Pilot Study of Short-Course Preoperative Stereotactic Body Radiation Therapy for Resectable Pancreatic Cancer
Phase: NA
Conditions: Pancreatic Cancer, Adenocarcinoma
Sponsor: University of Rochester

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NCT02347618
PILOT STUDY OF SHORT-COURSE PREOPERATIVE STEREOTACTIC BODY RADIATION THERAPY 
FOR RESECTABLE PANCREATIC CANCER 
Primary Investigator 
Alan W. Katz, MD, MPH, Department of Radiation Oncology, URMC, Box 647, Rochester, NY 
14642  
Co-Investigators 
Haoming Qiu MD, Department of Radiation Oncology, URMC, Box 647, Rochester, NY 14642  
Vivek Kaul MD, FACG, Department of Medicine, Division of Gastroenterology, URMC, Rochester, 
NY 14642 
Shivangi Kothari MD MS, Department of Medicine, Division of Gastroenterology, URMC, 
Rochester, NY 14642 
Sub-investigators: 
Eva Galka, MD, Department of Surgery, URMC, Rochester, NY 14642 
Luke Schoeniger, MD, PhD, Department of Surgery, URMC, Rochester, NY 14642 
Aram Hezel, MD, Department of Medicine, Division of Hematology and Oncology, URMC, 
Rochester, NY 14642 
Mohamedtaki Tejani, MD, Department of Medicine, Division of Hematology and Oncology, 
URMC, Rochester, NY 14642 
Supriya Mohile, MD, Department of Medicine, Division of Hematology and Oncology, URMC, 
Rochester, NY 14642 
Marcus Noel, MD, Department of Medicine, Division of Hematology and Oncology, URMC, 
Rochester, NY 14642 

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SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Phase I:  12 patients who undergo SBRT and surgical resection 
 
 
Resectable 
pancreatic 
adenocarcinoma 
 
- Signed consent 
- No metastatic 
disease 
SBRT (5 x 5Gy) over 
5-7 days 
 
Pancreatic resection 
within 3 weeks of 
completing RT. 
 
 

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PURPOSE 
The purpose of this study is to determine if giving stereotactic body radiation therapy (SBRT) to 
pancreatic adenocarcinoma before it is surgically resected is safe and feasible. 
 
 
1. 
BACKGROUND 
 
Adenocarcinoma of the pancreas is the fourth most common cause of cancer deaths in the 
United States. Most adenocarcinomas arise in the head of the pancreas in close approximation 
to the duodenum, celiac axis and superior mesenteric artery. Pancreaticoduodenectomy 
(Whipple resection) provides the only curative treatment, but only 10-15% of patients are 
eligible for upfront surgical resection. Unfortunately, even with resection, both locoregional 
and distant recurrence remains a common problem and 5 year survival rates is 25-30% for 
patients with node negative disease.1 Both adjuvant and neoadjuvant therapy have been 
studied in an attempt to improve current results.  
 
The optimal adjuvant treatment after surgical resection is not currently known. The CONKO-001 
trial showed that adjuvant gemcitabine chemotherapy increased 5 year overall survival to 21% 
from 10% in those who did not receive adjuvant therapy.2 Whether the addition of radiation 
therapy to adjuvant chemotherapy is beneficial is controversial. The EORTC 40013/ FFCD-
9203/GERCOR phase II study of 90 patients showed that gemcitabine based chemoradiotherapy 
resulted in improved local control compared with gemcitabine chemotherapy alone with similar 
median time of disease free and overall survival.3 The ESPAC-1 trial was a complex study in 
which patients were randomized to one of 4 adjuvant arms, chemoradiotherapy, 
chemotherapy, both or none.  In a subset analysis of 289 patients, intention to treat analysis 
showed significantly improved overall survival in patients randomized to receive chemotherapy. 
On the other hand, patients randomized to chemoradiotherapy had a trend towards worse 
overall survival.4 This trial was heavily criticized due to methodological flaws and for using 
outdated split course radiation techniques. A currently ongoing study RTOG 0848 is seeking to 
further answer this question by randomizing patients who have received adjuvant 
chemotherapy to further chemotherapy alone or chemoradiotherapy.5 
 
Although upfront surgery with adjuvant therapy is generally chosen, there are many reasons to 
consider the use of neoadjuvant therapy.  The morbidity of surgical resection often prevents 
the timely delivery of adjuvant therapy. Despite careful technique, there still remains a 
significant fraction of patients who have positive surgical margins and these patients have a 
poorer prognosis than those who are able to undergo an R0 resection. Lastly, post-operative 

