Phase I Trial of Adaptive Stereotactic Body Radiotherapy (SBRT) Dose Escalation in Pancreatic Cancer
Phase: NA
Conditions: Pancreatic Cancer
Sponsor: University of California, San Diego

 
 
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Moores UCSD Cancer Center 
University of California, San Diego   
 
 
 
 
 
 
Phase I Trial of Adaptive Stereotactic Body Radiotherapy (SBRT) Dose Escalation in 
Pancreatic Cancer  
 
 
 
 
Version Date: 04/22/2014 
 
 
 
 
PRINCIPAL INVESTIGATOR 
 
James Murphy, M.D., M.S. 
University of California, San Diego 
Moores Cancer Center 
3855 Health Sciences Drive #0865 
La Jolla, CA 92093-0865 
Phone:  (858)534-3508 
Fax:  (858)246-1505 
E-mail:  j2murphy@ucsd.edu 
 
 

 
 
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SUB-INVESTIGATORS 
 
Radiation Oncology (UCSD) 
James Murphy, M.D., M.S. 
University of California, San Diego 
Moores Cancer Center 
3855 Health Sciences Drive #0865 
La Jolla, CA 92093-0865 
Phone:  (858) 534-3508 
Fax:  (858) 246-1505 
E-mail:  j2murphy@ucsd.edu  
 
John Einck, M.D. 
University of California, San Diego 
Moores Cancer Center 
3855 Health Sciences Drive #0865 
La Jolla, CA 92093-0865 
Phone:  (858) 246--1506 
Fax:  (858) 246-1505 
E-mail:  jeinck@ucsd.edu 
Jona Hattangadi-Gluth, M.D. 
University of California, San Diego 
Moores Cancer Center 
3855 Health Sciences Drive #0865 
La Jolla, CA 92093-0865 
Phone:  (858) 534-1222 
Fax:  (858) 246-1505 
E-mail:  jhattangadi@ucsd.edu 
 
William Song, Ph.D. 
University of California, San Diego 
Moores Cancer Center 
3855 Health Sciences Drive #0865 
La Jolla, CA 92093-0865 
E-mail:  wysong@ucsd.edu 
 
Medical Oncology (UCSD) 
Gregory Heestand, M.D. 
University of California San Diego 
 
Moores Cancer Center 
 
 
 
3855 Health Sciences Drive #0987  
 
La Jolla, CA 92093 
 
 
 
 
(858) 822-3115 
 
 
gheestand@ucsd.edu  
Paul Fanta, M.D. 
University of California San Diego 
Moores Cancer Center 
 
 
 
3855 Health Sciences Drive #0987  
 
La Jolla, CA 92093 
(858) 822-6185  
pfanta@ucsd.edu  
 
Surgical Oncology (UCSD) 
Andrew Lowy, M.D. 
University of California San Diego 
Moores Cancer Center 
3855 Health Sciences Drive #0987 
La Jolla, CA 92093 
(858) 822-2124 
alowy@ucsd.edu 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Biostatistics (UCSD) 
Ronghui (Lily) Xu, PHD 
Division of Biostatistics and Bioinformatics 
Department of Family and Preventive 
Medicine, and Department of Mathematics 
Director, CTRI Biostatistics, Epidemiology, 
and Research Design 
University of California, San Diego 
9500 Gilman Drive, Mail Code 0112 
La Jolla, CA 92093-0112 
James Proudfoot, PhD 
CTRI Biostatistics 
University of California, San Diego 
9500 Gilman Drive, Mail Code 0112 
La Jolla, CA 92093-0112 
jproudfoot@ucsd.edu 

 
 
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Table of Contents 
 
SECTION 
PAGE 
SUB-INVESTIGATORS....................................................................................................... 2 
EXPERIMENTAL DESIGN SCHEMA ................................................................................ 5 
1.0 
INTRODUCTION ................................................................................................... 6 
1.1 
Pancreatic Cancer .................................................................................................. 6 
1.2 
Treatment options for locally advanced unresectable pancreatic cancer ............... 6 
1.3 
Radiation for locally advanced pancreatic cancer .................................................. 6 
1.4  
Stereotactic body radiotherapy (SBRT) in pancreatic cancer ................................ 6 
1.5  
Primary study hypothesis ....................................................................................... 8 
1.6 
Imaging/treatment correlative study background .................................................. 8 
2.0 
OBJECTIVES .......................................................................................................... 8 
2.1  
Primary Aim .......................................................................................................... 8 
2.2  
Secondary Aims ..................................................................................................... 8 
3.0 
PATIENT SELECTION ........................................................................................... 9 
3.1 
Inclusion Criteria ................................................................................................... 9 
3.2 
Exclusion Criteria .................................................................................................. 9 
4.0 
PRETREATMENT EVALUATIONS ...................................................................... 10 
4.1  
Required Evaluations ........................................................................................... 10 
5.0 
ENROLLMENT PROCEDURES .......................................................................... 10 
5.1 
Recruitment .......................................................................................................... 10 
5.2 
Informed Consent ................................................................................................ 10 
5.3 
Screening Procedures ........................................................................................... 10 
5.3 
Placement of Fiducial Markers ............................................................................ 11 
6.0 
RADIATION THERAPY ........................................................................................ 11 
6.1  
Pre-SBRT tests and procedures ........................................................................... 11 
6.1  
External Beam Radiation Therapy ....................................................................... 11 
6.2 Radiation Adverse Events ........................................................................................... 13 
7.0 
DRUG THERAPY ................................................................................................. 13 
7.1 
Chemotherapy ...................................................................................................... 14 
8.0 
OTHER THERAPY................................................................................................ 14 
8.1  
Permitted Supportive Therapy/Procedures: ......................................................... 14 
9.0  
PATHOLOGY ....................................................................................................... 14 
10.0   PATIENT ASSESSMENTS .................................................................................... 14 
10.1 
Study Parameters ................................................................................................. 14 
10.2 
Adverse Events (AEs) .......................................................................................... 15 
10.3 
Steps to Determine If Expedited Reporting for an Adverse Event is Indicated ... 16 
10.4 
Reporting Requirements for Adverse Events....................................................... 16 
10.5 
Criteria for Removal from Protocol Therapy ....................................................... 17 
10.6 
Criteria for Removal from Study ......................................................................... 17 
11.0 
DATA COLLECTION ........................................................................................... 17 
11.1 
Data and Safety Monitoring Plan ......................................................................... 17 
11.2 
Confidentiality Procedures................................................................................... 18 
12.0 
STATISTICAL CONSIDERATIONS...................................................................... 18 
12.1 
Statistical Analysis ............................................................................................... 18 
12.2 
Trial Design, Sample Size, and Study Duration .................................................. 20 
REFERENCES .................................................................................................................. 24 
APPENDICES ................................................................................................................... 25 

EXPERIMENTAL DESIGN SCHEMA 
 
SCHEMA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ꞏ Stereotactic body radiotherapy (SBRT) 
 
Cohort 
Dose level 
1 
8 Gy x 5 fractions  =  40 Gy 
2 
9 Gy x 5 fractions  =  45 Gy 
3 
10 Gy x 5 fractions  =  50 Gy 
4 
11 Gy x 5 fractions  =  55 Gy 
5 
12 Gy x 5 fractions  =  60 Gy 
 
 
 
 
Patient Population: Unresectable pancreatic adenocarcinoma. 
 
Sample size: 30  
 
 
 
Medically unresectable 
(stage I-II), or 
unresectable (stage III) 
pancreatic cancer 
Stable disease 
after 
chemotherapy 
Enroll in trial 
SBRT 
Metastatic (stage IV) 
disease pancreatic 
cancer 

 
 
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1.0 
INTRODUCTION 
 
1.1 
Pancreatic Cancer 
 
Pancreatic cancer is the 10th most common cause of cancer, and the 4th most common 
cause of cancer-related death in the United States, with an annual incidence of 45,220 
new diagnoses per year [1].  The only curative treatment for pancreatic cancer is 
surgery, yet approximately 75% of patients present with unresectable or metastatic 
disease. Of those patients with surgically resectable disease, the 5-year survival is 
around 20%.  Among those with unresectable disease distant metastatic spread remains 
the primary problem, though up to 1/3 of patients will die from local tumor progression 
[2].  Additionally, local tumor progression leads to pain, gastrointestinal obstruction, or 
bleeding, all of which substantially decrease a patient’s quality of life.  Thus, local tumor 
control remains a crucial part of treatment for patients with pancreatic cancer who are 
not candidates for curative therapy. 
 
1.2 
Treatment options for locally advanced unresectable pancreatic cancer 
 
The optimal treatment for locally advanced pancreatic cancer remains unclear, though 
current treatment often includes chemotherapy, or chemotherapy with radiotherapy.  
Unfortunately, patients with unresectable disease are not curable, and therefore 
chemotherapy is delivered with the intent of delaying disease progression, and 
lengthening life.  Radiotherapy focuses on controlling the primary pancreatic tumor.  
Unfortunately, neither chemotherapy nor radiation has proven effective with 
unresectable pancreatic cancer, and the median overall survival for this disease is only 
around 10-12 months. 
 
