SBRT for Close or Positive Margins After Resection of Pancreatic Adenocarcinoma A Prospective Evaluation in Select Patients With Resected Pancreas Cancer
Phase: NA
Conditions: Adenocarcinoma of the Pancreas
Sponsor: David A. Clump, MD, PhD

 
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SBRT for close or positive margins after resection of pancreatic 
adenocarcinoma 
A prospective evaluation in select patients with resected pancreas cancer (Version 4, 
6/29/2011) 
 
 
Study Chair: 
 
Dwight E. Heron, MD, FACRO 
 
 
 
Associate Professor 
 
 
 
Department of Radiation Oncology 
University of Pittsburgh Cancer Institute  
5230 Centre Avenue 
 
 
 
Pittsburgh, PA 15232 
heronD2@upmc.edu 
Ph. (412) 623 6720 
Fax (412) 623-4050 
 
Co-Chair: 
 
Rodney E. Wegner, MD 
 
 
 
Resident Physician 
 
 
 
Department of Radiation Oncology 
 
 
 
University of Pittsburgh Cancer Institute  
 
 
 
5230 Centre Avenue 
 
 
 
Pittsburgh, PA 15232 
 
 
 
wegnerr@upmc.edu  
 
 
 
Ph (412) 623-6722 
 
 
 
Fax (412)623-6725 
 
 
Study Co-Investigators: 
Radiation Oncology 
Susan Rakfal, MD (rakfalsm@upmc.edu)  
Steven A. Burton, MD (burtons@upmc.edu) 
John C. Flickinger, MD(flickingerjc@upmc.edu) 
Cihat Ozhasoglu, PhD (ozhasogluc@upmc.edu) 
Annette Quinn, MSN, OCN (quinnae@upmc.edu) 
 
Surgery 
Kenneth Lee, MD (leek@upmc.edu)  
A. James Moser, MD (moseraj@upmc.edu)  
Herbert Zeh, MD (zehxhx@upmc.edu) 
 
Pathology 
Alyssa Krasinskas, MD (kasam@upmc.edu) 
 
Biostatistics 
Hong Wang, PhD (how8@pitt.edu) 
 
 
 

 
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TABLE OF CONTENTS 
 
PROTOCOL SUMMARY …………………………………………………………………………… 4 
 
1.0 BACKGROUND …………………………………………………………………………...………5 
 
2.0 OBJECTIVES ……………………………………………………………………………………..8 
 
3.0 INVESTIGATIONAL PLAN……………………………………………………………………..9 
 
4.0 SUBJECT SELECTION AND ELIGIBILITY…………………………………………………11 
 
5.0 TREATMENT EVALUATION, ADMINISTRATION, AND MODIFICATION ………….13 
 
6.0 STUDY EVALUATIONS ………………………………………………………………………15 
 
7.0 STATISTICAL CONSIDERATIONS………………………………………………………….18 
 
8.0 DATA SAFETY AND MONITORING………………………………………………………...20 
 
9.0 REFERENCES …………………………………………………………………………………22 
 
 

 
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List of Abbreviations 
 
3D CRT 
 
3 Dimension Conformal External Beam Radiation Therapy 
5-FU  
 
5-fluorouracil 
AE                               Adverse Event 
CR 
 
 
Complete Response 
CT Scan 
 
Computed Tomography Scan 
CTCAE 
 
Common Terminology Criteria for Adverse Events 
CTV  
 
Clinical Treatment Volume 
CXR  
 
Chest X-Ray 
DSMC  
 
Data Safety Monitoring Committee 
EBRT  
 
External Beam Radiation Therapy 
ECOG  
 
Eastern Cooperative Oncology Group 
FACT-G 
Functional Assessment of Cancer Therapy - General 
FDG-PET/CT 
[18F]-flourodeoxyglucose Positron Emissions Tomography / Computed 
Tomography 
Fx 
 
 
Fraction 
Gy 
 
 
Gray 
LPFS  
 
Local Progression-Free Survival 
MD 
 
 
Maximum Dose 
OS 
 
 
Overall Survival 
PD 
 
 
Prescription Dose 
PD 
 
 
Progressive Disease 
PET/CT 
 
Positron Emissions Tomography / Computed Tomography 
PIV 
 
 
Prescription Isodose Volume 
PIV/TV 
 
Prescription Isodose Volume/Tumor Volume 
PTV 
 
 
Planning Target Volume 
QOL  
 
Quality of Life 
RT 
 
 
Radiation Therapy 
RTOG  
 
Radiation Therapy Oncology Group 
SD 
 
 
Stable Disease 
SBRT  
 
Stereotactic Body Radiotherapy 
TTP 
 
 
Time to Progression 
TV 
 
 
Tumor Volume 
WOOCBP 
 
Women of Child-Bearing Potential 
 

 
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PROTOCOL SUMMARY 
 
Title 
Stereotactic Body Radiotherapy (SBRT) for close or positive margins following resection of 
pancreatic adenocarcinoma  
 
Objectives 
The primary objectives of this study are to: 
1. To determine the rate of local progression-free survival (LPFS) achieved in subjects with close (<2.5 
mm) or positive margins after pancreatic cancer resection treated with SBRT 
 
The secondary objectives of this study are to: 
1. To determine the time to progression (TTP) and overall survival (OS)  
2. To evaluate the acute and late toxicities associated with SBRT in this patient population 
3. To evaluate quality of life (QOL) of locally-advanced pancreatic cancer subjects treated adjuvantly 
with SBRT  
 
Subject population 
Subjects with primary adenocarcinoma of the pancreas that has been resected with positive margins or 
close margins (<2.5 mm)   
 
Specific inclusion and exclusion criteria are detailed in Section 4.0 
 
Number of subjects 
50 
 
Study design and methodology 
This is a phase II study. 
 