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radiation therapy results in the radiation of significant volumes of bowel which often fall into 
the space previously occupied by the pancreatic head. This can result in significant GI toxicity. 
As a result, investigators have evaluated the use of neoadjuvant chemoradiation therapy for 
resectable patients. A study of 50.4 Gy of radiation given over 5.5 weeks in combination with 5-
FU demonstrated improved local control versus historical controls.6 However, toxicity from 
preoperative treatment resulted in hospital admission for one third of patients. This prompted 
a consideration of short course preoperative chemoradiation therapy in which 30 Gy in 2 weeks 
was delivered with concurrent 5-FU which resulted in similar efficacy but decreased grade 3 
toxicity.7,8 As with most other studies, distant metastases to the liver accounted for a majority 
of disease progression. Therefore, efforts were made to shorten the interval of neoadjuvant 
radiation therapy to allow patients to proceed more quickly to surgery and adjuvant 
chemotherapy which would presumably decrease the rate of metastatic disease.  
 
Short course radiation of 25 Gy in 5 fractions has been extensively studied in Europe for the 
neoadjuvant treatment of resectable rectal cancer and has been found to improve local control 
compared to surgery alone.9,10 In the Swedish Rectal Cancer Trial, patients underwent resection 
within 1 week after radiotherapy. 9 A comparison of 25 Gy in 5 fractions to conventional 
chemoradiation therapy to 50.4 Gy with 5-FU and Leucovorin showed similar rates of survival, 
local control and late toxicity.  In addition, 25 Gy in 5 fractions was associated with less grade 3 
or 4 toxicities (3.2% vs. 18.2%, p=<0.001) and higher compliance (97.9% vs. 59.2%) compared 
with conventional CRT.11  
 
Building upon this experience, a prospective study of 15 patients from Harvard demonstrated 
that neoadjuvant short course RT using 25 Gy in 5 fractions to the pancreatic bed and regional 
lymph nodes using proton therapy and concurrent capecitabine was feasible and well tolerated. 
Acute grade 3 toxicity was noted in 4 of 15 patients. 11 of 15 patients underwent surgical 
resection but no patients experienced delays or exclusion from surgery due to toxicity from 
neoadjuvant treatment. Evaluation of 30 day post-operative results showed no deaths or 
anastomotic leaks.  9 of 11 patients who underwent surgery had R0 resections and 10 of these 
patients were able to receive post-operative gemcitabine. After a median follow up of 12 
months, one year overall survival was 75% for the entire group. Of 11 surgical resected 
patients, 10 are still alive at last follow up. Of 15 patients treated with neoadjuvant therapy, 
only 1 patient with a positive surgical margin experienced local progression.  No patient 
experienced nodal or regional failure but 8 patients developed metastatic disease.12  
 
A similar study was repeated, also at Harvard, using photon (conventional x-rays) instead of 
proton radiation therapy. However, compared with the proton study a higher rate of fibrosis 
(63% vs. 27%) was noted during surgery leading to a mean increase in operative time of 69 

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minutes. Dosimetric comparisons revealed that patients undergoing photon irradiation had 
significantly increased low dose radiation exposure to the abdominal organs. Due to this 
complication, the study was terminated after accrual of 10 of 12 planned patients.13   
 
While the Harvard study with neoadjuvant proton therapy achieved excellent results, protons 
are not widely available at most centers including ours. Therefore, we believe that there is a 
need for continued investigation of neoadjuvant photon radiation therapy for pancreatic 
cancer. We hypothesize that delivering high dose photon radiation to the gross disease using 
stereotactic localization (SBRT) without elective nodal irradiation can effectively reduce local 
recurrence while minimizing the fibrosis noted in the Harvard Photon study.13 
 
We are not aware of any prospective reports of using SBRT alone as neoadjuvant treatment for 
resectable pancreatic cancer.  However, there are several single institution experiences which 
show that SBRT can be safely delivered for locally advanced pancreatic cancer (LAPC). Choung 
et al. reported treating LAPC with induction chemotherapy followed by 5 fraction SBRT. Dose 
painting technique of 7-10 Gy/ Fraction to the region of vessel abutment and 5-6 Gy/fraction to 
the reminder of the tumor was utilized.  Of 73 patients evaluated, no patients developed grade 
3 or higher acute toxicity and only 5% developed grade 3 or higher late toxicity.14 
 
Since SBRT requires large doses of radiation to be accurately delivered, Chuong et al and many 
other authors have utilized fiducial placement in the tumor for more precise radiotherapy 
targeting.12-14 Although biliary stents have sometimes been used as a surrogate for tumor 
location, a study of 11 patients demonstrated that biliary stents are not reliable enough to 
substitute for fiducials in SBRT targeting.15 Fiducial placement using endoscopic ultrasound 
(EUS) has been demonstrated to be both feasible and safe. 16  
 
