Pilot Study of Respiratory-gated Stereotactic Body Radiation Therapy for Borderline Resectable, Unresectable, or Recurrent/Residual Adenocarcinoma of the Pancreas or Periampullary Region
Phase: NA
Conditions: Pancreatic Neoplasms
Sponsor: Indiana University

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PILOT STUDY OF RESPIRATORY-GATED STEREOTACTIC BODY RADIATION 
THERAPY FOR BORDERLINE RESECTABLE, UNRESECTABLE, OR 
RECURRENT/RESIDUAL ADENOCARCINOMA OF THE PANCREAS OR PERIAMPULLARY 
REGION 
 
IUSCC-0565 
IRB# 1601638414  
 
Principal Investigator: 
Robert Miller, M.D. 
Radiation Oncology 
 
 
 
 
Indiana University School of Medicine 
535 N. Barnhill Dr. RT 041 
Indianapolis, Indiana 46202 
rmiller41@iuhealth.org   
 
 
 
Study Statistician: 
Yong Zang, PhD. 
 
 
 
Protocol Version Date:  
July 2, 2024

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TABLE OF CONTENTS 
1. 
SCHEMA .................................................................................................................................................................. 4 
2. 
BACKGROUND & RATIONALE ....................................................................................................................... 4 
2.1 
 NATURAL HISTORY AND MANAGEMENT OF PANCREATIC CANCER .......................................................... 4 
2.2 
 RATIONALE FOR THE USE OF STEREOTACTIC BODY RADIATION THERAPY IN PANCREATIC CANCER ... 5 
2.3 
 RATIONALE FOR SELECTION OF PATIENT POPULATION............................................................................. 7 
3. 
OBJECTIVES .......................................................................................................................................................... 8 
3.1 
 PRIMARY OBJECTIVE ........................................................................................................................................ 8 
3.2 
 SECONDARY OBJECTIVES ................................................................................................................................. 8 
3.3 
 OUTCOME MEASURES: ..................................................................................................................................... 8 
4. 
ELIGIBILITY CRITERIA ..................................................................................................................................... 9 
4.1 
 INCLUSION CRITERIA ........................................................................................................................................ 9 
4.2 
 EXCLUSION CRITERIA ..................................................................................................................................... 10 
5. 
STUDY DESIGN .................................................................................................................................................. 11 
6. 
PATIENT REGISTRATION ............................................................................................................................. 11 
7. 
SBRT ADMINISTRATION AND RADIATION TREATMENT .............................................................. 11 
7.1 
 PRE-LINAC-BASED SBRT TESTS, PROCEDURES, AND PLANNING .......................................................... 11 
7.2 
 LINAC-BASED SBRT TREATMENT DELIVERY ............................................................................................ 14 
7.3 
 FOLLOW-UP ..................................................................................................................................................... 15 
7.4 
 GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES .................................... 15 
8. 
TOXICITIES TO BE MONITORED/DOSAGE MODIFICATIONS ........................................................ 16 
9. 
STUDY PARAMETERS/CALENDAR ........................................................................................................... 17 
10. 
CRITERIA FOR EVALUATION/REMOVAL FROM STUDY ................................................................. 19 
10.1 ANTI-TUMOR EFFECT AND RESPONSE EVALUATIONS .............................................................................. 19 
10.2 DEFINITIONS ..................................................................................................................................................... 20 
10.3 RESPONSE REVIEW .......................................................................................................................................... 20 
10.4 CRITERIA FOR REMOVAL FROM STUDY ........................................................................................................ 20 
11. 
STATISTICAL METHODS ............................................................................................................................... 20 
11.1 GENERAL CONSIDERATIONS ........................................................................................................................... 20 
11.2 STUDY DESIGN .................................................................................................................................................. 20 
11.3 CRITERIA FOR STOPPING STUDY ................................................................................................................... 21 
11.4 ANALYSIS DATASETS ....................................................................................................................................... 21 
11.5 SAMPLE SIZE ..................................................................................................................................................... 21 
11.6 PATIENT CHARACTERISTICS AND SIGNIFICANT PROTOCOL VIOLATIONS .............................................. 21 
11.7 CONCOMITANT MEDICATIONS ....................................................................................................................... 21 
11.8 DISPOSITION ..................................................................................................................................................... 21 
11.9 ANALYSIS OF PRIMARY OBJECTIVE ............................................................................................................... 21 
11.10 
ANALYSIS OF SECONDARY OBJECTIVES ................................................................................................... 22 
11.11 
INTERIM ANALYSIS ..................................................................................................................................... 22 
11.12 
SUBGROUP ANALYSIS ................................................................................................................................. 22 
12. 
DATA FORMS AND SUBMISSION SCHEDULE ....................................................................................... 22 
13. 
PATIENT CONSENT AND PEER JUDGMENT .......................................................................................... 23 
14. 
DATA AND SAFETY MONITORING PLAN ............................................................................................... 23 

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14.1 STUDY AUDITING AND MONITORING ............................................................................................................ 23 
14.2 EARLY STUDY CLOSURE .................................................................................................................................. 23 
14.3 REPORTING GUIDELINES................................................................................................................................. 24 
14.4 REPORTING DEATH.......................................................................................................................................... 24 
14.5 STUDY ACCRUAL OVERSIGHT ......................................................................................................................... 24 
14.6 PROTOCOL DEVIATIONS .................................................................................................................................. 24 
15. 
REPORTING ADVERSE EVENTS ................................................................................................................. 24 
15.1 DEFINITIONS OF ADVERSE EVENTS .............................................................................................................. 24 
15.2 DETERMINING ATTRIBUTION TO THE INVESTIGATIONAL AGENT(S) ...................................................... 25 
15.3 ADVERSE EVENT (AE) AND SERIOUS ADVERSE EVENT (SAE) REPORTING ......................................... 26 
16. 
REFERENCES ...................................................................................................................................................... 26 
17. 
APPENDICES ....................................................................................................................................................... 29 
A1. 
APPENDIX I: NCI COMMON TOXICITY CRITERIA VERSION 4.0 ................................................................ 29 
A2. 
APPENDIX II: PERFORMANCE STATUS SCALES/SCORES ........................................................................... 30 
A3. 
APPENDIX III: DSMC CHECK SHEET ............................................................................................................ 31 
A4. 
APPENDIX IV: PAIN SCALE ............................................................................................................................. 32 
A5. 
APPENDIX V: QOL QUESTIONNAIRE ............................................................................................................ 32 
 
 

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1. SCHEMA  
2. BACKGROUND & RATIONALE 
 
2.1 
Natural History and Management of Pancreatic Cancer  
Over 40,000 cases of pancreatic cancer are diagnosed annually in the United States. 
Despite aggressive combined modality treatment approaches, the five-year survival of 
patients with pancreatic cancer is still less than 5%. (1)  Surgical resection is considered to 
be the only potentially curative treatment option. (2) However, more than 85% of patients 
have locally advanced or metastatic disease when initially diagnosed, and treatment 
paradigms for patients with all stages of disease continue to evolve.  Patients with 
resectable disease have high rates of both local recurrence and distant failure despite 
aggressive trimodality therapy, and controversy exists regarding whether or not radiation 
therapy should be included as part of routine postoperative therapy. (3-5) Neoadjuvant 
external beam radiotherapy is also frequently incorporated into treatment for borderline 
resectable pancreatic cancer in an attempt to increase the likelihood of margin-negative 
resection and improve local control. (6)  Nonetheless, rates of local recurrence remain high 
even in patients who have undergone surgery, and more effective strategies to improve 
local control and to treat locally recurrent disease are needed. 
Similarly, the role of radiation therapy in patients with unresectable disease continues 
to evolve.  Unresectable pancreatic cancer is associated with high rates of occult distant 
metastatic disease; therefore, despite initially promising results associated with immediate 
chemoradiation in patients with unresectable disease, current treatment standards 
recommend the use of induction chemotherapy in this setting. (7, 8)  For patients with 
unresectable disease, the use of induction chemotherapy can help to eliminate occult 
systemic micrometastases and to identify individuals with treatment-refractory distant 
metastases, who are unlikely to benefit from local therapies such as radiation.  A 
prospective series testing this approach was recently reported by Huguet et al. (7) Patients 
were initially randomized to gemcitabine or gemcitabine plus erlotinib; those without 
progression on this regimen were then randomized to capecitabine-based chemoradiation 
versus chemotherapy alone.  Forty percent of initially randomized patients developed 
progressive disease and did not proceed to the second randomization.  Although the study 
did not demonstrate an overall survival benefit for RT, local failure rates and time to 
treatment resumption were both significantly improved in the RT arm.  Furthermore, in 
patients with unresectable but localized pancreatic cancer at diagnosis, effective local 
therapy may play an important role in disease control.  Autopsy studies suggest that 
approximately 30% of pancreatic cancer patients die due to local disease progression, a 
Cohort A 
+ Prior RT      +Recurrent/Residual Disease 
 
