A Study of Stereotactic Body Radiation Therapy in Patients With Unresected Carcinoma of the Pancreas or Ampulla
Phase: PHASE1
Conditions: Pancreatic Cancer
Sponsor: University of Chicago

Stereotactic Body Radiation Therapy for Unresected Cancer of the Pancreas or Ampulla  
 
IRB Protocol 16866B             
 
 
 
 
 
       Version 09 02 2014 
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A  STUDY OF STEREOTACTIC BODY RADIATION THERAPY 
IN PATIENTS WITH UNRESECTED CARCINOMA 
OF THE PANCREAS OR AMPULLA 
 
 
Coordinating Center: 
University of Chicago Medical Center 
 
 
Principal Investigator: 
Stanley Liauw, M.D. 
Department of Radiation and Cellular Oncology 
5758 S Maryland Avenue MC 9006 
Chicago, IL 60637 
Phone: (773) 702-6870 
Fax: (773) 834-7340 
sliauw@radonc.uchicago.edu 
 
 
Co-Investigators: 
Department of Radiation and Cellular Oncology 
Bruce Minsky, M.D. 
Tianming Wu, Ph.D. 
Kamil Yenice, Ph.D. 
 
Department of Medicine, Section of Hematology/Oncology 
Daniel Catenacci, M.D. 
Hedy Kindler, M.D. 
Mark Kozloff, M.D. 
Blase Polite, M.D. 
 
Department of Surgery 
Mitch Posner, M.D. 
Kevin Roggin, M.D. 
 
 
 
 

Stereotactic Body Radiation Therapy for Unresected Cancer of the Pancreas or Ampulla  
 
IRB Protocol 16866B             
 
 
 
 
 
       Version 09 02 2014 
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SCHEMA 
 
 
 
Patient Population: (see section 3.0 for complete eligibility) 
• Biopsy-proven unresected cancer of the pancreas or ampulla 
• No prior complete surgical resection 
• ECOG performance status ≤2  
• No prior history of radiation therapy to the abdominal area 
• Primary tumor size ≤7.5 cm in largest diameter 
• No duodenal invasion 
• Patients with metastatic disease may be included if local symptoms are present 
 
Required Sample Size: upto 24 patients, with 1-2 patients accrued per month 
 
Study Center: University of Chicago Medical Center, Pritzker School of Medicine 
 
Concept and Rationale: Cancers involving the upper gastrointestinal tract often present at 
advanced stages, and as such, are associated with an overall survival that may be less than one 
year after diagnosis. Because these cancers may progress both locally and distantly, a standard of 
care for unresected, non-metastatic disease is to administer both Radiation Therapy (RT) and 
systemic chemotherapy. Typically, radiation therapy is given concurrently with radiosensitizing 
chemotherapy using conventional fraction sizes (1.8-2 Gy/fraction), requiring 5-6 weeks of 
treatment.  
 
In recent years, the ability to more precisely target and treat disease with RT has sparked interest 
in delivering larger fraction sizes (e.g., > 8 Gy/fraction), thereby reducing treatment time, and 
perhaps improving biologic effect. For other sites such as the lung and liver, this form of therapy 
(known as Stereotactic Body Radiation Therapy) has achieved high rates of local control, with 
no appreciable increase in toxicity of treatment in the observed time of follow-up.  
 
From a practical standpoint, if there existed an effective and safe means to achieve local control 
and contract the length of RT into two weeks, patients would be more likely to tolerate 
aggressive systemic therapy. Meanwhile, with a positive initial experience in the unresectable 
setting, SBRT could be studied in the preoperative setting (e.g., for resectable or borderline 
resectable patients). 
 
Primary Objective: To assess the maximum tolerated dose of delivering three fractions of SBRT 
and identify the appropriate dose for unresected carcinoma of the pancreas or ampulla  
Unresected  
carcinoma of 
the pancreas or 
ampulla 
 
 
RT planning 
 
 
 
SBRT over 8-10 days 
Level I: 10 Gy x 3 
Level II: 12.5 Gy x 3 
Level III: 15 Gy x 3 
 
1st RT dose ≥2 weeks 
after last chemotherapy 
Chemotherapy 
4 weeks after 
first fraction of 
RT  
Placement of fiducial 
markers and MRI, CT 
simulation 

Stereotactic Body Radiation Therapy for Unresected Cancer of the Pancreas or Ampulla  
 
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Secondary Objectives: To define toxicities, the post-treatment pain score, and quality of life, the 
rate of post-treatment resectability, and local control (as measured by CT or MRI and defined as 
lack of progressive disease by RECIST criteria).  
 
Study Design:  
 
• Dose escalation schema: Patients will be enrolled in a 3+3 dose escalation schema 
including doses of 10 Gy, 12.5 Gy, and 15 Gy. Once the MTD is reached, patients will be 
treated in an expanded cohort.  
• Radiation therapy: The primary tumor will be treated with stereotactic body radiation 
therapy in three fractions over 10 days. Fiducial markers will be placed prior to therapy, 
when possible, to assist with localization. Respiratory gating will be used to help address 
movement of the target due to respiratory motion. Constraints to surrounding critical 
structures (duodenum, liver, kidneys, and spinal cord) will be observed.  
• Chemotherapy: No concurrent chemotherapy will be administered with the RT. Patients 
will be allowed to receive chemotherapy prior to RT, although this is not required. Post-
RT chemotherapy will be at the discretion of the treating physicians.  
• Surgery: ability to achieve resection will be documented by completeness of resection 
(complete microscopic, incomplete microscopic, or gross residual). Re-evaluation for 
resectability will be at the discretion of the treating physician and not be a requirement of 
the study. 
 
Statistical Methods: A 3+3 dose escalation design will be used. The maximum tolerated dose 
will be exceeded if 2 or more patients out of 6 (or a third or more) experience a dose limiting 
toxicity (DLT) at that dose. The dose immediately below will be recommended for further study. 
DLTs are defined as any acute toxicity of Grade 4 nausea, Grade 4 skin toxicity, Grade 3+ liver 
toxicity (metabolic or ascites), or Grade 3+ enteritis. Severe late toxicities of interest (occurring 
beyond the 4 week period of evaluation and up to 12 months after RT) will include any Grade 3+ 
gastrointestinal toxicity (such as small bowel ulcer, stricture, perforation, bleed, liver damage, 
pancreatitis, or cholecystitis). If the rate of any severe late toxicity of interest exceeds 25% (i.e., 
7 or more patients in the expanded cohort of 18 treated at the MTD), the study committee will 
suspend accrual and determine whether further dose modifications are needed; the protocol will 
be amended accordingly.   
 

Stereotactic Body Radiation Therapy for Unresected Cancer of the Pancreas or Ampulla  
 
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TABLE OF CONTENTS 
 
SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   ii 
 
1. 
OBJECTIVES 
1 
1.1. 
Primary Objectives 
1 
1.2. 
Secondary Objectives 
1 
2. 
BACKGROUND 
1 
2.1 
 Unresectable carcinoma of the pancreas  
1 
2.2 
  Rationale 
1 
3. 
PATIENT SELECTION 
3 
3.1 
 Eligibility Criteria 
3 
3.2 
 Exclusion Criteria 
3 
3.3 
 Inclusion of Women and Minorities 
4 
4. 
TREATMENT PLAN 
4 
4.1 
 Radiation Therapy dose escalation 
4.2 
 Measuring Health Related Quality of Life                                                                      4 
4.3 
 Definition of Dose-Limiting Toxicity 
5 
44. 
 General Concomitant Medication and Supportive Care Guidelines 
7 
4.5 
 Duration of Therapy 
7 
4.6  
 Duration of Follow Up 
8 
4.7 
 Criteria for Removal from Study 
8 
5. 
RADIATION THERAPY GUIDELINES 
8 
5.1 
 Treatment related planning procedures 
8 
5.2  
RT planning parameters 
8 
5.3 
 RT Treatment 
10 
6. 
ADVERSE EVENTS 
10 
7. 
STUDY CALENDAR 
133 
8. 
MEASUREMENT OF EFFECT 
144 
8.1 
Antitumor Effect – Solid Tumors 
144 
9. 
 STATISTICAL CONSIDERATIONS 
155 
9.1 
 Study Design/Endpoints 
155 
9.2 
 Sample Size/Accrual Rate 
166 
9.3 
 Analysis of Secondary Endpoints 
166 
10.  CONFIDENTIALITY 
166 
10.1 
      Patient confidentiality issue17 
REFERENCES 
18 
APPENDIX A 
20 
APPENDIX B 
21 
APPENDIX C 
22 
APPENDIX D                                                                                                                                23

Stereotactic Body Radiation Therapy for Unresected Cancer of the Pancreas or Ampulla  
 
 
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1. 
OBJECTIVES 
 
1.1. 
Primary Objectives 
 
The primary objective is to assess the Maximum Tolerated Dose (MTD) of delivering 
three fractions of Stereotactic Body Radiation Therapy (SBRT), and identify the 
appropriate dose for treatment of unresected carcinoma of the ampulla or pancreas.  
 