Treatments administered 
12 Gy x 3 fractions (36 Gy total)  
 
 
Efficacy data collected 
The following evaluations will be conducted to assess the efficacy of SBRT: 
• Local progression-free survival (LPFS) 
• Locoregional and distant control  
• Time-to-progression (TTP) 
 
Safety data collected 
The following evaluations will be conducted to assess the safety of SBRT: 
• Recording of all toxicity data per NCI CTCAE version 4.0 
• Functional Assessment of Cancer Therapy – General (FACT-G) 
 

 
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 1.0 BACKGROUND 
 
1.1 Adenocarcinoma of the pancreas 
Pancreatic cancer is the 4th leading cause of death from cancer of both men and women in the United 
States.  There are expected to be 37,680 new cases and 34,290 deaths in the United States in 2008.  
Despite intensive research efforts into chemotherapy and radiotherapy, surgical resection remains 
the only treatment option associated with long-term survival.  Unfortunately, pancreatic cancer is 
rarely resectable upon diagnosis, with approximately 40% presenting with locally-advanced but 
unresectable disease and an additional 40% presenting with metastatic disease.  Within the United 
States, the 5-year survivals for local, locally-advanced and distant disease are 20%, 8% and 2% 
respectively, resulting in an overall 5-year survival for pancreatic cancer of only 5% (1).  These 
values represent all pancreatic cancers.  Adenocarcinoma of the pancreas, representing more than 
90% of all cases, is believed to be the most aggressive malignancy with an even worse prognosis.  
For patients that are able to undergo surgical resection, the choice of adjuvant therapy remains 
controversial with data available for anything ranging from observation to chemoradiation. 
 
 
1.2 Radiation therapy as adjuvant treatment in pancreatic adenocarcinoma  
For many years chemoradiation was considered the standard of care after patients underwent 
resection of pancreatic carcinoma.  This was mainly based on a small phase III randomized control 
trial by the Gastrointestinal Tumor Study Group (GITSG) (2).  This trial randomized 43 patients to 
surgery with or without adjuvant 5-FU based chemoradiation.  The radiation was delivered using 
outdated techniques (AP/PA and in a split course) to a total dose of 40 Gy.  The patients in the 
experimental arm also received 2 years of adjuvant 5-FU.  The experimental arm had a median OS 
of 20 months compared to 11 months in the control arm.  Regardless, 50% of patients in both arms 
still developed local recurrence.  There are also two large retrospective series from Johns Hopkins 
and the Mayo clinic.  The JHU series contains over 600 patients, with 44% having received 5-FU 
based CRT to a median dose of 50 Gy.  The other 44% did not receive adjuvant therapy.  The CRT 
group had a median OS of 21.2 months compared to 14.4 months in the observation group (3).  The 
Mayo series had 472 patients, all with an R0 resection.  The median RT dose was 50.4 Gy and 
almost all patients received 5-FU.  The median OS again favored CRT with a median OS of 25.2 
months compared to 19.2 months in patients who were observed (4).   
 
A few other studies have examined other adjuvant CRT regimens utilizing non-5-FU-based 
chemotherapy.  RTOG 9704 compared gemcitabine to 5-FU before and after 5-FU based CRT.  The 
study included 451 patients with gross total resection.  The radiation dose was 50.4 Gy delivered 
using modern methods.  There was a trend towards improved 3 year OS (31% vs. 22%) with the use 
of gemcitabine.  Local recurrence remained a significant source of failure, but was lower compared 
to older studies at approximately 25%.  Distant metastasis remained the most significant site of 
failure at greater than 70%, highlighting the importance of systemic therapy (5).  The ACOSOG also 
published a small phase II trial of 89 patients with R0/1 resection of pancreatic head 
adenocarcinoma treated to 50.4 Gy along with chemotherapy.  The chemotherapy was relatively 
intense, consisting of 5-FU, cisplatin, and alpha interferon and 96% of patients had grade 3 toxicity 
or greater.  Despite such intense therapy local recurrence still remained around 50%, but systemic 
therapy only made up 35% of failures (6).   
 
1.3 Chemotherapy alone as adjuvant therapy 
There are a few key studies supporting the adjuvant use of chemotherapy alone after resection of 
pancreatic cancer.  ESPAC-1 was a complex 2x2 factorial designed study with over 500 patients.  
The arms were 5-FU based CRT (split course technique), adjuvant 5-FU/leucovorin alone, both 

 
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CRT followed by chemo, or observation.  For all patients, chemotherapy improved median survival 
from 14 months to 19.7 months.  For patients that received chemotherapy the 5 year OS was 21% 
compared to 8%.  When analyzing the effect of CRT, it appeared to have a detriment, with a 5 year 
OS of 10% compared to 20% when chemoradiation was not given.  Drawbacks of this study include 
its complex design, use of outdated radiation techniques, lack of RT quality assurance, and the 
ability of treating physicians to give “background” therapy (7).  The CONKO-001 study 
randomized 368 patients with a R0/R1 resection to observation of gemcitabine alone for 6 cycles.  
The use of adjuvant gemcitabine improved disease free survival from 7 months to 14 months, but 
not OS (22 months vs. 20 months) (8).  There was also a metaanalysis published in 2005 examining 
outcomes of patients in randomized adjuvant trials.  This study included 875 patients from 6 trials.  
The investigators found that chemotherapy improved median OS from 14 months to 19 months.  
Chemoradiation did not provide a statistically significant benefit (15.2 months to 15.8 months).  Of 
interest, on subgroup analysis it was determined that CRT was more effective for patients with a 
positive margin resection (9).   
 
 
1.3 Stereotactic body radiotherapy (SBRT) 
SBRT is technique that combines highly conformal radiotherapy with real-time imaging to deliver 
high doses of radiation in a small number of fractions.  Modeled after intracranial stereotactic 
radiosurgery, SBRT has now been studied in a variety of extracranial locations including the spine, 
lung, liver, pancreas, and head and neck cancers.  Because of the precise targeting, SBRT has the 
potential to improve upon the local control achieved with conventional EBRT while minimizing the 
dose to normal tissue.  Most prospective randomized trials of conventionally fractionated EBRT for 
the treatment of locally-advanced pancreatic cancer have reported local control rates of 35%-55%  
(2-5).  Koong, et al established the feasibility of using SBRT for locally-advanced pancreatic cancer 
in a phase I dose escalation study which achieved 100% local control with no treatment limiting 
toxicities at 25 Gy in a single fraction (10). A follow-up study combined conventionally fractionated 
5-FU chemoradiotherapy with an SBRT boost resulting in 94% local control but no improvement in 
overall survival and an increase in toxicity compared to SBRT alone (11). A recent study combining 
full dose gemcitabine with single fraction SBRT reported 81% local control and 100% 1-year 
freedom from local progression.  While acute toxicities were minimal, a significant number of 
subjects (47%) experienced Grade 2 or greater late toxicities, primarily duodenal ulcers (12).  It is 
possible that these late toxicities may be reduced by increasing the degree of conformance of the 
radiation dose cloud and increasing the number of fractions, as studies comparing conventionally 
fractionated RT with hypofractionated RT have found an increased incidence of late GI toxicities in 
the hypofractionated group (13). 
 