1.3 
Radiation for locally advanced pancreatic cancer 
 
Conventional radiotherapy in pancreatic cancer is given daily over 5-6 weeks with 
concurrent chemotherapy.  The Gastrointestinal Tumor Study Group conducted a series 
of studies with chemoradiotherapy in pancreatic cancer defining its effectiveness.  More 
recent series on chemoradiotherapy have yielded mixed results, with some reports of 
improved efficacy, and others without.  A primarily limitation of chemoradiation relates to 
the side effects including nausea, vomiting, and fatigue, with a substantial fraction of 
patients experiencing grade 3-4 toxicity.  Unfortunately, despite its efforts, conventional 
chemoradiation has low local control rates often in the range of 50% or lower.  
Additionally, this 5-6 week treatment duration occupies a significant time burden for 
patients and caregivers, plus this can delay much needed systemic chemotherapy.  In 
an attempt to improve local control and reduce treatment time investigators have started 
to use shorter more intense courses of radiotherapy, specifically, stereotactic body 
radiotherapy (SBRT). 
 
1.4  
Stereotactic body radiotherapy (SBRT) in pancreatic cancer 
 
 
SBRT in pancreatic cancer shows great promise with initial studies showing high rates of 
local control.  The initial study from Stanford escalated the dose of single fraction 
radiotherapy from 15 Gy in a single fraction to 25 Gy in a single fraction [3].  A 
subsequent phase II study treated patients to 45 Gy in 25 fractions with conventionally 
fractionated radiation, followed by 25 Gy in a single fraction [4]. Two of the 16 patients in 
this trial (13%) had grade 3 toxicity.  Additional data with 25 Gy in a single fraction found 

 
 
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high rates of local tumor control with a 1-year freedom from local progression rate of 
84% [5].  Unfortunately, the Stanford group found increased risk of late toxicity with the 
25 Gy in 1 fraction regimen [6].  The close proximity of the stomach and duodenum put 
these organs at risk in radiotherapy directed at the pancreas.  Of 73 patients treated with 
25 Gy in a single fraction, 12 had grade 2-4 duodenal toxicity [6]. 
 
More recently, Stanford has preliminarily reported on a phase II trial 5-day course of 
SBRT [7].  This 5 fraction schedule going to 33 Gy was safe, with one reported toxicity 
event, though the efficacy was lower with decreased rates of local control.  The 
observation that 33 Gy in 5 fractions was safe but had lower local control suggests that 
there may be room for dose escalation.  This current trial will determine the maximal 
tolerated dose of SBRT in 5 fractions, for which the efficacy will be tested in a 
subsequent phase II trial. 
 
This trial will escalate the dose from 40 Gy in 5 fractions, to 60 Gy in 5 fractions, at 5 Gy 
intervals.  Comparing different radiation fractionation schedules is complex, though the 
standard metric used is the biologic effective doses (BED), and the BED of multiple 
radiation fractionation schedules is provided below in Table 1.  The selection of a dose 
range with this study was based on a number of factors.  First, the starting dose level of 
45 Gy has been found safe in recently reported hyporfactionated regimens in pancreatic 
cancer [8]. in five fractions is the natural extension beyond 33 Gy in five fractions found 
safe by the Stanford researchers.  The final dose level of 60 Gy in five translates into a 
BED of 132 for tumor response, and 300 for late toxicity. This final dose level is similar to 
that used by Koong, et al. with 141 for tumor response, and 305 for late toxicity. 
 
Table 1. Biologic effective dose of different radiation regimens in pancreatic cancer 
 
 
 
 
Biologic effective dose 
Radiation scheme 
 
Protocol 
 
Tumor 
response 
(α/β = 10) 
Late 
toxicity 
(α/β = 3) 
Conventional radiation 
 
 
 
 
 
 
50 Gy in 25 fractions 
 
 
 
60 
83 
 
 
 
 
 
 
Completed SBRT protocols 
 
 
 
 
 
 
25 Gy in 1 fraction 
 
Koong, et al [3] 
 
88 
233 
 
33 Gy in 5 fractions 
 
Herman, et al [7] 
 
55 
106 
 
45 Gy in 25 fractions, then 
  25 Gy in 1 fraction 
 
Koong, et al [4] 
 
141 
305 
 
45 Gy in 6 fractions 
 
Tozzi, et al [8] 
 
79 
158 
 
 
 
 
 
 
Proposed SBRT protocol 
 
 
 
 
 
 
Cohort 1: 40 Gy in 5 fractions 
 
72 
147 
 
Cohort 2: 45 Gy in 5 fractions (starting dose level) 
86 
180 
 
Cohort 3: 50 Gy in 5 fractions 
 
100 
217 
 
Cohort 4: 55 Gy in 5 fractions 
 
116 
257 
 
Cohort 5: 60 Gy in 5 fractions 
 
132 
300 
 

 
 
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1.5  
Primary study hypothesis 
 
The purpose of this study is to determine the maximum tolerated dose of five fraction 
stereotactic radiotherapy (SBRT) in pancreatic cancer. 
 
1.6 
Imaging/treatment correlative study background 
 
This trial is designed to find the maximum tolerated dose (MTD) under a fixed 5-fraction 
SBRT regimen. To do this, it is necessary to verify that the treatment accuracy remains 
consistent throughout, so as to not be a confounding factor in the outcome. Perhaps the 
biggest contributing uncertainties are the inter- and intra-fractional organ motion, 
principally driven by patients’ respiration. Physiological changes may also impact organ 
motion during SBRT. To compensate for organ motion, generic margins are commonly 
applied to the CTV, such as ITV and PTV. In this trial, 2-3 mm PTV margin will be used 
and may be trimmed further depending on the location of the duodenum or stomach.  
For such a tight margin, along with highly hypofractionated dose, it becomes prudent to 
validate that the image guidance technologies used in this trial are adequate to meet the 
demanded accuracy. To do this, this trial will employ the following sequence of imaging: 
1) kV/kV to bones, 2) CBCT to soft tissue and fiducial markers (4DCBCT if available), 3) 
fluoroscopy to fiducial markers during free-breathing, and 4) repeat CBCT to soft tissue 
and fiducial markers (4DCBCT if available) at the end of treatment. This sequence of 
imaging will help minimize the initial setup uncertainties due to inter-fractional motion 
(steps 1-3) as well as to monitor the intra-fractional motion (step 4). In addition to these 
primary objectives, the images will be further analyzed to determine 1) the minimum 
adequate margin in each principal direction per patient population, 2) identify anatomical 
motion surrogates for when fiducials are not available, and 3) potential for various 
adaptive RT strategies. 
 
2.0 
OBJECTIVES 
 
2.1  
Primary Aim 
 
2.1.1  To determine the maximum tolerated dose (MTD) of stereotactic body 
radiotherapy (SBRT) in pancreatic cancer. 
 
 
2.2  
Secondary Aims 
 
2.2.1 To estimate the rate of local tumor progression after SBRT. 
 
2.2.2 To estimate the rate of distant disease progression after SBRT. 
 
2.2.3 To measure overall survival after SBRT. 
 
2.2.4 To estimate a dose-response between radiation dose and local control. 
 
2.2.5 To measure longitudinal quality of life before and after SBRT. 
 

 
 
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2.2.6 To determine the correlation between quality of life, and disease progression 
after SBRT. 
 
2.2.7 To determine if any dose-volume parameters predict grade ≥3 duodenal toxicity. 
 
2.2.8 To determine if patients are able to receive additional chemotherapy after SBRT. 
 
2.2.9 To identify natural anatomical surrogates that best correlate with the motion of 
the fiducial markers. 
 
2.2.10 To determine if adaptive RT would be beneficial. 
 
 
 
3.0 
PATIENT SELECTION  
 
The eligibility criteria listed below are interpreted literally and cannot be waived. 
 
3.1 
Inclusion Criteria  
 
3.1.1 Diagnosis: Histologically-proven invasive adenocarcinoma of the pancreas. 
 
3.1.2 Disease Status: Medically unresectable (stage I-II), or locally advanced (stage 
III). Patients with distant metastases (stage IV) must have stable disease or 
improved disease (partial response, or complete response) per Response 
Evaluation Criteria In Solid Tumors (RECIST) criteria as determined on serial 
imaging following a course of chemotherapy.  
 
3.1.3 Tumor Location: Primary tumor may be located anywhere in the pancreas. 
 
3.1.4 Treatment eligibility:  The patient must be able to have fiducial markers implanted 
into the pancreatic tumor, and receive radiation regimen as specified in the 
protocol. 
 
