase in the sum of longest diameters of target measurable lesions 
over smallest sum observed (over baseline if no decrease during therapy) 
using the same techniques as baseline, clear worsening of any non-
measurable disease, reappearance of any lesion that had disappeared, 
appearance of any new lesion.   
 
6.0 TREATMENT PLAN 
Treatment will be given according to the Schema described in section 6.1.                
A treatment may be stopped for up to 4 weeks to allow for recovery from toxicities.  
Patients unable to safely resume treatment at that point will be taken off study. 12 
weeks constitutes one cycle of hormone therapy.   

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6.1 Treatment schedule: 
           6.1.1 Patients will begin radiation therapy only after they have demonstrated evidence of  
                    PSA normalization after initiation of androgen deprivation therapy (stable or           
                    declining PSA level of d 4 (or stable or declining PSA d pre-treatment level            
                    whichever is smaller) on two consecutive measurements. Patients who                    
                    do not meet these criteria will be taken off protocol.   
6.1.2 Patients will be divided into two strata: 
 
Stratum 1: 
a) Patients who are not on androgen deprivation therapy at the time of 
enrollment to the protocol will begin androgen deprivation and start radiation 
therapy after PSA normalization (see section 6.1.1)  
b) Patients who are already treated with androgen deprivation therapy at the 
time of enrollment to the protocol (see 5.1.4) will continue androgen 
deprivation therapy and begin radiation after meeting criteria for PSA 
normalization (see section 6.1.1). Radiation therapy will be finished before 
36 weeks (+2 weeks) of hormone therapy is completed. 
                         
 Stratum 2: 
Patients who are enrolled on the protocol towards the end (or after 
completion) of 36 weeks (+2 weeks) of androgen deprivation so radiation 
treatment cannot be finished before the completion of 36 weeks of androgen 
deprivation therapy can still initiate and/or complete radiation therapy as long 
as their serum testosterone level remains at the castrated levels (<50 ng/dL) 
and they meet the criteria for PSA normalization (section 6.1.1). Patients will 
not receive more than 36 weeks of androgen deprivation therapy.     
Androgen deprivation therapy will include LHRH agonist (goserelin 3.6 mg 
subcutaneously q 4 weeks or goserelin 10.8 mg subcutaneously q 12 weeks, 
or leuprolide 7.5 mg intramuscularly q 4 weeks or leuprolide 22.5 mg 
intramuscularly q 12 weeks) and bicalutamide 50 mg po q day. Androgen 
deprivation therapy will last for a total of 36 weeks (+2 weeks)  (i.e. patient 
who received 12 weeks of androgen deprivation therapy prior to enrollment 
to this protocol will receive additional 24 weeks of androgen deprivation 
treatment, patient who received 32 weeks of androgen deprivation therapy 
prior to enrollment to this protocol, will receive additional 4 weeks of 
androgen deprivation treatment etc.).   
Radiation therapy will be delivered to all known metastatic sites. Most are 
anticipated to be bone metastases or lymph node metastases. No more than 5 
metastatic sites and, if indicated, a primary site will be treated.  
                        6.1.3.  Duration of the protocol: 
Following 36 weeks (+2 weeks)  of androgen deprivation therapy patients will 
remain off treatment until PSA relapse (see 9.2.8) defined as increase in PSA 
level to the pre-androgen deprivation therapy level or > 10 (whichever is 
smaller). For example: patient with pre-treatment PSA level of 40 will resume 

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androgen deprivation therapy when PSA level increases to > 10, patient with 
pre-treatment PSA level of 3 will resume androgen deprivation therapy when 
PSA level is > 3. At the time when patients meet the criteria for re-treatment 
with androgen deprivation therapy they will be taken off the protocol. After 
patients are taken off protocol we will do a chart review for  long term 
outcomes.    
 