Another advantage to SBRT is the fractionation schedule.  First, the entire course of treatment is 
often completed over 1 to 7 days versus the 5 to 8 weeks required for conventionally fractionated 
EBRT.  Second, the accelerated fractionation schedule could improve overall survival by allowing 
earlier systemic doses of chemotherapy.  Because pancreatic cancer is often characterized by 
progression to metastatic disease, early delivery of systemic chemotherapy is imperative to address 
potential sites of microscopic disease.  In fact, some studies have evaluated the delivery of systemic 
chemotherapy followed by combined chemoradiotherapy for those subjects without evidence of 
disease progression. This strategy selects those subjects most likely to benefit from the local control 
provided by radiotherapy and in two separate studies has resulted in significant increases in TTP and 
OS for subjects treated with chemoradiotherapy compared to those receiving chemotherapy alone 
(14-15).  
 
1.3.1 Experience with SBRT at the University of Pittsburgh Cancer Institute 

 
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A retrospective review from our institution evaluated the outcome in 71 subjects with intact 
pancreatic cancer treated with SBRT (16).  With a median follow-up of 12.7 months the freedom 
from local progression at 6 months and 1 year was 72% and 49%, respectively.   Median overall 
survival for the entire group was 10.3 months.  Treatment-related toxicity was minimal with only 3 
patients experiencing acute grade 3 toxicity (4%).  There was no recorded late toxicity.  We have 
been treating patients with close or positive margins with SBRT as well.  We recently examined 
outcomes in 24 patients treated post-operatively with SBRT (17).  Sixty-six percent of the patients 
had positive margins and the remainder had close margins of 1-2.5mm.  The median follow-up was 
1 year.  The freedom from local progression at 6 months and 1 year was 95% and 66%.  There was 
no acute or late grade 3-4 toxicity, and two patients (8%) had late grade 1-2 toxicity, again 
demonstrating that when done properly, SBRT has a low potential for toxicity. 
The current study seeks to further investigate the impact of SBRT following resection with a close 
or positive margin.  We hope to improve local control, and through the use of a shortened treatment 
schedule, allow patients to begin systemic therapy earlier.   
 

 
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2.0 OBJECTIVES 
 
 
Primary 
 
2.1 To determine the rate of local progression-free survival (LPFS) with two years of follow-up in subjects 
with margin positive or close margins following resection of pancreatic adenocarcinoma treated with 
SBRT. 
 
Secondary 
 
2.2 To determine the time to progression (TTP) and overall survival (OS) in this patient population 
 
2.3 To evaluate the impact of SBRT on the QOL of subjects in the adjuvant setting 
 
2.5 To evaluate the acute and late toxicities associated with SBRT for pancreas cancer 
 
 

 
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3.0 INVESTIGATIONAL PLAN 
 
3.1 Overall design and plan of the study 
Detailed visit-by-visit study procedures and a study flow chart are provided in Section 6.0.  Prior to 
enrollment, all subjects will be evaluated with physical examination, review of surgical pathology, 
discussion in a multi-disciplinary setting, review of imaging with the operating surgeon, and review 
of post operative imaging to establish the target volume.    
 
3.2 Radiation simulation  
Contrast-enhanced CT based simulation will be obtained prior to any adjuvant treatment (2-4 weeks 
post-op depending on healing).   The target volume will be indentified based on fiducial marker 
placement at time of surgery as well as a detailed discussion and image review with the operating 
surgeon.   This area will be contoured on axial CT images obtained at 1.25 mm slice thickness.  
These volumes will then be reconstructed into a 3-dimensional image set for SBRT planning.  
Subjects will be simulated in the treatment position (supine with arms raised) on the CT scanner 
table the appropriate immobilization.  Optiray® contrast (125 mL Optiray 350; 350 mg/mL 
organically bound iodine; Ioversol; Mallinckrodt Inc., St. Louis, MO, USA) will be administered 
intravenously at a flow rate of 2.5 mL/s. A helical CT scan of the abdomen will be acquired with 
intravenous contrast starting 30 seconds prior to CT acquisition.   
 
A 4D CT data acquisition for the same axial extent will be obtained. The images will then be 
electronically transferred from the CT workstation via DICOM3 to the appropriate treatment 
planning workstation in the department of radiation oncology.  Based on axial CT images, fiducial 
marker placement, review of the pathology report, and a detailed discussion with the operating 
surgeon, contours will be drawn of the clinical target volume (CTV), which is defined as the area at 
risk for microscopic disease.  The planning target volume (PTV) will be equivalent to the CTV 
unless motion is detected on the 4D motion study.  If there is motion, the amount of motion in the 
superior-inferior, lateral, and anterior-posterior directions will be the margin given.   Surrounding 
normal and critical structures will also be contoured by the treating radiation oncologist including 
the kidneys, liver, small bowel, spinal cord, and stomach if necessary.   
 
3.3 Stereotactic Body Radiotherapy Planning 
An SBRT plan will be created by a medical physicist based on the PTV contoured on the CT scan.  
The plan will be to deliver fractionated SBRT to the isodose line best encompassing the PTV: 
 
12 Gy x 3 fractions (36 Gy total) 
 
In determining the radiation dose and fractionation scheme for this protocol, we used the 
linear-quadratic formalism for radiation cell killing to “equate” schemes that vary the dose/fraction 
and number of fractions. This concept of biologically equivalent dose (BED) states that the total 
effect is given by:  
  
nd x (1 + d/
 ()) 
  
where n is the # of fractions and d is the dose/fraction. The “alpha-beta ratio” characterizes the 
radiation response of a particular tissue; a higher value is indicative of a tissue that responds acutely 
to the effects of radiation. Due to their highly proliferative nature, most tumors fall into this 
category.  
This dose scheme (36 Gy in 3 fractions) is biologically equivalent to the previously studied doses in 
the literature (24 Gy in 1 fraction).  We would favor treating in three fractions, as opposed to one, to 

 
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allow more repair of normal tissue, reoxygenation of tumor cells, and redistribution of tumor cells 
to more radiosensitive parts of the cell cycle.  Using a smaller fraction size, 12 Gy compared to 24 
Gy, will also help reduce late effects of radiation therapy.  SBRT treatment will be given on an 
every other day schedule, excluding weekends.  The prescription dose will be prescribed to the 
isodose line best encompassing the planning target volume (PTV) depending on the volume of 
tumor.  
 