• 
Any prior combination of surgery/chemo 
• 
Must have received ≥ 2 chemo cycles 
• 
≥ 180 days since completing RT 
• 
≥ 7 days since last chemo dose 
• 
To receive 5 Gy x 5 
Cohort B 
No Prior RT     +Recurrent/Residual Disease 
 
• 
Any prior combination of surgery/chemo 
• 
Must have received ≥ 2 chemo cycles 
• 
≥ 7 days since last chemo dose 
• 
To receive 6.6 Gy x 5 

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statistic that is corroborated by clinical trial reports of local control rates of under 50% in 
patients with unresectable disease treated with definitive conventional chemoradiation. (9, 
10) Pancreatic tumor progression is also associated with significant morbidity, including 
pain, jaundice, and gastrointestinal tract obstruction. (11)   
Periampullary tumors are also frequently treated with radiation therapy. Patients with 
periampullary tumors have also been included in this trial because of anatomic and 
pathological similarities to patients with pancreatic cancer and the fact that the treatment 
paradigm for these cancers is similar to pancreatic cancer. Patients with periampullary 
tumors also have similar survival and recurrence patterns as patients with pancreatic 
cancers. (12) Periampullary adenocarcinoma is a rare malignancy, comprising less than 1% 
of all digestive cancers and occurring at an annual age-adjusted incidence of only 0.3 cases 
per 100,000 individuals. (13)  As a consequence of this low prevalence, few studies have 
been performed in this population, and patients who fail definitive therapy (surgical 
resection in association with neoadjuvant or adjuvant CRT/chemotherapy for resectable 
disease; conventional CRT or chemotherapy for unresectable disease) have limited options 
for further treatment. (14, 15) Unfortunately, even among patients with resectable 
periampullary adenocarcinoma, over 50% will recur following definitive treatment (16).  
This trial, therefore, seeks to study SBRT as a means of providing patients with 
borderline resectable, unresectable, or locally recurrent pancreatic/periampullary tumors 
with an additional treatment option after receiving prior combinations of 
surgery/chemotherapy.  
2.2 
Rationale for the use of stereotactic body radiation therapy in pancreatic 
cancer 
Recent advances in radiation treatment technology, including improvements in 
planning systems, patient immobilization equipment, image-guided radiation therapy 
technologies, and radiation delivery mechanisms, have permitted the development of 
stereotactic body radiation therapy (SBRT), which permits the intensification of therapy by 
delivering increased daily doses of radiation to highly focused targets within the body. 
Several phase II trials of SBRT in patients with pancreatic cancers have been performed, 
showing that the technique is well tolerated and is associated with improvements in local 
control rates compared with historical series of conventionally fractionated 
chemoradiation. Koong et al. used the CyberknifeTM stereotactic radiosurgery system to 
demonstrate that a single 25-Gy dose stereotactic body radiotherapy (SBRT) was feasible 
for patients with locally advanced pancreatic cancer. (17) Furthermore, this dose of 
radiation resulted in near 100% progression free survival and effectively palliated 
symptoms related to the local growth of pancreatic tumors. Based on this study, the same 
group also completed a phase II study assessing the efficacy of combining a standard five- 
week course of chemoradiotherapy followed by a stereotactic radiosurgery boost to the 
primary tumor in patients with locally advanced pancreatic cancer. In this cohort of 19 
patients, 100% of tumors were without local progression. However, all patients eventually 
developed metastases, with a median time to progression of 5.5 weeks. A more recent 
phase II study treated locally advanced pancreatic cancer patients with induction 
gemcitabine followed by single-fraction SBRT (25 Gy) and maintenance gemcitabine 
chemotherapy. In this study, the excellent progression free survival was confirmed from 
previous studies (81%). The median overall survival was 11.4 months, median time to 
progression was 9.7 months and the 1 year survival was 50%.(18) There were no 
significant acute GI toxicities; however, of the 15 patients alive >6 months after Linac 

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(linear-accelerator)-based SBRT, 7 (47%) experienced Grade 2 or greater GI toxicity, with 2 
(13%) of the 15 experiencing Grade 3 or greater GI toxicity.  
To decrease the risk of late GI toxicity, subsequent studies have therefore reduced the 
per-day dose and prolonged the treatment schedule.  For example, Hong et al. reported a 
neoadjuvant regimen delivering 5 Gy x 5 to the pancreatic tumor plus adjacent lymph 
nodes using proton beam radiation. (19) This regimen was shown to be safe, with no 
instances of dose limiting toxicity observed and only 4 of 15 patients developing grade 3 
toxicity (no patients experienced grade 4 toxicity). Herman et al. recently published the 
largest phase II study to date of definitive 5-fraction SBRT in pancreas cancer, which 
reported a median overall survival rate of 13.8 months. (20)  The regimen was also well 
tolerated, with acute and late grade 2 or greater toxicity rates of 2 and 11%, respectively.  
SBRT was associated with stable quality of life scores and improving pain scores.  Similarly, 
a grade 3 or greater toxicity rate of 7% was reported in an institutional series of 159 
patients treated using five-fraction regimens for both borderline resectable and 
unresectable tumors. (21) 
Using the linear-quadratic formulation, the biologically equivalent dose (BED) of the 
two proposed fractionation schedules are given in comparison to other commonly used 
schemes (table 1), including conventionally fractionated radiation, which is typically 
administered in 28 1.8-Gy fractions for a total dose of 50.4 Gy, usually with concurrent 
capecitabine-, 5-FU-, or gemcitabine-based chemotherapy. While the BED for the 5 Gy x 5 
schedule (early/late 37.5/66.7) must necessarily be lower because it will be used in 
patients who have already been treated with radiation to the pancreatic region, that of the 
proposed 6.6 Gy x 5 schedule (BED early/late 54.8/105.6) closely approximates that of 
standard chemoradiation (BED early/late 60/83.3), but without concurrent chemotherapy 
and treating a smaller tumor margin (0.3 cm vs. ~2 cm). Furthermore, the proposed 6.6 Gy 
x 5 fractionation schedule has a much lower late BED (105.6 vs. 233.3) with a similar early 
BED (54.8 vs. 87.5) as the previous 25 Gy x 1 regimen.  Finally, the use of five-fraction SBRT 
regimens may be able to spare circulating lymphocytes from radiation-induced toxicity that 
is mediated by high radiation doses to circulating blood.  As radiation-induced 
lymphopenia has been linked to inferior overall survival in patients with both unresectable 
and resectable pancreatic cancers, it is logical to explore potential ways to decrease the risk 
and severity of this toxicity. (22, 23) Circulating blood dose is directly proportional to 
radiation field size and fraction number, suggesting that SBRT is a potentially promising 
strategy to reduce the risk of radiation induced lymphopenia, perhaps leading to improved 
outcomes, in patients with pancreatic cancer.     
 
 

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Table 1. Comparison of Radiation Fractionation Schemes in Pancreatic Cancer. 
RT Dose 
(Gy) 
/# Fractions 
Regional Nodes 
Treated? 
Concurrent 
chemo? 
Early BED 
(Gy) 
(α/β = 10) 
Late BED 
(Gy) 
(α/β = 3) 
50.4/28 
Yes 
Yes  
60 Gy 
83.3 Gy 
30/10 
Yes 
Yes  
39 
60 
25/5 
No 
No 
37.5 
66.7 
33/5 
No 
No 
54.8 
105.6 
25/1 
No 
No 
87.5 
233.3 
 