1.2. 
Secondary Objectives 
 
 
Secondary objectives include defining toxicities, effect on pain score, and quality of 
life, the rate of post-treatment resectability, and local control (as measured by CT or 
MRI and defined as lack of progressive disease by RECIST criteria).  
 
 
 
2. 
BACKGROUND 
 
2.1  
Unresectable Carcinoma of the Pancreas 
 
Cancers involving the upper gastrointestinal tract often present at advanced stages. 
While surgical resection offers some potential for long-term disease control, few 
patients present when disease can be addressed with a successful resection. As such, 
many patients with this disease have an overall survival that is less than one year after 
diagnosis. Because these cancers may progress both locally and distantly, and cause 
significant symptoms, patients are candidates to receive a combination of local 
Radiation Therapy (RT) and systemic chemotherapy. For patients with non-metastatic 
pancreatic cancer, data support the use of 5-Fluorouracil and RT as a means to 
favorably impact overall survival (Moertel, 1981). Typically, RT is given concurrently 
with radiosensitizing chemotherapy using conventional fraction sizes (1.8-2 
Gy/fraction), over 5-6 weeks of treatment. Fewer data are available to support the use 
of RT for carcinoma of ampulla. However, it is known that these cancers are 
aggressive and have high rates of recurrence after surgical resection (Carter, 2008). In 
the unresectable setting, whether patients present with locally advanced or metastatic 
disease, lack of treatment may result in local symptoms including pain, 
gastrointestinal or biliary obstruction, bleeding, or perforation. For patients who are 
candidates to receive therapy, RT may be a useful adjunct to systemic chemotherapy 
to palliate patients of these symptoms (Boz, 2001). 
 
2.2   
Rationale   
 
In recent years, the ability to more precisely target and treat disease with RT has 
sparked interest in delivering larger fraction sizes (e.g., > 8 Gy/fraction), thereby 
reducing treatment time, and perhaps improving biologic effect. For other sites such as 
the lung and liver, this form of therapy (known as Stereotactic Body Radiation 
Therapy) has achieved high rates of local control, with no appreciable increase in 
toxicity of treatment with limited follow-up (Timmerman, 2007; Kavanagh, 2006). In 

Stereotactic Body Radiation Therapy for Unresected Cancer of the Pancreas or Ampulla  
 
 
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the setting of unresectable pancreatic cancer, there are two published experiences 
using SBRT techniques (Hoyer, 2005; Koong, 2004). The experience from Stanford 
(Koong, 2004) with 15-25 Gy in one fraction has been favorable, with only 5 of 15 
patients treated on this dose escalation protocol demonstrating grade 1-2 toxicity 
(nausea, diarrhea, abdominal pain) with no patient demonstrating grade 3+ toxicity on 
initial report. Meanwhile, all 6 patients treated to the highest dose of 25 Gy had local 
control of the disease. Longer term follow-up of 77 patients treated with 25 Gy 
demonstrated a local control rate of 84% at 1 year, with moderate late toxicity (Grade 
2+) in 10 (13%) of patients (Chang, 2008). The nature of the toxicity was related to 
gastrointestinal function, including ulceration of the small bowel (n=3) or stomach 
(n=3), stricture of the duodenum (n=1) or biliary system (n=2), or perforation of the 
small bowel (n=1). Toxicity was increased for men who received prior external beam 
radiation therapy in addition to the single stereotactic dose of 25 Gy. The risk of 
severe toxicity (G3+) was approximately 10% in patients treated with SBRT alone.  In 
contrast, a phase II study from Denmark (Hoyer, 2005) treated 22 patients with 45 Gy 
(15 Gy x 3 fractions) for unresectable pancreatic cancer and found lower rates of 
control. Local control was only 57% at 6 months. This lower rate of local control is 
consistent with the approximately 50% rates observed in other studies giving standard 
fractionation RT, including post-operative (Smeenk, 2007) and definitive settings 
(Moertel, 1981). Meanwhile, grade 2+ toxicity (defined in this study as performance 
status, nausea, diarrhea, or pain at day 14 assessment) was 79%. Of note, pretreatment 
evaluation revealed that patients had symptoms consistent with grade 2+ toxicity in 
approximately 63%, so the actual increase in toxicity over baseline is difficult to 
quantify given the grading schema used and the lack of follow-up past day 14.  These 
discrepant reports of SBRT indicate a need for further trials to help identify the role of 
SBRT for unresectable pancreatic cancer. With the poor ability to achieve local control, 
it is of interest to note whether SBRT could be more effective than standard 
fractionation. Furthermore, as neither of these studies followed detailed gastrointestinal 
toxicity according to prospectively defined dosimetric planning criteria, it is important to 
better characterize the nature and frequency of such treatment. 
 
From a practical standpoint, if there existed an effective and safe means to achieve 
local control and contract the length of RT into two weeks, patients would be more 
likely to tolerate aggressive systemic therapy. A recent phase III study randomizing 
patients with unresectable pancreatic cancer to gemcitabine chemotherapy with or 
without sandwich 5-FU, cisplatin, and concurrent RT found that the aggressive local 
therapy was associated with significant toxicity, which limited administration of 
systemic therapy and negatively impacted survival (Mornex, 2007). Meanwhile, 
“standard” administration of 5-FU with continuous course RT is also associated with a 
risk of severe toxicity. The RTOG 97-04 demonstrated a 59% risk of any Grade 3 
non-hematologic toxicity in patients who received 5-FU/RT and adjuvant systemic 
therapy after pancreaticoduodenectomy (Regine, 2008). The hypothesis of any SBRT 
approach for locally advanced, non-metastatic pancreatic cancer is that this 
combination of dose-intense local therapy over 2 weeks will be relatively well 
tolerated, and not preclude further aggressive systemic therapy. It is possible that the 
proposed treatment will result in less quality of life decline than standard fractionation. 
Meanwhile, with a positive initial experience in the unresectable setting, SBRT could 
be studied in the preoperative setting (e.g., for borderline resectable patients). RT with 

Stereotactic Body Radiation Therapy for Unresected Cancer of the Pancreas or Ampulla  
 
 
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standard fractionation has been studied in the preoperative setting, with disappointing 
results. It is estimated that, after careful selection of borderline resectable patients and 
treatment with preoperative radiation therapy and chemotherapy, approximately 40% 
of these patients are able to then undergo resection (Katz, 2008). Resectability is the 
most important prognostic factor for success after treatment, and as such, is an 
important potential endpoint to evaluate.   
 
 
3. 
PATIENT SELECTION 
 
3.1  
Eligibility Criteria  
 
3.1.1 
Patients must have histologically confirmed, unresected cancer of the pancreas 
or ampulla. The cancer may include any invasive histology (e.g. 
adenocarcinoma, neuroendocrine carcinoma). Patients with lymph node 
involvement or distant metastasis may be included if it is felt that local control 
of the primary site of disease would help reduce, or prevent the development 
of, local symptoms.  
 