3.1.5 Performance Level:  Karnofsky Performance Status ≥ 60 (see Appendix II) 
 
3.1.6 Adequate Renal Function Defined As: 
- 
Serum creatinine ≤ 1.5 x upper limit of normal 
 
3.1.7    Age: Patients must be 18 years of age or older. 
 
3.1.8 Informed Consent: All subjects must sign a written informed consent.  
 
3.2 
Exclusion Criteria 
 
3.2.1 Pregnancy or Breast-Feeding:  Pregnant or breast-feeding women will not be 
entered on this study due to risks of fetal and teratogenic adverse events. (Note: 
Serum Pregnancy tests must be obtained in women of child bearing potential). 
Sexually active females may not participate unless they have agreed to use an 
effective contraceptive method (such as abstinence, diaphragm, condom, or 
intrauterine device) to prevent pregnancy for the duration of the study. 

 
 
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3.2.2 Life expectancy < 6 months  
 
3.2.3 The patient cannot have had prior radiation therapy to the thorax or upper 
abdomen. 
3.2.4 Incarcerated individuals 
3.2.5 Subjects unable to give informed consent 
3.2.6 Subjects with uncontrolled distantly metastatic disease per RECIST criteria 
(progressive disease) on imaging following chemotherapy  
 
 
4.0 
PRETREATMENT EVALUATIONS 
 
The evaluations/interventions listed below should be done prior to the patient starting any 
protocol treatment (but may be done subsequent to the patient enrollment). In the unlikely event 
that results of any of these tests raise questions about the patient’s eligibility for this study, 
please contact Dr. James Murphy immediately (858) 534-3508. 
 
4.1  
Required Evaluations (In addition to the mandatory pre-testing for eligibility in Section 
3.0) 
4.1.1 History and physical examination including height, weight, and Karnofsky 
Performance Status (KPS). 
4.1.2 CT of the abdomen, and pelvis. 
4.1.3 Laboratory blood tests including CBC, comprehensive metabolic panel, and CA 
19-9. 
 
 
 
 
5.0 
ENROLLMENT PROCEDURES 
 
5.1 
Recruitment 
 
Subjects will be identified by study investigators and/or clinical research coordinators at 
participating centers.  Information regarding the study will be included on the Moores UC 
San Diego Cancer Center Clinical Trials webpage and Clinicaltrials.gov. 
 
5.2 
Informed Consent  
 
The investigational nature and objectives of the trial, the procedures and treatments 
involved and their attendant risks and discomforts, and potential alternative therapies will 
be carefully explained to the subject and a signed informed consent will be obtained. 
 
5.3 
Screening Procedures 
  
Written informed consent will be provided prior to any study procedures. Documentation 
of informed consent will be maintained in the subject’s research chart and medical 

 
 
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record. Studies or procedures that were performed for clinical indications or as standard 
of care (not exclusively to determine study eligibility) may be used for baseline values 
even if the studies were done before informed consent was obtained.  
 
5.3 
Placement of Fiducial Markers 
 
Treatment on this protocol requires placement of 3-5 gold fiducials for targeting 
purposes.  The fiducials will be used as surrogates for targeting the daily tumor position 
during treatment.  The fiducials will be placed directly into the tumor, or surrounding 
normal pancreatic tissue under endoscopic ultrasound or CT guidance.  Fiducials may 
be implanted prior to enrollment as this is an acceptable standard of care procedure for 
any patient receiving radiotherapy for locally advanced pancreatic cancer.  Also, if a 
patient had an attempted surgical resection that was aborted, fiducials may have been 
implanted intraoperatively, which is also allowable prior to study enrollment.   
 
Fiducial placement into pancreatic tumors carries a low risk of toxicity [9,10].  In one 
report of 50 patients who had fiducials implanted into the pancreas through endoscopy 
only one patient (2%) had minor bleeding without a significant drop in hemoglobin, and 
this event did not require hospitalization [10].  In another report of 61 patients who had 
fiducials implanted percutaneously under CT guidance only two patients (3.3%) had 
minor bleeding episodes [9]. 
 
6.0 
RADIATION THERAPY 
 
6.1  
Pre-SBRT tests and procedures 
 
6.1.0 Pre-SBRT tests 
- 
Medical history and clinical examination. 
- 
CBC, Chemistry Panel, CA19-9. 
- 
Gold fiducial seed placement percutaneously, intraoperatively, or under 
endoscopic ultrasound guidance, which may be performed prior to enrollment.   
- 
Signed informed consent document. 
 
6.1  
External Beam Radiation Therapy  
 
6.1.0 Patient setup and simulation 
 
6.1.0.1 Position 
CT simulation will be done in the supine position with patient in an Alpha Cradle, 
or Vac-Lok for immobilization. 
 
 
6.1.0.2 Imaging 
All subjects will undergo a 3-dimensional (3D) CT scan with intravenous contrast, 
and slice thickness ≤2.5 mm.  This 3D scan should preferably be done during an 
expiratory breath hold phase.  Following the 3D CT, a four-dimensional (4D) CT 
scan with respiratory gating will be done to account for tumor motion.  CT scans 
should include T4/T5 to L5/S1. 
 
6.1.0.3 Contrast  
Intravenous contrast is used during the CT simulation scan. If a patient cannot 

 
 
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receive IV contrast then an MRI can be done and fused to the treatment planning 
CT scan.  Oral contrast will consist of a cup of water that the patient will drink 30 
minutes before the simulation. 
 
6.1.1 Treatment planning 
 
6.1.1.1 Planning CT scan 
The treatment planning CT scan will be defined as the CT from simulation that 
most clearly shows the tumor and adjacent normal tissue, and can be any of the 
following: 
1) Expiratory phase of the 4D CT scan (50%);  
2) Expiratory 3D CT simulation scan 
3) Average of select sequences from the 4D CT scan around expiration 
including 30%, 40%, 50% (end expiration), 60%, and 70%. 
 
6.1.1.2 CT fusion 
When available, a recent diagnostic pancreas protocol CT, PET/CT, or 
abdominal MRI should be fused with the planning CT scan, using fiducial-to-
fiducial fusion if possible. 
 
6.1.1.3 Tumor target delineation 
The pancreas gross tumor volume (GTV) will be identified on the treatment 
planning CT scan.  The internal target volume (ITV) will be defined by the 
attending radiation oncologist using the 4D CT scan to account for respiratory 
motion. The final planning target volume (PTV) will consist of a 2-3 mm 
expansion around the ITV.  The PTV can be trimmed off of the duodenum or 
stomach at the treating physician’s discretion.  Elective nodal regions will not be 
irradiated. 
 
6.1.1.4 Treatment planning 
Treatment will consist of 6 MV or 15 MV photons directed at the PTV using 6-12 
fields or a modulated arc technique.  Intensity modulated radiation therapy 
(IMRT) techniques such as fixed-field IMRT, or volume modulated arc therapy 
(VMAT) can be used to reduce dose to surrounding normal tissues.  The dose 
should be prescribed as follows: 
1) 90-95% of the PTV (preferably 95%) should receive 100% of the 
prescription dose 
2) No more than 1 cm3 of the PTV can receive >120% of the prescription dose 
 
6.1.1.5 Normal tissue constraints 
Normal tissue dose should be minimized. Specific organ constraints are as 
follows. 
1) Duodenum: no more than 1 cm3 of duodenum may exceed the prescription 
dose. 
2) Stomach: no more than 1 cm3 of the stomach may exceed the prescription 
dose. 
3) Small bowel (excluding duodenum): no more than 1 cm3 of small bowel 
may exceed the prescription dose.  
4) Large bowel: no more than 1 cm3 of large bowel may exceed the 
prescription dose. 
5) Liver: 700 cm3 of normal liver should receive less than a mean dose of 15 

 
 
Page 13 
 
Gy. 
6) Kidneys (combined): combined volume should have 75% <12 Gy. 
7) Spinal cord: no more than 1 cm3 should exceed 8 Gy. 
8) If the above tumor and normal tissue constraints cannot be made then the 
prescription dose to the PTV can be reduced such that 100% of the GTV 
will receive the prescription dose.  If this constraint cannot be met, then the 
patient should be removed from the protocol.  
 
6.1.1.6 Heterogeneity corrections 
Heterogeneity corrections should be applied. 
 
6.1.2 Treatment delivery 
Patients will receive 5 fractions over a five day period.  Treatment should start 
preferably on Monday, and extend through the following Friday, though it may 
extend over 2 weeks if scheduling issues arise. 
 
 
Patient position will be verified daily before each treatment with the following 
1) Orthogonal kV/kV imaging focusing on bone anatomic alignment. 
2) Daily cone-beam CT before and after each treatment will be conducted to 
verify anatomic location and stability. 4DCBCT should be used if available. 
3) Fluoroscopy will be used to confirm that the tumor fiducials fall within the 
respiratory gating window (aperture). The gating window or patient position 
should be adjusted to ensure precise positioning.   
 