2.3 
Rationale for Selection of Patient Population 
As noted previously, local control rates remain unsatisfactory in patients with 
unresectable pancreatic cancer, up to 30% of whom die with uncontrolled local disease.  
Local progression of pancreatic cancer can cause distressing symptoms including pain, 
biliary and gastrointestinal tract obstruction, and pancreatic insufficiency.  Furthermore, 
preliminary data suggest that some patients treated with stereotactic body radiation 
therapy for unresectable disease achieve sufficient tumor response to proceed to surgical 
resection; (20) in patients with borderline resectable disease, neoadjuvant SBRT has also 
been associated with high rates of margin-negative resection.  (21) 
The development of recurrent pancreatic cancer after definitive treatment with 
surgery, radiation, chemotherapy, or a combination of these universally portends a dismal 
prognosis, with the 5-year survival for such patients being 5.6% or less. (24) Unfortunately, 
this scenario is not uncommon; even among the small number of patients (10-15%) able to 
undergo potentially curative surgical resection, more than 80% subsequently develop 
recurrent disease.(25) Following resection, 71-77% develop distant metastases within 2 
years, often accompanied by concurrent locoregional recurrence, while up to 30% exhibit 
isolated locoregional recurrence. (26-29) Patients who develop combined 
distant/locoregional recurrence have a median survival of 3 months from the time of 
recurrence, while those with isolated locoregional recurrence have a median survival of 7 
months. (28) Locoregional recurrence is, therefore, a common and serious problem both in 
the setting of metastatic disease and as an isolated entity. Symptomatic manifestations 
include pain, gastric outlet/small bowel obstruction, portal hypertension, biliary 
obstruction, and malnutrition. Although survival is determined chiefly by systemic disease 
control, local control greatly affects quality of life in pancreatic and periampullary cancer 
patients. (29, 30) Among the majority of patients with pancreatic cancer who present with 
unresectable disease, chemoradiation is able to transiently stabilize the disease in some 
patients and to prolong median survival to 8-14 months. (8, 9, 31)  Regardless of whether a 
tumor is resectable or unresectable at diagnosis, the symptoms associated with local 
recurrence or persistence of disease require swift and effective treatment.  
Preliminary data also supports the safety of re-irradiation of the upper abdomen in 
patients with pancreatic/peri-ampullary tumors who have previously been treated with 
conventionally fractionated radiation regimens.  In 2013, Herman et al. published their 
institutional experience of re-irradiation in a group of 18 patients. (32)  No grade 3 or 
greater toxicities were reported with a dose of 5 Gy x 5; reported one-year local control 
rates were 62%, and 57% of patients who had symptoms of pain before treatment 

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experienced pain relief.  This data provides initial support for exploring a 5 Gy x 5 regimen 
in patients with a history of radiation treatment in the upper abdomen.   
Considering the difficulty of surgical re-exploration due to extensive adhesions after 
previous resection, the risks of surgery and general anesthesia for patients who often have 
impaired performance status, and the prolonged time course and inferior local control 
associated with conventional CRT, we propose that SBRT may be a viable alternative 
treatment option for patients who have failed other modes of therapy through local 
recurrence or local progression. The paucity of studies focusing on this population and lack 
of a standardized treatment paradigm for these patients underscore the need for further 
investigation. The recent studies delineated above suggest that Linac-based respiratory 
gated SBRT is a safe and promising therapeutic option for pancreatic and periampullary 
cancers that merits further study in the specific patient population that will be treated 
using this protocol. However, further investigation of pancreatic SBRT should be 
performed in patients who have been more heavily pre-treated with intensive 
chemotherapy regimens such as FOLFIRINOX (5-FU, irinotecan, oxaliplatin), and 
gemcitabine in combination with nab-paclitaxel, which are currently commonly used in this 
setting but were not part of the standard approach in the previously cited phase I and II 
studies of pancreatic SBRT. 
3. OBJECTIVES 
3.1 
Primary Objective 
• To estimate rates of acute (within 3 months of treatment) grade 3 or greater 
gastrointestinal and hematologic toxicity in patients treated with Linac-
based SBRT for pancreatic or periampullary cancers who have previously 
received other treatment.  
3.2 
Secondary Objectives  
• To estimate rates of late (> 3 months after treatment) grade 2 gastritis, 
enteritis, fistula, and ulcer, or any other grade 3 or greater gastrointestinal 
toxicity in patients treated with Linac-based SBRT for pancreatic or 
periampullary cancers 
• To estimate rates of local progression, overall survival, metastasis-free 
survival, and progression-free survival in patients with pancreatic or 
periampullary cancers treated with fractionated Linac-based SBRT.  
• To evaluate the ability of Linac-based SBRT to provide pain control in 
patients with pain related to a pancreatic or periampullary tumor.  
• To evaluate quality of life in patients undergoing treatment with Linac-based 
SBRT for pancreatic or periampullary cancers. 
3.3 
Outcome Measures: 
3.3.1 Primary Outcome Measure 
• Rates of grade 3 acute GI and hematologic toxicity (as raw percentage) 
3.3.2 Secondary Outcome Measures 
• Late (> 3 months after treatment) toxicity rates (as raw percentage), as 
related to the RTOG Late Radiation Toxicity Grading Scale. 

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• One-year rates of overall, progression-free, and metastasis-free survival (will 
continue to obtain data on these outcomes at subsequent visits beyond 1 
year, but the 1 year time point will represent the outcome measure of 
interest) 
• Pain control at one and three months after treatment (based on reporting of 
standard pain score (0-10) with an option to record pain score based on 
FACES assessment scale) –will continue to obtain data on pain control at 
subsequent visits but these 2 time points will represent the main outcome 
measures of interest 
• Quality of life at each follow-up visit (measured by EORTC QOL-Q scale) - will 
continue to obtain data on quality of life at subsequent visits but these 2 time 
points will represent the main outcome measures of interest 
4. ELIGIBILITY CRITERIA 
4.1 
Inclusion Criteria 
• Age >18 years.  
• Karnofsky Performance Status >70% (see Appendix II).  
• Histologically confirmed adenocarcinoma of the pancreas or ampulla of Vater; at 
least the majority of the histopathologic specimen must be identified as 
adenocarcinoma as opposed to another histologic subtype. In patients with a 
diagnosis of recurrent disease (based on radiographic progression and/or rising 
CA19-9 levels) and a history of a biopsy-proven adenocarcinoma of the pancreas 
or the ampulla of Vater, repeat biopsy of the recurrence site is not required for 
participation of the trial. 
• Pancreatic or periampullary tumors must be less than 8.0 cm in greatest axial 
dimension at the time of treatment planning.  
• Patients who have been treated with any combination of surgical resection and 
neoadjuvant/adjuvant conventional chemoradiation therapy for resectable 
disease or conventional chemoradiation as definitive treatment for unresectable 
or borderline resectable disease are eligible for the study, provided that at least 
180 days have elapsed since completing any previous radiation treatment. 
Patients who have been receiving continued chemotherapy following their initial 
radiation treatment are eligible regardless of when the most recent 
chemotherapy was received. Those patients who have received prior radiation 
therapy will constitute Cohort A and will receive SBRT as 5 Gy x 5.  
• Patients who have not previously undergone radiation therapy can have a 
history of treatment with either chemotherapy (for unresectable/borderline 
resectable disease) or any combination of surgery and chemotherapy (for 
resectable disease). Patients with no history of prior radiation treatment will 
constitute Cohort B and will receive SBRT as 6.6 Gy x 5. Please note that patients 
must have received at least two cycles of chemotherapy (with selection of drugs 
at the discretion of the treating oncologist) before SBRT treatment on protocol.  
• Acceptable organ and marrow function as defined below (taken no earlier than 
time of CT Simulation, within 3 weeks prior to radiotherapy):  
o Leukocytes >3,000/μL  

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o Absolute neutrophil count >1,500μL  
o Platelets >100,000/μL  
o Total Bilirubin ≤1.5x institutional upper limit of normal  
o AST(SGOT)/ALT(SGPT) <2.5x institutional upper limit of normal  
o Creatinine ≤ institutional upper limit of normal OR creatinine 
clearance >60 mL/min/1.73 m2 for patients with creatinine levels 
above institutional normal  
• Ability to understand and the willingness to sign a written informed consent 
document.  
• Life expectancy > 3 months.  
• Radio-opaque markers must be present within the tumor bed.  In patients who 
have undergone surgical resection, radio-opaque surgical clips within the tumor 
bed can be used as fiducials.  Patients without surgical clips in the tumor bed 
must be able to have fiducials placed endoscopically, laparoscopically, or 
through a CT- or ultrasound-guided technique. If not, the tumor must be 
posterior and adjacent to the aorta, and treatment will only be permitted at the 
discretion of the Principal Investigator.  
4.2 
Exclusion Criteria 
• Age < 18 years.  
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection (or infections requiring systemic antibiotic treatment), active upper GI 
ulceration or hemorrhage, symptomatic congestive heart failure, unstable angina 
pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would 
limit compliance with study requirements.  
• Any concurrent malignancy other than non-melanoma skin cancer, non-invasive 
bladder cancer, early stage prostate cancer, or carcinoma in situ of the cervix. 
Patients with a previous non-pancreatic, non-periampullary malignancy without 
evidence of disease for > 5 years will be allowed to enter the trial.  
• Pregnant and breastfeeding women are excluded as are women of child-bearing 
potential who are unwilling or unable to use an acceptable method of birth 
control (hormonal or barrier method of birth control; abstinence) to avoid 
pregnancy for the duration of the study. Should a woman become pregnant or 
suspect she is pregnant while participating in this study, she should inform her 
treating physician immediately.  
• Women who are not post-menopausal (as defined in Appendix III) and have a 
positive urine or serum pregnancy test or refuse to take a pregnancy test.  
• Patients with a life expectancy of < 3 months.  
• Patients with metastatic disease.  
• Patients with evidence of gross tumor invasion into the lumen of the stomach or 
small bowel are not eligible; if imaging suggests luminal invasion of tumor, this 
must be ruled out endoscopically before the patient can be enrolled on study. 