6.2  Radiation: 
6.2.1    The gross tumor volume (GTV) will be defined as the radiological dimensions of 
            the lesion as identified by CT and/or MRI. The planning tumor volume (PTV) is 
            defined as the GTV plus 1 cm.  
6.2.2 For lesions that move with respiration (Rib and lung parenchymal lesions for 
example) CT simulation will be performed at inspiration and expiration to 
define lesion position during the respiratory cycle. The GTV will be defined 
based on lesion position during the respiratory cycle. 
6.2.3 All sites will be treated using one of the following fractionation schemes: 1) 300 
cGy/day to 3000 cGy; 2) 250 cGy/day to 3750 cGy; 3) 200 cGy/day to 4000 
cGy. 
6.2.4 All patients will be planned using helical tomotherapy given its ability to treat 
multiple sites with conformal RT in a single treatment session. However, at the 
discretion of the treating radiation oncologist, other technology, beam 
arrangements, photon energies and treatment plan is allowed if felt to be more 
appropriate for treatment of the specific lesion.  
6.2.5 If previously untreated, the primary tumor (GTV = prostate gland) and potential 
areas of regional spread (GTV = seminal vesicles and pelvic nodes) are to be 
treated the PTV is the GTV + 5 mm margin and tomotherapy with daily 3-D 
image-guidance must be utilized. The total dose to the PTV will be 4500 cGy to 
the nodes, 4500 to 5400 to the seminal vesicles, and 7500 to 7800 to the prostate 
at 180-200 cGy/day. 
             6 .3 Criteria for Removal From Treatment 
6.3.1 Progression of disease at the time of androgen deprivation therapy (minimum 
of 12 weeks of treatment if progression is by PSA criteria only) 
6.3.2 Patients do not meet the criteria for PSA normalization after 36 weeks of 
androgen deprivation (see section 6.1.1) 
6.3.3 Unacceptable toxicity (as defined in section 7.0.) 
6.3.4 Delay of treatment > 4 weeks from planned date of therapy due to toxicity. 
6.3.5 Patient may always discontinue treatment whenever he wishes. 
6.3.6 Patients will be taken off the protocol when they meet the criteria for PSA 
relapse following completion of 36 weeks of androgen deprivation therapy 
(see section 6.1.3) 
 

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7 
TOXICITIES MONITORED, DOSAGE MODIFICATIONS 
7.3 This study will use Common Terminology Criteria for Adverse Events v3, which can 
be found at the CTEP, website: http://ctep.cancer.gov/reporting/ctc.html  
7.4 Management of Anticipated Toxicities:  Missed days and doses will not be made up. 
Treatment should be stopped for any protocol treatment related Grade 3 toxicity or greater 
that cannot be controlled with good medical practice intervention. Treatment may be 
resumed upon resolution of that toxicity to Grade 2. A patient who experiences a Grade 3 
or higher toxicity again will be removed from the study. There are no provisions for dose 
reductions of hormone therapy. The maximum delay in treatment will be 28 days. 
8.0     STUDY PARAMETERS AND CALENDAR 
Assessment 
   Prior to 
Enrollment 
Day 1 of 
each cycle* 
Every 4 
weeks 
until 
PSA 
relapse 
At the time of 
PSA relapse  
History and Physical Exam 
X1 
X2 
 
 
Weight and WHO PS 
 
X1 
X2 
 
 
Toxicity using CTC v3.0 
 
X2  
 
 
CBC, Diff, Plts,  
Na, K, Cl, CO2, Creatinine, 
BUN, glucose, Calcium, 
phosphorus, albumin, LDH, 
SGPT (ALT), SGOT (AST), 
Alkaline Phos, Total Bilirubin 
X1 
X1 
 
 
 
 
 
X2  
 
 
 
 
 
 
 
EKG 
X3 
 
 
 
Chest X-Ray  
X3 
 
 
 
PSA  
X3 
 
X7 
 
Serum testosterone 
X3 
 
X8 
 
Tumor Measurements 
(measurable disease)  
X4 
X6 
 
X 
Tumor Evaluation 
(evaluable disease) 
X5 
X6 
 
X 
Treatment: LHRH agonist 
(goserelin or leuprolide) 
 
q 4 weeks x  9 doses or q 12 weeks x 3 
doses (total duration of androgen 
deprivation- see section 6.1) 9 
Treatment: bicalutamide 
 
daily x 36 weeks (total duration of 
androgen deprivation- see section 6.1) 9 

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Assessment 
   Prior to 
Enrollment 
Day 1 of 
each cycle* 
Every 4 
weeks 
until 
PSA 
relapse 
At the time of 
PSA relapse  
Treatment: Radiation 
 