3.1.2 
Patients must have measurable radiographic disease. Patients with previous 
complete resection are only eligible if there is measurable radiographic disease 
which is clearly felt to represent locally recurrent disease. 
 
3.1.3 
Patients may receive any number of cycles of chemotherapy prior to treatment 
with SBRT, but not within 2 weeks of the first fraction of RT. Patients are not 
required to receive any chemotherapy to be eligible for study enrollment.  
 
3.1.4 
Age >18 years.  The effects of this therapy are unstudied in the pediatric 
population.  
 
3.1.5 
ECOG performance status <2 (Karnofsky >60%, see Appendix A). 
 
3.1.6 
Life expectancy of greater than 3 months. 
 
3.1.7 
Patients must have normal organ and marrow function as defined below: 
 
-   Absolute neutrophil count (ANC)  
≥ 1,800 cells/mm3 
- Platelets  
 
≥ 100,000 cells/mm3 
- Hemoglobin  
 
≥ 8.0 g/dl  
- Creatinine 
≤2 X  institutional upper limit of normal 
- total bilirubin 
≤2.5 X institutional upper limit of normal 
- AST(SGOT) or ALT(SGPT) <2.5 X institutional upper limit of normal 
 
3.1.8 Ability to understand and the willingness to sign a written informed consent 
document. 
 
3.2  
Exclusion Criteria 
 

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3.2.1 
3.2.2 Concurrent investigational therapy delivered over the period of 
treatment or observation (28 days post-RT) for dose limiting toxicity. 
 
3.2.3 Prior radiation therapy to the abdominal area which would overlap with the 
proposed area of treatment. 
 
3.2.4 Pregnancy. Radiation therapy is known to have adverse effects on the fetus.  
 
3.2.5 Primary disease >7.5 cm in largest diameter as measured by CT or MRI. 
 
3.2.6 Gross extension of tumor into the lumen of the duodenum. 
 
3.2.7 Uncontrolled intercurrent illness including, but not limited to ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, 
cardiac arrhythmia, or psychiatric illness/social situations that would limit 
compliance with study requirements. 
 
3.2.8 Use of bevacizumab or vascular endothelial growth factor inhibitor 
chemotherapy within 3 months before RT or 6 months after RT. 
3.3  
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this 
trial.   
 
 
4. 
TREATMENT PLAN 
 
4.1  
Radiation Therapy Dose Escalation 
 
Treatment will be administered on an outpatient basis. Details regarding planning and 
administration of RT are described in Section 6. Reported adverse events and potential 
risks are described in Section 7.  
 
 
 
Dose-Escalation Schedule 
 
Dose Level 
 
 
 
Level -1 
 
7.5 Gy x 3 
 
Level 1 
 
10 Gy x 3 
 
Level 2 
 
12.5 Gy x 3 
 
Level 3 
 
15 Gy x 3 
 
 
 

Stereotactic Body Radiation Therapy for Unresected Cancer of the Pancreas or Ampulla  
 
 
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4.2             Measuring Health Related Quality of Life  
             
             Patient reported outcome measures will include the Functional Assessment of Cancer 
Therapy–Hepatobiliary (FACT-Hep) questionnaire, a 45-item self-reported instrument designed 
to measure health-related quality of life (HRQOL) in patients with hepatobiliary cancers 
including pancreatic cancers. The FACT-Hep consists of the 27-item FACT-G, which assesses 
generic HRQOL concerns including physical, emotional, social and functional well being, and the 
newly validated 18-item Hepatobiliary Subscale (HS), which assesses disease-specific issues (see 
Appendix D). The questionnaire will be administered to all patients on trial at baseline, post 
treatment at follow up exams at 1,2,4,6,9 and 12 months from the start of SBRT. The 
questionnaire will be completed in writing by the patients, and after 12 months from the start of 
radiation therapy it will not be required.  
4.3  
Definition of Dose-Limiting Toxicity 
 
The evaluation period of acute toxicity will be defined by the period of 28 days 
following the first fraction of RT. Dose Limiting Toxicity (DLT) will be defined 
according to Common Toxicity Criteria version 3.0 (See Appendix B) and includes 
the following acute toxicities: 
• Grade 4 nausea (life-threatening consequences) 
• Grade 4 skin toxicity (necrosis or ulceration of full thickness dermis, 
spontaneous bleeding from involved site) 
• Grade 3+ liver toxicity including symptomatic ascites requiring invasive 
procedure, or total bilirubin >3 x ULN, or AST >5 x ULN, or ALT >5 x ULN 
that persists until day 28, and is attributable to radiation therapy. 
• Grade 3+ enteritis (abdominal pain, fever, change in bowel habits with ileus, 
peritoneal signs) that is attributable to radiation therapy. 
 
Patients must have a minimum of 3 weeks of follow-up after RT start for patient data 
to contribute enough follow-up for consideration of dose-limiting toxicity. However, 
any DLT that occurs with shorter follow-up will count towards the dose escalation 
rules. In addition, any grade 5 toxicity (i.e., death) considered possibly, probably or 
likely related to RT will be considered a DLT. 
 
Any late toxicity that occurs beyond the 4 week period of evaluation will be closely 
followed and documented as a toxicity of interest. Included are the following severe 
late toxicities of RT: 
• Grade 3+ gastrointestinal ulcer, fistula, stricture, or perforation (symptomatic 
and severely altered GI function, IV fluids or TPN ≥24 hrs, intervention 
indicated) 
• Grade 3+ gastrointestinal mucositis (confluent ulcerations or 
pseudomembranes, bleeding with minor trauma) 
• Grade 3+ gastrointestinal bleed (transfusion, interventional radiology or 
endoscopic or operative intervention) 
• Grade 3+ gastrointestinal necrosis (inability to aliment adequately by GI tract, 
interventional radiology, intervention indicated) 
• Grade 3+ liver toxicity including symptomatic ascites requiring invasive 
procedure, or total bilirubin >3 x ULN, or AST >5 x ULN, or ALT >5 x ULN, 
or asterixis, that is attributable to radiation therapy.   

Stereotactic Body Radiation Therapy for Unresected Cancer of the Pancreas or Ampulla  
 
 
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• Grade 3+ enteritis (abdominal pain, fever, change in bowel habits with ileus, 
peritoneal signs) that is attributable to radiation therapy. 
• Grade 3+ pancreatitis (interventional radiology or operative intervention 
indicated) 
• Grade 3+ cholecystitis (interventional radiology or operative intervention 
indicated) 
 
These severe, late toxicities will be evaluated between 1 and 12 months of therapy. 
There is no minimum follow-up time after RT start required for patient data to 
contribute enough follow-up for toxicities of interest.  
 
Enrollment of 12 additional toxicity-evaluable patients at the MTD will provide a 
cohort of 18 patients at the putative MTD.  If six or fewer of the 18 patients 
experience a toxicity of interest during the evaluation period, the combination will be 
considered tolerable.  If 7 or more patients experience a toxicity of interest, the study 
committee will suspend accrual and determine whether further dose modifications are 
needed; the protocol will be amended accordingly.  If the true probability of DLT at 
the MTD is 50%, the combination will be identified as too toxic with probability 0.88. 
If the true probability of DLT at the MTD is 25%, the combination will be identified 
as having an acceptable toxicity profile with probability 0.86. 
 
Management associated with the above adverse events is outlined in Section 7.   
 
Dose escalation will proceed within each cohort according to the following scheme.   
Dose-limiting toxicity (DLT) is defined above.   
 
 
 
Number of Patients with DLT 
at a Given Dose Level 
 
Escalation Decision Rule 
 
0 out of 3 
 
Enter 3 patients at the next dose level 
 
> 2 
 
Dose escalation will be stopped.  This dose level will be 
declared the maximally administered dose (highest dose 
administered).  Three (3) additional patients will be entered at 
the next lowest dose level if only 3 patients were treated 
previously at that dose. 
 