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5. STUDY DESIGN 
This is a single center, single arm unblinded prospective study of the safety of 
pancreatic SBRT in patients with unresectable, borderline resectable, or recurrent 
pancreatic/periampullary cancers who have previously undergone treatment with 
chemotherapy, surgery, photodynamic therapy, conventionally fractionated radiation 
treatment, or any combination of these therapies.  
6. PATIENT REGISTRATION 
Potential patients will be identified per the recommendation of surgeons or GI 
Combined Modality Tumor Board or equivalent combined modality assessment. Potential 
patients will be recruited through self-referral and the advice of their attending physician. 
No advertisement will be used to recruit subjects. This trial will be registered at 
clinicaltrials.gov.  
Patients who appear to be eligible for this trial will undergo the Informed Consent 
Process and be screened for eligibility utilizing the Eligibility Criteria. Consent will be 
obtained after a clear and thorough discussion between the patient and the Principal 
Investigator or any of the co-investigators in clinic. Eligible patients who complete the 
Informed Consent Process will be registered in the OnCore® database and assigned a 
patient ID number. Regulatory files will be maintained by the Radiation Oncology Research 
Office or the IU Simon Cancer Center Clinical Trials Office. Applicable regulatory documents 
must be completed and on file prior to registration of any patients. 
7. SBRT ADMINISTRATION AND RADIATION TREATMENT  
7.1 
Pre-Linac-based SBRT Tests, Procedures, and Planning  
The following will be completed prior to Linac-based SBRT:  
• 
Medical history and clinical examination.  
• 
CBC with differential, chemistry panel, and CA19-9 measurement.  
• 
Gold fiducial seed placement percutaneously, intraoperatively, or under endoscopic 
ultrasound guidance, which may be performed prior to enrollment.  
• 
Pathologic confirmation of malignancy. (Core biopsies may be obtained during gold 
fiducial placement as needed; however, repeat biopsy is NOT required for study 
enrollment in patients who already have pathologically proved adenocarcinoma of 
the pancreas or periampullary region.) 
• 
Pancreatic-protocol CT or CT of the chest/abdomen/pelvis 
• 
Baseline FDG-PET/CT (dual phase) may be obtained for tumor staging and 
treatment planning purposes; however, patients who are unable to undergo PET CT 
scanning (e.g., due to insurance refusal of coverage) can still participate in the study.  
• 
Signed informed consent document.  
• 
Baseline collection of EORTC QLQ C-30/ PAN26 QOL.  
7.1.1 Fiducials 
Treatment on this protocol requires placement of 1-5 gold (99.9% pure, 1-5 mm 
length, or visicoils) 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 and/or periphery under endoscopic ultrasound or 

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CT guidance. When possible, clips or fiducials will also be placed in the proximal 
duodenum directly adjacent to the pancreatic tumor. 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 or periampullary 
cancer. Patients who have undergone surgical resection or attempted surgical 
resection may already have clips or fiducials in the tumor bed, which are acceptable 
markers for the purposes of this study.  
If fiducials are not placed intraoperatively and/or prior to enrollment, placement 
will be done and is expected to be done on an outpatient basis. In rare occurrences 
when fiducials/clips cannot be placed, patients may be treated at the discretion of 
the PI.  
7.1.2 Simulation  
Simulation should be done following placement of fiducials; however, this may 
vary and is at the discretion of the principal investigator. Patients will be positioned 
supine in a standard custom immobilization device. Standard free-breathing CT and 
respiratory-correlated 4-D pancreatic protocol CT will be obtained on each patient. 
The 4D-CT scan will be used for characterizing target motion during quiet 
respiration. For more accurate tumor delineation, an arterial phase pancreatic 
protocol CT may be obtained (typically during expiration breath hold, 1.25 mm 
slices). Fiducial to fiducial fusions between these scans should be utilized whenever 
possible. The simulation scan should include T4/T5 to L5/S1 (upper abdomen).  
IV and oral contrast must be used for simulation, unless the patient has an 
allergy that cannot be adequately premedicated. In these situations, the plan should 
be fused with a contrast-enhanced CT scan or MRI (ideally in a similar treatment 
position).  
Motion management can be addressed using respiratory gating, breath-hold, or 
respiratory tracking. Fluoroscopy will be used to assess the motion of the implanted 
gold fiducials during simulation. If the fiducial motion is greater than 5 mm, then the 
Varian Respiratory Management (RPM) system will be utilized for treatment 
delivery in either the breath hold or respiratory gating modes (dependent on 
patient’s ability to comply with breath hold).  If motion is less than 5 mm, an 
internal target volume (ITV) will be generated based on the 4-D CT scan, and no 
respiratory management will be required during radiation treatment.  As long as the 
specified dosimetric parameters for SBRT are reached, patients may be treated on 
any IGRT-enabled linear accelerator. All patients must start Linac-based SBRT 
within 4 weeks of the simulation scan.  
7.1.3 Treatment Planning  
When available, an FDG-PET scan can be used for treatment planning purposes 
and will be acquired on a flat table top with the same immobilization devices used 
for the simulation CT scan to enable accurate image fusion. An SBRT treatment plan 
will be developed using the Eclipse treatment planning system, based on tumor 
geometry and location. All treatment plans will be stored in their entirety on the 
Radiation Oncology Eclipse Servers for future reference. Institutional standards for 
radiation quality assurance and radiation delivery will be utilized. Target volumes  
will be contoured on the treatment planning CT by an attending physician in 

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radiation oncology at the IU Simon Cancer Center. Data from prior diagnostic CT 
scans, respiratory-correlated 4D-CT scan, and/or the FDG-PET/CT scan may be used 
to assist in treatment planning. The following three target volumes will be 
contoured:  
1) Gross tumor volume (GTV). This will consist of all visible tumor based 
on the free-breathing, IV contrast-enhanced CT scan. Data from the FDG-
PET scan may be used to assist in contouring this volume if the patient 
has undergone a PET scan.  
2) Tumor-vessel interface (TVI). This will include the entire 
circumferential contour of any major upper abdominal blood vessel 
[including the portal vein (PV)], superior mesenteric artery/vein 
(SMA/SMV), celiac artery (CA), and/or common hepatic artery (CHA)] 
that is in direct contact with the tumor. The craniocaudal extent of the 
TVI contour should match that of the GTV for any vessel that is included 
in the TVI.   
3) Tumor-gut interface (TGI). This volume is defined as GTV or TVI that 
directly abuts the stomach, duodenum, small bowel, or large bowel. It will 
be delineated by creating a planning organ at risk volume (gut PRV) that 
will consist of the stomach, duodenum, small bowel, and large bowel plus 
a 3-mm expansion margin. Any areas of the GTV-PTV or the TVI-PTV that 
overlap with the gut PRV will be considered as TGI.  
 
Table 2. Target volume expansion guide.  
Target Volume 
Base Structure 
Dose 
Expansion 
TGI 
GTV (minus gut PRV) 
30 Gy (6 Gy x 5) 
n/a 
GTV-PTV 
GTV 
33 Gy (6.6 Gy x 5) 
3 mm 
TVI-PTV 
TVI 
36 Gy (7.2 Gy x 5) 
3 mm 
 
 
 
The final PTV (planning treatment volume) expansion will consist of an additional 3 
mm of margin expansion to the GTV and TVI, except if the margin results in expansion into 
the duodenum or stomach. In these cases, margin expansion is allowed to be non-uniform. 
Please refer to Table 2. In patients who cannot tolerate or are otherwise not candidates for 
breath-hold radiation treatment (determination to be made at the discretion of the treating 
radiation oncologist), an internal target volume (ITV) for each of the above contours will be 
contoured based on the 4D CT scan in order to account for respiratory motion. The PTV 
expansion margins will then be added to the ITV in such cases. The dose will be prescribed 
to the isodose line that completely surrounds the PTV. It is recommended that 6-12 co-
planar fields be used in the radiation treatment plan. Contours of the fiducials used for 
target localization will be generated on the applicable image sets for use in patient setup 
and treatment.  
Radiation dose to the adjacent normal tissue will be minimized. Based on an analysis of 
duodenal toxicity representing pooled data from 3 previous prospective studies, the 