daily x 2-7 weeks during or after 
completion of androgen deprivation 
therapy (see section 6.1)  
*Each cycle = 12 weeks 
1Within 7 days of d1 of cycle #1 (can be done on d#1 cycle #1) 
2Except cycle 1 if done within 7 days of d1 of cycle #1 
3Within 14 days of d1 of cycle #1    
4Within 28 days of d1 of cycle #1   
5Within 42 days of d1 of cycle #1 
6At the time of completion of 36 weeks of androgen deprivation therapy or radiation therapy (whichever comes later) 
7 Can be done on the day of clinic visit or up to 14 days before or after.  
7 PSA; every 4 weeks for 2 years, and every 3mos after year 2, every 6 mos. thereafter or until relapse which ever occurs first. 
8 Four weeks after the first LHRH injection, afterwards no repeat measurements will be done until the day of the last LHRH 
injection, and then monthly until the normalization of testosterone levels or resumption of androgen deprivation therapy 
(whichever comes first). Testosterone level will also be drawn to confirm castrated levels in patients who completed 36 weeks 
of androgen ablation and are considered for radiation therapy (see section 6.1.2.) To simplify schedule, testosterone level can be 
drawn on the same day that PSA test 
9 + 2 weeks 
    
 
9.0       CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
Patients who complete radiation therapy and 1 cycle (12 weeks) of androgen deprivation 
treatment on protocol will be included in analysis of tumor response and time to PSA relapse 
9.1      Disease Status 
9.1.1 Measurable disease: Lesions that can be accurately measured in at least one 
dimension by 1) medical photograph (skin or oral lesion), palpation, plain X-
ray, CT, MRI, or other conventional technique with longest diameter 2 cm or 
greater in the axial plane (bone lesions not included), or 2) spiral CT with 
longest diameter 1 cm or greater. Ultrasound is only suitable for superficial 
disease (superficial palpable nodules, subcutaneous lesions, thyroid lesions). 
Conventional CT and MRI should be performed with cuts of 10 mm or less in 
slice thickness contiguously. Spiral CT should be performed using a 5 mm 
contiguous reconstruction algorithm.   
9.1.2 Non-measurable disease: Lesions too small to be considered measurable, 
masses with margins not clearly defined, bone disease, pleural or pericardial 
disease, leptomeningeal disease, pneumonitis, lymphangitis.  
9.2      Objective Status 
(To be recorded at each evaluation.) All measurable lesions (patients eligible for this 
protocol will have no more than 5 metastases) should be identified at baseline.  
Measurements must be provided for all measurable lesions, while presence or 
absence must be noted for non-measurable disease. Unless progression is observed, 
objective status can only be determined when all measurable and non-measurable 
sites and lesions are assessed. 

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9.2.1 Partial response in non-measurable disease (PRNM).  Decrease in PSA level 
of  > 50% compared to baseline pre-treatment level. No progression of non-
measurable disease. No new lesions. 
9.2.2 Partial response (PR):  Applies only to patients with at least one measurable 
lesion.  Greater than or equal to 30% decrease under baseline in the sum of 
longest diameters of all target measurable lesions.  No progression of non-
measurable disease.  No new lesions.  All measurable and non-measurable 
lesions and sites must be assessed using the same techniques as baseline. 
9.2.3 Complete response (CR):  Complete disappearance of all measurable and 
non-measurable disease.  No new lesions.  No disease-related symptoms.   
For patients status post previous prostatectomy - PSA level <0.2. For patients 
with remaining prostate declining or stable PSA level <1. All measurable, 
and non-measurable lesions and sites must be assessed using the same 
technique as baseline. 
9.2.4 Stable/No response:  Does not qualify for CR, PR, or progression.  All 
measurable and non-measurable sites must be assessed using the same 
techniques as baseline. 
9.2.5 Progression: One or more of the following must occur at the time of 
androgen deprivation therapy: Increase in PSA by 25% over baseline (to at 
least > 2 ng/ml), 20% increase in the sum of longest diameters of target 
measurable lesions over smallest sum observed (over baseline if no decrease 
during therapy) using the same techniques as baseline, clear worsening of any 
non-measurable disease, reappearance of any lesion that had disappeared, 
appearance of any new lesion/site, failure to return for evaluation due to 
death, deteriorating condition (unless clearly unrelated to this cancer).  
9.2.6 a) Non-measurable disease does not affect objective status except in 
determination of CR (must be absent - a patient who otherwise has CR, but 
who has non-measurable disease present or not assessed, will be classified as 
having a PR), and in determination of progression (if new sites of disease 
develop or if unequivocal progression occurs in the opinion of the treating 
physician). 
b) Appearance or worsening of pleural effusions do not constitute 
unequivocal progression unless cytologically proven of neoplastic origin. 
c) For “scan-only” bone disease, increased uptake in previously seen lesions 
does not constitute clear worsening.  
d) In cases for which initial tumor flare reaction is possible (hypercalcemia, 
increased bone pain, erythema of skin lesions), either symptoms must persist 
beyond 4 weeks or there must be additional evidence of progression. 
e) Lesions that appear to increase in size due to presence of necrotic tissue 
will not be considered to have progressed.  
9.2.7 Unknown: Progression has not been documented and one or more measurable 
or non-measurable sites have not been assessed. 