Careful evaluation of each plan will be conducted by the radiosurgical team to ensure that normal 
tissues and critical structures tolerances are maintained. 
 
 
The maximum dose (in Gy) within the treatment volume (MD), prescriptions dose (PD), and the 
ratio of MD/PD (as a measure of heterogeneity within the target volume), prescription isodose 
volume (PIV in mm3), tumor volume (TV in mm3), and the ratio of PIV/TV (as a measure of dose 
conformity of the treatment relative to the target) will be recorded.  This concept is illustrated in 
Figure 2. 
 
3.4 Quality of Life Assessment 
Quality of life assessment using the Functional Assessment of Cancer Therapy – General  
(FACT-G) tool, which is a validated tool, will be administered to all subjects prior to treatment and 
at each follow-up visit (Appendix A).   
 
3.5 Treatment following SBRT 
As described above, all patients will have been seen in a multi-disciplinary pancreatic cancer clinic.  
As such, they will be set up with a medical oncologist.  Following completion of SBRT as described 
in this protocol, the patient’s medical oncologist may, at his/her discretion, administer systemic 
therapy according to the current standard of care or the UPMC pathways.   
 
Figure 2: Example illustrating the concept of PIV/TV 
 
 

 
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4.0 SUBJECT SELECTION AND ELIGIBILITY 
 
4.1 Selection of subjects 
Enrollment is defined as the first day of protocol therapy. 
 
4.1.1 Number of subjects 
50 patients will be enrolled to the study.  The study has been designed to detect a 20% improvement 
in the rate of local progression-free response over that of historical controls. 
 
4.1.2 Inclusion criteria 
Each subject must meet all of the following inclusion criteria to be enrolled in the study: 
• Histologically or cytologically proven adenocarcinoma of the pancreas that has been resected 
with a close (<2.5mm) or positive margin based on surgical and pathological findings. 
• Subjects will be staged according to the 2010 AJCC staging system (Appendix D) with 
pathologic stage T1-4, N0-1 being eligible; and have a primary tumor of the pancreas (i.e., 
pancreatic head, neck, uncinate process, body/tail 
• PTV must be encompassed in a reasonable SBRT “portal” as defined by the treating radiation 
oncologist 
• Karnofsky performance status > 70 (ECOG 0-1) 
• Age > 18 
• Estimated life expectancy > 12 weeks 
• Patient must have adequate renal function as defined by serum creatinine<-2.5 mg/dl obtained 
within 28 days prior to registration 
• Patient must have adequate hepatic function as defined by total bilirubin <2.5 
xIULN(institutional upper limit of normal) and either SGOT or SGPT <3.0 xIULN, obtained 
within 28 days prior to registration.  
• Patient must be able to swallow enteral medications.  Patient must not require a feeding tube.  
Patient must not have intractable nausea or vomiting, GI tract disease resulting in an inability to 
take oral medication, malabsorption syndrome, or uncontrolled inflammatory bowel disease 
(Chron’s, ulcerative colitis).   
• Ability to provide written informed consent 
• Patient must not have uncontrolled intercurrent illness including, but not limited to, ongoing or 
active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, history of myocardial infarction or cerebrovascular accident within 3 months prior 
to registration, uncontrolled diarrhea, or psychiatric illness/social situations that would limit 
compliance with study requirements.  
• Patient must not be pregnant because of the risk of harm to the fetus.  Nursing women may 
participate only if nursing is discontinued, due to the possibility of harm to nursing infants from 
the treatment regimen.  Women/men of reproductive potential must agree to use an effective 
contraception method. 
 
 
4.1.3 Exclusion criteria 
Subjects meeting any of the following exclusion criteria are not to be enrolled in the study: 
• Non-adenocarcinomas, adenosquamous carcinomas, islet cell carcinomas, cystadenomas, 
cystadenocarcinomas, carcinoid tumors, duodenal carcinomas, distal bile duct, and ampullary 
carcinomas are not eligible. 
• Evidence of distant metastasis on upright chest x-ray (CXR), computed tomography (CT) or 
other staging studies 
• Subjects with recurrent disease 

 
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• Prior radiation therapy to the upper abdomen or liver  
• . 
• Subjects in their reproductive age group should use an effective method of birth control.  
Subjects who are breast-feeding, or have a positive pregnancy test will be excluded from the 
study 
• Any co-morbidity or condition of sufficient severity to limit full compliance with the protocol 
per assessment by the investigator 
• Concurrent serious infection 
• Previous or current malignancies of other histologies within the last 5 years, with the exception 
of cervical carcinoma in situ, adequately treated basal cell or squamous cell carcinoma of the 
skin, and treated low-risk prostate cancer. 
 

 
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5.0 TREATMENT EVALUATION, ADMINISTRATION, AND MODIFICATION 
 
SBRT guidelines  
 
5.1 Tissue constraints 
Appropriate beam “nodes” or angles shall be selected to treat the primary site and areas at risk for 
occult disease spread.  Careful target definition of these areas at risk is essential for optimal outcome.  
Beam shaping for treatment delivery shall be via conical or multi-leaf collimation (MLC).  Treatment 
shall be via linear accelerator (LINAC) commissioned and equipped to deliver SBRT. Normal tissues 
and sensitive critical structures (e.g. duodenum, spinal cord, stomach, bowel, kidneys, liver, etc) shall 
be countered and the dose to these organs limited.  See table below. 
 
Normal Tissue Constraints 
Organ 
Maximum Dose in 3 fractions 
Liver (700 cm3) 
15 Gy 
1/3 of total kidney volume (left and right) 
15 Gy 
Spinal Cord 
18 Gy 
Stomach 
30 Gy 
Duodenum/small bowel 
18 Gy 
 
 
As discussed above the CTV will be equivalent to the PTV, unless the motion study reveals motion in 
the target volume.  In that case, margins will be given to account for that motion.  
 