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following dose constraints must be met: V15< 9 cc, and V20< 3 cc. The duodenum, as 
defined for these dosing parameters, includes the entire duodenum on the same axial plane 
as the PTV and duodenum 1 cm above and 1 cm below the PTV. In patients who have 
undergone pancreaticoduodenectomy, the regions of the pancreaticojejunostomy, 
gastrojejunostomy, and hepaticojejunostomy that lie 1 cm above or below or lateral to the 
PTV will also be delineated as structures of interest. V15 and V20 are defined as the 
percent volume receiving 15 Gy and 20 Gy, respectively. No more than 1 cc of the proximal 
duodenum or proximal stomach may exceed 33 Gy for cohort B or 25 Gy for cohort A (re- 
irradiation patients). Dose to the remainder of the normal tissues will be limited as follows:  
• 
Liver (excluding tumor): 50% should be limited to <12 Gy (<8 Gy for cohort 
A/re-irradiation patients)  
• 
Kidney: Combined volume for both should have 75% <12 Gy (<8 Gy for 
cohort A/re-irradiation patients)  
• 
Stomach and duodenum: V15<9cc (V12<9 cc for cohort A) and V20<3cc 
(V15<3 cc for cohort A). 50% should be limited to <12 Gy (<8 Gy for cohort A). No 
more than 1 cc of proximal stomach can receive >33 Gy for cohort B, and no more 
than 1 cc of proximal stomach can receive >25 Gy for cohort A/re-irradiation 
patients. 
• 
Spinal cord: no more than 1cc can receive >8 Gy (>6 Gy for cohort A).  
• 
No more than 1cc of the PTV can receive >130% of the prescription dose 
(4290cGy for 6.6Gy x 5; 3250cGy for 5Gyx5, cohort A).  
• 
Greater than 90% of the PTV should receive 100% of the prescription dose 
(3300cGy for 6.6Gy x 5; 2500cGy for 5Gyx5).  
• 
If the above constraints cannot be achieved, the dose to the TGI will first be 
decreased to from 30 to 25 Gy in 0.5 Gy increments. If the TGI dose is reduced to 25 
Gy without meeting constraints, the dose to GTV-PTV will then be decreased from 
33 to 25 Gy in 0.5-Gy increments. If constraints still cannot be met, then the TVI-PTV 
dose can be decreased in similar fashion. In such cases, 100% of the GTV-PTV and 
the TVI-PTV must receive at least 25 Gy (20 Gy for cohort A) (an allowed minor 
deviation, which will be documented). The highest dose that permits the above 
stomach and duodenal constraints to be achieved will be used.  However, if even this 
constraint cannot be met, the patient should be removed from the protocol.  
7.2 
Linac-based SBRT Treatment Delivery 
Patients will receive 5 fractions of 5 Gy or 6.6 Gy delivered over a five-day period, as 
delineated above, based on whether or not they have received prior radiation therapy to 
the pancreatic region. Treatment may be delivered over 2 weeks, provided that the patient 
receives at least 2 fractions per week. Initial patient positioning will be based on 
volumetric kV (cone-beam CT) imaging with shifts to bony anatomy as appropriate. 
Orthogonal kV/MV or kV/kV projection imaging will be used to verify the location of the 
fiducials prior to delivery of the first treatment beam. A secondary shift based on the 
location of fiducials may be utilized, as indicated by the position of the fiducials. For free-
breathing treatments, kV fluoroscopic images should be obtained to confirm the 
anticipated position of these fiducials during the entire respiratory cycle. Active monitoring 
of treatment delivery accuracy will be accomplished using kV and/or MV projection 
imaging, either immediately before or during all (or a subset of) treatment fields. Patient-

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specific dosimetric quality assurance (QA) will be performed as per standard practice in 
the Department of Radiation Oncology, Indiana University School of Medicine.  
7.3 
Follow-Up 
Following Linac-based SBRT, all patients will be monitored clinically and with serial 
imaging (CT scans and/or PET/CT if possible and as deemed necessary by the treating 
physician). A detailed medical history with physical examination and quality of life 
assessment will be performed at 4-6 weeks, 4 months, 6 months, 9 months and 1 year after 
radiation treatment. In years 2-5, the follow up interval will be every 3-6 months, as 
determined by the principal investigator. Follow up intervals may also be more frequent as 
indicated clinically. A complete blood count (CBC) with differential, comprehensive 
chemistry panel, tumor marker studies, and quality of life assessment will be performed at 
each follow-up interval.  
We estimate that most patients will remain a subject in this study for approximately 
one year. Patients will remain enrolled on this protocol for a maximum of 5 years or until 
patient withdrawal. Patients that have completed the 5 year follow-up will continue being 
followed for survival information until death. The administration of subsequent 
chemotherapy and/or other antineoplastic treatment following Linac-based SBRT will be at 
the discretion of each patient’s attending medical oncologist.  If participants become very ill 
and cannot travel to IU for follow-up appointments, the study team will mail Quality of Life 
Questionnaires and request relevant medical records from local providers. This situation is 
expected due to progression profile, and if all protocol parameters are met, will not 
constitute a protocol deviation.  
7.4 
General Concomitant Medication and Supportive Care Guidelines  
7.4.1 Antidiarrheals and Anti-Emetics 
For symptoms of diarrhea and/or abdominal cramping, patients will be 
instructed to take over-the-counter anti-diarrheal medication (loperamide). 
Additional antidiarrheal therapies may be used at the discretion of the treating 
physician. Patients should be instructed to increase fluid intake to help maintain 
fluid and electrolyte balance during episodes of diarrhea. Prophylactic anti-emetics 
(generally ondansetron, unless patient has intolerance/allergy) will be encouraged 
one hour prior to Linac-based SBRT and for up to 5 days following Linac-based 
SBRT on an as-needed basis. Additionally, patients will be instructed to increase 
fluid intake. All patients will be prescribed proton pump inhibitors (PPIs), which 
should begin by the start of Linac-based SBRT and continue for a minimum of 6 
months following Linac-based SBRT.  
7.4.2 Other Concomitant Medications 
Therapies considered necessary for the patient's well-being may be given at the 
discretion of the investigator. Other concomitant medications should be avoided 
except for analgesics, chronic treatments for concomitant medical conditions, or 
agents required for life-threatening medical problems. Specifically, if the patient is 
being treated with chemotherapy, it is recommended that chemotherapy be 
discontinued at least one week prior to initiation of Linac-based SBRT and that 
resumption of chemotherapy be delayed for at least one week following the 
conclusion of Linac-based SBRT. In general, prescription of these medications will 
be presided over by the patient’s attending medical oncologist. 

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7.4.3 Use of Radioisotopes/Rad Machines 
Stereotactic radiotherapy treatments will be delivered using a linear accelerator 
(“linac”). The radiation treatment plan will be designed to use multiple beams of 
radiation to concentrate large doses of radiation within a tumor. Cone beam CT 
imaging and diagnostic-energy (kV) imaging will be used to deliver image-guided 
radiation therapy (IGRT). IGRT allows delivery of highly accurate, stereotactic 
radiation treatment. The use of cone beam CT images during IGRT is considered 
standard of care. Uncertainties in tumor location are minimized because these 
machines have on-board, volumetric imaging for accuracy in initial patient setup; kV 
and MV projection imaging during treatment is used to monitor delivery accuracy 
and/or make corrections to the patients’ position. The radioactive tracer FDG will be 
used to perform PET scans (when available), a special imaging procedure. Positron 
emission tomography (PET) is a type of nuclear medicine examination, which is 
based on the administration of a small amount of a radioactive FDG agent. The 
tracer (FDG) is a modified form of glucose, a sugar normally found in the 
bloodstream and used by cells in the body for energy. FDG is eliminated in the urine. 
With special imaging equipment, it is possible to detect radiation from the 
administered radioactive agent and obtain images of the body. 
8. TOXICITIES TO BE MONITORED/DOSAGE MODIFICATIONS 
It is difficult at this time to predict with confidence the percentage risk of complications 
from the proposed Linac-based SBRT treatment. However, it is reasonable to extrapolate 
from the current experience with radiotherapy in and around the pancreas. Based upon 
prior phase I and phase II studies, we anticipate that the toxicities associated with this 
treatment will be acceptable. We estimate that ≤20% of patients will experience grade 2 or 
higher late Radiation-related GI toxicity within one year. Late GI toxicities are those events 
occurring more than 3 months after Linac-based SBRT. Acute GI toxicities are those events 
occurring within 3 months following Linac-based SBRT.  Acute toxicities commonly 
associated with such treatment include nausea, vomiting, fatigue, anorexia and weight loss. 
Severe side effects such as gastrointestinal (GI) obstruction, perforation, or hemorrhage 
are uncommon complications, occurring in <5% of patients undergoing standard radiation 
therapy for pancreatic cancer. The major serious toxicity in this group of patients is the 
development of duodenal/gastric ulcers. Most of these are successfully managed medically. 
However, Stanford has observed 2 cases of duodenal perforation associated with Linac-
based SBRT. We anticipate that because of refinements in radiation treatment planning 
techniques and because the dose will be divided over five treatments (as opposed to one), 
the biological equivalent and actual dose to the duodenum will be less than prior studies.  
Although we expect a comparable rate of complications with fractionated Linac-based 
SBRT, it is important to note that vomiting, GI obstruction, GI hemorrhage, anorexia and 
weight loss are also commonly associated with pancreatic cancer progression. Clinical and 
radiographic assessments will be performed in an effort to identify these effects, ascertain 
their etiology and provide the most appropriate palliative measures. Hepatic and renal 
radiation toxicity is not anticipated given the expectation of limited incidental irradiation of 
these organs and we have not observed any to date in the patients treated with Linac-based 
SBRT. Complications, if any, will be graded according to the CTCAE, National Cancer 
Institute, version 4.0 (see Appendix I). We will also utilize the RTOG scale for grading acute 
and chronic radiotherapy toxicities. 