 
 
 
 
 
6.2 Radiation Adverse Events 
 
Risks and side effects related to radiation include: 
 
Likely (more than 10%)  
 Tiredness 
 Nausea 
 Damage to the duodenum, stomach, or intestine including ulceration, bleeding, 
or perforation which may require surgery or hospitalization. 
 
Less Likely (3-9%) 
 Redness and skin irritation in the treatment area  
 Vomiting or dehydration 
 
Rare, but serious (less than 2%)  
 Development of an abnormal pathway or connection between organs (fistulae) 
including the duodenum, stomach, and blood vessels in the abdomen such as 
the aorta which may require hospitalization or surgery  
 Damage to the liver causing liver failure 
 Damage to the kidney causing kidney failure 
 Damage to the spinal cord resulting in paralysis 
 
7.0 
DRUG THERAPY 
 

 
 
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7.1 
Chemotherapy 
Chemotherapy is not specified per protocol. Prior to enrollment, or after completion of 
SBRT patients may receive standard chemotherapy, or other investigational agents at 
the discretion of their treating oncologist. Patients may not receive chemotherapy during 
or within 7 days (before or after) pancreas SBRT. 
 
 
8.0 
OTHER THERAPY  
 
8.1  
Permitted Supportive Therapy/Procedures: 
 
8.1.1  Antiemetic Agents 
Standard antiemetic agents are allowed at the discretion of the treating 
physician. 
 
8.1.2  Antidiarrheal Agents 
Standard antidiarrheal agents are allowed at the discretion of the treating 
physician. 
 
8.1.3  Analgesics 
Standard analgesics, both narcotic and non-narcotics, are allowed at the 
discretion of the treating physician. 
 
8.1.4  Nutritional supplementation 
Nutritional supplementation, both by mouth and by enteric feeding tube, is 
allowed at the discretion of the treating physician.  
 
9.0  
PATHOLOGY 
 
All patients will have pathologically confirmed pancreatic adenocarcinoma. Central review of 
pathology is not required. 
 
10.0  PATIENT ASSESSMENTS 
 
10.1 
Study Parameters 
 
Table 2 
 
Study Procedures 
Pre-
Treatment 
Week 1 
Post-Treatment b 
Informed Consent 
X 
 
 
History and Physical 
X 
 
 
Physical Exam with Vital 
Signs 
X 
X 
1,3,6,9, 12 months, and every 
6 months thereafter 
CBC with differential, and 
comprehensive metabolic 
panel a 
X 
 
 

 
 
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CA 19-9 
X 
 
3, 6, 12, and every 6 months 
thereafter, or until disease 
progression 
CT Abdomen, and Pelvis 
X 
 
3, 6, 12, and every 6 months 
thereafter, or until disease 
progression 
Treatment: 
 
 
 
SBRT 
 
D1-5 
 
Clinical evaluation for 
Toxicity 
X 
X 
1,3,6,9, 12 months, and every 
6 months thereafter 
EORTC QLQ C-30/PAN26 
questionnairec 
X 
 
1,3,6,9, 12 months, and every 
6 months thereafter 
 
a Electrolytes including Creatinine, Bilirubin, SGOT, and SGPT  
 
b Visit should occur at timepoints above +/- 28 days 
 
c See appendix for details on questionnaire 
 
 
10.2 
Adverse Events (AEs) 
 
Adverse event information will be documented on appropriate case report forms (CRF) 
which will include timing, severity and perceived causation of the events and followed 
until they either stabilize or resolve. 
 
This study will utilize the Common Terminology Criteria for adverse events (CTCAE) of 
the National Cancer Institute for reporting of adverse events within 90 days after 
completion of radiation therapy.  A copy of the current version of the CTCAE version 4.0 
can be downloaded from the CTEP home page (http://ctep.cancer.gov/ 
reporting/ctc.html). Adverse events after 90 days after completion of radiation therapy 
will be scored with the RTOG/EORTC Late Radiation Morbidity Scoring Schema. A copy 
of the current version of the RTOG/EORTC scale is available on the RTOG home page 
(http://www.rtog.org/ResearchAssociates/AdverseEventReporting/RTOGEORTCLateRa
diationMorbidityScoringSchema.aspx).  
 
Definition of an AE: any untoward medical occurrence in a patient receiving study 
treatment and which does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including a clinically 
significant abnormal laboratory finding), symptom, or disease temporally associated with 
the use of an experimental intervention, whether or not related to the intervention. 
 
Serious Adverse Events (SAEs) 
A serious adverse event is defined in regulatory terminology as any untoward medical 
occurrence that: 
 
Results in death. 
If death results from (progression of) the disease, the disease should be reported 
as event (SAE) itself. 
 
Is life-threatening. 
(the patient was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it were more severe). 
 
Requires 
in-patient 
hospitalization 
or 
prolongation 
of 
existing 
hospitalization for ≥ 24 hours. 
 
Results in persistent or significant disability or incapacity. 

 
 
Page 16 
 
 
Is a congenital anomaly/birth defect 
 
Is an important medical event 
Any event that does not meet the above criteria, but that in the judgment of the 
investigator jeopardizes the patient, may be considered for reporting as a serious 
adverse event. The event may require medical or surgical intervention to prevent 
one of the outcomes listed in the definition of “Serious Adverse Event”.  
 
 
10.3 
Steps to Determine If Expedited Reporting for an Adverse Event is Indicated 
 
Step 1:  Identify the type of adverse event using the CTCAE v4.  The CTCAE v4 
provides descriptive terminology and a grading scale for each adverse event listed.  A 
copy of the CTCAE v4 can be downloaded from the CTEP home page 
(http://ctep.cancer.gov/reporting/ctc.html).  Additionally, if assistance is needed, the NCI 
has an Index to the CTCAE v4 that provides help for classifying and locating terms.   
 
 
Step 2:  Grade the adverse event using the NCI CTCAE v4. 
 
Step 3:  Determine whether the adverse event is related to the protocol therapy  
Attribution categories are as follows: 
Unrelated, Unlikely Related, Possibly Related, Probably Related, and Definitely 
Related. 
Note:  This includes all events that occur within 30 days of the last dose of 
protocol treatment.  Any event that occurs more than 30 days after the last dose 
of treatment and is attributed (possibly, probably, or definitely) to the agent(s) 
must also be reported according to the instructions above. 
 
Step 4:  Determine the prior experience of the adverse event.  Expected events are 
those that have been previously identified as resulting from administration of the agent.  
An adverse event is considered unexpected, for expedited reporting purposes only, 
when either the type of event or the severity of the event is not listed in: 
 
 the current known adverse events listed in the Agent Information Section of this 
protocol; 
 the investigator’s brochure or the drug package insert  
 
 
Step 5:  Review Section 10.6 to determine if: 
 there are any protocol-specific requirements for expedited reporting of specific 
adverse events that require special monitoring; and/or 
 there are any protocol-specific exceptions to the reporting requirements. 
 
10.4 
Reporting Requirements for Adverse Events  
 
Expedited Reporting 
 
 
The Principal Investigator must be notified within 24 hours of learning of any 
serious adverse events, regardless of attribution, occurring during the study. 
 
The UCSD Human Research Protections Program (HRPP) and the Moores 
Cancer Center Data and Safety Monitoring Board (DSMB) must be notified 

 
 
Page 17 
 
within 10 business days of “any unanticipated problems involving risk to 
subjects or others” (UPR). 
The following events meet the definition of UPR: 
1. Any serious event (injuries, side effects, deaths or other problems), which in 
the opinion of the Principal Investigator was unanticipated, involved risk to 
subjects or others, and was possibly related to the research procedures. 
2. Any serious accidental or unintentional change to the IRB-approved 
protocol that alters the level of risk. 
3. Any deviation from the protocol taken without prior IRB review to eliminate 
apparent immediate hazard to a research subject. 
4. Any new information (e.g., publication, safety monitoring report, updated 
sponsor safety report), interim result or other finding that indicates an 
unexpected change to the risk/benefit ratio for the research. 
5. Any breach in confidentiality that may involve risk to the subject or others. 
6. Any complaint of a subject that indicates an unanticipated risk or that 
cannot be resolved by the Principal Investigator. 
 
Routine Reporting 
 
 
The UCSD HRPP will be notified of any adverse events that are not 
unanticipated problems involving risk to subjects or others (non-UPRs) at the 
time of the annual Continuing Review.  
 
The FDA will be notified of all other adverse events that do not meet the criteria 
for expedited reporting at the time of the IND Annual Report.  
 
10.5 
Criteria for Removal from Protocol Therapy  
 
a) 
Adverse Events requiring removal from study. 
b) 
Non-compliance that in the opinion of the investigator does not allow for ongoing 
participation. 
c) 
Physician determines it is in the subject’s best interest. 
 
10.6 
Criteria for Removal from Study 
 
a) 
Loss to follow-up. 
b) 
Withdrawal of consent for any further data submission. 
 