Based on data from the aforementioned studies, we believe that our protocol which uses 
photon irradiation of 25 Gy in 5 fractions to the gross disease alone using fiducial localization 
and stereotactic guidance without chemotherapy will be able to achieve a favorable 
therapeutic ratio. The rationale is to deliver a dose of radiation that will sterilize microscopic 
disease at the margins thus decreasing the risk of local recurrence. By targeting the gross 
disease alone, we hope to minimize the volume of tissue treated and avoid the increase in 
fibrosis noted in the Harvard photon study.  Using radiation therapy alone without 
chemotherapy will decrease the duration and toxicity of neoadjuvant therapy thereby allowing 
patients to proceed quickly to definitive surgical resection. After, resection, full dose 
chemotherapy can then be delivered without interruption with the aim of reducing distant 
metastatic disease. 
 

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2. 
STUDY DESIGN 
 
2.1  
Overview 
This will be a Phase I, single center, prospective, single arm feasibility study of the use of 
stereotactic body radiotherapy (SBRT) for the preoperative treatment of surgically resectable 
pancreatic adenocarcinoma.  
 
2.2  
Primary Objectives 
a) To evaluate the feasibility and tolerability of short course preoperative stereotactic body 
radiation therapy for resectable pancreas cancer 
b) To determine the rate of Grade 2 or greater acute toxicity of neoadjuvant stereotactic 
body radiation therapy  
c) To determine intraoperative and postoperative surgical morbidity following 
neoadjuvant treatment including the amount of fibrosis and total operative time.  
 
2.3 
Secondary Objectives 
a) To determine local control and recurrence patterns of treated patients relative to 
historical controls. 
b) To determine progression free survival of treated patients 
c) To determine overall survival of treated patients 
 
 
3. 
CHARACTERISTIC OF THE RESEARCH POPULATION 
 
3.1  
Subject Characteristics 
We aim to enroll 18 patients into this Phase I trial with the goal of 12 evaluable cases.  We will 
recruit from the population of patients who are referred to URMC for diagnosis and workup of 
their suspected pancreatic adenocarcinoma.  We expect that patients will be approximately 50-
70 years old with an equal distribution of males and females and racial and ethnic backgrounds. 
No vulnerable subjects will be enrolled.  
 
3.2 
Inclusion Criteria 
a) Patient with pathologically proven diagnosis of adenocarcinoma of the head of the 
pancreas  
b) CT w/ contrast or MRI of the abdomen with contrast within 6 weeks prior to registration 
c) CT chest or PET/CT within 6 weeks prior to registration  
d) Clinically determined to be resectable based on NCCN Criteria: 

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e) No radiographic evidence of superior mesenteric vein or portal vein distortion 
f) No evidence of distant metastasis 
g) Clear fat planes around the celiac axis, hepatic artery, and superior mesenteric artery  
h) No enlarged lymph nodes per CT criteria or PET avid lymph nodes 
i) No lymphadenopathy outside the surgical field (i.e. celiac or para-aortic adenopathy) 
j) Adequate cardiopulmonary reserves to tolerate surgery 
k)  Karnofsky performance status ≥ 70 
l) Age ≥ 18 
m) Adequate bone marrow function defined as follows: 
• Absolute neutrophil count (ANC) ≥ 1800 cells/mm3 
• Platelets ≥ 100,000 cells/mm3 
• Hemoglobin ≥ 8.0 g/dl (Note: The use of transfusion or other intervention to 
achieve Hgb ≥ 8 g/dl is acceptable.) 
n) Pregnancy test must be negative for women of childbearing potential within 7 days prior 
to study entry 
o) Patient must sign study specific informed consent prior to study entry   
 
 
3.3 
Exclusion Criteria  
a) Prior surgical resection of any pancreatic malignancy 
b) Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free 
for a minimum of 3 years  
c) Any prior chemotherapy or radiation for treatment of the patient’s pancreatic tumor. 
d) Prior radiotherapy to the region of the study cancer that would result in overlap of 
radiation therapy fields 
e) Severe, active comorbidity, defined as follows: 
1. Unstable angina and/or congestive heart failure requiring hospitalization within 
the last 12 months 
2. Transmural myocardial infarction within the last 6 months  
3. Acute bacterial or fungal infection requiring intravenous antibiotics at the time 
of registration  
4. Chronic obstructive pulmonary disease exacerbation or other respiratory illness 
requiring hospitalization or precluding study therapy within 30 days prior to 
registration.  
f) Severe, uncorrectable hepatic insufficiency and/or coagulation defects due to liver 
failure 
g) Any evidence of distant metastases (M1)  
h) Pregnancy or women of childbearing potential and men who are sexually active and not 