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9. STUDY PARAMETERS/CALENDAR 
 
Pre-Study1 
Treatment 
-------------------------Follow-Up4------------------------- 
 
 
Week 1 
Week 2 
4-6 
weeks6 
3 months 6 months 9 months 12 
months 
Yrs 2-5 
Initial Consult 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
History/Physical 
X 
X5 
X5 
X 
X 
X 
X 
X 
Q6 
months 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Biopsy 
confirmation of 
adenocarcinoma 
X 
 
 
 
 
 
 
 
 
CBC with 
differential 
X 
X 
X 
X 
X 
X 
X 
X 
Q 6 
months 
CMP 
X 
X 
X 
X 
X 
X 
X 
X 
Q 6 
months 
CA 19-9 
X 
 
 
X 
X 
X 
X 
X 
Q 6 
months 
Negative 
Pregnancy Test2 
X 
 
 
 
 
 
 
 
 
Fiducial Placement 
X 
 
 
 
 
 
 
 
 
Simulation Scan 
X 
 
 
 
 
 
 
 
 
SBRT 
 
X 
X 
 
 
 
 
 
 
Radiographic Eval3 
CT 
 
 
CT 
CT  
CT 
CT 
CT 
CT 
QoL/Pain 
Questionnaires 
X 
X 
X 
X 
X 
X 
X 
X 
Q 6 
months 
AE Evaluation 
 
 
 
X 
X 
X 
X 
X 
Q 6 
months 
 
 

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Footnotes:  
1Within 45 days of commencing study treatment. 
2Urine or serum pregnancy test must be negative in all premenopausal women who have not undergone surgical sterilization 
procedures. 
3FDG PET scan optional at baseline and at all follow-up intervals. 
4All follow-up visits subsequent to the 4-6 week visit may be completed at an outside hospital. However, all records and imaging 
(copies of images in addition to reports) must be reviewed at IU. Follow-up appointments have a 30-day tolerance window. QoL 
surveys may be returned by mail for patients who are completing follow-up visits at an outside clinic. 
5A treatment evaluation will be done in lieu of history/physical exam at these visits. 
6 Surgical oncology visit note is acceptable if patient has undergone surgical procedures and is limited to travel to clinic

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10. CRITERIA FOR EVALUATION/REMOVAL FROM STUDY 
10.1 Anti-Tumor Effect and Response Evaluations 
Patients will be evaluated for anti-tumor effect by follow-up imaging (pancreas protocol 
CT and/or PET-CT imaging) as outlined above. All subsequent scans (post-treatment) will 
be compared to the same pretreatment CT or PET/CT that was performed for radiation 
treatment planning. Evaluation of pancreatic and periampullary tumor response will be 
based on standard radiographic criteria for the treated lesion and will be prospectively 
recorded in the study database. Radiographic response of the pancreatic or periampullary 
tumor by diagnostic CT scans will be defined according to RECIST criteria as described 
below:  
• CR = complete disappearance of index lesion 
• PR = at least 30% decrease in the longest diameter of the index lesion PD = more 
than 20% increase in the longest diameter of the index lesion SD = does not meet 
criteria for PR or PD  
• Local tumor progression will be defined as >=20% increased size on CT scan 
compared to a CT scan from prior to treatment.  
• Distant progression will be defined as any new tumor found outside of the 
pancreas or periampullary region on CT scan. 
Pancreatic or periampullary tumor response will also be assessed by FDG-PET scans 
(when available) according to the following criteria:  
• CR = target lesion becomes photopenic or standardized uptake value (SUV) ratio 
of tumor/liver less than or equal to 1 
• PR = decrease in SUV ratio of tumor/liver (at least 30%) PD = increase in SUV 
ratio of tumor/liver (at least 20%)  
• SD = no significant change in SUV ratio of tumor/liver  
We will also determine PET response (in those patients who have undergone follow-up 
FDG PET scanning) with the new PERCIST criteria as reported by Wahl et al., defined as 
follows: (33) 
• Complete metabolic response (CMR): complete resolution of 18F-FDG uptake within 
the measurable target lesions so that it is less than mean liver activity and 
indistinguishable from surrounding background blood-pool levels with no new 18F-
FDG avid lesions 
• Partial metabolic response (PMR): reduction by a minimum of 30% in the target 
lesion’s 18F-FDG peak 
• Stable metabolic disease (SMD): disease other than CMR, PMR, or progressive 
metabolic disease 
• Progressive metabolic disease (PMD): 30% or greater increase in 18F-FDG peak in 
the target lesion or the development of new 18F-FDG avid lesions that are typical of 
cancer. 
Patients’ responses to therapy will also be evaluated clinically after completion of their 
Linac-based SBRT. The following are clinical definitions for response:  
• CR = complete alleviation of pain or other symptoms thought to be related  

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• to the index lesion 
• PR = improvement, but not complete elimination, of pain or other symptoms 
thought to be related to the index lesion 
• PD = worsening of pain or other symptoms thought to be related to the index 
lesion  
• SD = does not meet criteria for PR or PD  
10.2 Definitions 
• Duration of Response: time elapsed between SBRT completion (i.e., the last day 
of treatment) and the first sign of local progression or the development of new 
metastatic disease.  
• Progression-Free Survival: time elapsed from SBRT completion to documented 
local/regional or distant progression or death. Local PFS will be measured as the 
duration from SBRT to local progression or death from any cause.  
• Overall Survival: Duration from SBRT completion to patient death. 
10.3 Response Review 
All responses will be reviewed independently by a board certified radiologist at the 
study’s completion. Each image also will be reviewed by the PI with a concurrent review of 
the patient’s medical records.  
10.4 Criteria for Removal from Study  
Patients will be removed from the study if consent is withdrawn or death occurs. The 
protocol director may also withdraw a patient from the study for one or more of the 
following reasons: failure of the patient to follow the instructions of the protocol study 
staff, the protocol director decides that continuing participation could be harmful to the 
patient, pregnancy (if applicable), the patient needs treatment not allowed in the study, the 
study is cancelled, other administrative reasons, or unanticipated circumstances. Patients 
who have been removed from or discontinue the study for administrative reasons will be 
followed for survival information until death.  
11. STATISTICAL METHODS 
11.1 General Considerations 
Statistical analysis of this study will be the responsibility of the Department of 
Biostatistics at Indiana University School of Medicine. Parameter estimates and relevant 
summary statistics will be reported for both efficacy and safety outcomes. Continuous 
variables will be summarized by means, medians, minima, maxima and standard 
deviations. Categorical variables will be summarized by frequencies and percentages. 
Missing data will not be imputed. Additional exploratory analysis will be conducted when 
appropriate. Changes from the analysis plan will not require an amendment to the protocol 
unless it changes a significant feature in the protocol. The statistical analysis methods are 
outlined below. 
11.2 Study Design  
This is an open-label pilot study. No randomization or blinding is involved. Patients will 
be placed into dosing cohorts (A or B) depending on previous radiation therapy and 
followed for at least 1 year post-SBRT. 
 