11.0 
DATA COLLECTION 
 
11.1 
Data and Safety Monitoring Plan 
 
In addition to adverse event monitoring and clinical oversight by the principal investigator 
and co-investigators, quality assurance of the study will be performed by the clinical 
trials office internal monitor. Monitoring intervals will be dependent upon the number of 
patients enrolled.  
 

 
 
Page 18 
 
This study will also use the UCSD Moores Cancer Center Data Safety and Monitoring 
Board to provide oversight in the event that this treatment approach leads to unforeseen 
toxicities. The DSMB will review data from this study semi-annually.   
 
Data from this study will be reported semi-annually and will include: 
 
1) the protocol title, IRB protocol number, and the activation date of the study.  
2) the number of patients enrolled to date  
3) the date of first and most recent patient enrollment 
4) a summary of all adverse events regardless of grade and attribution   
5) a response evaluation for evaluable patients  
6) a summary of any recent literature that may affect the ethics of the study. 
 
11.2 
Confidentiality Procedures 
 
Recruitment procedures will involve the review of patient records by designated study 
personnel (e.g., investigators and/or study coordinators) in order to identify potentially 
eligible patients.  Since Protected Health Information (PHI) will be accessed via the 
hospital’s medical record database and scheduling system (e.g., CPRS) prior to 
contacting the potential subject about the research study, we are requesting a partial 
waiver of HIPAA authorization for access to PHI for purposes of prescreening only.  
Standard HIPAA authorization to collect research data from the subject's medical record 
will be obtained at the time of informed consent. 
 
Protected health information (PHI) will be maintained in the subjects' medical charts and 
thus confidentiality is protected via routine procedures.  Data specific to this study will be 
kept in an electronic database to which only the principal investigator and involved study 
personnel will have access.  The database will be de-identified by removing subjects' 
names and assigning a unique identifier to each subject.  The database will be 
maintained on a protected disk drive in the radiation oncology department. 
 
 
12.0 
STATISTICAL CONSIDERATIONS 
 
12.1 
Statistical Analysis 
 
12.1.1 Primary Endpoint: The purpose of this study is to determine the maximum 
tolerated dose (MTD) of five fraction SBRT in pancreatic cancer.  The MTD will be 
defined from dose limiting toxicity, which will represent grade ≥3 gastrointestinal (GI) 
toxicity.  GI toxicity from SBRT can occur anywhere from 6 weeks to 1 year after SBRT, 
with the median time to a toxic event being 6 months [6].  Because of the long “window” 
for toxicity a classic phase I 3+3 dose-escalation trial design would require a substantial 
amount of time between enrolled subjects to observe for toxic events. Therefore, to 
improve efficiency this study will use a time to event continual reassessment method 
(TITE-CRM) trial design [11], described in more detail below. 
 
 
12.1.2  Secondary Endpoints  
 
12.1.2.1 Local control. The cumulative incidence of local failure will be 
determined for all patients treating distant progression or death as a competing 

 
 
Page 19 
 
risk. Local progression will be defined as a ≥20% increase in size on CT 
compared with CT prior to SBRT. 
 
12.1.2.2 Distant metastatic progression rate. The cumulative incidence of distant 
metastatic failure will be determined for all patients treating death as a competing 
risk. In patients initially presenting with locally advanced disease, distant disease 
progression will be defined as the appearance of new metastatic lesions. In 
patients presenting with metastatic disease, distant progression will be defined 
as a ≥20% increase in size on CT of the previously noted metastatic lesions. 
 
12.1.2.3 Overall survival. Overall survival will be measured from the date of 
diagnosis through death of any cause. Survival will also be reported from the 
date of SBRT for comparisons to other trials in the literature. Finally, survival will 
be stratified by those with locally advanced disease, and those with metastatic 
disease on presentation. 
 
12.1.2.4 Dose response. An exploratory analysis evaluating for a correlation 
between radiation dose response and local control will be done with a competing 
risk analysis, dividing patients into two groups stratified by the median dose.. 
 
12.1.2.5 Longitudinal quality of life. We will track longitudinal quality of life using 
the European Organization for Research and Treatment in Cancer (EORTC) 
quality of life core cancer questionnaire with the pancreatic cancer module 
(EORTC QLQ C-30/ PAN26) (see appendix). The questionnaire will be given 
prior to treatment, and periodically during follow-up visits after treatment has 
concluded.  Trends will be assessed with a linear mixed effects model. 
 
12.1.2.6 Correlation between quality of life and disease progression. Disease 
progression is a commonly used surrogate endpoint in clinical trial with pancreas 
cancer, however its relationship with quality of life has not clearly been 
demonstrated. Therefore, we will assess for correlation between quality of life 
and local or distant disease progression. 
 
12.1.2.7 Dose-volume relationship with duodenal/gastric toxicity. We will plan to 
use logistic regression models to determine the relationship between grade ≥3 
duodenal or gastric toxicity and dose to these structures. The dose to the 
duodenum will be extracted from our treatment planning system. 
 
12.1.2.8 Ability to receive additional chemotherapy. We will determine the 
fraction of patients who are able to receive additional chemotherapy among 
those whose initial intent was to do so. After consultation with an oncologist, but 
prior to treatment, we will record whether patients wish to receive additional 
chemotherapy after the course of chemo-radiotherapy delivered with this study. 
Possible responses include: yes, no, or undecided. We will then record who 
receives subsequent chemotherapy after completing treatment in our protocol. 
 
12.1.2.9 Surrogate target discovery. We will determine the natural anatomical 
surrogates that best correlate with the motion of the fiducial markers. Potential 
surrogates include the superior mesenteric vessels, aorta, portal vein, and soft-
tissue border of the pancreas. This information will help treat pancreas cancer 

 
 
Page 20 
 
patients using image guidance technologies who could not have the markers 
placed. 
 
12.1.2.10 Adaptive RT strategies. We will conduct a study to determine the best 
adaptive RT strategies that maximize the therapeutic ratio based on analyzing 
the information contained in the daily imaging studies to be performed on the 
patients. 
 
 
12.2 
Trial Design, Sample Size, and Study Duration 
 
12.2.1 Trial Design: We will use a time to event continual reassessment method (TITE-
CRM) trial design [11] to enroll a maximum of 30 patients onto this protocol. 
 
The primary goal of this trial will be to determine the SBRT dose associated with a dose-
limiting toxicity (DLT) in 20% of patients. DLT will be defined as grade ≥3 gastrointestinal 
toxicity (defined further below). 
 
The TITE-CRM extends the original CRM by weighting each patient’s contribution to the 
likelihood function described below.  To determine the recommended dose for a newly 
enrolled patient, model parameters are estimated via the weighted likelihood. All 
previously enrolled patients who had either experienced toxicity or had completed the 
12-month observation period without toxicity are assigned weights of 1; otherwise they 
are assigned weights equal to the proportion of the observation period they have 
completed. 
 
The first patient in this study will enroll at dose level #2.  Dose de-escalation can occur at 
anytime, though dose escalation will be restricted to 1 level between sequential patients.  
Additionally, before escalating the dose to the next level two conditions must be met: 1) 
the sum of the observation periods for all patients at the current dose level must be at 
least 12 months; and 2) at least one patient must have been under observation for at 
least 6 month at the current dose level.  The rationale for these two conditions is mainly 
due to the short life expectancy of this patient population, which has a median survival of 
8.25 months. 
 
A two-parameter logistic regression model will be used to estimate the probability of 
toxicity at each dose level after each patient has been enrolled, which will inform the 
decision as to whether we should dose-escalate the patient in question.  A final two-
parameter logistic model will be fitted using follow-up data from 6 months after accrual of 
the last patient  
 
Table 3. A priori toxicity estimation 
Dose level 
Probability of dose limiting toxicity 
1 
0.01 
2 
0.05 
3 
0.10 
4 
0.20 
5 
0.30 
 
12.2.2 Dose Limiting Toxicity: The only toxicity observed thus far in pancreas SBRT has 
been related to nearby normal gastrointestinal organs, namely the duodenum and 

 
 
Page 21 
 
stomach.  Dose limiting toxicity in this study will be defined as any grade 3-5 
gastrointestinal toxicity as measured by the Common Terminology for Adverse Events, 
version 4.0 (see appendix). 
 
12.2.3 Maximum Sample Size: 30 
 
12.2.4 Study duration: We anticipate accruing 12 patients per year, and will follow the 
last patient for a minimum of 6 months. 
 
12.2.5 Interim analysis: This TITE-CRM trial design will de-escalate the radiation dose 
rapidly according to the observed dose-limiting toxicity. In addition to this built-in dose 
de-escalation we plan to conduct interim safety analysis after enrollment of every  
patient.  We will stop the trial early if either of the following three conditions are met: 
Condition 1 for early trial stoppage: more than 50% of patients at any dose level 
experience a dose-limiting toxicity. 
Condition 2 for early trial stoppage: more than 34% of patients at dose level #1 
experience a dose-limiting toxicity. 
 