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9.2.8 PSA relapse after completion of initial 36 weeks of androgen deprivation 
therapy is defined as an increase in PSA value to above pre-therapy level or > 
10 (whichever is smaller). For example patient with pre-treatment PSA level 
of 40 will resume androgen deprivation therapy when PSA level is > 10, 
patient with pre-treatment PSA level of 3 will resume androgen deprivation 
therapy when PSA level is > 3. 
9.3      Best Response: This is calculated from the sequence of objective statuses 
a) CR: Two or more objective statuses of CR a minimum of four weeks apart 
documented before progression or symptomatic deterioration. 
b) PR:  Two or more objective statuses of PR or better a minimum of four weeks 
apart documented before progression or symptomatic deterioration, but not 
qualifying as CR. 
c) Unconfirmed CR: One objective status of CR documented before progression or 
symptomatic deterioration but not qualifying as CR or PR. 
d) Unconfirmed PR: One objective status of PR documented before progression or 
symptomatic deterioration but not qualifying as CR, PR or unconfirmed CR. 
e) Stable/no response: At least one objective status of stable/no response 
documented at least six weeks after registration and before progression or 
symptomatic deterioration, but not qualifying as anything else above. 
f) Increasing disease: Objective status of progression or symptomatic deterioration 
within twelve weeks of registration, not qualifying as anything else above. 
g) Inadequate assessment, response unknown: Progression or symptomatic 
deterioration greater than twelve weeks after registration and no other response 
category applies. 
9.4 
Time-Related Endpoint Definitions 
9.4.1 Survival: Defined as the time from registration to time of death due to any 
cause. If a patient is not known to have died, survival time is censored at the 
time of last follow-up. 
9.4.2 Progression-free survival: Defined as the time from registration to the first 
observation of disease progression (as defined in 9.2.5) or death due to any 
cause.  If a patient has not progressed or died, progression-free survival is 
censored at the time of last follow-up. 
9.4.3 Time to treatment failure: Defined as the time from registration to the first 
observation of disease progression, death due to any cause, or early 
discontinuation of treatment.  If failure has not occurred, failure time is 
censored at the time of last follow-up. 
9.4.4 Time to PSA relapse: Time from the date of the last dose of bicalutamide or 
the last day of radiation therapy (whichever comes later) until the date the 
criteria are met for the PSA relapse (see 9.2.8)  
    

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10.0     STATISTICAL CONSIDERATIONS 
This is a phase II study to evaluate the efficacy and safety of radiation to metastatic sites plus 36 
weeks months of androgen deprivation in patients with hormone-sensitive prostate cancer. The 
primary endpoint in this trial will be time to PSA relapse as defined in 9.2.8 and 9.4.4. Secondary 
endpoints include PSA response to treatment, safety, feasibility and tolerability.  
 