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11.3 Criteria for Stopping Study 
We expect the safety profile to be similar for Cohort A and B so will evaluate the 
stopping rule in the combined cohort.  The expected Grade 4 or 5 treatment related AE rate 
from gemcitabine with SBRT is approximately 6% (Herman ref), and we would consider a 
10% rate in our study to be unacceptable.  An interim safety analysis is planned after every 
six patients are accrued and followed for 1 year to assess Grade 4 or 5 treatment-related 
AEs. If 3 or more out of 6, 4 or more out of 12, 5 or more out of 18, or 6 or more out of 24 
patients have a Grade 4 or 5 treatment-related AE within one year, accrual will be 
terminated. These stopping boundaries represent where the lower bound of a 90% exact 
binomial confidence interval would be in excess of 10%.    
11.4 Analysis Datasets 
• Enrolled Population - The enrolled population consists of all patients who enroll 
in the study. 
• Efficacy Population - The efficacy population comprises all patients who meet 
the eligibility criteria, are registered onto the study, get at least one session of 
Linac-based SBRT, and have at least one follow-up evaluation. This set will be 
used for efficacy analysis. 
• Safety Population - The safety population comprises all patients who have 
received at least one session of Linac-based SBRT. This set will be used for safety 
analysis. 
11.5 Sample Size 
It is anticipated that this study will last approximately 42 months (30 months of accrual 
and 12 months of additional follow-up while cohort matures).   The total enrollment will be 
38.  With a 1 to 5 ratio of prior RT treatment to no prior RT treatment, we expect to enroll 
approximately 6 subjects in Cohort A and 30 in Cohort B.  Six subjects in Cohort A will allow 
us to obtain only a preliminary sense of efficacy; however, we do not want to exclude this 
important cohort from the study since our focus is on safety.  A sample size of 38 will allow 
us to estimate the primary outcome of acute (within 3 months of treatment) grade 3 or 
greater gastrointestinal and hematologic toxicity to within approximately 12% using a 90% 
exact confidence interval assuming the rate is similar to Herman et al. (28%).  
11.6 Patient Characteristics and Significant Protocol Violations 
Baseline patient characteristics will be tabulated, such as demographics (age, race, 
gender), and disease characteristics will be displayed combined and by cohort. Significant 
protocol violations such as with respect to eligibility criteria and treatment plan will be 
tabulated by cohort. 
11.7 Concomitant Medications 
Medications that might affect the study treatment will be tabulated. 
11.8 Disposition 
Frequencies and percentages of all patients enrolled, discontinuing the study, and 
completing the study will be presented by cohort. The reasons for discontinuation will also 
be summarized. 
11.9 Analysis of Primary Objective 
The primary outcome of acute (within 3 months of treatment) grade 3 or greater 
gastrointestinal and hematologic toxicity will be estimated with a 90% exact binomial 

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confidence interval in the two cohorts combined, since the safety profile is expected to be 
similar for Cohort A and B. 
11.10 Analysis of Secondary Objectives 
Acute toxicities according to CTCAE 4.0 will be summarized by frequencies and rates 
calculated as the proportion of patients in the safety population experiencing SAEs, 
discontinuations due to AEs, and AEs for the two cohorts combined. For the secondary 
objective of estimating rates of late (> 3 months after treatment) grade 2 gastritis, enteritis, 
fistula, and ulcer, or any other grade 3 or greater gastrointestinal toxicity, the proportion of 
patients with each condition and its 90% confidence interval will be calculated.   
In Cohort B only, Kaplan-Meier estimates will be used to estimate the median and 90% 
confidence intervals for time to local progression, overall survival, metastasis-free survival 
and progression-free survival.  The 1-year rates and 90% confidence intervals will be also 
be estimated from these curves. A listing of clinical outcomes will be generated for Cohort 
A. 
Pain control (based on reporting of standard pain score (0-10) with the option to use 
the FACES 0-10 scale) will be evaluated before and after Linac-based SBRT and the change 
in pain scores will be evaluated and summarized through descriptive statistics separately 
for each cohort.  For Cohort B, linear mixed models will be used to model changes in pain 
over time.  A similar approach will be used for the EORTC QOL-Q scale. 
11.11 Interim Analysis 
No interim analyses are planned other than assessing Grade 4 or 5 treatment-related 
AEs after every 6th patient. 
11.12 Subgroup Analysis 
No subgroup analyses are planned other than the separation of efficacy analyses for 
Cohorts A and B. 
12. DATA FORMS AND SUBMISSION SCHEDULE 
This study will utilize electronic Case Report Form completion in the OnCore® database. 
A calendar of events and required forms are available in OnCore®.  The OnCore® database 
is a comprehensive, web-based, Clinical Trial Management System (CTMS) which utilizes 
an Oracle database. OnCore® was developed by Forte Research Systems, Inc. and is used by 
the IUSCC Clinical Trials Office (CTO) and supported by the Indiana Clinical and 
Translational Sciences Institute (CTSI).   
OnCore® provides users secure access with unique IDs/passwords and restricts access 
by assigned roles, from any location, to record, manage, and report on data associated with 
the operation and conduct of clinical trials. 
All source documents are to remain in the patient’s clinic file.  All documents should be 
kept according to applicable federal guidelines.  Clinical trial data in OnCore® are 
periodically monitored by the IU Simon Cancer Center Data Safety Monitoring Committee.   
Participant data that will be collected include the following:  
• Eligibility or inclusion/exclusion criteria  
• Patient demographics  
• Pre-study evaluation  

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• Surgical procedures, with dates and findings (including EUS, biopsy (if needed), 
fiducial placement, and/or stent placement (if recommended) 
• Scan dates (PET/CT (if available) and/or CT)  
• Treatment planning date  
• Pre-Study labs including hematology, chemistry, and tumor markers (CBC, CMP, and 
CA 19-9)  
• Radiation therapy dates and toxicities reported  
• Follow-up evaluations including H&P data, laboratory studies, imaging, and toxicity 
data 
• QOL and pain questionnaires  
• Subject study withdrawal, date, and reason  
• Participant report of compliance with protocol prescribed medications, specifically 
PPIs and antiemetics 
13. PATIENT CONSENT AND PEER JUDGMENT 
The protocol and informed consent form for this study must be approved in writing by 
the appropriate Institutional Review Board (IRB) prior to any patient being registered on 
this study.   
Changes to the protocol, as well as a change of principal investigator, must also be 
approved by the Board.  Records of the Institutional Review Board review and approval of 
all documents pertaining to this study must be kept on file by the investigator (housed in 
the Radiation Oncology Research Office or Clinical Trials Office) and are subject to 
inspection at any time during the study.  Periodic status reports must be submitted to the 
Institutional Review Board at least yearly, as well as notification of completion of the study 
and a final report within 3 months of study completion or termination.   
The study will be conducted in compliance with ICH guidelines and with all applicable 
federal (including 21 CFR parts 56 & 50), state or local laws. 
14. DATA AND SAFETY MONITORING PLAN 
Investigators will conduct continuous review of data and patient safety. Monthly review 
meetings for moderate risk trials are required and will include the principal investigator, 
clinical research specialist and/or research nurse (other members per principal 
investigator’s discretion). Monthly meeting summaries should include review of data, the 
number of patients, significant toxicities as described in the protocol, and responses 
observed. Summaries will be submitted and reviewed monthly by the IUSCC Data Safety 
Monitoring Committee (DSMC). Submit to DSMC@iupui.edu. 
14.1 Study Auditing and Monitoring  
All trials conducted at the IUSCC are subject to auditing and/or monitoring. Reports will 
be reviewed by the full DSMC at the time of study review. Moderate risk trials are reviewed 
annually by the DSMC. 
14.2 Early Study Closure  
At any time during the conduct of the trial, if it is the opinion of the investigators that 
the risks (or benefits) to the patient warrant early closure of the study, this 
recommendation should be made in writing to the DSMC. Alternatively, the DSMC may 

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initiate suspension or early closure of the study based on its review of the investigator 
reports.  
14.3 Reporting Guidelines  
The DSMC has streamlined the reporting process by utilizing reports from OnCore®. 
This has allowed direct view of reports within the Clinical Trials Management System 
(CTMS); thus discontinuing paper reports. SAE reports are entered into OnCore® monthly 
and reviewed by the DSMC chair and/or coordinator monthly. Findings will be reported to 
the full DSMC at the time of study review.  
14.4 Reporting Death 
Death will be reported per local IRB reporting guidelines. 
14.5 Study Accrual Oversight  
Accrual data will be entered into the IUSCC OnCore® system. The Protocol Progress 
Committee (PPC) reviews study accrual twice per year while the PPC coordinator reviews 
accrual quarterly. 
14.6 Protocol Deviations  
Protocol deviations are entered into OnCore® and reviewed by the DSMC chair and/or 
coordinator monthly. Findings will be reported to the full DSMC at the time of study review. 
15. REPORTING ADVERSE EVENTS 
Low-grade toxicities are to be expected given the disease profile. Any toxicity below 
CTCAE v4.0 grade 3 will not be reported on the Master AE Log or Case Report Forms. 
However, this information will be retained in patient charts. Towards end of life, 
hospitalization events increase within this patient population. Unplanned hospitalizations 
that occur greater than 30 days from the last fraction of SBRT and that are not attributable 
to research intervention will be recorded on the Master AE Log and reported at the time of 
continuing review and SMC monitoring. These parameters are drafted in accordance with 
CFR21, and provide realistic expectations based on the sickness of this patient population. 
15.1 Definitions of Adverse Events 
15.1.1 Adverse Event (AE) 
An adverse event is defined as untoward medical occurrence associated with 
the use of a medical intervention in humans, whether or not considered related to 
the medical intervention. An adverse event can be ANY unfavorable and unintended 
sign (e.g. an abnormal laboratory finding), symptom, or disease temporarily 
associated with the use of a medicinal (investigational) product, whether or not 
considered related to the medicinal (investigational) product (attribution of 
‘unrelated’, ‘unlikely’, ‘possible’, ‘probable’, or ‘definite’).  Acute adverse events will 
be graded according to the NCI Common Toxicity Criteria, Version 4.0. 
15.1.2 Serious Adverse Event (SAE) 
A serious adverse event is any untoward medical occurrence resulting in one or 
more of the following: 
• 
Results in death or ANY death occurring within 28 days of the last fraction of 
SBRT (even if it is not felt to be related to the medical intervention)  