1 out of 3 
 
Enter at least 3 more patients at this dose level. 
• 
If 0 of these 3 patients experience DLT, proceed to the next 
dose level. 
• 
If 1 or more of this group suffer DLT, then dose escalation 
is stopped, and this dose is declared the maximally 
administered dose.  Three (3) additional patients will be 
entered at the next lowest dose level if only 3 patients were 
treated previously at that dose. 
 
<1 out of 6 at highest dose level 
below the maximally 
administered dose 
 
This is generally the recommended phase 2 dose.  At least 6 
patients must be entered at the recommended phase 2 dose. 
 

Stereotactic Body Radiation Therapy for Unresected Cancer of the Pancreas or Ampulla  
 
 
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4.4  
General Concomitant Medication and Supportive Care Guidelines 
 
There is no restriction towards the use of any non-chemotherapeutic agent during 
administration of RT as specified for the symptom management.  
 
A proton pump inhibitor is recommended one week prior and for three months 
following RT. Ondansetron 8 mg will be administered prior to each radiation 
treatment. It is optional for patients to receive corticosteroid premedication (e.g. 
dexamethasone 4 mg p.o. in a single dose) 15-60 minutes prior to each of three 
treatments. Analgesic premedication to avoid general discomfort during long radiation 
planning or treatment durations is also recommended when appropriate. Antiemetics 
will be ordered at the discretion of the attending physician. Mucositis/esophagitis may 
be treated with sulcrafate or a GI cocktail (e.g. Tylenol #3 suspension, benadryl elixir, 
Maalox, viscous lidocaine). Intravenous hydration is recommended in patients with 
inadequate oral intake. Treatment-related diarrhea may be managed with loperamide.  
The recommended dose of loperamide is 4 mg initially (two capsules) then 2 mg after 
each loose stool, not to exceed 16 mg daily.  
 
Administration of chemotherapy concurrent with RT is not allowed. 
Chemotherapeutic agents given before or after RT are at the discretion of the treating 
physician, with exclusion of bevacizumab or vascular endothelial growth factor 
inhibitor, given concern for RT-related wound healing issues particularly regarding 
small bowel. 
 
 
 
4.5 Duration of Therapy 
 
Duration of SBRT is to occur within a 10 day time period. Completion of the three 
fractions of RT will be delayed or foregone if: 
• Intercurrent illness that prevents further administration of treatment, 
• Further treatment is felt to be likely to result in severe and permanent 
impairment, or death (life-threatening toxicity),  
• The patient decides to withdraw from the study, or 
• General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
 
The use of chemotherapy after RT will be at the discretion of the treating physician.  
 
4.6  
Duration of Follow Up 
 
Patients will be followed on protocol for 12 months after initiation of RT or until 
death, whichever occurs first.  Patients removed from protocol therapy for 
unacceptable adverse events will be followed until resolution or stabilization of the 
adverse event. 
 
4.7 Criteria for Removal from Study 
 

Stereotactic Body Radiation Therapy for Unresected Cancer of the Pancreas or Ampulla  
 
 
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Patients will be removed from study (but followed for potential of toxicity) when any 
of the criteria listed in Section 4.4 applies. The reason for study removal and the date 
the patient was removed must be documented in the Case Report Form. 
 
 
 
5. 
Radiation Therapy Guidelines  
 
5.1  
Treatment Related Planning Procedures 
 5.1.1.   All patients will be evaluated prior to simulation for placement of fiducial markers 
(by endoscopic approach or interventional radiology) in or around the primary 
tumor, for purposes of stereotactic localization prior to SBRT. Marker placement 
is preferred but not required.   
 5.1.2.  When done, the ideal timing of MRI will be ≥2 days after placement of fiducial 
markers. 
 5.1.3.  All patients will undergo CT simulation ≥2 days after placement of markers, and 
prior to the first treatment using appropriate immobilization. Patients should have 
no food 2 hours prior to undergoing simulation. However, medications may be 
taken with liquid.  
 5.1.4.  Patients will be positioned in a stable position capable of allowing accurate 
reproducibility of the target position from treatment to treatment.  
 5.1.5.  Simulation with respiratory gating and acquisition of a 4D CT scan for retrospective 
respiration phase-based imaged sorting is highly preferred but not required.  
 
5.2  
RT Planning Parameters 
 
5.2.1.   The definition of volumes will be in accordance with the ICRU Report 62: 
Prescribing, Recording and Reporting Photon Beam Therapy. (ICRU, 1999) 
 
5.2.1.1. A gross tumor volume (GTV) will be entered for each lesion, based on available 
imaging data.  
 
5.2.1.2. In the absence of respiratory gating, an internal target volume (ITV) will be 
defined as the volume that accounts for intrafraction target motion. 
 
5.2.1.3. A clinical target volume (CTV) will be defined as the GTV or ITV (when 
available) plus a margin for microscopic extension.  
 
5.2.1.4. A planning target volume (PTV) will be determined which will correspond to 
CTV plus appropriate margin for tumor motion and set-up uncertainty.  
 
5.2.2.   3D coplanar or non-coplanar beam arrangements will be custom designed for each 
case to deliver highly conformal prescription dose distributions. The treatment plan 
used for each patient will be based on an analysis of the volumetric dose, including 
dose volume histogram of the PTV and normal structures. 3D “forward” planning or 
“inverse” planning with beamlet intensity modulated treatment planning are 
allowed. 
 
5.2.3. Treatment is to be delivered using a linear accelerator and photon energies ≥ 6 MV. 
 
5.2.4. Corrections will be made to account for tissue heterogeneity. 
 
5.2.5. RT is to be delivered to each site in 3 fractions over a period of up to 10 total days.   
 5.2.6. RT Dose:  A phase I escalation of doses will be performed in order to determine in 
MTD in Gy. Doses of radiation will start at Level 1 and increase as follows in 
order to determine the MTD in Gy: 
 
Level 1:  10 Gy/ fraction x 3 fractions = 30 Gy 

Stereotactic Body Radiation Therapy for Unresected Cancer of the Pancreas or Ampulla  
 
 
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Level 2: 12.5 Gy/fraction x 3 fractions = 37.5 Gy 
 
Level 3: 15 Gy/fraction x 3 fractions = 45 Gy 
 
If DLT is met at Level 1, dose will be de-escalated to Level -1: 7.5 Gy x 3 
fractions = 22. 5 Gy  
 5.2.7. Doses will be prescribed to the PTV. The PTV may be covered by a lower isodose 
line than usually used in conventional radiotherapy planning, typically around 
80% but ranging from 60-100%. Ideally, the prescription dose will cover >90% of 
the GTV (V100 GTV > 90%, and V95PTV > 90%). A lower coverage goal (with 
no minimum requirement of PTV coverage) will be acceptable if necessary to 
meet normal tissue constraints, which will be assigned priority over tumor 
coverage. 
 5.2.7.1. Any dose > 110% must be within the PTV.  
 5.2.8.   Dose/volume constraints:  The following table lists maximum dose limits to a 
point or volume within several critical organs. These are absolute limits, and are 
listed as total over 3 fractions and per fraction. In order to verify each of these 
limits, the organs must be contoured such that appropriate dose volume histograms 
(DVHs) can be generated.  
 