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willing/able to use medically acceptable forms of contraception; this exclusion is 
necessary because the treatment involved in this study may be significantly teratogenic 
 
 
4. 
METHODS AND STUDY PROCEDURES 
 
4.1 
Pretreatment Evaluation (please see schedule in Appendix B for table layout) 
Within 6 weeks prior to study enrollment patients must undergo the following evaluations:  
a) History and physical by Radiation Oncologist, Gastroenterologist and Surgical Oncologist 
b) CT or MRI scan of the abdomen and pelvis with IV contrast or PET/CT  
c) CT chest or PET/CT within 6 weeks prior to registration  
d) Informed Consent obtained by a member of the study team 
e) Lab studies [CBC with diff, Na, K, BUN, Cr, Glucose, Phosphorous, Calcium, Albumin, AST, 
ALT, Total bilirubin, Alkaline phosphatase, CA19-9, CEA, INR and a pregnancy test (urine 
or serum HCG) for women of childbearing potential]. 
f) If clinically indicated, fiducial placement in/near the tumor via endoscopic ultrasound by 
gastroenterology service at least one week prior to CT simulation  
g) Patients will be placed on proton pump inhibitors 1 week prior to SBRT to continue until 
the day of surgery to minimize bowel toxicity.   
h) Any bile stent manipulation should be done 7-10 days prior to SBRT 
 
 
4.2 
Evaluation during study Period  
a) History, physical and vital signs during the weekly “on treatment visit” during radiation 
therapy 
b) History, physical and vital signs and laboratory evaluation obtained by surgery team 
prior to resection. Specific tests needed will be determined by surgical team.  
c) Following resection, patients will be assessed within 30 days after discharge for post-
operative morbidity by the surgery team.   
d) Patients will be followed at least every 6 months for a minimum of 5 years by a 
physician from either radiation, surgical or medical oncology service. Closer follow up 
may be needed based on clinical situation.   
 
4.3 
Treatment 
4.3.1 Radiation Therapy 
 
4.3.1a  Simulation and Planning 

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Patients should abstain from oral intake for 2 hours prior to CT Simulation.  Water and 
medications are acceptable. Patients will be simulated supine and Exac-trac body markers will 
be placed on the skin for patient positioning and respiratory management. In order to minimize 
treatment volume, patients will be asked to perform end-expiratory breath hold during 
simulation and treatment.  If patient is unable to tolerate and/or comply with breath hold, 
simulation and treatment will be done using shallow free breathing.  A Vac-bag custom 
immobilization device will be made.  
 
With the patient in the treatment position and in end-expiratory breath hold, a non-contrast CT 
will be first performed. This will be followed by a contrast CT scan (if no contraindications) also 
using breath hold technique. The maximum slice thickness will be 2.5mm. If intravenous 
contrast is not used during CT Simulation, a diagnostic CT or MRI using intravenous contrast or 
PET/CT must be available as a reference for target delineation.  
 
Gross tumor volume (GTV) will be defined on the basis of CT and MRI imaging findings.  The 
GTV alone will be treated with a planning target volume (PTV) margin of -5 mm to account for 
setup inaccuracy and patient and organ movement. If needed, PTV can be reduced to 3mm or 
less in order to avoid high doses to the duodenum and stomach. 25 Gy in 5 fractions will be 
prescribed to the 70-90% isodose line. Patients will be treated in 5 fractions delivered over 5-7 
days.  
 
4.3.1b Plan Evaluation 
Prior to starting treatment, the radiation plan for each patient will be evaluated by the 
radiation oncologists who will review the isodose curves on the treatment planning scan and 
evaluate the dose-volume histograms (DVH).   
 
Target Dose 
25 Gy in 5 fractions will be prescribed to the 70-90% isodose line. The prescription isodose line 
will be chosen so that at least 95% of the PTV is conformally covered by the prescription 
isodose surface.  Target doses less than 95% of prescription dose are limited to areas adjacent 
to an organ at risk (OAR). 
  
 

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Figure 1. Schematic of Radiation Prescription 
 
1. Prescription dose 25 Gy 
2. Prescription isodose 70-90%  
3. At least 95% of PTV covered by prescription isodose  
4. Normalization to be at isocenter 
 
Normal Tissue Tolerance adapted from Chuong et al.  14:  
• Mean kidney dose <10 Gy 
• Duodenum/small bowel/stomach: maximum dose (0.5cc) <35 Gy, mean dose <20 Gy, 
volume receiving 30 Gy <5 cc 
• Liver: volume receiving 30 Gy <10% 
• Spinal cord maximum point dose -20 Gy 
 
 
4.3.1c Quality Assurance 
 
The prescription isodose line selected will be 70-90% of the maximum dose within the PTV.  As 
a result a “hotspot” will exist within the PTV that is equal to the prescription dose divided by 
the prescription isodose line (e.g. 25 Gy/0.8 = 31.25 Gy when 25 Gy is prescribed to the 80% 
isodose line). Doses higher than the prescription dose (i.e. hotspots) must occur within the 
target and not within an OAR. 
 