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• 
Is life-threatening (defined as an event in which the patient was at risk of 
death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
NOTE: Hospitalizations that are not considered SAEs are:  
 Hospitalization planned prior to first administration of study 
treatment 
 Hospitalization for elective treatment of a pre-existing condition 
unrelated to the study treatment 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly or birth defect 
• 
Is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but,  based 
upon appropriate medical and scientific judgment, may jeopardize the 
patient or may require intervention (e.g., medical, surgical) to prevent one of 
the other serious outcomes listed in the definition above).  Examples of such 
events include, but are not limited to, intensive treatment in an emergency 
room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
not resulting in hospitalization; or the development of drug dependency or 
drug abuse. 
• Pregnancy 
Pregnancy of a patient during the study or within 30 days after the last 
fraction of SBRT should be reported via an SAE report.  Should pregnancy 
occur in a female participant during the treatment period, SBRT should be 
discontinued.   
15.1.3 Unexpected Adverse Event 
An adverse event not mentioned in the informed consent or the specificity or 
severity of which is not consistent with the informed consent, or is not common 
within the patient population. 
15.2 Determining Attribution to the Investigational Agent(s) 
Attribution: An assessment of the relationship between the AE and the medical 
intervention. CTCAE does not define an AE as necessarily “caused by a therapeutic 
intervention”. After naming and grading the event, the clinical investigator must 
assign an attribution to the AE using the following attribution categories: 
 
Relationship 
Attribution 
Description 
Unrelated to 
investigational 
agent/intervention 
Unrelated 
The AE is clearly NOT related 
Unlikely 
The AE is doubtfully related 
Related to investigational 
agent/intervention 
Possible 
The AE may be related 
Probable 
The AE is likely related 

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Definite 
The AE is clearly related 
 
15.3 Adverse Event (AE) and Serious Adverse Event (SAE) Reporting 
Acute adverse events (CTCAEs) will be recorded from the time of first SBRT and for at 
least 90 days after treatment discontinuation, regardless of whether or not the event(s) are 
considered related to SBRT.  All Acute AEs considered related to SBRT will be followed 
until resolution, return to baseline, or deemed clinically insignificant, even if this occurs 
post-trial. 
All SAE’s should be collected from the first fraction of SBRT until death or the patient 
enrolls in hospice. SAE’s related or possibly related to study treatment or a study 
procedure should be reported until the patient is off study. Any death occurring within 30 
days after the last fraction of SBRT or last study procedure must be reported as an SAE 
regardless of attribution. 
15.3.1 Reporting to the IRB  
Unanticipated problems involving risks to subjects or others will be reported 
promptly to the IRB if they:  
• unexpected; 
• related or possibly related to participation in the research; and 
• suggests that the research places subjects or others at a greater risk of 
harm than was previously known or recognized.   
If the serious adverse event does not meet all three (3) criteria listed above, the 
event does not have to be promptly reported to the Indiana University 
IRB.  However, it should be reported at the time of continuing review. 
Prompt reporting of unanticipated problems to the IRB is defined as within 5 
days from becoming aware of the event. 
15.3.2 Reporting to the IUSCC Data Safety Monitoring Committee (DSMC)  
Regardless of study sponsorship, the study team must enter all initial and follow-
up SAE, expedited, and noncompliance reports into OnCore® for review by the 
DSMC chair and/or coordinator. Expedited reports may include IRB Prompt Report 
Forms and additional SAE forms as required by the sponsor. When follow-up 
information is received, a follow-up report should also be created in OnCore®. This 
DSMC reporting requirement is in addition to any other regulatory bodies to be 
notified (i.e. IRB, FDA, pharmaceutical company, etc.). The DSMC chair and/or 
coordinator will review all SAE, expedited, and noncompliance reports monthly. 
16. REFERENCES 
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17. Koong AC, Le QT, Ho A, Fong B, Fisher G, Cho C, et al. Phase I study of stereotactic 
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Between Chemoradiation-related Lymphopenia and Clinical Outcomes in Patients With 
Locally Advanced Pancreatic Adenocarcinoma. Am J Clin Oncol. 2013 May 2. 
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pancreatic ductal adenocarcinoma. Ann Surg. 2007 Apr;245(4):566-72. 
25. Yeo CJ, Abrams RA, Grochow LB, Sohn TA, Ord SE, Hruban RH, et al. 
Pancreaticoduodenectomy for pancreatic adenocarcinoma: postoperative adjuvant 
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1997 May;225(5):621,33; discussion 633-6. 
26. Sperti C, Pasquali C, Piccoli A, Pedrazzoli S. Recurrence after resection for ductal 
adenocarcinoma of the pancreas. World J Surg. 1997 Feb;21(2):195-200. 
27. Sharma C, Eltawil KM, Renfrew PD, Walsh MJ, Molinari M. Advances in diagnosis, 
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28. Yeo CJ, Cameron JL, Lillemoe KD, Sitzmann JV, Hruban RH, Goodman SN, et al. 
Pancreaticoduodenectomy for cancer of the head of the pancreas. 201 patients. Ann Surg. 
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31. Moertel CG, Childs DS,Jr, Reitemeier RJ, Colby MY,Jr, Holbrook MA. Combined 5-
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17. APPENDICES 
A1. Appendix I: NCI Common Toxicity Criteria Version 4.0 
Due to the size of the latest version of the Common Toxicity Criteria, copies of this 
appendix are not included with this protocol document. 
An electronic copy is available on the CTEP web site, 
http://ctep.cancer.gov/reporting/ctc.html 

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A2. Appendix II: Performance Status Scales/Scores 
 
       ECOG or Zubrod                              Karnofsky                  Lansky 
 
 
 
 
Score        Activity               Score                Activity                      Score               Activity 
0 
Fully active, able 
to carry on all pre-
disease 
performance 
without restriction. 
100 
 
 
90 
Normal, no complaints, no 
evidence of disease. 
 
Able to carry on normal 
activity; minor signs or 
symptoms of disease. 
 
100 
 
 
90 
Fully active, normal. 
 
 
Minor restrictions in physically 
strenuous activity. 
1 
Restricted in 
physically 
strenuous activity 
but ambulatory 
and able to carry 
out work of a light 
or sedentary 
nature, e.g., light 
housework, office 
work. 
80 
 
 
 
 
70 
Normal activity with effort; 
some signs or symptoms of 
disease. 
 
Cares for self, unable to 
carry on normal activity or 
do active work. 
80 
 
 
 
 
70 
Active, but tires more quickly. 
 
 
 
Both greater restriction of and 
less time spent in play activity. 
2 
Ambulatory and 
capable of all 
selfcare but unable 
to carry out any 
work activities.  
Up and about more 
than 50% of 
waking hours. 
 
 
60 
 
 
 
50 
Requires occasional 
assistance, but is able to 
care for most of his/her 
needs. 
 
Requires considerable 
assistance and frequent 
medical care. 
 
 
60 
 
 
 
50 
Up and around, but minimal 
active play; keeps busy with 
quieter activities. 
 
 
Gets dressed, but lies around 
much of the day; no active play; 
able to participate in all quiet 
play and activities. 
3 
Capable of only 
limited selfcare, 
confined to bed or 
chair more than 
50% of waking 
hours. 
40 
 
 
 
30 
Disabled, requires special 
care and assistance. 
 
Severely disabled, 
hospitalization indicated.  
Death not imminent. 
40 
 
 
 
30 
Mostly in bed; participates in 
quiet activities. 
 
In bed; needs assistance even 
for quiet play. 
4 
Completely 
disabled.  Cannot 
carry on any 
selfcare. Totally 
confined to bed or 
chair. 
20 
 
 
10 
Very sick, hospitalization 
indicated.  Death not 
imminent. 
Moribund, fatal processes 
progressing rapidly. 
20 
 
 
10 
 
Often sleeping; play entirely 
limited to very passive 
activities. 
No play; does not get out of 
bed. 
 

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A3. Appendix III: DSMC Check Sheet 
 

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A4. Appendix IV: Pain Scale 
 
A5. Appendix V: QOL Questionnaire 
See attached PDF “EORTC QLQ-30 (version 3)”