5.2.9. Contouring of normal tissue structures 
• 
Spinal cord. The spinal cord will be contoured based on the bony limits of the 
spinal canal. The spinal cord should be contoured starting at least 10 cm above the 
superior extent of the PTV and continuing on every CT slice to at least 10 below 
the inferior extent of the PTV. 
• 
Esophagus. The esophagus will be contoured using mediastinal windowing on CT 
to correspond to the mucosal, submucosa, and all muscular layers out to the fatty 
adventitia. The esophagus should be contoured starting at least 10 cm above the 
superior extent of the PTV and continuing on every CT slice to at least 10 below 
the inferior extent of the PTV. 
• 
Stomach. The outer wall of the stomach will be contoured to include the cardia of 
the stomach to the pylorus. 
• 
Heart/pericardium. The heart will be contoured along with the pericardial sac. The 
superior aspect (or base) for purposes of contouring will begin at the level of the 
inferior aspect of the aortic arch (aortopulmonary window) and extend inferiorly to 
the apex of the heart. 
Organ 
Volume 
Dose 
Spinal cord 
Any point 
21 Gy (7 Gy per fraction) 
Esophagus 
Any point 
27 Gy (9 Gy per fraction) 
Stomach 
<2 cc 
24 Gy (8 Gy per fraction) 
 
Any point 
30 Gy (10 Gy per fraction) 
Heart/pericardium 
Any point 
30 Gy (10 Gy per fraction) 
Liver 
700 cc 
17 Gy (5.66 Gy per fraction) 
Duodenum 
<2 cc 
24 Gy (8 Gy per fraction) 
 
Any point 
30 Gy (10 Gy per fraction) 
Jejunum/ileum 
<2 cc 
24 Gy (8 Gy per fraction) 
 
Any point 
30 Gy (10 Gy per fraction) 
Total kidney 
200 cc 
15 Gy (5 Gy per fraction) 
Skin 
Any point 
24 Gy (8 Gy per fraction) 

Stereotactic Body Radiation Therapy for Unresected Cancer of the Pancreas or Ampulla  
 
 
10
• 
Liver. The normal liver is defined as that portion of liver not radiographically 
involved by gross tumor (Normal liver volume minus GTV). 
• 
Duodenum. The outer wall of the duodenum will be contoured from the edge of 
the pylorus of the stomach to the start of the jejunum, and include four segments 
of the duodenum. 
• 
Jejunum/ileum. The jejunum and ileum will be contoured to include the outer wall 
of the small bowel distal to the duodenum to the end of the ileum, and also include 
the mesentery and vessels anterior to the aorta.  
• 
Total kidney. Kidneys will be contoured to include the renal capsule and 
parenchyma up to the hilum. 
• 
Skin. The skin will be defined as the outer 0.3 cm of the body surface. As such it 
is a rind of uniform thickness (0.3 cm) which envelopes the entire body in the 
axial planes. The cranial and caudal surface of the superior and inferior limits of 
the planning CT should not be contoured as skin unless skin is actually present in 
these locations (e.g., the scalp on the top of the head). 
 
 
5.3  
RT Treatment  
5.3.1. The first fraction of RT should occur no earlier than 2 weeks after administration 
of the last dose of chemotherapy. 
5.3.2. Patients should have no food 2 hours prior to receiving treatment. However, 
medications may be taken with liquid. 
 5.3.2.   Orthogonal portal films (imaging to visualize fiducial markers) or cone beam CT 
must be obtained and approved by the radiation oncologist prior to each treatment. 
Treatment will preferably be administered with respiratory gating. 
  
 
 
6. 
ADVERSE EVENTS  
 
Adverse event (AE) monitoring and reporting will be performed.  
 
• Radiation side effects are limited to the area involved in the treatment field.  Acute and 
late toxicity related to radiation therapy may include fatigue, nausea and vomiting, skin 
erythema, subcutaneous fibrosis, esophagitis, pericarditis, diarrhea, myelitis, damage to 
the small bowel (including stricture or obstruction, bleed, fistula formation, or 
perforation), liver dysfunction, kidney damage, and radiation enteritis. 
 
• Acute toxicity including Grade 4 nausea, Grade 4 skin toxicity, and Grade 3 liver toxicity 
will be referred to as dose limiting toxicities (DLT). 
 
• Late toxicity including any Grade 3+ GI toxicity (small bowel damage including stricture 
or obstruction, bleed, fistula formation, or perforation; liver damage including ascites but 
not including abnormal lab values only; pancreatitis, cholecystitis) will be considered a 
toxicity of interest.  
 
• All life-threatening Grade 4 and all fatal toxicities (Grade 5) must be reported 
immediately and evaluated.   

Stereotactic Body Radiation Therapy for Unresected Cancer of the Pancreas or Ampulla  
 
 
11
 
• Acute toxicity:  Acute side effects are considered as occurring ≤ 28 days from the start of 
radiation therapy.  They will be documented using the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 3.0 (A copy can be downloaded from 
http://ctep.info.nih.gov). The relevant sections are included in the appendix.  
 
• Late toxicity:  Late side effects are considered as occurring > 28 days from the start of 
radiation therapy through a 12 month total evaluation period.  They will also be 
documented using the NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 3.0. The relevant sections are included in the appendix. 
 
• University of Chicago Reporting Guidelines 
 
o If the reaction requires reporting, the Research Nurse or MD reports the adverse reaction 
to the Cancer Clinical Trials Office (CCTO) at 773-702-5149 by the end of the business 
day when he/she becomes aware of the event.  Events occurring after business hours will 
be reported to the CCTO by 12 pm (noon) the next business day. 
 
 
o The following information is required when calling in the event: 
 
 Caller’s Name and Telephone Number 
 Patient Initials 
 Patient Medical Record Number 
 IRB Protocol Number 
 PI of Study 
 Attending Physician 
 Date of Event 
 Description of Event (including grade of the event and attribution of the event and 
if the event required hospitalization) 
 
o E-mail is sent to the research nurse, attending physician and PI of the study informing 
them that adverse reaction notification has been received. 
 
o The University of Chicago’s IRB Serious Adverse Event Form must be sent to the CCTO 
within 5 calendar days of event occurrence.  The UC IRB Serious Adverse Event form 
is available on-line at: http://ors.bsd.uchicago.edu/HS/newirbforms. This form must be 
typed. Once the forms are completed, the original is forwarded to the study PI to review 
and sign. The signed report is delivered to the QA Coordinator. A weekly report of 
delinquent or pending documents will be forwarded to the applicable person who reported 
the event. All delinquent reporting (greater than 10 days from event occurrence) must 
include documentation of reason for delinquency and may require implementation of an 
action plan.   
o Once the appropriate AE documents have been received, the CCTO forwards these to the 
IRB. A copy will be forwarded to the appropriate Research Nurse. 
 
• Data Safety and Monitoring 
 

Stereotactic Body Radiation Therapy for Unresected Cancer of the Pancreas or Ampulla  
 
 
12
o Data Safety and Monitoring will occur at the weekly University of Chicago GI oncology 
phase I/II conference meetings, which are lead by senior level medical oncologists.  At 
each meeting, all active studies will be reviewed for safety and progress toward 
completion. Toxicities and adverse events will be reviewed at each meeting and a Data 
Safety and Monitoring form will be completed for each protocol and signed by either the 
Principal Investigator, the Chairman of the Department or by his designate if the 
Chairman is not available. 

Stereotactic Body Radiation Therapy for Unresected Cancer of the Pancreas or Ampulla  
 
 
13
7. 
STUDY CALENDAR 
 
Baseline evaluations (including pain score, performance status, and medications) are to be 
conducted within 21 days prior to start of protocol therapy.  Scans must be done within 28 
days prior to the start of therapy.  In the event that the patient's condition is deteriorating, 
laboratory evaluations should be repeated within 48 hours prior to initiation of therapy. 
 