4.3.1d Treatment 

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Patients will be immobilized in the Vac-Bag device. They will be treated in the manner in which 
they were simulated; either expiratory breath hold or shallow breathing.  They will initially be 
positioned using ExacTrac body markers. Treatment position will then be confirmed by fiducials 
alignment via ExacTrac KV imaging. Final anatomic confirmation will be made by cone-beam CT 
immediately prior to treatment.  
 
4.3.2 Supportive Treatment During Radiation 
a) Narcotic pain medications and anti-nausea medications will be prescribed as needed 
b) NSAID medications will be stopped prior to SBRT and not restarted until after surgery.  
 
4.3.3 Surgery 
Surgery will be performed no more than 3 weeks after completion of radiation therapy. A 
pancreaticoduodenectomy (Whipple procedure) with standard lymphadenectomy will be done.   
 Restaging is not required prior to surgery.  However if re-staging scans are obtained and 
demonstrate metastatic disease, surgery will not be performed.  
 
An attempted resection may also be aborted when more advanced or metastatic disease is 
found at the time of laparotomy. If surgical resection cannot be completed due to the presence 
of advanced disease, the patient will be withdrawn from the protocol at that time and will 
continue their care with standard treatment and follow up based on their clinical characteristic.   
 
4.3.4 Adjuvant Therapy 
Adjuvant chemotherapy may be given after pancreaticoduodenectomy at the discretion of the 
medical oncologist.  
Postoperative radiotherapy would not routinely be given after SBRT.  
 
4.4 
Cost of Treatments to the Subject 
Some of the tests/procedures/exams involved in the study such as imaging and laboratory 
analysis for oncologic staging and the surgical resection are standard care.  The patient and/or 
his/her insurance company will be responsible for paying for any tests/procedures/exams that 
are done as part of the standard of care. The patient and his/her insurance company will also 
be required to pay for the SBRT radiation received through this study. The provider will attempt 
to obtain prior authorization for the radiation treatment from the subject’s insurance provider. 
Any difficulties obtaining authorization will be discussed with the subject prior to your 
treatment.  
 
The patient will be encouraged to discuss their coverage with the insurance provider prior to 
initiating treatment. The cost of SBRT will be offset by omitting fractionated radiotherapy that 
would otherwise be given as the standard of care after surgery and chemotherapy.  

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There will be no payments made to patients on the study.  
 
 
5 
EVALUATION OF EFFICACY 
 
5.1 
After Radiation 
No routine oncologic evaluation will be performed after SBRT therapy. Further workup may be 
needed if patients demonstrate clinical signs of disease progression.  
 
5.2 
After Surgery  
5.2.1 Pathology 
Following surgical resection, all patients will undergo pathologic staging according to the AJCC 
Cancer Staging Manual, 7th Edition including T,N,M staging.  Pancreatic transection margin, bile 
duct, and uncinate margin will be evaluated on frozen section.  Recorded on permanent section 
will be: tumor size, degree of differentiation (well, moderate, poor), lymph node status, margin 
status. The amount of necrosis in the tumor and any other effects of treatment should also be 
noted.  
 
5.2.2 Post-Treatment Surveillance 
NCCN guidelines will be followed. Surveillance will be every 3-6 month for 2 years then annually 
thereafter and will include: 
• History and Physical 
• CA 19-9 Levels 
• CT or MRI imaging with IV contrast  
 
6. 
ADVERSE EVENTS 
6.1 
Definition of Adverse Event 
An adverse event is any symptom, sign, illness, or experience which develops or worsens during 
the course of the study, whether or not the event is considered related to the study 
intervention.  
 
The investigator will be responsible for assessing the etiology of any adverse events and 
determining if these can be considered a treatment related adverse event (TRAE) which arose 
directly or indirectly as a result of SBRT. Adverse events will be graded according to the NCI 
CTCAE Version 4.0.  TRAE will be considered “acute” if they occur within 1-4 weeks post SBRT 
and prior to surgical resection and “late” if they occur after this time period.  
 