5.2 Dose Specification, Homogeneity Considerations & Plan Evaluation 
The treatment plan used shall be based on the assessment of the dose-volume histogram (DVH) with 
attention to coverage of the planning tumor volume (PTV) and critical normal structures.  
The prescription dose is the isodose cloud that encompasses at least 95% of the PTV.   
No more than 20% of any PTV shall receive doses >110% its prescribed dose 
No more than 2% of any PTV shall receive <93% of its prescribed dose 
No more than 5% of any normal tissue shall receive doses in excess of 110% 
  
of the primary PTV dose. 
 
5.3 On-Treatment assessment and post-treatment toxicity evaluation 
 
All subjects will be seen prior to delivery of each fraction of SBRT with toxicity evaluated by 
physical examination.  Subsequently, subjects will be evaluated for toxicity 10-12 weeks later and 
then every 3 months until at least 2 years.  Toxicities will be scored by the NCI CTC AE version 4.0. 
Also see Section 6.0. 
 
5.4 Stereotactic Body Radiotherapy Risks 
Short-term side effects include but not limited to skin reaction, local hair loss, fatigue, abdominal 
pain, nausea, vomiting, diarrhea, increasing liver function abnormality, GI bleeding or perforation 
which may require surgical intervention.  Long term side effects are less likely to occur but if they 
do occur are more likely to be permanent.  They include local hair loss, liver function abnormality, 
diarrhea, small bowel obstruction which may require surgical intervention, spinal cord injury which 
could result in paralysis, and kidney function abnormality.   
 
5.3.4 Fidiucial placement  

 
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It is currently standard practice at our institution for the operating surgeon to place fiducial markers 
intraoperatively at the areas he feels will be at risk for positive or close margins.  As such, patients 
will not need to undergo a separate procedure for fiducial marker placement.   
 
5.3.5 CT Risks 
The subject will be exposed to radiation associated with the CT scans performed to assess response 
to therapy.  CT scans are routinely performed as standard-of-care for tumor staging and to monitor 
response to therapy, and the radiation dose associated with these diagnostic scans are felt to 
represent minimal risk.    
 
Claustrophobia:  Possible anxiety, claustrophobia, and/or temporary discomfort may occur as a 
result of being placed in the scanning devices.   Subjects will be monitored and removed from the 
scanner if required 
 
 

 
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6.0 STUDY EVALUATIONS 
 
6.1 Pretreatment evaluation 
The following tests/procedures will be performed in order to ascertain subject eligibility within 28 days 
prior to registration unless otherwise specified. 
 
6.1.1 Medical history 
 
6.1.2 Physical examination, including Karnofsky status, ECOG performance status and vital signs. 
 
6.1.3 Signed informed consent 
 
6.1.4 Subject body weight and height taken within 1 week of the study start.   
6.1.5 Histologic and/morphologic confirmation of diagnosis as well as margin status 
6.1.6 CBC including: WBC with complete differential, platelets, RBC, hemoglobin, hematocrit, 
within 30 days prior to study start. 
 
6.1.7 Blood chemistries including BUN, creatinine, total bilirubin, AST, ALT, alkaline phosphatase, 
sodium, potassium, calcium, phosphorus, chloride, magnesium within 30 days of study start. 
 
6.1.8 Urine or blood HCG test for female subjects of child-bearing potential (women who are not at 
least 1 year post-menopause or who have not undergone a surgical sterilization procedure) within 
14 days prior to study start.  Female subjects of child-bearing potential will be instructed to use 
contraception from the time of the screening pregnancy test until study completion. 
 
6.1.9 CT of the abdomen and pelvis 
 
6.2 Evaluation during treatment 
 
The subjects will be carefully followed while on active treatment and post-treatment for 24 months, or 
until death.  Evaluation during treatment will consist of the following activities: 
 
6.2.1 Administration of SBRT 
 
6.2.3 Interim medical history and physical examination at baseline, prior to SBRT treatment, at the 
end of SBRT, and 10-12 weeks after SBRT then every 3 months thereafter for up to 24 months.   
 
6.2.4 Serum chemistry and electrolytes to include BUN, creatinine, sodium, potassium, bicarbonate, 
chloride, calcium, magnesium, glucose, total bilirubin, AST, ALT, alkaline phosphatase 
post-treatment as clinically indicated 
6.2.5 Hematologic studies to include CBC with differential and platelet count prior to SBRT and 
repeated 10-12 weeks later and then at follow-up as clinically indicated. 
 
6.2.6 CT scan will be obtained at 10-12 weeks post-treatment and will be reviewed for evidence of 
response.  Since these subjects will likely have no gross disease on imaging, the main goal of the 
follow-up scans is to monitor for local and distant progression as defined below.   
 

 
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6.3 Treatment schedule 
 
 
Parameter 
Pre-Study 
SBRT 
10-12 weeks 
post-treatment 
Q 3 months until 24 
months 
Fx 
1 
Fx
2 
Fx3 
History 
X 
X 
 
X 
X 
X 
Physical exam 
X 
X 
 
X 
X 
X 
Measurement of 
disease 
X 
 
 
 
X 
X 
Performance Status 
X 
 
 
 
X 
X 
Serum Chemistry 
X* 
 
 
 
X▲ 
X▲ 
Hematologic 
Studies including 
CBC 
X* 
 
 
 
X 
X▲ 
CT Scan 
X 
 
 
 
X 
XΩ 
Serum or Urine 
Pregnancy Test for 
WOCBP 
X 
 
 
 
 
 
Histologic and 
Morphologic 
Confirmation and 
Margin Status 
X 
 
 
 
 
 
QOL assessment 
X 
 
 
 
X 
X 
* Within 30 days of study start 
▲If clinically indicated 
Ω May be modified by oncology team if patient receives system therapy 
 
6.4 Post-treatment evaluation and plan 
 
6.4.1 Evaluation of CT Imaging 
A follow-up CT scan will be obtained at 10-12 weeks post-SBRT and then every 3 months until end 
of study.  If the patient goes on to receive systemic therapy, the follow-up CT schedule can be 
modified at the discretion of the oncology team.   
6.4.2. Definition Local Progression Free Survival 
In this study, LPFS is defined as the time from enrollment to first documentation of progressive 
disease (PD) in the target lesion. Death or development of distant disease is not regarded as an 
event.   For patients that undergo surgical resection, local progression will be defined as disease 
recurrence detected on follow-up imaging (CT or FDG-PET/CT) that is located within the SBRT 
target volume.   
6.4.3 Definition of OS and TTP 
TTP is defined as the time from enrollment to disease progression. Disease progression will be 
defined as PD in the target volume, or development of distant disease.  OS is defined as the length 
of time from enrollment to confirmed death from any cause.  