 
Pre-
treatment 
Week 1 of 
RT 
Week 2 of 
RT 
Post-
treatment 
Inclusion/exclusion 
X 
 
 
 
Informed consent 
X 
 
 
 
Pathology confirming cancer 
X 
 
 
 
History and physical 
X 
X 
X 
Xf 
Vital signs 
X 
X 
X 
Xf 
Performance status and pain 
score 
X 
X 
X 
Xf 
Documentation of current 
medicines 
X 
X 
X 
Xf 
CT or MRI of abdomena 
X 
 
 
Xa 
Hematologyb 
X 
X 
X 
Xf 
Chemistryc 
X 
X 
X 
Xf 
β-HCGd 
X 
 
 
 
Patient QOL Questionnaire 
X 
 
 
Xf 
Toxicity assessmente 
 
Xe 
Xe 
Xf 
a = Imaging will be done within 28 days of RT start, and in follow up at 3-5 weeks after completion of RT. 
Further abdominal imaging will be performed every 6 months for the first year after RT. 
b = CBC with differential, platelet count 
c = comprehensive metabolic profile (glucose, sodium, potassium, chloride, carbon dioxide, BUN, creatinine, 
calcium, total bilirubin, alkaline phosphatase, AST, ALT). CA19-9 will be measured at months 1, 6, 12 from the 
start of radiation therapy, then every 6 months indefinitely (off protocol). 
d = for women of child bearing potential, serum beta-hCG  
e = prior to each radiation treatment after the first fraction, and with all other post-treatment clinic visits 
f = From the start of radiation therapy, visits will be q2 weeks for the first month; then at months 2, 4, 6, 9, and 
12; then every 6 months indefinitely (off protocol).  
 
 
 

Stereotactic Body Radiation Therapy for Unresected Cancer of the Pancreas or Ampulla  
 
 
14
8. 
MEASUREMENT OF EFFECT 
 
Although response is not the primary endpoint of this trial, patients with measurable disease 
will be assessed by standard criteria.  For the purposes of this study, patients should be re-
evaluated with CT or MRI of the abdomen at 3-5 weeks after RT, and every 6 months for the 
first year.  
 
8.1 Antitumor Effect – Solid Tumors 
 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) 
Committee (Therasse, 2000).  Changes in only the largest diameter (unidimensional 
measurement) of the tumor lesions are used in the RECIST criteria. 
 
8.1.1 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of 
their first treatment with RT. 
 
Evaluable for objective response.  Only those patients who have measurable 
disease present at baseline and have had their disease re-evaluated will be 
considered evaluable for response.  These patients will have their response 
classified according to the definitions stated below.  
 
8.1.2 Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be recorded) as 
>10 mm with CT or MRI.  All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters). 
 
Non-measurable disease.  All other lesions (or sites of disease), including small 
lesions (longest diameter <20 mm with conventional techniques or <10 mm using 
spiral CT scan), are considered non-measurable disease.   
 
Target lesions.  The primary lesion (with immediately adjacent lesions) that will 
be treated with RT should be identified as the target lesion(s) and recorded and 
measured at baseline.  Target lesions should be selected on the basis of their size 
(lesions with the longest diameter) and their suitability for accurate repeated 
measurements (either by imaging techniques or clinically).  A sum of the longest 
diameter (LD) for all target lesions will be calculated and reported as the baseline 
sum LD.  The baseline sum LD will be used as reference by which to characterize 
the objective tumor response. 
 
 
 
 
8.1.3 Methods for Evaluation of Measurable Disease 

Stereotactic Body Radiation Therapy for Unresected Cancer of the Pancreas or Ampulla  
 
 
15
 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to 
the beginning of treatment and never more than 4 weeks before the beginning of 
the treatment. 
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up.  
 
CT and MRI  These techniques should be performed with cuts of 5 mm or less in 
slice thickness contiguously.     
 
8.1.4 Response Criteria 
 
8.1.4.1 Evaluation of Target Lesions 
 
Complete Response (CR):Disappearance of the primary target lesion(s) 
 
Partial Response (PR): 
At least a 30% decrease in the sum of the 
longest diameter (LD) of target lesions, 
taking as reference the baseline sum LD 
 
Progressive Disease (PD): 
At least a 20% increase in the sum of the LD 
of target lesions, taking as reference the 
smallest sum LD recorded since the 
treatment started or the appearance of one or 
more new lesions 
 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR 
nor sufficient increase to qualify for PD, 
taking as reference the smallest sum LD 
since the treatment started 
 
 
9. 
 STATISTICAL CONSIDERATIONS 
 
9.1  
Study Design/Endpoints 
 
The study is a phase I/II study that will escalate dose according to determination of 
dose limiting toxicities, in a 3+3 design as outlined in section 5.2. The MTD will be 
exceeded if 2 or more patients out of 6 (or a third or more) experience a DLT at that 
dose.  The dose immediately below will be recommended for further study. . The 
phase II portion of the study will continue accrual at the maximum tolerated dose and 
measure the efficacy and health related quality of life after SBRT. 
 
 
 
 

Stereotactic Body Radiation Therapy for Unresected Cancer of the Pancreas or Ampulla  
 
 
16
9.2  
Sample Size/Accrual Rate 
 
The study will accrue 18 patients at the putatitive maximum tolerated dose, giving a 
sample size of up to 24 patients.  Accrual will likely be 1-2 patients per month. 
Toxicities of interest that occur within the 1-12 month time frame after RT start will 
be documented. For further detail regarding modification of enrollment or dose 
escalation based on late toxicities of interest, see section 5.2.  
 
9.3  
Analysis of Secondary Endpoints 
 
Secondary endpoints will include post-treatment surgical resectability, and local 
control. Patients who are able to undergo surgical resection will be documented as 
having a microscopically complete (R0), microscopically incomplete (R1), or gross 
incomplete (R2) resection.  
 
All patients included in the study will be assessed for response to treatment.  Patients 
who do not demonstrate any local progression (patients with CR+PR+SD) at the 
primary site (using RECIST criteria by CT or MRI) will be considered to be locally 
controlled. Duration of local control (TLC) will be defined to be the time from the 
start of RT until clinical or RECIST progression, death from treatment toxicity, or last 
patient follow-up. Patients who experience clinical or RECIST progression, or death 
from treatment toxicity will be considered to have experienced a local control event; 
otherwise patients will be considered censored at last contact. The probability of LC 
as a function of time since RT will be quantified by the method of Kaplan and Meier 
(Kalbfleisch, 2002). The relative hazard for LC event according to assigned RT level 
will be calculated using the relative risk regression model of Cox, but formal 
statistical conclusions will not be drawn from this analysis. 
 
10.  CONFIDENTIALITY 
 
10.1 
      Patient Confidentiality Issues 
 
Study records that identify patients will be kept confidential. Study records will 
contain patients’ name, address, and medical history number and will be available to 
the study doctor, research nurse, and data coordinator.  Data collected in this study 
will be maintained on a password protected computer that only the primary 
investigator, co-investigators, research nurse, and data coordinator will be able to 
access.  Study records will be secured in locked offices in the Department of Radiation 
and Cellular Oncology.  Neither patient’s name nor other personally identifying 
information will be used in any publication resulting from the research study. 
 

Stereotactic Body Radiation Therapy for Unresected Cancer of the Pancreas or Ampulla  
 
 
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REFERENCES 
Boz G, De Paoli A, Innocente R, Rossi C, Tosolini G, Pederzoli P, Talamini R, Trovò 
MG. Radiotherapy and continuous infusion 5-fluorouracil in patients with nonresectable 
pancreatic carcinoma. Int J Radiat Oncol Biol Phys. 2001 Nov 1;51(3):736-40. 
 
Carter JT, Grenert JP, Rubenstein L, Stewart L, Way LW. Tumors of the ampulla of vater: 
histopathologic classification and predictors of survival. J Am Coll Surg. 2008 
Aug;207(2):210-8. 
 
Chang DT, Schellenberg D, Shen J, Kim J, Goodman KA, Fisher GA, Ford JM, Desser T, 
Quon A, Koong AC. Stereotactic Radiotherapy for Unresectable Adenocarcinoma of the 
Pancreas. Cancer. 2009 115:665-72. 
 
Hoyer M, Roed H, Sengelov L, Traberg A, Ohlhuis L, Pedersen J, Nellemann H, Kiil 
Berthelsen A, Eberholst F, Engelholm SA, von der Maase H. Phase-II study on 
stereotactic radiotherapy of locally advanced pancreatic carcinoma. Radiother Oncol. 
2005 Jul;76(1):48-53. 
 