12.2.6 Operating Characteristics of the design: We used simulation to investigate the 
operating characteristics of our TITE-CRM configuration.  We set the prior probability of 
toxicity at dose levels as in the table above, and investigate four different scenarios for 
the true underlying probabilities of toxicity: 
 
 
Scenario 1: Toxicity probabilities (.01, .05, .10, .20, .30) for dose 1-5, 
respectively (Prior Probability = True Probability) 
 
Scenario 2: Toxicity probabilities (.01, .05, .07, .10, .15) for dose 1-5, 
respectively (Prior Probability > True Probability) 
 
Scenario 3: Toxicity probabilities (.01, .05, .07, .10, .25) for dose 1-5, 
respectively (Prior Probability > True Probability) 
 
Scenario 4: Toxicity probabilities (.05, .10, .20, .30, .50) for dose 1-5, 
respectively (Prior Probability < True Probability) 
 
We set our target rate of toxicity at the MTD to be .20, and set a vague normal prior with 
mean 0 and variance 1.34 (9).  When a simulated patient enters the study, they are 
assigned to the dose chosen by the ‘titecrm’ function in the R library dfcrm (10), 
following the rules for dose escalation above. The incoming patient experiences a 
toxicity with probability given by the true underlying rate of toxicity for their assigned 
dose level, with toxicity time occurring uniformly between 0 and 12 months.  Potential 
drop out (i.e. death) times are drawn randomly (with replacement) from the literature [5].  
We set the number of simulations for each scenario at 5000. 
 
Operating characteristics of the TITE-CRM simulation under different scenarios are 
included in the table below. 'Power' is defined as the simulated probability that the 
algorithm will recommend the correct MTD, defined in our simulation as the dose whose 
true toxicity probability is closest to, but not great than, the target (dose 4, 5, 4, and 3 for 
each of the four scenarios, respectively) at the trials conclusion.  Trial duration is the 
amount of time (in months) from the first patients’ enrollment to the end of the final 
patients observation period.  Total Obs. is the cumulative observation time (in months) 
on all 30 patients.  Pr(Tox.) is the simulated probability of toxicity in that configuration, 
and Pr(Tox. Above MTD) is the simulated probability of a subject having toxicity at a 
dose above the MTD. 

 
 
Page 22 
 
 
Table 4. Operating characteristics 
 
 
‘Power’ 
Trial Duration 
Total Obs.  Time 
Pr(Tox.) 
Pr(Tox.  Above MTD) 
Scenario 1 
0.341 
39.4 
237.0 
0.091 
0.016 
Scenario 2 
0.436 
39.4 
240.5 
0.062 
0.014 
Scenario 3 
0.369 
39.5 
239.1 
0.071 
0.022 
Scenario 4 
0.334 
39.5 
233.9 
0.116 
0.029 
 
 
The probability of recommending each dose as the MTD by scenario is included in the 
table below.  
 
Table 5. Probability of recommending each dose as the MTD 
 
Dose  1 
Dose  2 
Dose  3 
Dose  4 
Dose  5 
MTD and (MTD - 1) 
Scenario 1 
0.000 
0.123 
0.386 
0.341 
0.150 
0.727 
Scenario 2 
0.001 
0.068 
0.195 
0.299 
0.436 
0.736 
Scenario 3 
0.003 
0.069 
0.204 
0.369 
0.356 
0.573 
Scenario 4 
0.062 
0.500 
0.334 
0.094 
0.011 
0.834 
 
 
A boxplot of the number of patients treated above the MTD (treated above dose 4, 4, 
and 3, respectively) in scenarios 1, 3 and 4 is below.  
 
 
 
A barplot of the average number of patients treated at each dose level with each 
scenario is below. 
 
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# subjects treated above MTD
Number of subjects treated above MTD by scenario.

 
 
Page 23 
 
 
    
 
 
 
 
0.0
0.1
0.2
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0.4
Proportion of subjects treated at each dose
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5
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Scenario 1
Scenario 2
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Scenario 4

 
 
Page 24 
 
REFERENCES 
 
1. 
Siegel R, Naishadham D Jemal A. Cancer statistics, 2013. CA Cancer J Clin 2013;63:11-
30. 
2. 
Iacobuzio-Donahue CA, Fu B, Yachida S, et al. DPC4 gene status of the primary 
carcinoma correlates with patterns of failure in patients with pancreatic cancer. J Clin 
Oncol 2009;27:1806-1813. 
3. 
Koong AC, Le QT, Ho A, et al. Phase I study of stereotactic radiosurgery in patients with 
locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys 2004;58:1017-1021. 
4. 
Koong AC, Christofferson E, Le QT, et al. Phase II study to assess the efficacy of 
conventionally fractionated radiotherapy followed by a stereotactic radiosurgery boost in 
patients with locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys 
2005;63:320-323. 
5. 
Chang DT, Schellenberg D, Shen J, et al. Stereotactic radiotherapy for unresectable 
adenocarcinoma of the pancreas. Cancer 2009;115:665-672. 
6. 
Murphy JD, Christman-Skieller C, Kim J, et al. A dosimetric model of duodenal toxicity 
after stereotactic body radiotherapy for pancreatic cancer. Int J Radiat Oncol Biol Phys 
2010;78:1420-1426. 
7. 
Herman JM. A Phase II Multi-Center Study to Evaluate Gemcitabine and Fractionated 
Stereotactic Body Radiotherapy for Locally Advanced Pancreatic Adenocarcinoma. 
Proceedings of the 55th Annual ASTRO Meeting September 2013. 
8. 
Tozzi A, Comito T, Alongi F, et al. SBRT in unresectable advanced pancreatic cancer: 
preliminary results of a mono-institutional experience. Radiat Oncol 2013;8:148. 
9. 
Kothary N, Heit JJ, Louie JD, et al. Safety and efficacy of percutaneous fiducial marker 
implantation for image-guided radiation therapy. J Vasc Interv Radiol 2009;20:235-239. 
10. 
Park WG, Yan BM, Schellenberg D, et al. EUS-guided gold fiducial insertion for image-
guided radiation therapy of pancreatic cancer: 50 successful cases without fluoroscopy. 
Gastrointest Endosc 2010;71:513-518. 
11. 
Normolle D Lawrence T. Designing dose-escalation trials with late-onset toxicities using 
the time-to-event continual reassessment method. J Clin Oncol 2006;24:4426-4433. 
 
 
 

 
 
Page 25 
 
APPENDICES 
 
APPENDIX I 
AJCC CANCER STAGING SYSTEM, PANCREAS 
(AJCC, 2010, 7th Edition)  
 
Primary Tumor (T) 
TX 
Primary tumor cannot be assessed 
T0 
No evidence of primary tumor 
Tis 
Carcinoma in situ * 
T1 
Tumor limited to the pancreas, 2 cm or less in greatest dimension 
T2 
Tumor limited to the pancreas, more than 2 cm in greatest dimension 
T3 
Tumor extends beyond the pancreas but without involvement of the celiac axis or the 
superior mesenteric artery 
T4 
Tumor involves the celiac axis or the superior mesenteric artery (unresectable 
primary tumor) 
* This also includes the “PanInIII” classification. 
 
Regional Lymph Nodes (N) 
NX 
Regional lymph nodes cannot be assessed 
N0 
No regional lymph node metastasis 
N1 
Regional lymph node metastasis 
 
Distant Metastasis (M) 
M0 
No distant metastasis 
M1 
Distant metastasis 
 
Stage grouping 
Stage 0 
Tis 
N0 
M0 
Stage IA 
T1 
N0 
M0 
Stage IB 
T2 
N0 
M0 
Stage IIA 
T3 
N0 
M0 
Stage IIB 
T1 
N1 
M0 
 
T2 
N1 
M0 
 
T3 
N1 
M0 
Stage III 
T4 
Any N 
M0 
Stage IV 
Any T 
Any N 
M1 
 
 
  
 

 
 
Page 26 
 
 
APPENDIX II 
KARNOFSKY PERFORMANCE SCALE 
 
100  
Normal; no complaints; no evidence of disease  
90  
Able to carry on normal activity; minor signs or symptoms of disease  
80  
Normal activity with effort; some sign or symptoms of disease  
70  
Cares for self; unable to carry on normal activity or do active work  
60  
Requires occasional assistance, but is able to care for most personal 
needs  
50  
Requires considerable assistance and frequent medical care  
40  
Disabled; requires special care and assistance  
30  
Severely disabled; hospitalization is indicated, although death not 
imminent  
20  
Very sick; hospitalization necessary; active support treatment is 
necessary  
10  
Moribund; fatal processes progressing rapidly  
0  
Dead  
 
 
 
 

 
 
Page 27 
 
APPENDIX III 
QUALITY OF LIFE QUESTIONNAIRE
 
 

 
 
Page 28 
 
 
 

 
 
Page 29 
 
 
 

                                                         
 