 
Page 17 of 27 
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6.4.4 QOL evaluation 
QOL evaluation will be carried out according to the treatment schema in section 6.0.  The survey 
will be the FACT-G and will be administered prior to SBRT, after completion of SBRT, and at each 
follow-up.  See appendix A for more details.   
6.4.5 Safety evaluation 
All patients will be monitored for potential treatment-related toxicity throughout treatment as 
detailed in the schema.  Toxicity will be graded according to the CTCAE, which is further detailed 
in section 8.2.1.  Acute toxicity is defined as toxicity occurring within 3 months of completion of 
SBRT.  Late toxicity is defined as toxicity occurring greater than 3 months after treatment. 
 
 
 

 
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7.0 STATISTICAL CONSIDERATIONS  
 
7.1 Study Objectives and Design 
 
The primary objective is to determine the LPFS in subjects with resected pancreatic adenocarcinoma 
with close or positive margins treated with SBRT. Secondary objectives include the evaluation of 
TTP, OS, acute and late toxicities, and QOL. These study endpoints are defined in Section 6.4. 
 
This clinical trial is planned as a prospective single-arm phase II study. The treatment schema is 
shown in Section 6.3a. 
 
7.2 Sample Size and Accrual Rate 
7.2.1 Sample Size 
 
From the Investigators’ treatment experience, the 2-year local progression-free survival rate for the 
standard of care is 40%.  This phase II study aims to improve it to 60% with SBRT. We plan to have 
24 months of accrual, and 24 months of follow-up beyond the last patient enrolled on study. Under 
assumption of exponential survival, a total of 50 patients will provide 94% power to detect a 
statistically significant improvement in survival by one-sided log-rank test at significance level 0.05. 
Assuming that there will be no loss to follow up and no ineligible case, a total of 50 patients will be 
accrued for this trial.  
 
7.2.2 Rate of Accrual 
 
We anticipate that 2 to 4 study-eligible patients will be enrolled per month. Thus, our planned study 
size of 50 patients to be enrolled within 24 months is well within our capacity. 
 
7.3. Statistical Analyses 
 
7.3.1. Analysis Set 
 
The data from all evaluable patients will be used in the analyses of survival, safety, tumor response, 
and health related QOL. Evaluable patients are those meeting all of the protocol inclusion/exclusion 
criteria and receiving at least one fraction of SBRT. 
 
7.3.2. Baseline Characteristics 
 
Baseline descriptive statistics on all evaluable patients will be provided on demographic variables 
(age, sex, race/ethnicity), ECOG performance status, laboratory parameters, the chemotherapy 
regimens that were previously used, the number of treatment cycles and irradiation fractions 
involved, and disease characteristics, including tumor size and stage.   
 
7.3.3 Analysis of Study Endpoints 
 
Survival (LPFS, OS, TTP) will be estimated by the Kaplan-Meier method for all evaluable patients 
and the corresponding median survival times (with 95% confidence interval) reported. The 2-year 
LPFS will also be estimated along with its 95% confidence interval. The effect of variables listed in 
Section 7.3.2 will be explored with Cox regression models. 
 
 

 
Page 19 of 27 
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For the QOL data analysis, each item of the FACT-G will be individually assessed. The mean and 
standard deviation of the observed data will be summarized at each collection time and plotted 
against time, from baseline through the end of patient follow-up. Generalized linear models (such as 
cumulative logit models18) for repeated measures will be used to explore if there are significant 
changes in HRQOL over time. 
 
Using NCI Common Terminology Criteria for Adverse Events (CTCAE v4.0), the number of 
patients experiencing adverse events over their course of treatment will be characterized by type of 
adverse event and grade, by the time of onset in relation to the first day of therapy, and whether the 
event is clinically significant. Attribution of adverse events to treatment (unrelated, unlikely, 
possibly, probably, or definitely) will also be summarized for any serious adverse events (SAEs), 
CTCAE grade 3 or higher. The percentage of patients experiencing SAEs that are considered to be 
treatment-related (probable or definite) will be determined. The percentage of patients experiencing 
the acute and late toxicities associated with SBRT (as defined in Section 6.4) will also be estimated 
along with its 95% confidence interval. 
 
7.4. Early Stopping for Toxicity 
 
Toxicity will be monitored continuously, with protocol amendment being made as needed. For 
safety, we will consider that regimen to be excessively toxic and stop accrual if, at any time, the 
observed rate of grade 3-5 acute or late toxicity as defined above in Section 6.4.5  ≥ 33% and at least 
4 toxicities have been observed.  
 

 
Page 20 of 27 
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8.0 DATA SAFETY AND MONITORING 
 
8.1 Data safety monitoring plan 
All subject data will be collected by the University of Pittsburgh Cancer Institute’s Protocol Office.  
All data will be secured in a password protected file with observance of all applicable HIPAA 
regulation.  A data safety monitoring board will meet monthly to evaluate toxicity for this trial. 
Subjects/adverse events will be discussed at these monthly disease center meetings. Unexpected 
serious adverse events will be reported to the IRB and DSMC, and minutes of the monthly disease 
center meetings will be reviewed at the DSMC meetings. 
 
8.1.1  Subject Removal Criteria 
 
1. Disease progression 
2. Development of a serious medical illness 
3. Evidence of dose-limiting toxicity 
4. Voluntary withdrawal 
5. Protocol violation 
6. Discretion of the principal investigator 
7. Development of grade 4 toxicity related to experimental therapeutic 
 
 
8.2   Safety Reporting 
 
8.2.1   Adverse Event Characteristics  
 
CTCAE term (AE description) and grade:  The descriptions and grading scales found in the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be 
utilized for AE reporting.  All appropriate treatment areas will have access to a copy of the CTCAE 
version 4.0.  A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov). 
 
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product that does not necessarily have a causal relationship with 
this treatment.  An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product. 
 
It may include worsening or increase in severity of signs or symptoms of the illness, increase in 
frequency of signs and symptoms of an intermittent illness, or the appearance of a new 
manifestation/complication. 
 