Based on the prior data, the median time to PSA relapse (PSAR) following 36 weeks of androgen 
deprivation therapy, is approximately 40 weeks. This study would then look to detect an improvement 
beyond 40 weeks. For a one-sample, one-sided, 0.05-level test using the large-sample normal 
approximation for the distribution of the logarithm of the maximum likelihood estimator of the 
exponential parameter, with 28 patients and assuming accrual of 24 months and follow-up of 12 
months, there will be 83% power for the test of the null hypothesis that the median PSAR is 9 
months vs. the alternative that the median PSAR is 16 months as measured from the end of the 
twelve months of androgen deprivation therapy.  If the parametric estimate of median PSAR is 13 
months, this would suggest activity for the addition of radiation therapy.  The initial analysis will 
include all patients, although analysis by strata will also be conducted in an exploratory fashion as 
will the role of previous adjuvant hormone treatment.  
 
In addition to obtaining an early estimate of the effect of this therapy based on survival, feasibility and 
toxicity will also be carefully monitored in this novel approach.  
 
 
 
10.1 Interim analysis for toxicity 
 
With 28 patients, we will be able to estimate the complication rate (any grade 3 or 
higher toxicity attributable to the radiation or combination of androgen deprivation/ 
radiation therapy) with a maximum standard error of 19%.  If less than 2 cases have 
radiation induced complications, we can rule out a 17% complication rate or higher 
with 95% confidence.  Since this therapy is not expected to cause severe toxicities, if 
at any time more than 25% of the patients experience a radiation induced 
complication, the study will be halted pending review. 
 
The outcome status (in terms of toxicity, response, reason off study, progression, and 
survival) of all eligible patients who are registered will be reported.  All patients who 
receive any treatment will be included in the summaries of toxicities.  The CTCAE 
v. 3.0 toxicity criteria will be used. Toxicity information recorded will include the 
type, severity, time of onset, time of resolution, and the probable association with the 
study regimen. Time to progression and overall survival will be estimated using the 
product-limit method of Kaplan and Meier.  
 
The sample-size, as justified above, is 28 patients. With an expected accrual of 14 
patients per year, it will take approximately two years to complete the accrual. 
 
11.0     REGISTRATION GUIDELINES 
11.1 Registration will be done at City of Hope. 

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11.2 Once all pretreatment evaluations have been performed, patients will be entered on        
        study after review of patient eligibility by a member of the Department of Biostatistics. 
        Patients may be screened for registration by calling the City of Hope Department of       
        Biostatistics, ext. 62468. 
 
12.0    RECORDS TO BE KEPT, DATA COLLECTION AND SUBMISSION SCHEDULE 
12.1 Confidentiality of Records: The forms will be kept in secure cabinets in the Department of 
Biostatistics.   
12.2  Patient Consent Form: At the time of registration, three signed and dated copies of the 
patient Informed Consent form with the Human Rights must be available (for patient, 
patient’s medical chart and one for the Biostatistics Office. 
12.3 Data collection forms and submission schedule: All data will be collected using COH 
Biostatistics Information Tracking System (BITS) data collection forms.  Copies of the 
completed forms will be submitted to City of Hope Department of Biostatistics for 
entry and stored in a secure location.  The original data collection forms will reside at   
the originating institution in secure location. 
12.3.1 The data manager will complete the Eligibility Checklist Worksheet at the 
time of registration. 
12.3.2 Within two weeks of registration, the data manager will complete the On-
Study Form (Form OS). 
12.3.3 Within four weeks of completion of each course of treatment, the data 
manager   must complete the following: 
12.3.3.1 
Treatment and Adverse Event Form 
12.3.3.2 
Supplemental data form (if applicable) 
12.3.3.3 
Flow sheets (These are to be submitted along with each 
treatment form)  
12.3.4 Each time a patient is evaluated for response and/or new follow-up 
information is obtained the data manager will complete the Response/Off-
Study/Follow-Up Form. 
12.4 Analysis will be carried out by Department of Biostatistics. 
 
13.0     MINORITIES AND WOMEN STATEMENT 
Prostate cancer is limited to men. Patients from all racial/ethnic groups are eligible for this 
study if they meet the eligibility criteria outlined in Section 5.0.   
 
14.0     ETHICAL AND REGULATORY CONSIDERATIONS 
All institutional, NCI, Federal, and State of California regulations will be fulfilled. 
 