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APPENDIX IV 
COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS 
 
CTCAE v4.0 Term 
CTCAE v4.0 AE Term Definition 
Grade 3    
Grade 4    
Grade 5 
Colitis 
A disorder characterized by inflammation of the colon. 
Severe abdominal pain; change in 
bowel habits; medical intervention 
indicated; peritoneal signs 
Life-threatening consequences; 
urgent intervention indicated 
Death 
Colonic fistula 
A disorder characterized by an abnormal communication between 
the large intestine and another organ or anatomic site. 
Severely altered GI function; bowel 
rest, TPN or hospitalization 
indicated; elective operative 
intervention indicated 
Life-threatening consequences; 
urgent intervention indicated 
Death 
Colonic 
hemorrhage 
A disorder characterized by bleeding from the colon. 
Transfusion, radiologic, endoscopic, 
or elective operative intervention 
indicated 
Life-threatening consequences; 
urgent intervention indicated 
Death 
Colonic obstruction 
A disorder characterized by blockage of the normal flow of the 
intestinal contents in the colon. 
Hospitalization indicated; elective 
operative intervention indicated; 
disabling 
Life-threatening consequences; 
urgent operative intervention 
indicated 
Death 
Colonic perforation 
A disorder characterized by a rupture in the colonic wall. 
Severe symptoms; elective operative 
intervention indicated 
Life-threatening consequences; 
urgent intervention indicated 
Death 
Colonic stenosis 
A disorder characterized by a narrowing of the lumen of the colon. 
Severely altered GI function; tube 
feeding or hospitalization indicated; 
elective operative intervention 
indicated 
Life-threatening consequences; 
urgent operative intervention 
indicated 
Death 
Colonic ulcer 
A disorder characterized by a circumscribed, inflammatory and 
necrotic erosive lesion on the mucosal surface of the colon. 
Severely altered GI function; TPN 
indicated; elective operative or 
endoscopic intervention indicated; 
disabling 
Life-threatening consequences; 
urgent operative intervention 
indicated 
Death 
Diarrhea 
A disorder characterized by frequent and watery bowel 
movements. 
Increase of >=7 stools per day over 
baseline; incontinence; 
hospitalization indicated; severe 
increase in ostomy output compared 
to baseline; limiting self care ADL 
Life-threatening consequences; 
urgent intervention indicated 
Death 
Duodenal fistula 
A disorder characterized by an abnormal communication between 
the duodenum and another organ or anatomic site. 
Severely altered GI function; tube 
feeding, TPN or hospitalization 
indicated; elective operative 
intervention indicated 
Life-threatening consequences; 
urgent intervention indicated 
Death 
Duodenal 
hemorrhage 
A disorder characterized by bleeding from the duodenum. 
Transfusion, radiologic, endoscopic, 
or elective operative intervention 
indicated 
Life-threatening consequences; 
urgent intervention indicated 
Death 
 
 
 
  
CTCAE v4.0 Term 
CTCAE v4.0 AE Term Definition 
Grade 3    
Grade 4    
Grade 5 

                                                         
 
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Duodenal 
obstruction 
A disorder characterized by blockage of the normal flow of 
stomach contents through the duodenum. 
Hospitalization or elective operative 
intervention indicated; disabling 
Life-threatening consequences; 
urgent operative intervention 
indicated 
Death 
Duodenal 
perforation 
A disorder characterized by a rupture in the duodenal wall. 
Severe symptoms; elective operative 
intervention indicated 
Life-threatening consequences; 
urgent operative intervention 
indicated 
Death 
Duodenal stenosis 
A disorder characterized by a narrowing of the lumen of the 
duodenum. 
Severely altered GI function; tube 
feeding; hospitalization indicated; 
elective operative intervention 
indicated 
Life-threatening consequences; 
urgent operative intervention 
indicated 
Death 
Duodenal ulcer 
A disorder characterized by a circumscribed, inflammatory and 
necrotic erosive lesion on the mucosal surface of the duodenal 
wall. 
Severely altered GI function; TPN 
indicated; elective operative or 
endoscopic intervention indicated; 
limiting self care ADL; disabling 
Life-threatening consequences; 
urgent operative intervention 
indicated 
Death 
Dyspepsia 
A disorder characterized by an uncomfortable, often painful 
feeling in the stomach, resulting from impaired digestion. 
Symptoms include burning stomach, bloating, heartburn, nausea 
and vomiting. 
Severe symptoms; surgical 
intervention indicated 
 - 
 - 
Enterocolitis 
A disorder characterized by inflammation of the small and large 
intestines. 
Severe or persistent abdominal pain; 
fever; ileus; peritoneal signs 
Life-threatening consequences; 
urgent intervention indicated 
Death 
Gastric fistula 
A disorder characterized by an abnormal communication between 
the stomach and another organ or anatomic site. 
Severely altered GI function; bowel 
rest; tube feeding, TPN or 
hospitalization indicated; elective 
operative intervention indicated 
Life-threatening consequences; 
urgent operative intervention 
indicated 
Death 
Gastric 
hemorrhage 
A disorder characterized by bleeding from the gastric wall. 
Transfusion, radiologic, endoscopic, 
or elective operative intervention 
indicated 
Life-threatening consequences; 
urgent intervention indicated 
Death 
Gastric necrosis 
A disorder characterized by a necrotic process occurring in the 
gastric wall. 
Inability to aliment adequately by GI 
tract; radiologic, endoscopic, or 
operative intervention indicated 
Life-threatening consequences; 
urgent operative intervention 
indicated 
Death 
Gastric perforation 
A disorder characterized by a rupture in the stomach wall. 
Severe symptoms; elective operative 
intervention indicated 
Life-threatening consequences; 
urgent operative intervention 
indicated 
Death 
Gastric stenosis 
A disorder characterized by a narrowing of the lumen of the 
stomach. 
Severely altered GI function; tube 
feeding; hospitalization indicated; 
elective operative intervention 
indicated 
Life-threatening consequences; 
urgent operative intervention 
indicated 
Death 
 
 
 
 
  
CTCAE v4.0 Term 
CTCAE v4.0 AE Term Definition 
Grade 3    
Grade 4    
Grade 5 

                                                         
 
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Gastric ulcer 
A disorder characterized by a circumscribed, inflammatory and 
necrotic erosive lesion on the mucosal surface of the stomach. 
Severely altered GI function; TPN 
indicated; elective operative or 
endoscopic intervention indicated; 
limiting self care ADL; disabling 
Life-threatening consequences; 
urgent operative intervention 
indicated 
Death 
Gastritis 
A disorder characterized by inflammation of the stomach. 
Severely altered eating or gastric 
function; TPN or hospitalization 
indicated 
Life-threatening consequences; 
urgent operative intervention 
indicated 
Death 
Gastroesophageal 
reflux disease 
A disorder characterized by reflux of the gastric and/or duodenal 
contents into the distal esophagus. It is chronic in nature and 
usually caused by incompetence of the lower esophageal 
sphincter, and may result in injury to the esophageal mucosal. 
Symptoms include heartburn and acid indigestion. 
Severe symptoms; surgical 
intervention indicated 
 - 
 - 
Gastrointestinal 
fistula 
A disorder characterized by an abnormal communication between 
any part of the gastrointestinal system and another organ or 
anatomic site. 
Severely altered GI function; tube 
feeding, TPN or hospitalization 
indicated 
Life-threatening consequences; 
urgent operative intervention 
indicated 
Death 
Gastrointestinal 
pain 
A disorder characterized by a sensation of marked discomfort in 
the gastrointestinal region. 
Severe pain; limiting self care ADL 
 - 
 - 
Ileal fistula 
A disorder characterized by an abnormal communication between 
the ileum and another organ or anatomic site. 
Severely altered GI function; TPN or 
hospitalization indicated; elective 
operative intervention indicated 
Life-threatening consequences; 
urgent intervention indicated 
Death 
Ileal hemorrhage 
A disorder characterized by bleeding from the ileal wall. 
Transfusion, radiologic, endoscopic, 
or elective operative intervention 
indicated 
Life-threatening consequences; 
urgent intervention indicated 
Death 
Ileal obstruction 
A disorder characterized by blockage of the normal flow of the 
intestinal contents in the ileum. 
Hospitalization indicated; elective 
operative intervention indicated; 
limiting self care ADL; disabling 
Life-threatening consequences; 
urgent operative intervention 
indicated 
Death 
Ileal perforation 
A disorder characterized by a rupture in the ileal wall. 
Severe symptoms; elective operative 
intervention indicated 
Life-threatening consequences; 
urgent operative intervention 
indicated 
Death 
Ileal stenosis 
A disorder characterized by a narrowing of the lumen of the ileum. 
Severely altered GI function; tube 
feeding or hospitalization indicated; 
elective operative intervention 
indicated 
Life-threatening consequences; 
urgent operative intervention 
indicated 
Death 
Ileal ulcer 
A disorder characterized by a circumscribed, inflammatory and 
necrotic erosive lesion on the mucosal surface of the ileum. 
Severely altered GI function; TPN 
indicated; elective operative or 
endoscopic intervention indicated; 
disabling 
Life-threatening consequences; 
urgent operative intervention 
indicated 
Death 
Ileus 
A disorder characterized by failure of the ileum to transport 
intestinal contents. 
Severely altered GI function; TPN 
indicated 
Life-threatening consequences; 
urgent intervention indicated 
Death 
 