Exacerbation of a pre-existing illness should be considered when a subject requires new or 
additional concomitant drug or non-drug therapy for the treatment of that illness during the study.  
Lack of or insufficient clinical response, benefit, efficacy, or therapeutic effect should not be 
recorded as an adverse event.  The investigator must make the distinction between exacerbation of 
pre-existing illness and lack of therapeutic efficacy. 
 
In addition, abnormal objective test findings (e.g., electrocardiogram changes, abnormal 

 
Page 21 of 27 
10-123  
laboratory test results) that can result in a change in study drug dosage or in discontinuation of the 
drug, or require intervention or diagnostic evaluation to assess the risk to the subject, should also 
be recorded as adverse events.  Clinically significant changes in physical examination findings 
should also be recorded as adverse events.  For all adverse events, the investigator must pursue and 
obtain information adequate both to determine the outcome of the adverse event and to assess 
whether it meets the criteria for classification as a serious adverse event requiring immediate 
notification to UPCI or its designated representative. 
 
All observed or volunteered adverse events regardless of treatment group or suspected causal 
relationship to study drug will be recorded on the adverse event page(s) of the CRF.  The 
investigator will record all adverse events in the CRF and assess each event as to severity and 
causal relationship to study drug. 
‘Expectedness’: AEs can be ‘Unexpected’ or ‘Expected’ for expedited reporting purposes only.   
 
Attribution of the AE: 
Definite – The AE is clearly related to the study treatment. 
Probable – The AE is likely related to the study treatment. 
Possible – The AE may be related to the study treatment. 
Unlikely – The AE is doubtfully related to the study treatment. 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
For all adverse events, sufficient information should be obtained by the investigator to determine 
the causality, (i.e., study drug or other illness).  The investigator is required to assess causality and 
indicate that assessment on the CRF.  Follow-up of the adverse event, after the date of therapy 
discontinuation, is required if the adverse event or its sequelae persist.  Follow-up is required until 
the event or its sequelae resolve or stabilize at a level acceptable to the investigator.  Adverse 
events that continue, or emerge within 30 days, after the subject’s discontinuation or completion of 
the study will be followed until the events resolve, are considered stable, or can be ascribed to 
causes other than study treatment.  
 
All serious AE shall be reported meeting criteria for reporting can be found on the University of 
Pittsburgh Institutional Review Board’s website at http://www.irb.pitt.edu. In the event of such 
adverse event, the investigator must report the event(s) via phone within 24 hours and a written 
report filed within 24 hours to the Principal Investigator, or the UPCI’s Clinical Research Office. 
 
 
 
 
 
 
 
 
 
 
 

 
Page 22 of 27 
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9.0 REFERENCES 
 
1.  
Jemal A, Siegel E, Ward E, et al.  Cancer statistics, 2008.  CA Cancer J Clin 58:71-69, 2008 
2. 
Kalser M,  Ellenberg S. Pancreatic cancer.  Adjuvant combined radiation and chemotherapy 
following curative resection.  Arch Surg.  120(8): 899-903, 1985.   
3.   
Corsini MM, Miller RC, Haddock MG, et al.  Adjuvant radiotherapy and chemotherapy for 
pancreatic carcinoma: The Mayo Clinic experience.  J Clin Oncol 21: 3511-16, 2008.  
4. 
Herman JM, Swartz MJ, Hsu CC, et al.  Analysis of fluorouracil-based adjuvant chemotherapy and 
radiation after pancreaticoduodenectomy for ductal adenocarcinoma of the pancreas.  J Clin 
Oncol.  26(21): 3503-3510, 2008.   
5.   
Regine WF, Winter KA, Abrams RA, et al.  Fluoruracil vs gemcitabine chemotherapy before and 
after fluorouracil-based chemoradiation.  JAMA 299(9): 1019-26, 2008.   
6.    
Picozzi VJ, Abrams RA, Traverso LW, et al.  ACOSOG Z05031: Initial report of a multi-center 
phase II trial of a novel CRT protocol.  ASCO 2008 GI Cancers Symposium, abstract 125.   
7.    
Neoptolemos JP, Stocken DD, Friess H, et al.  ESPAC-1: A randomized trial of CRT and 
chemotherapy after resection of pancreatic cancer.  N Engl J Med.  350(12): 1200-1210, 2004.   
8.    
Oettle H, Post S, Neuhaus P, et al.  Adjuvant chemotherapy with gemcitabine vs observation in 
patients undergoing curative-intent resection of pancreatic cancer.  JAMA.  297(3): 267-76, 2007.   
9.   
Stocken DD, Buchler WW, Dervenis C, et al.  Meta-analysis of randomised adjuvant therapy trials 
for pancreatic cancer.  Br J Cancer.  92(8): 1372-81, 2005.    
10. 
Koong AC, Le QT, Ho A, et al. Phase I study of stereotactic radiosurgery in patients with 
locally-advanced pancreatic cancer. Int J Radiat Oncol Biol Phys 58(4):1017-21, 2004. 
11. 
Koong AC, Christofferson E, Le QT, et al.  Phase II study to assess the efficacy of conventionally 
fractionated radiotherapy followed by a stereotactic radiosurgery boost in patients with 
locally-advanced pancreatic cancer. Int J Radiat Oncol Biol Phys  63:320-323, 2005 
12. 
Schellenberg D, Goodman KA, Lee F, et al.  Gemcitabine chemotherapy and single-fraction 
stereotactic body radiotherapy for locally-advanced pancreatic cancer.  Int J Radiat Oncol Biol 
Phys  2008 [epub ahead of print] 
13. 
Symon Z, Rabin T, Levin D, et al.  Tolerability of standard fractionation vs. hypofractionation in 
chemoradiotherapy of pancreatic cancer.  Int J Radiat Oncol Biol Phys 66:S284, 2006. 
14. 
Huguet F, Andre T, Hammel P, et al.  Impact of chemoradiotherapy after diasease control with 
chemotherapy in locally-advanced pancreatic adenocarcinoma in GERCOR phase II and phase III 
studies.  J Clin Oncol  25:326, 2007 
15. 
Krishnan S, Rana V, Janjan NA, et al.  Induction chemotherapy selects patients with 
locally-advanced, unresectable pancreatic cancer for optimal benefit from consolidatitive 
chemoradiation therapy.  Cancer  110:47, 2007 
16. 
Rwigema JC, Parikh SD, Heron DE, et al.  SBRT in the treatment of advanced adenocarcinoma of 
the pancreas.  Am J Clin Oncol.  2010 Mar 19. [Epub ahead of print].   
17. 
Rwigema JC, Heron DE, Parikh SD, et al.  Adjuvant SBRT for resected pancreatic 
adenocarcinoma with close or positive margins.  J Gastrointest Cancer.  2010 [Epub ahead of 
print]. 
18.     Agresti, Alan. Categorical data analysis. John Wiley & Sons (New York; Chichester). ISBN: 
0-471-36093-7 
 

 
Page 23 of 27 
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APPENDIX A: Functional Assessment of Cancer Therapy - General (FACT-G) 
 
Below is a list of statements that other people with your illness have said are important. Please 
circle or mark one number per line to indicate your response as it applies to the past 7 days. 
 