15.0    PATHOLOGY REVIEW 
All patients will have malignancy confirmed by review of their biopsy specimens by the 
Division of Pathology of the City of Hope National Medical Center. 

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16.0 
DATA AND SAFETY MONITORING 
A)   Definition of Risk Level 
  
This is a Risk Level 3 study, as defined in the “Guidance, Policy and Procedures for Data 
and Safety Monitoring for In-House Trials at City of Hope”, 
http://www.infosci.coh.org/gcrc/doc/dsmp.doc because it is a Phase II clinical trial where the 
risks are at least balanced by the potential benefit to subjects and the importance of 
knowledge that may result.  
  
B)   Monitoring and Personnel Responsible for Monitoring 
  
  The Protocol Management Team (PMT) consisting of the PI, Collaborating Investigator, CRA, 
protocol nurse, and statistician is responsible for monitoring the data and safety of this study, 
including implementation of any stopping rules for safety and efficacy.  
Data and safety will be reported to the COH DSMB. Reporting of data to DSMB will occur at 
intervals separated by no more than 12 months, 14 patients or a treatment related death. The 
PMT report will include a summary of accrual, adverse events and treatment related mortality. 
C)    Adverse Events 
 
Reporting: Adverse events will be reported to the COH DSMB, and IRB according to 
definitions and guidelines at http://www.infosci.coh.org/gcrc/doc/dsmp.doc and 
http://resadmin.coh.org/doc/irb3810.doc, which are defined below.  AEs will be monitored 
by the PMT. Less than serious adverse events will be reported only at the time of protocol 
continuation reports.  
  
Adverse Event - An adverse event (AE) is any untoward medical experience or change of 
an existing condition that occurs during or after treatment, whether or not it is considered to 
be related to the protocol intervention. All AEs occurring during this study, whether 
observed by the physician, nurse, or reported by the patient, will be recorded on the City of 
Hope National Medical Center Adverse Events (COH AER) form 
(http://resadmin.coh.org/doc/irb3820.doc) form.   
 
Serious Adverse Event- A serious adverse event (SAE) is defined as any expected or 
unexpected adverse event (AE, generally equivalent to CTCAE grades 3, 4 or 5) that is 
related or unrelated to the intervention that results in any of the following outcomes: 
 Death 
 A life-threatening event 
 In-patient hospitalization (not required as part of the treatment) or prolongation of existing 
hospitalization 
 A persistent or significant disability/incapacity 
 A congenital anomaly/birth defect 
 Causes cancer 
 Is an overdose 

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 Certain medical events that may not result in death, be life threatening, or require 
Hospitalization, may also be considered a serious adverse event when appropriate medical or 
surgical intervention is necessary to prevent one of the outcomes listed above. 
  
Unexpected Adverse Event – Any event in which the severity or specificity is not consistent 
with the risk information described in the protocol, and the event is not anticipated from the 
subject's disease history or status. 
  
Expected Adverse Event - Any event in which the severity or specificity is consistent with the 
risk information described in the protocol or is anticipated based on the subject's medical 
history. 
  
Attribution - For reporting purposes, attribution is the assessment of the likelihood that an AE 
is caused by the research agent or protocol intervention.  The attribution is assigned by the 
Principal Investigator after considering the clinical information, the medical history of the 
subject, and past experience with the research agent/intervention.  This is recorded using the 
Adverse Event Report (COH AER) form (http://resadmin.coh.org/doc/irb3820.doc) in one of 5 
categories scored as the following: 5=related, 4=probably related, 3=possibly related, 
2=unlikely related and 1=unrelated.  The attribution is subject to change as follow-up 
information becomes available, and it can be changed by the DSMB or by the IRB in the 
process of review. 
 
 
 
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JF:  Reduction in radiation dose to lung and other normal tissues using helical tomotherapy to 
treat lung cancer, in comparison to conventional field arrangements.  Am J Clin Oncol 26: 70-
8, 2003. 

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APPENDIX A 
 
A Common Terminology Criteria for Adverse Events v3 (CTCAE Publish date 
12/12/03) 
 
Website:  ctep.cancer.gov/reporting/ctc.html