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6.2 
Evaluation of Adverse Events 
Patients will be assessed for treatment related adverse events weekly during on treatment visit 
during radiation therapy, at the pre-operative evaluation visit and at follow up visits for at least 
5 years. Additional patient visits may be needed as clinically indicated. At these visits, study 
staff will assess adverse events by recording all voluntary complaints of the subject and by 
assessment of clinical, radiologic and laboratory features as indicated by the schedule in 
Appendix B and as clinically warranted.  At each study visit, the subject should be questioned 
directly regarding the occurrence of any adverse experience since his/her last visit.   
 
6.3 
Documentation of Adverse Events 
All adverse events, whether observed by the Investigator, elicited from or volunteered by the 
subject, will be documented.  Each adverse event will include a brief description of the 
experience, the date of onset, the date of resolution, the duration and type of experience, the 
severity, and the relationship to SBRT, contributing factors, and any action taken with respect 
to the planned radiation therapy. In addition, any toxicity leading to radiation treatment break 
and delay in surgical resection beyond 3 weeks post SBRT will noted.  
 
All patients are expected to undergo surgical resection within 3 weeks after radiation therapy. 
Any Intraoperative complications including blood loss, total operative time and amount of 
fibrosis noted by the surgeon will be recorded in the operative report. Post-operative 
complications including delayed wound healing, blood loss, infection, length of hospital stay, 
incidence of pancreatic leak, hospital readmissions for complications will also be recorded.  
Appendix A lists the data the surgical oncology team is responsible for recording.  
Treatment related late complications including but not limited to duodenal and intestinal 
ulceration, perforation, gastritis, bowel adhesions and obstruction, will be recorded at follow 
ups up to 5 years after treatment. 
 
6.4  
Serious Adverse Events (SAEs) 
A serious adverse event is any adverse event that results in any of the following outcomes: 
• death; 
• is life-threatening; 
• requires inpatient hospitalization or prolongation of existing hospitalization; 
• results in persistent or significant disability/incapacity; 
• is a congenital anomaly/birth defect; or 
• requires medical or surgical intervention to prevent permanent impairment or damage. 
 

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Any serious adverse events will be communicated directly to the primary investigator (Dr. Alan 
Katz) within 24 hours and documented in the patient’s medical chart. Dr. Katz will determine 
how to respond to the event and whether the patient will continue on the study.   
All SAEs will be reported to the IRB per local institutional policy. 
 
6.5 
Treatment Modification due to adverse events 
We do not anticipate any serious treatment related adverse events will take place during or 
immediately following SBRT treatment. We expect that the most common acute toxicities of 
radiation therapy will be mild nausea, fatigue and loose bowel movements.  
Patients will finish planned radiation if they experience up to grade 2 treatment related toxicity. 
If patients develop any serious adverse event or any grade 3 or higher treatment related 
toxicity, SBRT radiation will be stopped and the patients will proceed directly to surgical 
resection if deemed appropriate by surgical oncology.  
 
7.  
RISK/BENEFIT ASSESSMENT 
This study is being conducted because the investigators believe that treating pancreatic 
adenocarcinoma with preoperative SBRT may improve outcome compared with more 
conventional treatment. There have been several small-scale studies at other institutions (as 
documented in the introduction) which have shown delivering SBRT to the pancreas can be safe 
and effective. However, this technique has not been attempted at URMC. We aim to study 
whether neoadjuvant SBRT is feasible at URMC. There are benefits and risks associated with 
this study as documented below. The investigators believe that the benefits outweigh the 
potential risks for patients enrolled on this study.  
 
7.1  
Benefits of Participation 
a) In conventional treatment, radiation is delivered to the surgical bed which contains a 
large of bowel that has been surgically manipulated. This study calls for radiation to be 
delivered prior to surgery. This allows the radiation to be targeted at the gross tumor 
directly which will decrease the amount of normal bowel that is treated.  In addition, 
the tumor vascular supply preoperatively is generally more robust than postoperatively 
allowing better oxygenation to the tissue which is critical for the tumoricidal effect of 
radiation.  
b) In conventional treatment, radiation is delivered in conjunction with radio-sensitizing 
chemotherapy over a period of 5-6 weeks. This chemotherapy is generally not as 
effective at controlling micrometastatic disease compared to definitive chemotherapy 
which may increase the risk of metastatic progression.  This study calls for a shorter 

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course of radiation treatment to be delivered over 1-2 weeks preoperatively. This will 
allow the patient to receive full dose chemotherapy without interruption after surgery. 
This could reduce the risk of metastatic disease which is a major problem in the 
treatment of pancreatic cancer.  
c) Conventional radiation treatment delivers a small dose of radiation spread over 5-6 
weeks. It is known that pancreatic cancer is relatively resistant to radiation therapy. The 
radiation in this study is delivered in larger doses over a shorter period of time which 
may help to overcome some of the resistance of pancreatic cancer. 
 