International Commission on Radiation Units and MeasurementsICRU Report 62. 
Prescribing, recording, and reporting photon beam therapy (Supplement to ICRU Report 
50), ICRU, Bethesda, MD (1999). 
 
Kalbfleisch JD and Prentice RL.  The statistical analysis of failure time data. John Wiley 
and Sons, New York, 2002 
 
Kavanagh BD, Schefter TE, Cardenes HR, Stieber VW, Raben D, Timmerman RD, 
McCarter MD, Burri S, Nedzi LA, Sawyer TE, Gaspar LE. Interim analysis of a 
prospective phase I/II trial of SBRT for liver metastases. Acta Oncol. 2006;45(7):848-55. 
 
Katz MH, Pisters PW, Evans DB, Sun CC, Lee JE, Fleming JB, Vauthey JN, Abdalla EK, 
Crane CH, Wolff RA, Varadhachary GR, Hwang RF. Borderline resectable pancreatic 
cancer: the importance of this emerging stage of disease. J Am Coll Surg. 2008 
May;206(5):833-46. 
 
Koong AC, Le QT, Ho A, Fong B, Fisher G, Cho C, Ford J, Poen J, Gibbs IC, Mehta VK, 
Kee S, Trueblood W, Yang G, Bastidas JA. Phase I study of stereotactic radiosurgery in 
patients with locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys. 2004 Mar 
15;58(4):1017-21. 
 
Moertel CG, Frytak S, Hahn RG, O'Connell MJ, Reitemeier RJ, Rubin J, Schutt AJ, 
Weiland LH, Childs DS, Holbrook MA, Lavin PT, Livstone E, Spiro H, Knowlton A, 
Kalser M, Barkin J, Lessner H, Mann-Kaplan R, Ramming K, Douglas HO Jr, Thomas P, 
Nave H, Bateman J, Lokich J, Brooks J, Chaffey J, Corson JM, Zamcheck N, Novak JW. 
Therapy of locally unresectable pancreatic carcinoma: a randomized comparison of high 
dose (6000 rads) radiation alone, moderate dose radiation (4000 rads + 5-fluorouracil), 
and high dose radiation + 5-fluorouracil: The Gastrointestinal Tumor Study Group. 
Cancer. 1981 Oct 15;48(8):1705-10. 
 

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Mornex F, Chauffert B, Bonnetain F, Triboulet J, Bouche O, Rougier P, Bosset J, 
Aparicio T, Masskouri F, Bedenne L. Definitive Results of the French FFCD-SFRO 
2000-01 Study: Phase III Trial Comparing Chemoradiotherapy (Cisplatin and Infusional 
5-FU) Followed by Gemcitabine vs. Gemcitabine Alone in Patients With Locally 
Advanced Non Metastatic Pancreatic Cancer. Int J Rad Oncol Biol Phys, Volume 69, 
Issue 3, Supplement 1, 1 November 2007, Page S77. 
 
Regine WF, Winter KA, Abrams RA, Safran H, Hoffman JP, Konski A, Benson AB, 
Macdonald JS, Kudrimoti MR, Fromm ML, Haddock MG, Schaefer P, Willett CG, Rich 
TA. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based 
chemoradiation following resection of pancreatic adenocarcinoma: a randomized 
controlled trial. JAMA. 2008 Mar 5;299(9):1019-26. 
 
Smeenk HG, van Eijck CH, Hop WC, Erdmann J, Tran KC, Debois M, van Cutsem E, 
van Dekken H, Klinkenbijl JH, Jeekel J. Long-term survival and metastatic pattern of 
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term results of EORTC trial 40891. Ann Surg. 2007 Nov;246(5):734-40. 
 
Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, 
Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG. New guidelines to 
evaluate the response to treatment in solid tumors. European Organization for Research 
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Institute of Canada. J Natl Cancer Inst. 2000 Feb 2;92(3):205-16. 
 
Timmerman RD, Kavanagh BD, Cho LC, Papiez L, Xing L. Stereotactic body radiation 
therapy in multiple organ sites. J Clin Oncol. 2007 Mar 10;25(8):947-52.  
 

Stereotactic Body Radiation Therapy for Unresected Cancer of the Pancreas or Ampulla  
 
 
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APPENDIX A 
 
Performance Status Criteria 
 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 

Stereotactic Body Radiation Therapy for Unresected Cancer of the Pancreas or Ampulla  
 
 
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APPENDIX B 
  
TOXICITY 
 
Acute toxicity 
 
Grade 
Adverse event 
1 
2 
3 
4 
5 
Skin, dermatitis 
Faint erythema 
or dry 
desquamation 
Moderate to 
brisk 
erythema; patchy 
moist 
desquamation, 
mostly 
confined to skin 
folds and 
creases; 
moderate 
edema 
Moist 
desquamation 
other 
than skin folds 
and 
creases; bleeding 
induced by 
minor trauma 
or abrasion 
Skin necrosis or 
ulceration of full 
thickness 
dermis; 
spontaneous 
bleeding from 
involved 
site 
Death 
Nausea 
Loss of appetite 
without 
alteration in 
eating habits 
Oral intake 
decreased 
without 
significant 
weight 
loss, dehydration 
or 
malnutrition; IV 
fluids 
indicated <24 
hrs 
Inadequate oral 
caloric or 
fluid intake; IV 
fluids, tube 
feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
Consequences 
Death 
AST (SGPT) or 
ALT (SGOT) 
>ULN – 2.5 x 
ULN 
>2.5 – 5.0 x 
ULN 
>5.0 – 20.0 x 
ULN 
>20.0 x ULN 
- 
Total bilirubin 
>ULN – 1.5 x 
ULN 
>1.5 – 3.0 x 
ULN 
>3.0 – 10.0 x 
ULN 
>10.0 x ULN 
- 
Ascites 
Asymptomatic 
Symptomatic, 
medical 
intervention 
indicated 
Symptomatic, 
invasive 
procedure 
indicated 
Life-threatening 
Consequences 
Death 
Enteritis 
 
Asymptomatic, 
pathologic 
or radiographic 
findings 
only 
Abdominal pain; 
mucus 
or blood in stool 
Abdominal pain, 
fever, 
change in bowel 
habits 
with ileus; 
peritoneal 
signs 
Life-threatening 
consequences 
(e.g., 
perforation, 
bleeding, 
ischemia, 
necrosis) 
Death 
 
Late toxicity 
 
Grade 
Adverse event 
1 
2 
3 
4 
5 
Ascites 
Asymptomatic 
Symptomatic, 
medical 
intervention 
indicated 
Symptomatic, 
invasive 
procedure 
indicated 
Life-threatening 
Consequences 
Death 
Enteritis 
 
Asymptomatic, 
pathologic 
or radiographic 
Abdominal pain; 
mucus 
or blood in stool 
Abdominal pain, 
fever, 
change in bowel 
Life-threatening 
consequences 
(e.g., 
Death 

Stereotactic Body Radiation Therapy for Unresected Cancer of the Pancreas or Ampulla  
 