  
CTCAE v4.0 Term 
CTCAE v4.0 AE Term Definition 
Grade 3    
Grade 4    
Grade 5 

                                                         
 
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Intra-abdominal 
hemorrhage 
A disorder characterized by bleeding in the abdominal cavity. 
Transfusion, radiologic, endoscopic, 
or elective operative intervention 
indicated 
Life-threatening consequences; 
urgent intervention indicated 
Death 
Jejunal fistula 
A disorder characterized by an abnormal communication between 
the jejunum and another organ or anatomic site. 
Severely altered GI function; TPN or 
hospitalization indicated; elective 
operative intervention indicated 
Life-threatening consequences; 
urgent intervention indicated 
Death 
Jejunal 
hemorrhage 
A disorder characterized by bleeding from the jejunal wall. 
Transfusion, radiologic, endoscopic, 
or elective operative intervention 
indicated 
Life-threatening consequences; 
urgent intervention indicated 
Death 
Jejunal obstruction 
A disorder characterized by blockage of the normal flow of the 
intestinal contents in the jejunum. 
Hospitalization indicated; elective 
operative intervention indicated; 
limiting self care ADL; disabling 
Life-threatening consequences; 
urgent operative intervention 
indicated 
Death 
Jejunal perforation 
A disorder characterized by a rupture in the jejunal wall. 
Severe symptoms; elective operative 
intervention indicated 
Life-threatening consequences; 
urgent operative intervention 
indicated 
Death 
Jejunal stenosis 
A disorder characterized by a narrowing of the lumen of the 
jejunum. 
Severely altered GI function; tube 
feeding or hospitalization indicated; 
elective operative intervention 
indicated 
Life-threatening consequences; 
urgent operative intervention 
indicated 
Death 
Jejunal ulcer 
A disorder characterized by a circumscribed, inflammatory and 
necrotic erosive lesion on the mucosal surface of the jejunum. 
Severely altered GI function; TPN 
indicated; elective operative or 
endoscopic intervention indicated; 
disabling 
Life-threatening consequences; 
urgent operative intervention 
indicated 
Death 
Lower 
gastrointestinal 
hemorrhage 
A disorder characterized by bleeding from the lower 
gastrointestinal tract (small intestine, large intestine, and anus). 
Transfusion, radiologic, endoscopic, 
or elective operative intervention 
indicated 
Life-threatening consequences; 
urgent intervention indicated 
Death 
Nausea 
A disorder characterized by a queasy sensation and/or the urge to 
vomit. 
Inadequate oral caloric or fluid 
intake; tube feeding, TPN, or 
hospitalization indicated 
 - 
 - 
Obstruction gastric 
A disorder characterized by blockage of the normal flow of the 
contents in the stomach. 
Hospitalization indicated; elective 
operative intervention indicated; 
limiting self care ADL; disabling 
Life-threatening consequences; 
urgent operative intervention 
indicated 
Death 
Pancreatic duct 
stenosis 
A disorder characterized by a narrowing of the lumen of the 
pancreatic duct. 
Severely altered GI function; tube 
feeding or hospitalization indicated; 
elective operative intervention 
indicated 
Life-threatening consequences; 
urgent operative intervention 
indicated 
Death 
Pancreatic fistula 
A disorder characterized by an abnormal communication between 
the pancreas and another organ or anatomic site. 
Severely altered GI function; tube 
feeding or TPN or hospitalization 
indicated; elective operative 
intervention indicated 
Life-threatening consequences; 
urgent operative intervention 
indicated 
Death 
CTCAE v4.0 Term 
CTCAE v4.0 AE Term Definition 
Grade 3    
Grade 4    
Grade 5 

                                                         
 
Page 35 
 
Pancreatic 
hemorrhage 
A disorder characterized by bleeding from the pancreas. 
Transfusion, radiologic, endoscopic, 
or elective operative intervention 
indicated 
Life-threatening consequences; 
urgent intervention indicated 
Death 
Pancreatic 
necrosis 
A disorder characterized by a necrotic process occurring in the 
pancreas. 
Tube feeding or TPN indicated; 
radiologic, endoscopic, or operative 
intervention indicated 
Life-threatening consequences; 
urgent operative intervention 
indicated 
Death 
Pancreatitis 
A disorder characterized by inflammation of the pancreas. 
Severe pain; vomiting; medical 
intervention indicated (e.g., 
analgesia, nutritional support) 
Life-threatening consequences; 
urgent intervention indicated 
Death 
Peritoneal necrosis 
A disorder characterized by a necrotic process occurring in the 
peritoneum. 
Tube feeding or TPN  indicated; 
radiologic, endoscopic, or operative 
intervention indicated 
Life-threatening consequences; 
urgent operative intervention 
indicated 
Death 
Retroperitoneal 
hemorrhage 
A disorder characterized by bleeding from the retroperitoneal 
area. 
Transfusion, medical, radiologic, 
endoscopic, or elective operative 
intervention indicated 
Life-threatening consequences; 
urgent intervention indicated 
Death 
Small intestinal 
mucositis 
A disorder characterized by inflammation of the mucous 
membrane of the small intestine. 
Severe pain; interfering with oral 
intake; tube feeding, TPN or 
hospitalization indicated; limiting self 
care ADL 
Life-threatening consequences; 
urgent intervention indicated 
Death 
Small intestinal 
obstruction 
A disorder characterized by blockage of the normal flow of the 
intestinal contents. 
Hospitalization indicated; elective 
operative intervention indicated; 
limiting self care ADL; disabling 
Life-threatening consequences; 
urgent operative intervention 
indicated 
Death 
Upper 
gastrointestinal 
hemorrhage 
A disorder characterized by bleeding from the upper 
gastrointestinal tract (oral cavity, pharynx, esophagus, and 
stomach). 
Transfusion, radiologic, endoscopic, 
or elective operative intervention 
indicated 
Life-threatening consequences; 
urgent intervention indicated 
Death 
Vomiting 
A disorder characterized by the reflexive act of ejecting the 
contents of the stomach through the mouth. 
>=6 episodes (separated by 5 
minutes) in 24 hrs; tube feeding, 
TPN or hospitalization indicated 
Life-threatening consequences; 
urgent intervention indicated 
Death 
Gastrointestinal 
disorders - Other, 
specify 
 
Severe or medically significant but 
not immediately life-threatening; 
hospitalization or prolongation of 
existing hospitalization indicated; 
disabling;  limiting self care ADL 
Life-threatening consequences; 
urgent intervention indicated 
Death 
Bile duct stenosis 
A disorder characterized by a narrowing of the lumen of the bile 
duct. 
Severely altered GI function; 
radiologic, endoscopic or elective 
operative intervention indicated 
Life-threatening consequences; 
urgent operative intervention 
indicated 
Death 
Biliary fistula 
A disorder characterized by an abnormal communication between 
the bile ducts and another organ or anatomic site. 
Severely altered GI function; TPN 
indicated; endoscopic intervention 
indicated; elective operative 
intervention indicated 
Life-threatening consequences; 
urgent operative intervention 
indicated 
Death 
CTCAE v4.0 Term 
CTCAE v4.0 AE Term Definition 
Grade 3    
Grade 4    
Grade 5 

                                                         
 
Page 36 
 
Hepatic failure 
A disorder characterized by the inability of the liver to metabolize 
chemicals in the body. Laboratory test results reveal abnormal 
plasma levels of ammonia, bilirubin, lactic dehydrogenase, and 
alkaline phosphatase. 
Asterixis; mild encephalopathy; 
limiting self care ADL 
Moderate to severe encephalopathy; 
coma; life-threatening consequences 
Death 
Hepatic 
hemorrhage 
A disorder characterized by bleeding from the liver. 
Transfusion indicated 
Life-threatening consequences; 
urgent intervention indicated 
Death 
Hepatic necrosis 
A disorder characterized by a necrotic process occurring in the 
hepatic parenchyma. 
 - 
Life-threatening consequences; 
urgent radiologic or operative 
intervention indicated 
Death 
Hepatic pain 
A disorder characterized by a sensation of marked discomfort in 
the liver region. 
Severe pain; limiting self care ADL 
 - 
 - 
Perforation bile 
duct 
A disorder characterized by a rupture in the wall of the 
extrahepatic or intrahepatic bile duct. 
Radiologic, endoscopic or elective 
operative intervention indicated 
Life-threatening consequences; 
urgent operative intervention 
indicated 
Death