 
7.2  
Risks of Participation 
a) Preoperative SBRT could cause toxicities that could delay or even prevent surgical 
resection which is the most important treatment for resectable pancreatic cancer. 
However, previous studies have demonstrated that the vast majority of patients who 
undergo preoperative radiation can safely undergo surgery in a timely fashion.  
b) Radiation therapy can cause both acute and delayed side effects. Acute side effects that 
take place during or immediately after treatment can include fatigue, nausea, vomiting, 
diarrhea, loss of appetite and weight loss. These effects are expected to be uncommon 
and can be managed with supportive care such as anti-nausea or anti-diarrheal 
medicines. Delayed side effects can take place months to years after radiation and can 
include delayed wound healing, scar tissue formation and bowel obstruction and 
structuring. These effects are expected to be very rare. These effects are expected to be 
similar or decreased compared with the toxicities associated with conventional 
radiation.     
c) There is a risk of invasion of patient privacy.  All the information gathered from patient 
chart or records, including name and any other identifying information will be strictly 
confidential and will be kept under lock and key.  The patients will not be identified nor 
will any information that would make it possible for anyone to identify the patient be 
used in any presentation or written reports about this study.  Only summarized data will 
be presented at meetings or in any publications. 
 
8. 
 CONFIDENTIALIATY OF DATA AND INFORMATION STORAGE  
All protected health information will be de-identified prior to storage in the research database. 
Subjects in the research database will be only identified by an ID number based on their order 
of enrollment (i.e. Subject 1, Subject 2 etc.). The primary investigator, Dr. Katz will maintain a 
password-protected file that will link the subject ID code to the patient’s medical record 
number in the electronic medical record system at URMC.  All research data will be kept in 

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secure data servers in the department of radiation oncology. All research spreadsheets will 
have passwords protection that will only be known to the study investigators.  
 
The patient’s enrollment on the trial and any clinical data relevant to the patient’s care will be 
documented in the patient’s electronic medical record at URMC.  
 
9. 
 DATA ANALYSIS AND MONITORING 
The purpose of this pilot study is to determine feasibility of preoperative SBRT followed by 
surgical resection at URMC and to determine its safety and tolerability in a small population of 
patients.    For this phase 1 trial, we plan to enroll 18 patients over 1-2 years with a goal of 12 
evaluable cases. This is a generally accepted number of patients for phase 1 trials and will 
minimize the risks to patients in case the treatment is found to be unsafe. We will stop 
recruitment and analyze the safety data if there appears to be any grade 3 or greater toxicity on 
any subject that can be directly attributed to SBRT or if any patients are made ineligible for 
surgical resection solely due to toxicities from SBRT.  
 
In the case where any patient becomes ineligible for resection due solely to toxicity from SBRT, 
the study will be immediately closed to accrual. We will stop recruitment and any patient who 
has not started radiation therapy will have their planned radiation treatment canceled. A 
patient who has started radiation therapy will undergo an individual discussion with Dr. Katz 
about the risks and benefits of continued treatment. 
 
If a patient experiences grade 3 or greater toxicity directly attributable to SBRT that is reversible 
and ultimately able to undergo resection, we will analyze the event and attempt to 
prevent/reduce the adverse event from taking place again. We will discuss the risks and 
benefits of continued recruitment into the study with our co-investigators and determine 
whether or not to continue the study. If we believe that modifications can be made that will 
reasonably reduce the risk of a future event from occurring, we will continue recruitment to the 
study. 
 
The investigators plan to evaluate the rates of acute toxicity after 12 patients have been 
enrolled and undergone SBRT and surgical resection.  Long term safety and efficacy will be 
evaluated after all 12 patients have undergone surgical resection and have either been followed 
for at least 6 month or have died.  The primary investigator, Dr. Alan Katz will have access to all 
of the study data.  
 
The Cancer Center Data & Safety Monitoring Committee will monitor the study for safety. Study 