 
21
findings 
only 
habits 
with ileus; 
peritoneal 
signs 
perforation, 
bleeding, 
ischemia, 
necrosis) 
Fistula 
Asymptomatic, 
radiographic 
findings only 
Symptomatic; 
altered GI 
function (e.g., 
altered 
dietary habits, 
diarrhea, 
or GI fluid loss); 
IV fluids 
indicated <24 hrs 
Symptomatic and 
severely altered GI 
function (e.g., 
altered 
dietary habits, 
diarrhea, 
or GI fluid loss); 
IV fluids, 
tube feedings, or 
TPN 
indicated ≥24 hrs 
Life-threatening 
Consequences 
Death 
Mucositis 
Erythema of the 
mucosa 
Patchy ulcerations 
or 
Pseudomembranes 
Confluent 
ulcerations or 
pseudomembranes; 
bleeding with 
minor 
trauma 
Tissue necrosis; 
significant 
spontaneous 
bleeding; life-
threatening 
consequences 
Death 
Necrosis  
- 
- 
Inability to aliment 
adequately by GI 
tract 
(e.g., requiring 
enteral or 
parenteral 
nutrition); 
interventional 
radiology, 
endoscopic, or 
operative 
intervention 
indicated 
Life-threatening 
consequences; 
operative 
intervention 
requiring 
complete organ 
resection 
(e.g., total 
colectomy) 
Death 
Obstruction 
Asymptomatic 
radiographic 
findings only 
Symptomatic; 
altered GI 
function (e.g., 
altered 
dietary habits, 
vomiting, 
diarrhea, or GI 
fluid loss); 
IV fluids indicated 
<24 
Hrs 
Symptomatic and 
severely altered GI 
function (e.g., 
altered 
dietary habits, 
vomiting, 
diarrhea, or GI 
fluid loss); 
IV fluids, tube 
feedings, 
or TPN indicated 
≥24 hrs; 
operative 
intervention 
indicated 
Life-threatening 
consequences; 
operative 
intervention 
requiring 
complete organ 
resection 
(e.g., total 
colectomy) 
Death 
Perforation 
Asymptomatic 
radiographic 
findings only 
Medical 
intervention 
indicated; IV 
fluids 
indicated <24 hrs 
IV fluids, tube 
feedings, 
or TPN indicated 
≥24 hrs; 
operative 
intervention 
indicated 
Life-threatening 
Consequences 
Death 
Stricture/stenosis 
Asymptomatic 
radiographic 
Symptomatic; 
altered GI 
Symptomatic and 
severely altered GI 
Life-threatening 
consequences; 
Death 

Stereotactic Body Radiation Therapy for Unresected Cancer of the Pancreas or Ampulla  
 
 
22
findings only 
function (e.g., 
altered 
dietary habits, 
vomiting, 
bleeding, 
diarrhea); IV 
fluids indicated 
<24 hrs 
function (e.g., 
altered 
dietary habits, 
diarrhea, 
or GI fluid loss); 
IV fluids, 
tube feedings, or 
TPN 
indicated ≥24 hrs; 
operative 
intervention 
indicated 
operative 
intervention 
requiring 
complete organ 
resection 
(e.g., total 
colectomy) 
Ulcer 
Asymptomatic, 
radiographic or 
endoscopic 
findings only 
Symptomatic; 
altered GI 
function (e.g., 
altered 
dietary habits, oral 
supplements); IV 
fluids 
indicated <24 hrs 
Symptomatic and 
severely altered GI 
function (e.g., 
inadequate 
oral caloric or 
fluid 
intake); IV fluids, 
tube 
feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
Consequences 
Death 
Hemorrhage, GI 
Mild, 
intervention 
(other 
than iron 
supplements) 
not indicated 
Symptomatic and 
medical 
intervention or 
minor 
cauterization 
indicated 
Transfusion, 
interventional 
radiology, 
endoscopic, or 
operative 
intervention 
indicated; 
radiation therapy 
(i.e., 
hemostasis of 
bleeding 
site) 
Life-threatening 
consequences; 
major 
urgent 
intervention 
indicated 
Death 
Liver 
dysfunction 
- 
Jaundice 
Asterixis 
Encephalopathy 
or coma 
Death 
Pancreatitis 
Asymptomatic, 
enzyme 
elevation and/or 
radiographic 
findings 
Symptomatic, 
medical 
intervention 
indicated 
Interventional 
radiology or 
operative 
intervention 
indicated 
Life-threatening 
consequences 
(e.g., circulatory 
failure, 
hemorrhage, 
sepsis) 
Death 
Cholecystitis 
Asymptomatic, 
radiographic 
findings only 
Symptomatic, 
medical 
intervention 
indicated 
Interventional 
radiology, 
endoscopic, or 
operative 
intervention 
indicated 
Life-threatening 
consequences 
(e.g., 
sepsis or 
perforation) 
Death 
AST (SGPT) or 
ALT (SGOT) 
>ULN – 2.5 x 
ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
- 
Total bilirubin 
>ULN – 1.5 x 
ULN 
>1.5 – 3.0 x ULN 
>3.0 – 10.0 x ULN 
>10.0 x ULN 
- 
 
 
 
APPENDIX C 
Pain score (report numerical scale only) 

Stereotactic Body Radiation Therapy for Unresected Cancer of the Pancreas or Ampulla  
 
 
23
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX D 
 
 
 
 
 
 
 
 
  
 
FACT-Hep (Version 4)  
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.  
Not      A little      Some-    Quite      Very 
at all      bit         what      a bit       much  

Stereotactic Body Radiation Therapy for Unresected Cancer of the Pancreas or Ampulla  
 
 
24
  
 
  
Because of my physical condition, I have trouble 
meeting the needs of my family ..........                   0        1           2           3          4  
GP3  
I am forced to spend time in bed.................................... 0         1          2           3           4  
Not       A little     Some-     Quite       Very 
at all      bit         what      a bit        much  
PHYSICAL WELL-BEING  
GP1  
I have a lack of energy ................................................... 0         1           2           3          4  
GP2  
I have nausea .................................................................. 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  
SOCIAL/FAMILY WELL-BEING  
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  
 

Stereotactic Body Radiation Therapy for Unresected Cancer of the Pancreas or Ampulla  
 
 
25
 
 
FACT-Hep (Version 4)  
Please circle or mark one number per line to indicate your response as it applies to the past 7 days.  
EMOTIONAL WELL-BEING  
at all     bit      what     a bit     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  
Not    A little     Some-   Quite     Very 
Not      A little   Some-   Quite    Very 
at all   bit         what     a bit      much  
FUNCTIONAL WELL-BEING  
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  

Stereotactic Body Radiation Therapy for Unresected Cancer of the Pancreas or Ampulla  
 
 
26
 
I am content with the quality of my life right now.............. 0       1          2         3         4  
FACT-Hep (Version 4)  
Please circle or mark one number per line to indicate your response as it applies to the past 7 days.  
Not at    A little    Some-   Quite     Very 
all        bit        what     a bit     much  
  
ADDITIONAL CONCERNS  
I have swelling or cramps in my stomach area ................... 0         1          2        3         4  
I am losing weight............................................................... 0         1           2       3          4  
I have control of my bowels................................................ 0         1           2       3          4  
I can digest my food well .................................................... 0         1          2       3           4  
I have diarrhea (diarrhoea) .................................................. 0         1          2       3           4  
I have a good appetite ......................................................... 0         1          2       3           4  
I am unhappy about a change in my appearance................. 0         1          2       3           4 
I have pain in my back ........................................................ 0         1          2       3           4 
I am bothered by constipation............................................. 0          1         2        3           4  
I feel fatigued ...................................................................... 0          1         2        3           4  
I am able to do my usual activities...................................... 0          1         2        3           4  
I am bothered by jaundice or yellow color to my skin........ 0          1         2        3           4 
I have had fevers (episodes of high body temperature) ...... 0          1         2        3           4 
I have had itching ................................................................ 0          1         2        3           4 
I have had a change in the way food tastes ......................... 0          1         2        3           4 
I have had chills .................................................................. 0           1        2        3           4 
My mouth is dry .................................................................. 0           1        2        3           4 
I have discomfort or pain in my stomach area .................... 0           1        2        3 4 
 
C1 
 
C2 
 
C3 
 
C4 
C5 
C6 
 
Hep1 
CNS 
  7 
Cx6 
H17 
An7 
Hep2 
Hep3 
Hep4 
Hep5 
Hep6 
HN2 
Hep8 
 
 
 

Stereotactic Body Radiation Therapy for Unresected Cancer of the Pancreas or Ampulla  
 
 
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