 
 
 
PHYSICAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
GP1 
I have a lack of energy ........................................................
0 
1 
2 
3 
4 
GP2 
I have nausea ......................................................................
0 
1 
2 
3 
4 
GP3 
Because of my physical condition, I have trouble meeting 
the needs of my family .......................................................
 
0 
 
1 
 
2 
 
3 
 
4 
GP4 
I have pain ..........................................................................
0 
1 
2 
3 
4 
GP5 
I am bothered by side effects of treatment .........................
0 
1 
2 
3 
4 
GP6 
I feel ill ...............................................................................
0 
1 
2 
3 
4 
GP7 
I am forced to spend time in bed ........................................
0 
1 
2 
3 
4 
 
 
SOCIAL/FAMILY WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
GS1 
I feel close to my friends ....................................................
0 
1 
2 
3 
4 
GS2 
I get emotional support from my family ............................
0 
1 
2 
3 
4 
GS3 
I get support from my friends .............................................
0 
1 
2 
3 
4 
GS4 
My family has accepted my illness ....................................
0 
1 
2 
3 
4 
GS5 
I am satisfied with family communication about my 
illness ..................................................................................
 
0 
 
1 
 
2 
 
3 
 
4 
GS6 
I feel close to my partner (or the person who is my main 
support) ...............................................................................
 
0 
 
1 
 
2 
 
3 
 
4 
Q1 
Regardless of your current level of sexual activity, please 
answer the following question. If you prefer not to answer it, 
please mark this box           and go to the next section. 
 
 
 
 
 
GS7 
I am satisfied with my sex life .............................................
0 
1 
2 
3 
4 

 
Page 24 of 27 
10-123  
 
 
Please circle or mark one number per line to indicate your response as it applies to the past 
7 days. 
 
 
 
EMOTIONAL WELL-BEING 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
GE1 
I feel sad ..............................................................................
0 
1 
2 
3 
4 
GE2 
I am satisfied with how I am coping with my illness ..........
0 
1 
2 
3 
4 
GE3 
I am losing hope in the fight against my illness ..................
0 
1 
2 
3 
4 
GE4 
I feel nervous .......................................................................
0 
1 
2 
3 
4 
GE5 
I worry about dying .............................................................
0 
1 
2 
3 
4 
GE6 
I worry that my condition will get worse ............................
0 
1 
2 
3 
4 
 
 
 
 
FUNCTIONAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
 
GF1 
I am able to work (include work at home) ..........................
0 
1 
2 
3 
4 
GF2 
My work (include work at home) is fulfilling .....................
0 
1 
2 
3 
4 
GF3 
I am able to enjoy life ..........................................................
0 
1 
2 
3 
4 
GF4 
I have accepted my illness ...................................................
0 
1 
2 
3 
4 
GF5 
I am sleeping well ................................................................
0 
1 
2 
3 
4 
GF6 
I am enjoying the things I usually do for fun ......................
0 
1 
2 
3 
4 
GF7 
I am content with the quality of my life right now ..............
0 
1 
2 
3 
4 
 
 
 
 
 
 
 
 
 

 
Page 25 of 27 
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APPENDIX B: Karnofsky Performance Scale 
 
 
100  
Normal; no complaints; no evidence of disease 
 
90  
Able to carry on normal activity; minor signs or symptoms of disease 
 
80 
 Normal activity with effort; some sign or symptoms of disease 
 
70 
 Cares for self; unable to carry on normal activity or do active work 
 
60 
 Requires occasional assistance, but is able to care for most personal needs 
 
50 
 Requires considerable assistance and frequent medical care 
 
40 
 Disabled; requires special care and assistance 
 
30  
Severely disabled; hospitalization is indicated, although death not imminent 
 
20 
 Very sick; hospitalization necessary; active support treatment is necessary 
 
10  
Moribund; fatal processes progressing rapidly 
 
0 
 Dead 

 
Page 26 of 27 
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APPENDIX C:  ECOG Performance Status 
 
 
Grade 
ECOG 
0  
Fully active, able to carry on all pre-disease performance without restriction 
1  
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2  
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3  
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours 
4  
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair 
5  
Dead 
 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And 
Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. 
 
 

 
Page 27 of 27 
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APPENDIX D: Staging for Pancreas 
 
Primary Tumor (T) 
TX  
Primary tumor cannot be assessed 
T0  
No evidence of primary tumor 
Tis  
in situ carcinoma 
T1  
Tumor limited to the pancreas 2 cm or less in greatest dimension 
T2  
Tumor limited to the pancreas more than 2 cm in greatest dimension 
T3  
Tumor extends beyond the pancreas but without involvement of the celiac axis or the superior 
mesenteric artery 
T4  
Tumor involves the celiac axis or the superior mesenteric artery (unresectable primary tumor) 
 
Regional Lymph Nodes (N) 
NX  
Regional lymph nodes cannot be assessed 
N0  
No regional lymph node metastasis 
N1  
Regional lymph node metastasis 
 
Distant Metastasis (M) 
MX  
Presence of distant metastasis cannot be assessed 
M0  
No distant metastasis 
M1  
Distant metastasis 
 
Stage Grouping 
Stage 0  
Tis  
N0  
M0 
Stage Ia  
T1  
N0  
M0 
Stage Ib 
T2  
N0  
M0 
Stage IIa  
T3  
N0  
M0 
Stage IIb 
T1-3    N1 
M0 
Stage III  
T4  
Any N  M0 
Stage IV  
Any T  Any N M1 
 
From American Joint Committee on Cancer.  AJCC Cancer Staging Manual, 6th ed.  New York:  
Springer-Yearlab, 2010:157-164