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Investigators will conduct continuous review of data and patient safety.  The Investigator will 
submit quarterly progress reports of these data to the Clinical Trials Monitoring Committee for 
review [Appendix C].  The review will include for each treatment arm/dose level:  the number 
of patients enrolled, withdrawals, significant toxicities as described in the protocol, serious 
adverse events both expected and unexpected, dose adjustments, and responses 
observed.  The PI maintains a database of all adverse events with toxicity grade and information 
regarding treatment required, complications, or sequelae.  The Investigator will submit a copy 
of the AE spreadsheet along with the Progress Report to the Clinical Trials Monitoring 
Committee for review. Actual review dates will be assigned when the 1st patient is accrued. 
• Any serious adverse event that is serious, related AND unexpected must be reported 
within 10 calendar days to both the Safety Coordinator and the RSRB (see RSRB 
guidelines).  The DSMC Chair will determine whether further action is required, and 
when patient safety is of concern, an interim meeting may be called. 
• Serious adverse events that are related AND expected or unrelated AND unexpected will 
be reported to the Committee for review at the quarterly meeting.  SAE reports are 
expected to include sufficient detail so that the DSMC can determine the severity, 
toxicity grade, expectedness, treatment required, and a follow up report documenting 
resolution or if there are sequelae.  Unless otherwise specified in the protocol, serious 
adverse events that require detailed reports (but not necessarily expedited) are 
expected, related, non-hematologic toxicities of grades 3, 4 or 5. 
 
We plan to publish a descriptive analysis of the results including acute and late toxicity 
including surgical morbidity. We plan to report oncologic outcomes including median overall 
survival, progression free survival, local progression free survival and distant progression free 
survival. Analysis will be using Kaplan-Meier method. Survival time will be measured from the 
date of diagnosis. A local recurrence will be defined as any evidence of tumor recurrence within 
the PTV. Whether local recurrence occurred in conjunction with, before or after distant 
recurrence will be noted. 
 
 

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Appendix A  
Assessment of Acute Toxicity Form to be completed by Surgical Team immediately after 
resection and at the Post Op Visit.  
 
Field 
Result 
To be Recorded in the Operative Note 
 
Operating Time (min) 
 
Estimated Blood Loss (ml) 
 
Surgeon’s Assessment of Fibrosis 
(Expected, Increased, Markedly Increased) 
 
 
 
To be Recorded at the Post Op Visit  
Date of Visit: 
Length of Hospitalization post-surgery 
including any re-admissions (days). Described 
any re-admissions 
 
Anastomotic Leak (yes/no) If so described 
 
Post-Surgery Infection Requiring Antibiotics 
(yes/no) If so described 
 
Wound healing complications that are worse 
than usual? (yes/no) If so described 
 
 
Name of person completing the form: 
 
Date form completed: 
 
 
 
 

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Appendix B 
Required Evaluations 
 
Tests and Observation 
Within 6 weeks 
prior to Study 
enrollment 
On Treatment 
visit during RT 
Post-Op Toxicity 
Eval by surgery 
team  
Clinical Follow Up 
every 3-6 months for 
2 years, then annually 
per NCCN 
Signed informed consent 
X 
 
 
 
History + Physical Examination 
X 
X 
X 
X 
Complete blood count with 
differential, Comprehensive 
metabolic panel, creatinine 
clearance, Phosphorous, INR 
X* 
 
 
 
Pregnancy test** 
X 
 
 
 
CA 19-9 Level 
X 
 
 
X 
CEA Level 
X 
 
 
 
CT or MRI scan of the abdomen 
and pelvis with IV contrast or 
PET/CT.  
 
X 
 
 
X 
CT chest or PET/CT 
 
X 
 
 
 
*  Other laboratory tests such as coagulation studies may be ordered by surgical team as needed 
** Pregnancy test results need to be obtained within 7 days of study entry for those of childbearing potential.  
 
 
 
 
 
 
 
 
 

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Appendix C 
 
James P. Wilmot Cancer Center (JPWCC) 
Data Safety Monitoring Committee (DSMC) 
Study Progress Summary Report 
 
Study name and URCC # 
PI: 
 
 
DSMC Review Date:    
 
Date of 1st accrual:  _______Status:  open___   closed to accrual___     closed  _______ 
 
 
 
 
 
 
 
 
 
 
 
(date) 
DATA SUMMARY: 
 
1. 
ENROLLMENT 
Since last Report:       
Total to Date:       
Total Planned:       
 
Comments:       
 
 
2. 
ADVERSE EVENTS 
 
Serious / Related / 
Unexpected1: 
Other Serious2: 
Non-Serious: 
 
Since Last Report:       
      
      
 
Total:       
      
      
 
Comments:        
      
      
1Serious, possibly/probably/definitely related events that are considered unexpected require prompt reporting to RSRB and 
DSMC. 
2Serious events which are unrelated and/or expected require reporting to the RSRB at least annually and to the DSMC per DSMC 
reporting requirements. 
 
3. 
SUBJECT WITHDRAWALS 
 
Investigator-
initiated: 
Reason(s): 
Subject-
initiated: 
Reason(s): 
Since last report:       
      
      
      
Total:       
      
      
      
 
DMSC RECOMMENDATIONS: 
<indicate DSMC recommendations, if any – i.e., requested actions or state ‘No recommendations at this 
time; study should continue as planned.’> 
 
 

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